Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)c(C)c1
Product: COC(=O)c1nc(C)sc1-c1ccc(C)c(C)c1

Procedure:
prepared by reaction of 3-chloro-3-(3,4-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.96 min; [M+H]+=262.3.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[N:9]=[N:10][N:11]([CH:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([O:16]CC)=[O:15])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[C:25]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[N:9]=[N:10][N:11]([CH:13]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:14]([OH:16])=[O:15])[N:12]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(c1ccccc1)n1nnc(C(c2ccccc2)c2ccccc2)n1
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: O=C(O)C(c1ccccc1)n1nnc(C(c2ccccc2)c2ccccc2)n1

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl (±)-5-(diphenylmethyl)-α-phenyl-2H-tetrazole-2-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained, mp 158°-161° C.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[C:4](=[O:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][Cl:30]>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH2:28][CH2:29][Cl:30])[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[C:4](=[O:14])[C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClCCBr
Reactant: O=c1[nH]c(Cl)c(-c2ccccc2)c(=O)n1CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c(Cl)n(CCCl)c(=O)n1CCCCCl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 2.43 g (7.7 mmol) of 6-chloro-3-(4-chlorobutyl)-5-phenylpyrimidine-2,4(1H,3H)-dione and 1.70 g (12.3 mmol) of potassium carbonate in 40 ml of N,N-dimethylformamide, 1.25 ml (15 mmol) of 1-bromo-2-chloroethane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→2/1) to yield 1.56 g (54.5%, white powder) of the desired product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:11]N1C(=O)CCC1=O>>[Br:11][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)c1ccc(O)c(Br)c1
Yield: 65.4 %

Procedure:
To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>CC(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: CC(C)O
Product: Cc1nc2ccc(Cl)cc2c(=O)o1
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 2-Amino-5-chlorobenzoic acid (90 g, 524 mmole) and acetic anhydride (160 ml) was heated to reflux under nitrogen for 3 hours. The reaction became a solution during heating. The reaction was cooled to room temperature. Some solid came out during this period of time. The reaction mixture was slurried with 1 L IPA and filtered. The solid was washed with more IPA (50 ml) and dried under vacuum at room temperature for 18 hours. Product was collected as solid (91 g, yield: 89%). 1H NMR (CDCl3): 8.14 (d, J=6 Hz, 1H), 7.73 (dd, J=21 Hz, 6 Hz, 1H), 7.50 (d, J=21 Hz, 1H), 2.47 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[S:9][C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH3:2][NH:3][CH2:4][C:5]1[S:9][C:8]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1
Reactant: CNCc1cc(-c2ccccc2)c(C(=O)c2ccccc2)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(-c2ccccc2)c(C(O)c2ccccc2)s1
Reaction time: 3 h
Yield: 43 %

Procedure:
The free base of {5-[(methylamino)methyl]-3-phenyl-2-thienyl}(phenyl)methanone (274 mg) obtained in Example 13 was dissolved in tetrahydrofuran (3 mL) and methanol (2 mL), and sodium borohydride (51 mg) was added at room temperature. After stirring for 3 hr, the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:9) to give a free base of the title compound (106 mg) as a pale-yellow oil. To a solution of fumaric acid (40 mg) in ethanol (3 mL) was added a solution of the obtained free base in ethyl acetate (4 mL), and the solvent was evaporated under reduced pressure. The residue was crystallized from a mixed solvent of ethyl acetate and 2-propanol and recrystallized from ethanol to give the title compound as colorless crystals (yield 40 mg, yield 32%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:36][C:37]=1[F:38]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1cc(-c2c3c(nn2C2CCCC2)CCNCC3)ccc1Cl
Yield: 28.8 %

Procedure:
The title compound (31 mg) was prepared according to Example 180 using 146 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 168 mg of 3-chloro-4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C18H21ClFN3, 333.14; found, m/z 334.4 [M+H]+, 336.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.31 (m, 2H), 7.22-7.18 (m, 1H), 4.37 (m, 1H), 3.31-3.28 (m, 2H), 3.07-3.03 (m, 2H), 2.67-2.64 (m, 2H), 2.11-1.78 (m, 6H), 1.56-1.47 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH:6]=[CH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[C:14]1([C:20]2O[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:12]2[C:13]3[C:5]([C:6]4[C:20]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[C:28]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]5=[C:22]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:7]=4[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c3c(cccc13)C=C2
Reactant: c1ccc(-c2oc(-c3ccccc3)c3ccccc23)cc1
Solvent: Cc1ccccc1C
Product: Brc1ccc2c3c(cccc13)-c1c-2c(-c2ccccc2)c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.7 %

Procedure:
200 ml of xylene was added to a mixture of 5-bromoacenaphthylene (14.5 g, 62.8 mmol) and diphenylisobenzofuran (17.1 g, 63.3 mmol), and stirred for 5 hours under reflux of xylene. The mixture obtained was cooled to room temperature, and thereafter the solvent was distilled off, and 26 ml of trifluoroacetic anhydride and 260 ml of chloroform were added thereto and stirred for 1 hour under reflux. The mixture obtained was cooled to room temperature, and thereafter the solvent was distilled off, and then the resultant residue was purified by silica gel column chromatography (mobile phase; toluene:heptane=1:3) to produce as a yellow solid 16 g of 4-bromo-7,12-diphenylbenzo[k]fluoranthene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19]1>>[CH2:23]([CH:21]1[CH2:20][O:19][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:22]1)[CH2:24][CH3:25]
Reactant: COc1ccccc1N
Reactant: CCCC1COC(CBr)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCC1COC(CNc2ccccc2OC)O1

Procedure:
2-Methoxyaniline (0.05 mole) and sodium carbonate (30 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4-propyl-1,3-dioxolane (0.55 mole) is slowly added and the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and additional sodium carbonate (5 grams) is added to the filtrate. The mixture is then distilled under reduced pressure to yield the desired product N-(4-propyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([NH:61][C@H:62]([C:67](O)=[O:68])[CH2:63][CH:64]([CH3:66])[CH3:65])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]>>[C:51]([NH:61][C@H:62]([C:67]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:68])[CH2:63][CH:64]([CH3:65])[CH3:66])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-L-leucine.
Reaction SMILES: C([N:9]1[CH2:23][CH2:22][C:12]2([S:17][C:16]3[S:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13]2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[ClH:24]>C(O)C>[ClH:24].[S:18]1[C:16]2[S:17][C:12]3([CH2:22][CH2:23][NH:9][CH2:10][CH2:11]3)[CH2:13][C:14](=[O:21])[C:15]=2[CH:20]=[CH:19]1
Reactant: O=C1CC2(CCN(C(=O)c3ccccc3)CC2)Sc2sccc21
Agent: Cl
Solvent: CCO
Product: O=C1CC2(CCNCC2)Sc2sccc21
Temperature: 25 °C

Procedure:
A solution of 14 g (40.99 mmol) of 1-benzoylspiro(piperidine-4,6'-(6H)thieno[2,3-b]thiopyran)-4'-(5'H)-one in 150 ml of ethanol was treated with 50 ml of 6N HCl and heated at reflux for 2 days. The reaction was cooled to room temperature and the solid collected by filtration. The solid was dried overnight in vacuo to give 9.03 g of the product. mp=280° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1F)[NH:7][C:6](=[O:12])[C:5]2=[O:13].[S-:14][CH2:15][CH3:16].[Na+].FC1C=C2C(=CC=1SC)NC=C2>>[CH2:15]([S:14][C:10]1[CH:9]=[C:8]2[C:4]([C:5](=[O:13])[C:6](=[O:12])[NH:7]2)=[CH:3][C:2]=1[F:1])[CH3:16]
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Reactant: CC[S-]
Agent: CSc1cc2[nH]ccc2cc1F
Agent: [Na+]
Product: CCSc1cc2c(cc1F)C(=O)C(=O)N2

Procedure:
6-Ethylthio-5-fluoroindole-2,3-dione was prepared from 5,6-difluoroindole-2,3-dione using sodium thioethoxide according to the method described in the synthesis of 5-fluoro-6-methylthioindole as a brown solid (2.53 g, 19%): mp 215° C.; IR νmax (Nujol)/cm−1 3286, 2926, 2855, 1766, 1712, 1619, 1467 and 1038; NMR δH (400 MHz, DMSO-d6) 1.32 (3H, t, J 7.5 Hz), 3.13 (2H, q, J 7.5 Hz), 6.77 (1H, d, J 6.0 Hz), 7.39 (1H, d, J 8.5 Hz), 10.97 (1H, brs).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC1OCCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]#[C:22][C:12]1[CH:13]=[C:14]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([F:28])[CH:34]=4)[CH:3]=3)[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: CC(C)(C)C#Cc1ccc2c(c1)[C@@]1(COCC(N)=N1)c1cc(Br)cnc1O2
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)C#Cc1ccc2c(c1)[C@@]1(COCC(N)=N1)c1cc(-c3ccnc(F)c3)cnc1O2
Temperature: 80 °C
Yield: 46.8 %

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine, diisopropylamine (0.785 mL, 5.51 mmol), Pd(PPh3)4 (0.127 g, 0.110 mmol), copper(I) iodide (0.021 g, 0.110 mmol), and 3,3-dimethyl-1-butyne (0.203 mL, 1.652 mmol). DMF (3 mL) were added, the vial was sealed under argon and heated to 90° C. for 60 minutes. The reaction mixture was diluted with 2-MeTHF then washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-3-bromo-7-(3,3-dimethylbut-1-ynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.120 g, 0.281 mmol, 25.6% yield) as a white solid. Step 2: A vial was charged with (S)-3-bromo-7-(3,3-dimethylbut-1-ynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.060 g, 0.141 mmol), 2-fluoropyridin-4-ylboronic acid (0.050 g, 0.352 mmol), potassium phosphate (0.299 g, 1.407 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.98 mg, 7.04 μmol) Dioxane (2 mL) and water (0.5 mL) were added, the vial was sealed under argon and heated to 80° C. for 1 hour. The reaction mixture was then diluted with 2-MeTHF, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (95:5 EtOAc/MeOH)/DCM] gave (S)-7-(3,3-dimethylbut-1-ynyl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.029 g, 0.066 mmol, 46.6% yield) as a yellow solid. [M+H]+=443.0
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=2)[NH:3]1.[N:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]2[C:35]3[C:30](=[CH:31][C:32]([CH:36]=O)=[CH:33][CH:34]=3)[NH:29][N:28]=2)=[CH:21][CH:20]=1>>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:36]\[C:32]1[CH:31]=[C:30]3[C:35]([C:27](/[CH:26]=[CH:25]/[C:22]4[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=4)=[N:28][NH:29]3)=[CH:34][CH:33]=1)=[CH:8][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:6][CH:5]=2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Yield: 75.4 %

Procedure:
The title compound (102 mg, 76%) was synthesized as orange-yellow solid according to the method described for Example A11B from tert-butyl 2-oxoindolin-5-ylcarbamate (70 mg, 0.282 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (70 mg, 0.282 mmol). 1H NMR (400 MHz, d6-DMSO) δ 13.53 (s, 1H), 10.47 (s, 1H), 9.14 (s, 1H), 8.55 (d, J=6.5 Hz, 2H), 8.33 (d, J=8.8 Hz, 1H), 7.88-7.83 (m, 3H), 7.74 (s, 2H), 7.69 (d, J=6.5 Hz, 2H), 7.56-7.50 (m, 2H), 6.75 (d, J=8.2 Hz, 1H), 1.34 (s, 9H); MS ESI 480.3 [M+H]+, calcd for [C28H25N5O3+H]+ 480.20.
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(#N)C.[CH2:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17]>O>[CH2:1]([NH:10][CH2:14][CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C=C(C(F)(F)F)C(F)(F)F
Reactant: CCCCCCCCCN
Solvent: O
Solvent: CC#N
Product: CCCCCCCCCNCC(C(F)(F)F)C(F)(F)F

Procedure:
To a mixture of nonylamine (7.5 g) and acetonitrile (10 mL) was added HFIB in several portions over a period of about 0.5 h until a gentle reflux of HFIB was observed which did not dissipate. A dry-ice condenser was used to obtain the gentle reflux of HFIB at 25° C. for 15 h. The reaction mixture was poured into water (150 mL) and the bottom layer separated, and washed with water to provide N-nonyl N-(2-trifluoromethyl-3,3,3-trifluoropropyl)amine (13.5 g): 1H NMR (CDCl3) 0.88 (t, J=7 Hz, 3H), 1.28 (m, 12H), 1.47 (quintet, J=7 Hz, 2H), 2.62 (t, J=7 Hz, 2H), 3.09 (m, 3H) ppm; 19F NMR (CDCl3) −67.0 (d, J=8 Hz) ppm; MS (m/e) 307 (M+, 2.5%), 292 (0.2%), 278 (0.3%), 264 (0.5%), 250 (0.8%), 236 (0.5%), 208 (2.6%),194 (100%),156 (5.9%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(-c2ccnc(Cl)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Clc1nccc(-c2ccc(OCCN3CCOCC3)cc2)n1
Yield: 96.4 %

Procedure:
To a solution of 18 (1.8 g, 8.71 mmol) in acetone (80 mL) were added 4-(2-chloroethyl)morpholine hydrochloride (1.95 g, 10.5 mmol), potassium iodide (360 mg, 2.2 mmol) and potassium carbonate (6.0 g, 44.0 mmol), respectively. The reaction mixture was refluxed for 16 h and concentrated. The residue was diluted with water and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to form a residue was purified by flash chromatography on silica gel (EtOAc/CH2Cl2, 50/50 to MeOH/CH2Cl2: 2/98) to afford the title compound 19 (2.7 g, 8.4 mmol, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:29])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH3:27])[C:20]=2[CH:28]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:30][O:31][C:32](=[O:44])[C:33]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:36](Cl)=[N:35][CH:34]=1.C1N2CCN(CC2)C1>>[CH3:30][O:31][C:32](=[O:44])[C:33]1[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:29])[C:10]([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH3:27])[C:20]=4[CH:28]=3)([OH:15])[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][CH:34]=1
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(O)cc3Cl)C(F)(F)F)cc21
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: C1CN2CCN1CC2
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(Oc4cc(C(F)(F)F)c(C(=O)OC)cn4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-ethyl-4H-benzo[1,4]oxazin-3-one (Example 64, step 5) was reacted with methyl-6-chloro-4-(trifluoromethyl)nicotinate and DABCO to give the title compound as a white solid. MS (m/e)=633.4 [M+H+].
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:20](=[O:32])[NH:21][C@H:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH3:24])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.CS(O)(=O)=O>C(O)C.[Pd]>[C:28]([O:27][C:25]([C@@H:22]([NH:21][C:20]([C@H:12]([NH2:11])[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:32])[CH2:23][CH3:24])=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC[C@H](NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CC[C@H](NC(=O)[C@H](N)c1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
A mixture of (R)-N-Benzyloxycarbonyl-α-{N-[(S)-1-(t-butoxycarbonyl)propyl]carbamoyl}-4-hydroxybenzylamine Method 18; 1.80 g, 4.07 mmol) and Pd/C (0.2 g, 5%) in ethanol (30 ml, 95%) was stirred under hydrogen gas at room temperature for 2 hours. The reaction mixture was filtered through silica gel (2 g) and concentrated. The residue was dissolved in acetone (20 ml) and methanesulphonic acid (0.40 g, 4.16 mmol) was added. No crystallization was obtained and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC using a gradient of 20–50% MeCN in 0.1M ammonium acetate buffer as eluent. The title compound was obtained in 0.350 g (28%) as a white solid. NMR (400 MHz, DMSO-d6): 0.75 (3H, t), 1.40 (9H, s), 1.50–1.75 (2H, m), 2.70 (1H, s), 4.00–4.10 (1H, m), 4.30 (1H, s), 6.65 (2H, d), 7.15 (2H, d), 8.15 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:18](=[O:23])N(OC)C)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[C:25]([NH:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[CH3:38])([CH3:28])([CH3:27])[CH3:26]>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C:18](=[O:23])[CH2:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:30](=[O:39])[NH:29][C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)ccc1C(=O)NC(C)(C)C
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1CC(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2,5-Difluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.5 g, 7.4 mmol) and N-tert-Butyl-4-chloro-2-methyl-benzamide (5.0 g, 22 mmol) followed by purification by silica gel flash column chromatography gives the title compound.