Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][NH2:3].CN(C)[C@@H]1CCN(CC2C=CC(C(O)=O)=CC=2)C1.FC(F)(F)C(O)=O.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][C:31]=1[NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52](O)=[O:53])=[CH:46][CH:45]=1)=[O:43].CO>C(Cl)Cl>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][C:31]=1[NH:41][C:42](=[O:43])[C:44]1[CH:45]=[CH:46][C:47](/[CH:50]=[CH:51]/[C:52]([NH:3][OH:2])=[O:53])=[CH:48][CH:49]=1
Reactant: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(/C=C/C(=O)O)cc1
Reactant: NO
Agent: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(/C=C/C(=O)NO)cc1
Yield: 79 %

Procedure:
Following the same procedure as described in Example 1, step 6 (scheme 1), but substituting compound 4 for N-hydroxylamine hydrochloride salt and compound 7 for compound 226, the title compound 227 was obtained as a yellowish solid in 79% yield [purified by flash chromatography (eluent: 5% to 66% MeOH in DCM)].
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:11][N:12]1[CH2:17][NH:16][C:15](=[S:18])[NH:14][CH2:13]1>CC(C)=O>[OH:3][C:2]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:16]2[CH2:17][N:12]([CH3:11])[CH2:13][N:14]=[C:15]2[S:18][CH2:1]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CN1CNC(=S)NC1
Solvent: CC(C)=O
Product: CN1CN=C2SCC(O)(c3ccccc3)N2C1

Procedure:
A solution of 5.0 grams (0.025 moles) of phenacylbromide in 40 milliliters of acetone was mixed with a solution of 3.27 grams (0.025 moles) of 3,4,5,6-tetrahydro-5-methyl-s-triazin 2(1H)thione in 450 milliliters of acetone. 6-Hydroxy-3-methyl-6-phenyl-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide crystallized out as a colourless solid, m.p. 149°-150° C. (decomposition). The yield was 7.35 grams (89%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22].Cl>CN(C)C=O>[CH3:22][O:21][CH2:20][CH2:19][O:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COc2cccc(O)c21
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc2c1C(=O)CO2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A mixture of 4-hydroxy-benzofuran-3-one (CAS no: 19278-81-0) (4.9 g, 9 mmol), potassium carbonate (1.66 g, 12 mmol) and 2-bromoethyl methylether (1.13 mL, 12 mmol) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 1.5 h. Cooled to 23° C., poured into 1 N HCl, extracted four times with ethyl acetate, dried combined organic layer over Na2SO4. Removal of the solvent in vacuum left a yellow residue which was purified by silica gel column chromatography with heptane/ethyl acetate to give the title compound as a white solid (1.3 g, 63%); MS: m/e=177.2 (M−OMe+H+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=[CH2:13])C>C1COCC1.O>[Br:1][CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13]
Reactant: C=C(OCC)c1ncccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: COc1cccnc1C(=O)CBr
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Add N-bromo-succinimide (306 mg, 1.7 mmol) to a stirred solution of 2-(1-ethoxy-vinyl)-3-methoxy-pyridine (305 mg, 1.7 mg) in THF (30 mL) and water (2 mL). Stir for 15 mins. at RT under N2. Adsorb on SiO2 and purify by flash chromatography on silica gel eluting with 0-40% EtOAc/hexanes to afford the title compound (211 mg, 54%).
Reaction SMILES: [CH3:1][C:2]1C=C(C)C=CC=1S(CCC)(=O)=O.[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([CH3:25])[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:18][C:17]=1[N+:30]([O-:32])=[O:31]>>[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([CH3:25])[C:19]([S:26]([CH2:29][CH2:1][CH3:2])(=[O:28])=[O:27])=[CH:18][C:17]=1[N+:30]([O-:32])=[O:31]
Reactant: Cc1c([N+](=O)[O-])cc(S(C)(=O)=O)c(C)c1[N+](=O)[O-]
Reactant: CCCS(=O)(=O)c1ccc(C)cc1C
Product: CCCS(=O)(=O)c1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1C

Procedure:
2,4-Dimethyl-1-propylsulfonylbenzene (Beilstein H 5, page 491) was dinitrated analogously to (a).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>CN(C)C=O>[Br:16][C:11]1[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][N:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Cn1ccc(-c2ccc(Cl)s2)n1
Solvent: CN(C)C=O
Product: CC(C)Cn1cc(Br)c(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of 3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazole (1 eq, 0.045 mol) in dry N,N-dimethylformamide (130 mL) was added N-bromosuccinimide (1.1 eq, 0.05 mol) slowly and the resulting mixture was stirred at room temperature for 3 h. After completion reaction monitored by TLC, the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organics layer were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated to afford 12 g of 4-bromo-3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazole (82% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:10].[H][H]>[Pd].CO>[ClH:10].[OH:9][C:5]1[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: N#Cc1cccc(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccc(O)c1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Methanol (100 mL) and 10% palladium on carbon (2 g) were charged to a 250 mL Parr bottle followed by 3-cyanophenol (19.0 g, 0.1595 mol) and concentrated HCl (16.66 mL, 0.2 mol). The mixture was hydrogenated at room temperature and 50 psi until the uptake of hydrogen stopped (about 10 h). The reaction was filtered through a bed of Celite and the filter cake was washed with methanol (3×25 mL). The combined filtrates were evaporated under reduced pressure. Remaining volatiles were removed by evaporating the residue twice from 50 mL portions of absolute ethanol. The crude amine hydrochloride, essentially free of residual HCl, was dissolved with warming in a minimum amount of absolute ethanol (80 mL) and the stirred solution was diluted with anhydrous diethyl ether (500 mL). The mixture was stirred in an ice bath for 1 h then the colorless crystalline product was filtered off, washed with anhydrous diethyl ether (3×50 mL) and dried in vacuo to furnish (3-hydroxyphenyl)methylamine hydrochloride salt (20.6 g, 80.9%), mp 146-148° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].[CH2:15](Cl)[CH:16]=[CH:17][CH3:18].[I-].[Li+]>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([O:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH:10]([OH:12])[CH3:11])=[CH:5][C:6]=1[I:9])[CH:16]=[CH:17][CH3:18]
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Reactant: CC=CCCl
Agent: [H-]
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC=CCOc1c(I)cc(C(C)O)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2-Chloro-3-hydroxy-6-(1-hydroxyethyl)-4-iodo-pyridine (4.49 g, 15 mmole) was dissolved in 25 ml dry dimethylformamide in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C., was treated with sodium hydride (600 mg, 15 mmole), and the mixture was stirred 1 h at room temperature. The mixture was treated with crotyl chloride (1.6 ml, 16.5 mmole) and one crystal of lithium iodide and the reaction mixture was stirred 20 h at room temperature. The reaction mixture was diluted with 100 ml ethyl acetate, was washed with 4×50 ml 50% saturated 1:1 sodium chloride/sodium bicarbonate, and was dried over anhydrous magnesium sulfate/potassium carbonate. The dried organics were concentrated in vacuo to a yellow oil which was crystallized from hexane to give 4.72 g (89%) of 3-(2-butenyloxy)-2-chloro-6-(1-hydroxyethyl)-4-iodo-pyridine as a white solid (Melting Point: 61-62.50° C.).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:3]=1.O=[C:14]1[CH2:19][CH2:18][CH2:17][S:16][CH:15]1[C:20](OCC)=[O:21]>C(O)(=O)C.O>[N:7]1([C:4]2[N:3]=[C:2]3[NH:1][C:14]4[CH2:19][CH2:18][CH2:17][S:16][C:15]=4[C:20](=[O:21])[N:6]3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nc(N2CCCCC2)n[nH]1
Reactant: CCOC(=O)C1SCCCC1=O
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2c([nH]c3nc(N4CCCCC4)nn13)CCCS2
Reaction time: 0.17 h
Yield: 80 %

Procedure:
16.7 g (0.1 mole) of 5-amino-3-piperidino-1H-1,2,4-triazole are dissolved in 10 ml of acetic acid and 18.8 g (0.1 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added, then the reaction mixture is boiled for 10 minutes. The thick crystal mass thus obtained is diluted with 100 ml of water, the precipitated product is filtered off, washed with i-propanol and recrystallized from dimethylformamide. Thus 23.3 g (82.2%) of 2-piperidino-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained with a melting point above 350° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])(O)=[O:8].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.CN(C=O)C.CN(C)C(=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:18]2[C:17]3[C:22](=[CH:23][C:14]([O:13][CH2:12][CH2:11][CH2:10][C:7]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:8])=[C:15]([O:33][CH3:34])[CH:16]=3)[N:21]=[CH:20][N:19]=2)=[C:26]([F:32])[CH:27]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70.1 %

Procedure:
Oxalyl chloride (0.4 ml, 2.2 mmol) was added to a suspension of 7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (260 mg, 0.64 mmol), (prepared as described for the starting material in Example 42), in methylene chloride (25 ml) followed by 1 drop of DMF. The mixture was stirred at ambient temperature for 2.5 hours and the volatiles were removed by evaporation. A solution of pyrrolidine (0.13 ml, 2.1 mmol) in N,N-dimethylacetamide (8 ml) was added to the solid residue and the mixture was stirred at ambient temperature for 2 hours. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with acetone, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidin-1-ylcarbonylpropoxy)quinazoline (206 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][C:15]([OH:17])=O)=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:18](=[O:23])[NH:19][CH:20]1[CH2:22][CH2:21]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[F:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][NH2:62])=[CH:59][CH:58]=1>CN(C=O)C.C1COCC1>[CH:20]1([NH:19][C:18]([C:3]2[S:4][C:5]3=[N:6][C:7]([O:13][CH2:14][C:15](=[O:17])[NH:62][CH2:61][C:60]4[CH:63]=[CH:64][C:57]([F:56])=[CH:58][CH:59]=4)=[C:8]([Cl:12])[C:9]([CH3:11])=[C:10]3[C:2]=2[NH2:1])=[O:23])[CH2:22][CH2:21]1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1c(Cl)c(OCC(=O)O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)c(OCC(=O)NCc2ccc(F)cc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (0.300 g, 0.843 mmol) in a 1:1 mixture of THF:DMF (2.0 ml each) are added 1-hydroxybenzotriazole hydrate (0.148 g, 1.096 mmol), N,N-diisopropylethylamine (0.163 g, 1.265 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.242 g, 1.265 mmol), and 4-fluorobenzylamine (0.317 g, 2.529 mmol). The resulting solution is stirred at room temperature for 16 hours. The reaction is quenched by the addition of water (25 ml). A yellow precipitate is formed. The mixture is cooled to 0° C. and stirred for 10 minutes, then filtered. The collected solid is slurried in 10:1 hexane:EtOAc and stirred for 10 minutes. The solid is collected by filtration and dried in the vacuum oven at 50° C. for 1 hour. This affords the title compound as a pale yellow solid (0.143 g, 37%). Mass (m/z): 463.1 (M++1), 461.1 (M+−1).
Reaction SMILES: C(O)C.COC1C=CC([C:10](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]2[CH:16]=CC(OC)=C[CH:12]=2)=CC=1>C1COCC1.Cl.N1C=CC=CC=1>[CH:11]12[CH2:10][CH:19]3[CH2:20][CH:21]([CH2:22][CH:23]([CH2:24]3)[CH2:16]1)[CH2:12]2
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: C1C2CC3CC1CC(C2)C3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To prepare compound 5 (1-O-(4,4'-dimethoxytrityl)-3-O-(N-adamantoyl-3-aminopropyl) glycerol), 8.56 g, (24.35 mmole) compound 4 was dissolved in a mixture of THF (48.7 ml) and 1M aqueous HCl (48.7 ml). The solution was stirred at room temperature for 30 minutes. 50 ml absolute ethanol (50 ml) was then added. The solution was concentrated, the residue was redissolved in 50 ml absolute ethanol, and the solution concentrated again. The resultant product was dried by co-evaporation with pyridine (2×50 ml) to give an oil which was redissolved in dry pyridine (150 ml). 8.25 g (24.35 mmole) 4,4'-dimethoxytrityl chloride was then added in two portions with stirring for 15 minutes. The resulting solution was left for 1 hour. 50 ml absolute ethanol was added and the solution was concentrated. The residue was dissolved in 200 ml dichloromethane and then washed with saturated sodium bicarbonate solution (2×60 ml). The aqueous layer was washed with dichloromethane (2×30 ml) and the organic extracts were combined, dried and evaporated. The residue was chromatographed on silica column (300 g) and eluted with a mixture of dichloromethane: methanol (19:1) to give a white foamy product (9.16 g (61.3%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][C:21]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)=[CH:20][C:19]=4[N:18]=[C:17]([NH2:32])[C:16]=3[N:15]=[C:14]2[CH2:33][O:34][CH2:35][CH3:36])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:32][C:17]1[C:16]2[N:15]=[C:14]([CH2:33][O:34][CH2:35][CH3:36])[N:13]([CH2:12][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][CH:37]=3)[C:25]=2[C:24]2[CH:23]=[CH:22][C:21]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:20][C:19]=2[N:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CNS(C)(=O)=O)cc1
Reaction time: 16 h
Yield: 38.7 %

Procedure:
Methanesulfonyl chloride (0.13 mL, 1.7 mmol) was added dropwise to a mixture of 1-(4-aminomethylbenzyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.520 g, 1.2 mmol) in dichloromethane (10 mL). The reaction was stirred for 16 hours and then saturated aqueous sodium carbonate was added. The layers were separated and the aqueous fraction was extracted with 95:5 chloroform/methanol. The organic fractions were combined and washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography with a gradient of CMA (2%-10%) in chloroform as the eluent. A final recrystallization from 2-propanol provided 0.240 g of N-{4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}methanesulfonamide as white granular crystals, mp 228.0-229.0° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14])=[O:5])#[N:2].CO[CH:17]=[CH:18][C:19](=O)[CH3:20].N12CCN(CC1)CC2>COCCOCCO.C(OCC)(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])=[C:8]([CH3:14])[CH:9]=1
Reactant: Cc1cc(F)ccc1NC(=O)CC#N
Reactant: COC=CC(C)=O
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: COCCOCCO
Product: Cc1cc(F)ccc1-n1c(C)ccc(C#N)c1=O
Temperature: 120 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
2-Cyano-N-(4-fluoro-2-methylphenyl)acetamide (2.0 g, 10 mmol) and 4-methoxybut-3-en-2-one (1.4 mL, 13 mmol) were suspended in 2-(2-methoxyethoxy)ethanol (20 mL), and 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10 mmol) was added. The mixture was stirred at 120° C. for 6 hr, and cooled to room temperature. The mixture was diluted with ethyl acetate (40 mL), and washed with saturated aqueous sodium hydrogen carbonate solution. Then the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane-ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (630 mg, 25%) as a yellow solid.
Reaction SMILES: [C:1]12([CH2:11][C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.CN(C)CCCN=C=NCC.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:37])=[C:31]2[CH3:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:37][C:32]1[NH:33][C:34]2[C:30]([C:31]=1[CH3:38])=[CH:29][C:28]([NH:27][C:12](=[O:14])[CH2:11][C:1]13[CH2:2][CH:3]4[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]4)[CH2:10]1)[CH2:8]3)=[CH:36][CH:35]=2
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1[nH]c2ccc(NC(=O)CC34CC5CC(CC(C5)C3)C4)cc2c1C
Reaction time: 8 h

Procedure:
To a solution of 1-adamantaneacetic acid (0.30 g) in dichloromethane (10 ml) were added 4-dimethylaminopyridine (0.19 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.30 g). The reaction mixture was stirred for 0.5 hour before addition of 5-amino-2,3-dimethylindole (0.25 g). Stirring was then continued overnight at ambient temperature. The next day the reaction mixture was washed with dilute hydrochloric acid, water and brine, dried over sodium sulphate (Na2SO4) and finally concentrated under reduced pressure to leave a residue. Purification of the residue by silica gel chromatography, eluting with 40% ethyl acetate in isohexanes, gawe the title compound as a white solid (0.14 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]3[N:14]=[CH:15][NH:16][C:10]=3[CH2:9]2)[C:5]([N:17]([CH3:19])[CH3:18])=[CH:4][N:3]=1.O.Cl.[CH3:22][N:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:24]>O1CCOCC1.CN(C=O)C>[CH3:24][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][C:11]4[N:14]=[CH:15][NH:16][C:10]=4[CH2:9]3)[C:5]([N:17]([CH3:19])[CH3:18])=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:22]
Reactant: CN(C)c1cnc(Cl)nc1N1CCc2nc[nH]c2C1
Reactant: CN(C)Cc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: CN(C)Cc1ccc(Nc2ncc(N(C)C)c(N3CCc4nc[nH]c4C3)n2)cc1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
50 mg 2-chloro-4-(3,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-5-dimethylamino-pyrimidine are suspended in 60 μL of 1,4-dioxane, 20 μL water and 90 μL of a 5 M hydrochloric acid (in 1,4-dioxane) and mixed with 55 mg 4-dimethylaminomethyl-phenylamine. This mixture is heated to 95° C. and stirred for 20 h at this temperature. The suspension obtained is diluted with DMF and then purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists at the starting point of 95% water (10 mM ammonium hydrogen carbonate and 38 mM ammonia) and 5% acetonitrile and at the finishing point of 50% water and 50% acetonitrile. The fractions are freeze-dried. The residue is taken up in acetonitrile, combined with aqueous hydrochloric acid and freeze-dried once more.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=O>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:14][CH:16]=2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: COC(=O)c1ccc(CC(N)=S)cc1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: COC(=O)c1ccc(Cc2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1
Yield: 93.1 %

Procedure:
To a solution of the compound (209 mg, 1.0 mmol) obtained in Example 178a in ethanol (4 ml) was added 2-bromo-1-(3,4-dichlorophenyl)ethanone (268 mg, 1.00 mmol), and the mixture was heated under reflux for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diluted aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (352 mg, 93%) as a yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]4([CH3:32])[CH2:31][O:30][CH2:29]4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[F:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:36]1[C:41]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]5([CH3:32])[CH2:29][O:30][CH2:31]5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)COC1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1

Procedure:
A vial was charged with (S)-2′-amino-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (50.0 mg, 0.101 mmol), 2-fluoropyridin-3-ylboronic acid (21.33 mg, 0.151 mmol), potassium carbonate (69.7 mg, 0.505 mmol), and Pd(PPh3)4 (11.66 mg, 10.09 μmol). The vial was flushed with Ar (g), then dioxane (505 μL) and water (0.25 mL) were added in sequence. The vial was sealed and placed in a 70° C. oil for 1 hour. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12-g Redi-Sep column with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give a pink solid. The solid was dissolved in MeOH and loaded onto a 500-mg SCX-2 column. The column was first eluted with methanol, then with 2N ammonia in methanol to remove the product. The filtrate was evaporated to give (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as pale yellow solid. Found MS: MH+=443.0.