Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7](C(N)=O)=[C:6]([C:11]([NH2:13])=O)[CH:5]=[CH:4][C:3]=1[Br:14].C[O-].[Na+]>CO>[Br:14][C:3]1[CH:4]=[CH:5][C:6]([C:11]2[N:13]=[CH:5][CH:6]=[CH:11][N:13]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1c(Br)ccc(C(N)=O)c1C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(-c2ncccn2)ccc1Br
Yield: 300.1 %

Procedure:
To a solution of 5.0 g (23.46 mmol) of the title compound of Step A in 15 mL of methanol ("MeOH"), 7.94 g (35.2 mmol) of the title compound of Step B and 1.9 g (35.2 mmol) of sodium methoxide were added and the mixture stirred at room temperature under argon for 1 hr. The solution was then refluxed for 4 hrs and concentrated to about 10 mL. The residue was then added to 200 mL of water and extracted with 4×150 mL of ethyl acetate ("EtOAc"). The combined organic extracts were washed once with water and dried and evaporated. The residue was chromatographed on 100 g of silica gel using Hexanes/EtOAc 4:1 to provide 1.65 g (28%) of the title compound of this step as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:27]I>>[CH3:27][O:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CI
Reactant: OC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCCOCC1
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCCOCC1
Yield: 36 %

Procedure:
Using the procedure described in Example 1, 4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane was reacted with methyl iodide to give 4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane (36%), m.p. 69°-70° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[H-].[Na+].[Cl:15][CH2:16][CH2:17][CH2:18]I.O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:18][CH2:17][CH2:16][Cl:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCl)c1ccccc1Br
Reaction time: 0.17 h

Procedure:
A solution of methyl 2-bromophenylacetate (2.0 g) in DMF (5 mL) was added to a suspension of sodium hydride (containing mineral oil at 40%, 384 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (1.96 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product of methyl 2-(2-bromophenyl)-5-chloropentanoate. Hydrazine monohydrate (4 mL) was added to a solution of the resulting crude methyl 2-(2-bromophenyl)-5-chloropentanoate (2.895 g) in ethanol (20 mL), and the reaction solution was stirred at room temperature for three hours. Hydrazine monohydrate (8 mL) was further added to the reaction solution, and the reaction solution was stirred at room temperature for two days. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.504 g of the crude purified title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH2:8])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:61]([N:68]([CH2:70][C:71](O)=[O:72])C)(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:71](=[O:72])[CH2:70][NH:68][CH3:61])[CH3:2]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNC(=O)CNC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of the compound of Example 48 (50 mg, 127 μmol) in THF (2 mL) and DMF (2 mL), EDC hydrochloride (27 mg, 139 μmol), HOBt (19 mg, 139 μmol), DIPEA (25 mg, 190 μmol) and BOC-sarcosine (26 mg, 139 μmol) is added. The mixture is stirred at rt for 1 h before it is concentrated. The residue is dissolved in 4 M HCl in dioxane (2 mL) and the mixture is stirred at rt for 30 min, concentrated and separated by prep. HPLC to give the title compound (23 mg) as a reddish oil; LC-MS: tR=0.89 min, [M+H]+=466.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: N
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3-chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 473) in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 160 mg, 45%). mp 59–62° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.05 (s, 6H), 1.73 (t, 2H, J=6 Hz), 4.32 (s, 1H), 4.54 (t, J=6 Hz, 2H), 7.50 (s, 2H), 7.60 (t, J=9 Hz, 1H), 7.66 (m, 1H), 7.73 (d, J=9 Hz, 2H), 7.74 (d, J=9 Hz, 2H), 7.75 (m, 1H), 8.22 (s, 1H); MS (DCI/NH3) m/z 482 (M+H)+. Anal. calcd. for C21H21FClN3O5S: C, 52.33; H, 4.39; N, 8.71. Found: C, 52.30; H, 5.03; N. 8.10.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[C:6]([CH2:14]Br)[C:7]([C:10](OC)=[O:11])=[N:8][CH:9]=1>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[CH2:14][N:2]([CH3:1])[C:10](=[O:11])[C:7]2=[N:8][CH:9]=1
Reactant: CN
Reactant: COC(=O)c1ncc(Br)cc1CBr
Solvent: C1CCOC1
Product: CN1Cc2cc(Br)cnc2C1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Methylamine (2M in THF, 9.05 mL) was added to methyl 5-bromo-3-(bromomethyl)picolinate (Example 32, step (i), 1.036 g) in tetrahydrofuran (5 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 70° C. for 30 min. The reaction mixture was cooled and filtered, and the filtrate evaporated to dryness to afford crude product. The crude product was purified by chromatography on silica eluting with ethyl acetate/dichloromethane (5:95 to 100:0). The solid collected during the filtration was dissolved in ethyl acetate and washed with water, extracted with dichloromethane, and then washed with saturated aqueous sodium bicarbonate solution and extracted again with dichloromethane. The combined organic extracts were dried over magnesium sulfate, and then combined with the chromatographed material to afford the sub-titled compound (0.372 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[C:1]([O:5][C:6]([NH:8][NH:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)CCCCCNNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 35.2 %

Procedure:
A mixture of 25 g of tert-butoxycarbonyl hydrazine, 37 g of ethyl 6-bromohexanoate, 26 g of potassium carbonate and 40 ml of hexamethylphosphoramide (HMPA) was stirred at room temperature for 3.5 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=3:1) to give 16 g of ethyl 6-(N'-tert-butoxycarbonylhydrazino)hexanoate (state: oily product, IR: 3350, 1740, 1720 cm-1).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=C[CH:25]=1>C(OC(OCC)(OCC)C)C>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([N:16]1[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]=[C:24]1[CH3:25])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1NC1CC2CCC(C1)N2Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(C)(OCC)OCC
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7.7 g (25.08 mmol) N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)benzene-1,2-diamine was refluxed in 200 ml of 1,1,1-triethoxyethane for 18 hrs. The mixture was cooled to ambient temperature and the solvent was then removed. The residue was dissolved in toluene and 1.8 g (9.47 mmol) of p-toluenesulfonic acid was added and the reaction mixture was heated to reflux while stirring for 18 hrs. The mixture was cooled to ambient temperature and filtered off solid and removed toluene under reduced pressure. The crude product was purified by flash column chromatography with 5% methanol and 0.5% ammonium hydroxide in dichloromethane on silica gel. 2.2 g of the product was recovered as a yellow residue.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][OH:5].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[O:26]1[C:13]([CH3:15])([CH3:14])[C:12]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:17])=[CH:8][CH2:7][CH2:6][C:2]([CH3:1])=[CH:3][CH2:4][OH:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=CCO)CCC=C(C)CCC(C)=C(C)C
Solvent: ClCCl
Product: CC(=CCO)CCC=C(C)CCC1(C)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 23.6 g. of 3,7,10,11-tetramethyl-2,6,10-dodecatrien-1-ol in 500 ml. of methylene chloride, there was added under ice cooling 22.6 g. of m-chloroperbenzoic acid (79% by weight water solution). This addition was carried out portionwise. After this addition, the mixture was agitated for 2 hours at 0°C. After this period, the reaction mixture was diluted with 1,000 ml. of diethyl ether and washed with ice cold 1N aqueous sodium hydroxide and a saturated sodium chloride solution. After washing, the reaction mixture was dried over sodium sulfate and evaporated. By chromatography on Kieselgel, there was obtained 10,11-epoxy-3,7,10,11-tetramethyl-2,6-dodecadien-1-ol, b.p. 104°- 107°C./0.02 mmHg; nD20 = 1.4867.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[C:12]([CH:13]=O)=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26]>ClCCl>[CH3:23][O:24][C:25](=[O:26])/[CH:27]=[CH:13]/[C:12]1[C:3]([N:2]([CH3:22])[CH3:1])=[N:4][C:5]2[C:10]([C:11]=1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1c(N(C)C)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
2-(Dimethylamino)-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde (4.20 g) is dissolved in 100 ml of dichloromethane and (5.25 g, 1.1 equivalents) of methyl (triphenylphosphoranylidene) acetate is added in one portion. The reaction is stirred at room temperature for three days, evaporated, and the residue eluted through a 3-inch silica column to give 4.60 g of (E)-methyl-3-[2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinyl]-2-propenoate as an orange solid; 1H NMR (chloroform-d): δ 7.78-6.87 (m, 9H), 5.98 (d, 1H), 3.60 (s, 3H), 2.95 (s, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15].[CH3:27][N:28]1[C:32]([CH2:33][NH2:34])=[CH:31][N:30]=[CH:29]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:34][CH2:33][C:32]3[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=3)=[O:24])=[CH:20][CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15]
Reactant: Cn1cncc1CN
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)sc1C(=O)c1c(F)cccc1F
Product: Cn1cncc1CNC(=O)c1ccc(Nc2nc(N)c(C(=O)c3c(F)cccc3F)s2)cc1

Procedure:
The title compound was prepared in a manner analogous to Step 3 of Method A, from 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and C-(3-methyl-3H-imidazol-4-yl)-methylamine. Purified via preparative HPLC.
Reaction SMILES: C(O[CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=O)C1C=CC=CC=1.[Cl-].[Cl-].[CH2:26]([Al+2])C(C)C>C1(C)C=CC=CC=1>[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:26]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Reactant: CC(C)C[Al+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (2S-trans)-2,3-bis[(benzyloxy)methyl]cyclobutanone (0.5 g., 1.61 mmole) in toluene (1 ml.) was added dropwise to a solution of isobutylaluminum dichloride (0.71M in hexane, 3.41 ml., 2.42 mmole) at -78° C. The mixture was allowed to warm slowly to room temperature over 2 hours. After stirring for 30 minutes at room temperature, the mixture was allowed to stand at 0° C. overnight. After dilution with ethyl acetate, the reaction mixture was quenched with 10% hydrochloric acid. The organic phase was washed with brine, dried (magnesium sulfate) and the solvent evaporated to give [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzyl ether; TLC (50% ethyl acetate/hexane) Rf =0.53.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[N:14]=[CH:13][N:12]([CH2:16][CH3:17])[C:11]=2[CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=1)[CH3:6].[OH:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.ClC(Cl)C.C1CCCCC1>>[CH2:16]([N:12]1[C:11]2[CH:10]=[C:9]([C:18]([F:21])([F:19])[F:20])[CH:8]=[C:7]([CH:5]([O:25][CH2:26][C:27]3([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH3:6])[C:15]=2[N:14]=[CH:13]1)[CH3:17]
Reactant: CCn1cnc2c(C(C)OC(=N)C(Cl)(Cl)Cl)cc(C(F)(F)F)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Solvent: CC(Cl)Cl
Solvent: C1CCCCC1
Product: CCn1cnc2c(C(C)OCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Temperature: 0 °C

Procedure:
(±)-(1-(1-Ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethyl 2,2,2-trichloroacetimidate (670 mg, 1.664 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (727 mg, 2.496 mmol) were combined in a dichloroethane/cyclohexane mixture (4:2, 6 mL) and cooled to 0° C. The reaction mixture was treated with tetrafluoroboric acid-diethyl ether complex (91 μL, 0.67 mmol), and subsequent processing including extractive work up and purification were carried out as described in example 8 to give 274 mg (30.7%) as white foam-like solid. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 7.97 (s, 1 H), 7.54 (s, 1 H), 7.29-7.37 (m, 5 H), 7.16-7.24 (m, 1 H), 5.11 (q, J=6.4 Hz, 1 H), 4.20-4.29 (m, 2 H), 3.64-3.80 (m, J=13.1 Hz, 2 H), 3.29-3.37 (m, 2 H), 2.93-3.10 (m, 2 H), 2.09-2.22 (m, 2 H), 1.87-2.03 (m, 2 H), 1.56 (t, 3 H), 1.39-1.48 (m, 12 H). 532.40 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.CCCCCCC.[C:20](OCC)(=[O:22])[CH3:21]>ClCCl>[F:1][C:2]1[C:7]([CH2:8][CH2:21][CH2:20][OH:22])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(F)c(C=O)c1O
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1ccc(F)c(CCCO)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 50 ml solution of 4.46 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde in dichloromethane there was added 10 g of (triphenylphosphoranilidene)acetic acid ethyl ester while cooling on ice. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a silica gel column and elution was performed with heptane-ethyl acetate=3:1. The eluate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate, and 1 g of 10% palladium-carbon was added prior to stirring for 7 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of THF, 2 g of lithium borohydride was added while cooling on ice and the mixture was stirred overnight at room temperature. After then adding 1N hydrochloric acid to the reaction mixture while cooling on ice, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the target compound (4.78 g) as a solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.[CH3:30][C:31]1([CH3:49])[C:35]([CH3:37])([CH3:36])[O:34][B:33]([C:38]2[C:39]([C:45]([F:48])([F:47])[F:46])=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)[O:32]1>>[CH3:36][C:35]1([CH3:37])[C:31]([CH3:30])([CH3:49])[O:32][B:33]([C:38]2[C:39]([C:45]([F:46])([F:47])[F:48])=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)[O:34]1.[NH2:44][C:41]1[N:40]=[C:39]([C:45]([F:48])([F:46])[F:47])[C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[C:8]([CH3:23])[C:6]=3[N:7]=2)=[CH:43][N:42]=1
Reactant: Cc1c(CN2CCN(C(=O)C(C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: CC1(C)OB(c2cnc(N)nc2C(F)(F)F)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3C(F)(F)F)nc12

Procedure:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-pyrimidin-2-ylamine was prepared according to WO2007/084786. 110 mg of 1-[4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one, prepared as in Example 118, was coupled to 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-pyrimidin-2-ylamine via General Procedure A to yield 20 mg of 325 MS (Q1) 567.2 (M)+.
Reaction SMILES: [S:1]1CC(O)S[CH2:3][CH:2]1O.[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:1][CH:2]=[CH:3][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(N)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)c1ccsc1N
Temperature: 70 °C
Yield: 63.5 %

Procedure:
1,4-dithian-2,5-diol (4.56 g, 30 mmole) and 2-cyanoacetamide (2.52 g, 30 mmole) were combined in ethanol (50 ml). Triethylamine (6 ml) was added and heated to 70° C. for 1 hour. The volume of solvent was reduced under vacuum, and the product was isolated by filtration. Product was recrystallized from ethanol to give 2.71 g of product (yield 64%).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3][S:2]1(=[O:12])=[O:11]>[Pd].CO>[NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][S:2]1(=[O:11])=[O:12]
Reactant: O=S1(=O)C=Cc2ccccc2N1
Agent: [Pd]
Solvent: CO
Product: O=S1(=O)CCc2ccccc2N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.1 %

Procedure:
A solution of 1H-benzo[c][1,2]thiazine 2,2-dioxide (0.381 g, 2.1 mmol) and 10% palladium on carbon (0.05 g) in anhydrous methanol (6 mL) was placed under a hydrogen filled balloon and stirred at room temperature for 17 hours. The mixture was filtered through Celite and concentrated to give a white solid (0.366 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.25-7.16 (m, 2H), 7.07-7.01 (m, 1H), 6.76-6.73 (d, 1H, J=8.4 Hz), 3.51-3.46 (t, 2H, J=6.8 Hz), 3.34-3.29 (br t, 1H, J=6.9 Hz).
Reaction SMILES: [OH-].[K+].C([NH:6][CH2:7][CH2:8][C:9]1[N:10]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[CH:15][C:14]([Cl:30])=[CH:13][CH:12]=2)(=O)C.Cl>O.CO>[NH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=1)=[CH:15][C:14]([Cl:30])=[CH:13][CH:12]=2
Reactant: CC(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 86 °C
Yield: 96.9 %

Procedure:
Methanol (660 mL), water (165 mL) and potassium hydroxide (365 g, 5.53 mol) was combined with 4-{2-[2-(2-Acetylamino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid (165 g, 0.291 mol). The reaction mixture was stirred at 86° C. (gentle reflux) for 16-24 hours. The reaction mixture was cooled to 75° C. and methanol (1.5 L) was added keeping the internal temperature 50° C.-55° C. The reaction mixture was neutralized (pH 5-7) by adding concentrated HCl (450 mL) over 30 minutes maintaining 60° C.-65° C. The reaction mixture became thicker and lighter in color. Water (3 L) was added to the mixture over 30 minute maintaining 60° C.-65° C. The reaction mixture was cooled to 22° C.-28° C. The product was collected by vacuum filtration followed by waster wash (3×500 mL) and cold (0°-5° C.) methanol (2×300 mL). The product was dried to give the desired product (148 g, 96.5% purity, HPLC). 1HNMR (DMSO−d6): δ7.75 (d, 2H, J=8 Hz), 7.64 (d,1H, J=2 Hz), 7.30 (m, 5H), 7.17 (brs, 1H), 7.09 (d, 1H, J=2 Hz), 7.07 (s, 1H), 6.81 (dd, 1H, J=9 Hz, 2 Hz), 6.72 (d, 2H, J=9 Hz), 6.55 (d, 1H, J=9 Hz), 4.09 (br m, 2H), 3.16 (br m, 4H), 2.50 (br m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20](OCC)(OCC)OCC>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:20]=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Solvent: Cc1ccccc1C
Product: Clc1ccc2c(c1)c(-c1ccccc1)cc1nncn12

Procedure:
In the manner given in Example 2, 6-chloro-4-phenyl-2-hydrazinoquinoline and triethyl orthoformate are refluxed in xylene to give 7-chloro-5-phenyl-s-triazolo[4,3-a]quinoline of melting point 265°-266.5° C.