Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:26][C:25]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39].[CH:41](=[O:43])[CH3:42]>O1CCCC1>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]([CH:41]([OH:43])[CH3:42])[C:25]([C:31]3[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=3)([C:27]([F:30])([F:28])[F:29])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2C(C)O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (0.24 ml) in dry tetrahydrofuran (6 ml) stirred under argon at 0° C., was added butyl lithium (2.5M in hexane) (0.80 ml). The solution was stirred at 0° C. for 30 minutes then was cooled to −85° C. To this solution was added a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (preparation described in, for example, EP 1,731,512) (404 mg) in dry tetrahydrofuran (3 ml). The reaction mixture was stirred at −85° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added acetaldehyde (0.14 ml) and the reaction mixture was stirred at −85° C. for 1.5 hours. The reaction was quenched by addition of aqueous ammonium chloride (saturated) at −85° C. The mixture allowed to warm to ambient temperature and was then extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/diethyl ether 60:40) to give 4-[5-(3,5-dichloro-phenyl)-4-(1-hydroxy-ethyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (290 mg) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.98-7.96 (d, 1H), 7.60-7.45 (m, 5H), 4.09-4.08 (m, 1H), 3.96-3.91 (m, 1H), 3.91 (s, 3H), 2.63 (s, 3H), 1.07 and 0.94 (d, 3H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([NH:22][C:23](=[O:37])[C@@H:24]2[CH2:28][C@H:27]([OH:29])[CH2:26][N:25]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:13]=1>CN(C)C1C=CN=CC=1.ClCCl>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([NH:22][C:23](=[O:37])[C@@H:24]2[CH2:28][C@H:27]([O:29][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:26][N:25]2[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)Nc3cnc4ccccc4c3)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
4-Dimethylaminopyridine (395 mg) and p-toluenesulfonyl chloride (468 mg) were added to a solution of N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline 3-quinolylamide (B, 572 mg) in dichloromethane (10 mL) at 0° C. After stirring at room temperature for 2.5 hr, additional 4-dimethylaminopyridine (399 mg) and p-toluenesulfonyl chloride (465 mg) were added. Additional 4-dimethylaminopyridine (400 mg) and p-toluenesulfonyl chloride (467 mg) were added again after 2 hr. The resulting solution was stirred at room temperature for 14 hr, and the solvent was evaporated in vacuo. The residue was diluted with ethyl acetate, and washed with 0.5 M citric acid, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=50:1, v/v) to afford the title compound (805 mg) as a pale yellow sticky oil: 1H NMR (400 MHz, CD3OD) δ 1.3-1.5 (m, 9H), 2.23 (m, 3H), 2.3-2.7 (m, 2H), 3.4-3.8 (m, 2H), 4.5 (m, 1H), 5.25 (m, 1H), 7.20 (m, 2H), 7.7-7.9 (m, 5H), 8.00 (d, 1H), 8.58 (br s, 1H), and 8.85 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH:7]3[CH:11]([CH:12]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=4)[C:4]=2[CH:3]=1)[CH2:10][NH:9][CH2:8]3.[CH2:22]=O>C(O)=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH:7]3[CH:11]([CH:12]([C:13]4[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[C:4]=2[CH:3]=1)[CH2:10][N:9]([CH3:22])[CH2:8]3
Reactant: C=O
Reactant: Clc1ccc(C2c3cc(Cl)ccc3CC3CNCC32)cc1
Solvent: O=CO
Product: CN1CC2Cc3ccc(Cl)cc3C(c3ccc(Cl)cc3)C2C1

Procedure:
A mixture of 1.5 g of (3aRS,4SR,9aSR)-6-chloro-4-(p-chlorophenyl)-3a,4,9,9a-tetrahydro-benz[f]isoindoline, 10 cc of 100% formic acid and 10 cc of a 40% aqueous formaldehyde solution is heated to the boil at reflux for 2 hours in an atmosphere of nitrogen. The mixture is concentrated by evaporation, the residue is taken up in water, the solution is made alkaline with concentrated caustic soda solution and is extracted with methylene chloride. Ether is added to the dried extracts until they are turbid, filtration through Hyflo and concentration by evaporation are effected, whereby the title compound is obtained as residue. M.P. 133°-135° (after crystallization from ether).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]#[N:17].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:16]#[N:17])=[CH:4][CH:3]=1
Reactant: N#CC1CCCCC1=O
Reactant: Nc1ccc(F)cc1
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(F)cc2)CCCC1

Procedure:
4-Fluoro-aniline (1.11 g, 10.0 mmol), cyano-ketone (Example 32) (1.25 g, 10.2 mmol), calcium chloride (1.5 g, 13.5 mmol) and T.H.F. (20 ml) were heated under reflux for 17 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (135° C., 0.08 mmHg) gave the product as a pale yellow powder.
Reaction SMILES: CS[C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][C:24]#[N:25])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)OCC>C(O)C>[N+:12]([C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3](=[C:23]([C:19]3[N:18]=[C:17]([C:16]([F:27])([F:15])[F:26])[CH:22]=[CH:21][N:20]=3)[C:24]#[N:25])[S:4][C:5]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: CSc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: N#CCc1nccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC(=C1Nc2ccc([N+](=O)[O-])cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 160 °C
Yield: 95.5 %

Procedure:
To a solution of 2-(methylthio)-6-nitro-1,3-benzothiazole (226 mg, 1.0 mmol) in ethanol (3.5 mL) was added 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (187 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol). The orange mixture was heated in the microwave at 160° C. for 15 min, then cooled and poured into EA (60 mL). The organic layer was washed twice with 1N hydrochloric acid (25 mL each), brine (25 mL), and water (5 mL), then dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-(6-nitrobenzothiazol-2(3H)-ylidene)-2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (349 mg, 96% yield) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: CC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O

Procedure:
6.0 g (34.5 mmol) of 4-bromopyridin-2(1H)-one and 7.9 g (37.9 mmol) of tert-butyl 2-bromopropanoate (racemate) were reacted according to General Method 4B. After removal of the DMF, the desired product was precipitated with water and then purified further by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 7.4 g (69% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[C:23]2[CH2:22][CH2:21][NH:20][CH:19]([CH3:24])[C:18]=2[S:17][CH:16]=1>>[Br:14][C:15]1[C:23]2[CH2:22][CH2:21][N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:19]([CH3:24])[C:18]=2[S:17][CH:16]=1
Reactant: CC1NCCc2c(Br)csc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2scc(Br)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-bromo-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.[CH3:8][C:9]1[N:14]=[C:13]([SH:15])[N:12]=[C:11]([OH:16])[CH:10]=1.C(N(CC)CC)C>C(O)C>[CH3:8][C:9]1[N:14]=[C:13]([S:15][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)[N:12]=[C:11]([OH:16])[CH:10]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cncs1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cncs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.9 %

Procedure:
A mixture of 5-(bromomethyl)-1,3-thiazole (4.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (427 mg, 3.0 mmol), and triethylamine (1.7 mL, 12.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The mixture was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/CH2Cl2), affording the title compound (28 mg, 4% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 4.64 (s, 2H), 4.16 (s, 2H), 6.02 (s (br), 1H), 7.87 (d, 1H, J=0.8 Hz), 8.94 (s, 1H); M+240.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:4][C:5]([NH2:16])=[N:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[C:10]1([C:9]#[C:8][C:7]2[N:6]=[C:5]([NH2:16])[CH:4]=[C:3]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:2]=2[C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1cncnc1
Reactant: Nc1cc(-c2ccncc2)c(Br)c(C#Cc2ccccc2)n1
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: [Na+]
Solvent: CC#N
Product: Nc1cc(-c2ccncc2)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (30 mg, 26 μmol) is added to a mixture of 5-bromo-6-(2-phenylethynyl)-4-(pyridin-4-yl)pyridin-2-amine G8 (90 mg, 0.26 mmol), pyrimidine-5-boronic acid (48 mg, 0.39 mmol), sodium carbonate (aqueous solution, 2 mol/l, 0.39 ml, 0.78 mmol) and ACN (2.4 ml) under nitrogen atmosphere at RT and is stirred at 150° C. for 1 h. The mixture is concentrated in vacuo and the product purified by NP chromatography. Yield: 72 mg (80%). HPLC-MS: M+H=350; tR=1.11 min (METHOD—5).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[OH:36][C@@H:37]([CH3:41])[C:38]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)=[O:39]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[NH:3][CH:2]=1.C(N(CC)CC)C.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:21]([N:3]1[C:4]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[CH:2]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc2nc[nH]c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1.12 g of methyl 3H-benzimidazole-4-carboxylate in 25 ml of dichloromethane is admixed with 0.97 ml of triethylamine and a solution of 2.010 g of trityl chloride in 25 ml of dichloromethane. The reaction mixture is stirred at room temperature over 16 hours and subsequently poured onto a 100 ml of semisaturated aqueous sodium hydrogencarbonate solution. The phases are separated and the aqueous phase is extracted with 100 ml of dichloromethane. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by flash chromatography (SiO2 60F). Rf (1:2 EtOAc-heptane)=0.25; Rt=4.31;
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10][N:9]=N[C:7]=2[O:6][CH2:5]1.[CH3:13][C:14]1N=CC=C2C(=O)COC=12>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:13]([CH3:14])[N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: CON=C1COc2nnccc21
Reactant: Cc1nccc2c1OCC2=O
Product: CON=C1COc2c1ccnc2C

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 7-methylfuro[2,3-c]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one;
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[CH3:14])=[CH:9][CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: CC(N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NC(C)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 62a, a mixture of acryloyl chloride (58.2 g) was added to 1-(4-chlorophenyl)ethylamine (100 g) and triethylamine (65.2 g) in dichloromethane (400 ml) to give N-[1-(4-chlorophenyl)ethyl]acrylamide, m.p. 103°-104° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CC(O)=O>[CH2:3]1[C:2]2[NH:18][C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]=2[CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: NNc1ccccc1
Reactant: CC(=O)NC1CCCC(=O)C1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NC1CCc2c([nH]c3ccccc23)C1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A stirred solution of 140.9 g (0.909 mol) of N-(3-oxocyclohexyl)acetamide in 900 ml of glacial HOAc was heated at 85°-95° C. while 98.2 g (0.909 mol) of phenylhydrazine was added dropwise during 1 hr. After an additional 3 hr at 95°±5°, the hot solution was poured into 5 l. of H2O. When the initially formed gum had solidified, the product was filtered, washed with 2.5 l. of H2O, then 2 l. of Et2O to give 167.6 g (81%) of a grey solid, mp 203°-206°. Recrystallization was best effected by dissolving the crude solid in boiling Me2CO (1 g/25 ml) and boiling down to 1 g/10 ml. The resulting yellow solid (133.5 g, mp 208°-209°) was recrystallized again from Me2CO to yield 111.8 g of white solid, mp 208°-209°. To remove Me2CO occluded by the crystalline solid, the product was further recrystallized from EtOH, 86% recovery of white solid, mp 208°-209°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH:13]=[CH2:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: C=CCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(NC(C)=O)cc1

Procedure:
4-Acetamidophenol (383 g, 2.53 mole), allyl bromide (338 g, 2.79 mole), and anhydrous potassium carbonate (350 g, 2.53 mole) were added to acetone (2250 ml). Under intense stirring, the heterogeneous mixture was refluxed overnight. After cooling, the inorganic salts were filtered off and the filtrate concentrated under reduced pressure. The obtained solid was used for step 2 without purification.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12]C)=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO.O>[S:1]1[C:9]2[CH:8]=[C:7]([C:10]([OH:12])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc2sccc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2sccc2cn1
Temperature: 25 °C
Yield: 43 %

Procedure:
Methyl thieno[3,2-c]pyridine-6-carboxylate (C155) (678 mg, 3.5 mmol) is dissolved in MeOH (16 mL) and water (2 mL). 2M NaOH (1.8 mL, 3.6 mmol) is added drop-wise, and the solution stirred at rt. After 2 days (complete disappearance of ester by TLC), the solution is concentrated in vacuo. The residue is dissolved in water (12 mL), and the pH is adjusted to 3.5 with 10% HCl. The precipitated solid is removed by filtration, and the solid is rinsed with ether, affording thieno[3,2-c]pyridine-6-carboxylic acid (C160) as a white solid (43% yield). HRMS (FAB) calculated for C8H5NO2S+H: 180.0119, found 180.0123 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccc2cccnc2c1
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2ccc3cccnc3c2)cc1

Procedure:
N,N-Dimethyl-4-(quinolin-7-yl)aniline T504 was prepared using general procedure A from 7-bromoquinoline (52 mg, 0.25 mmol) and (4-(dimethylamino)phenyl)boronic acid (41 mg, 0.25 mmol). The product T504 was obtained as a yellow solid (52 mg, 83%). 1H NMR (400 MHz, CDCl3): δ 8.89 (dd, J=4.4, 1.6 Hz, 1H), 8.28 (m, 1H), 8.12 (dq, J=8.4, 0.8 Hz, 1H), 7.81 (d, J=1.2 Hz, 2H), 7.68 (m, 2H), 7.33 (dd, J=8.4, 4.4 Hz, 1H), 6.84 (m, 2H), 3.00 (s, 3H); MS (ESI): 249 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)=[O:24])=[CH:4][CH2:3]1.[CH3:33][NH:34][CH3:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:33][N:34]([CH3:35])[CH:17]1[CH2:18][CH2:19][C:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:22][C:23]([C:25]3[NH:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)=[O:24])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:1])([CH3:32])[CH2:3][CH:4]=3)[CH:13]=2)([OH:21])[CH2:15][CH2:16]1
Reactant: CNC
Reactant: CC1(C)CC=C(c2cc(C3(O)CCC(=O)CC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(C)C1CCC(O)(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-4-oxo-cyclohexyl)-phenyl]-amide (as prepared in Example 21) and dimethylamine (solution in THF) using NaBH(OAc)3 according to literature procedure (J. Org. Chem., 61, 3849-62 (1996)).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:41]=[C:40]2[O:42][C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([OH:52])=[C:47]([CH3:53])[CH:46]=3)=[N:44][C:39]2=[CH:38][CH:37]=1.O[C:59]([CH3:68])([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>O1CCCC1.C(N(CC)CC)C>[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:41]=[C:40]2[O:42][C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([O:52][C:59]([CH3:68])([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[C:47]([CH3:53])[CH:46]=3)=[N:44][C:39]2=[CH:38][CH:37]=1
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OC(C)(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
With ice cooling, 72 mg of triphenylphosphine were dissolved in 1 ml of dry tetrahydrofuran, and 47 mg of diethyl azodicarboxylate were added. After 15 min, 80 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol were added, followed by 32 μl of triethylamine and 44 mg of tert-butyl alpha-hydroxyisobutyrate. The reaction mixture was then stirred at room temperature for 16 hours, and another 72 mg of triphenylphosphine and 47 mg of diethyl azodicarboxylate were added with ice cooling. After a further 4 h at room temperature, the reaction was concentrated and purified by preparative HPLC. This gave 60 mg (53%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[F:23])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.CCOC(C)=O.[CH3:33][NH:34][CH3:35]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[F:23])[CH2:10][N:34]([CH3:35])[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cccc(Cl)c1F
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
A solution of methanesulfonic acid (S)-2-tert-butoxycarbonylamino-2-(3-chloro-2-fluoro-phenyl)-ethyl ester (690 mg, 1.88 mmol) in 33% dimethylamine in EtOH (5.6 M, 7.5 mL, 42 mmol) was heated at 80° C. for 2 h in a sealed tube. The reaction mixture was concentrated and the crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give a pale yellow oil. TLC, Rf (EtOAc): 0.60; MS (UPLC/MS): 317.3/319.3 [M+H]+; tR (HPLC conditions a): 3.19 min.
Reaction SMILES: B(Br)(Br)Br.[NH:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([N:16]3[C@@H:25]4[C@@H:20]([C:21]5[CH:29]=[CH:28][CH:27]=[C:26]([O:30]C)[C:22]=5[CH2:23][CH2:24]4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1.C([O-])(O)=O.[Na+]>ClCCl>[NH:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([N:16]3[C@@H:25]4[C@@H:20]([C:21]5[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[C:22]=5[CH2:23][CH2:24]4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cccc(O)c3CC[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (1 mol/L in dichloromethane, 0.5 mL) is added to a solution of (1H-benzoimidazol-5-yl)-(cis-7-methoxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)-methanone (60 mg) in dichloromethane (5 mL) at room temperature. The resulting solution is stirred at room temperature for 2 h. Aqueous half-saturated NaHCO3 solution is added and the resulting neutral mixture is extracted with dichloromethane and dichloromethane/methanol (95:5). The combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is triturated with diethyl ether and dried to give the title compound as a colorless solid. Yield: 30 mg (52% of theory); TLC: rf=0.45 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=348 [M+H]+.