Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH:26](/[CH:28]=[CH:29]/[CH3:30])[O:25][C:24](=[O:31])[CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C[Si](Cl)(C)C>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH:26]=[CH:28][C@@H:29]([CH3:30])[C@@H:23]2[C:24]([OH:25])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C/C=C/C1CN(S(=O)(=O)c2ccc(OC)cc2)CC(=O)O1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(S(=O)(=O)N2CC=C[C@@H](C)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (2.67 mmol, 1.0 M in tetrahydrofuran) in tethydrofuran (5.0 ml) at −78° C. is added a solution of (±)-(E)-4-(4-methoxybenzenesulfonyl)-6-propenylmorpholine-2-one crude from the previous step. After 15 minutes, trimethylsilyl chloride (1.53 ml, 12.15 mmol) is added and the mixture warmed to room temperature. The solvent is removed (in vacuo) and replaced with toluene (10 ml). The resulting mixture is heated at 110° C. for 3 hours, cooled to room temperature and treated with 1N hydrochloric acid solution. After stirring for 10 minutes, the mixture is extracted with ethyl acetate and the combined extracts are dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 2:1 ethyl acetate-hexanes with 1% acetic acid) to provide (±)-(2R*,3R*)-1-(4-methoxy-benzenesulfonyl)-3-methyl-1,2,3,6-tetrahydropyridine-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>CN1CCCC1=O>[C:20]1([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-amino-2-methoxy-pyridine (30 mg, 0.24 mmol) and potassium carbonate (167 mg, 1.20 mmol) are dissolved in N-methyl 2-pyrrolidone (1 ml). Phenyl chloroformate (36 μl, 0.29 mmol) is added and the reaction mixture is stirred at room temperature for 2 hours.
Reaction SMILES: Cl.C(OC([N:9]1[C@H:14]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:13][C@H:12]2[C@@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1>[C@H:10]12[CH2:11][C@H:12]1[CH2:13][C@@H:14]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@H](CNC(=O)C(F)(F)F)C[C@@H]2C[C@@H]21
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F

Procedure:
A solution of HCl in dioxane (4 M, 25 mL) is added to a solution of (1S,3S,5S)-3-[(2,2,2-trifluoro-acetylamino)-methyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (5.74 mmol) in dioxane (25 mL). After 2 h the solvents are removed in vacuo to give the desired product as a white solid which is used without further purification in the next step. LC-MS (acidic): tR=0.30 min; [M+H]+=209.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].NC1C(Cl)=CC(Cl)=C(C)N=1.[N+:20]([C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([N+:33]([O-:35])=[O:34])[C:24]=1Cl)([O-:22])=[O:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH:8][C:24]1[C:25]([N+:33]([O-:35])=[O:34])=[CH:26][C:27]([C:29]([F:32])([F:30])[F:31])=[CH:28][C:23]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cc1nc(N)c(Cl)cc1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1c(Cl)cncc1Cl

Procedure:
In accordance with the process of Preparation No. 2 except using 1.63 g. of 3,5-dichloro-4-aminopyridine instead of 1.8 g. of 2-amino-3,5-dichloro-6-methylpyridine; and using 50 ml. of dimethylformamide instead of 30 ml. of the same and using 2.7 g. of 2,6-dinitro-4-trifluoromethylchlorobenzene instead of 3.07 g. of the same, the process was carried out to obtain 2.8 g. of the object compound having the melting point of 138° to 140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CN1CCN(CCCCN)CC1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(NCCCCN3CCN(C)CC3)nc21
Yield: 41 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1253 g (0.732 mmol) of 4-(4-methyl-piperazin-1-yl)-butylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 0.0527 g (41%) of the title compound: HPLC=94% pure.
Reaction SMILES: C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:23][CH3:24])=[CH:10][CH:9]=1)(=O)CC.[Li+].[OH-]>CO.C1COCC1>[CH2:23]([C:15]1[N:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][OH:5])=[CH:13][CH:12]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1)[CH3:24]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86356.6 %

Procedure:
To a solution of 2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (1.3 g, 4 mmol) in methanol/THF (v/v, 1:1, 32 mL) was added 4N aqueous LiOH (8 mL, 8 mmol) and the resulting mixture was stirred at room temperature. After 3 h, the mixture was concentrated. The residue was dissolved in water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 0:1) to afford 920 g (86%) of the title compound as pale brown solids: 1H-NMR (CDCl3)δ1.26 (3H, t, J=7.5 Hz), 2.80 (2H, q, J=7.5 Hz), 3.00 (2H, t, J=6.5 Hz), 3.98 (2H, t, J=6.5 Hz), 7.25-7.08 (3H, m), 7.31 (2H, d, J=8.3 Hz), 7.45 (2H, d, J=8.3 Hz), 7.81-7.75 (1H, m).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>ClCCl>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])=[O:3]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1cccc(C#N)c1
Yield: 84 %

Procedure:
A mixture of 3-Acetyl-benzonitrile (36.2 g, 249 mmol) in dimethylformamide dimethylacetal (200 mL, excess) was heated to reflux overnight. The solvent was evaporated in vacuo to afford an orange solid. The solid was dissolved in dichloromethane and filtered over a plug of silica gel eluting with 20% ethyl acetate/dichloromethane. The filtrate was concentrated in vacuo to afford 42.0 g (84%) of the title compound as an orange solid.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:22][C:23]([NH2:25])=[S:24].C([O-])(=O)C.[Na+].C(O)C>O>[NH2:25][C:23]1[S:24][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:22]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)c1csc(N)n1
Yield: 32.1 %

Procedure:
Ethyl 4-chloro-2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 37.3 g.), thiourea (8.1 g.), sodium acetate (8.7 g.), ethanol (100 ml.) and water (100 ml.) were treated in a similar manner to that of Example C-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)acetate (syn isomer, 12.7 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([NH:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[N:15][C:11]=2[CH:10]=1)=[O:7])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([NH:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[N:15][C:11]=2[CH:10]=1)=[O:7]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3N)ccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{5-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (30 mg, 66 μmol) in a mixture of ethanol and water (4:1, 5 mL), was added palladium on carbon (6.0 mg, 10% w/w Pd) and ammonium formate (20 mg, 317 μmol). The suspension was heated to reflux for 3 hours, then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated in vacuo to afford the title compound, 1H NMR: (CD3OD), 8.48 (s, 1H), 8.06 (s, 1H), 7.64 (dd, J=7.69, 1.46, 1H), 7.50-7.35 (br, 7H), 7.28-7.24 (m, 1H), 6.82 (dd, J=8.42, 0.73 1H), 6.74-6.70 (m, 1H), 6.18 (dd, J=9.52, 5.86, 1H), 4.09 (1, J=7.32, 2H), 3.66 (dd, J=16.11, 9.52, 1H), 3.51 (dd, J=16.11, 5.86, 1H), 1.13 (t, J=7.32, 3H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=2)[N:5]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[C:4]=1[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([O:33][CH:34]([CH:36]2[CH2:38][CH2:37]2)[CH3:35])=[O:32])=[CH:26][CH:25]=1)#[N:2].C([Sn](CCCC)(CCCC)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)CCC.[F-].[Cs+].[F-].[K+]>CN(C=O)C.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.[Cu]I.CCOCC>[CH:36]1([CH:34]([O:33][C:31](=[O:32])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([C:4]3[N:5]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[C:6]4[C:11]([C:3]=3[C:1]#[N:2])=[CH:10][CH:9]=[C:8]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:7]=4)=[CH:25][CH:26]=2)[CH3:35])[CH2:37][CH2:38]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OS(=O)(=O)C(F)(F)F)cc3n2C2CCC2)cc1)C1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(-c4ccccn4)cc3n2C2CCC2)cc1)C1CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-cyano-1-cyclobutyl-2-[4-(1-cyclopropyl-ethoxycarbonylamino)-phenyl]-1H-indol-6-yl ester prepared as in Example 1CU Step A (200 mg, 0.37 mmol) in DMF (2.0 mL) was added 2-(tributylstannyl)pyridine (160 mg, 0.44 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol), CuI (7 mg, 0.037 mmol) and CsF (111 mg, 0.73 mmol). The mixture was stirred at 80° C. for 2 h, treated with ether (20 mL) and potassium fluoride (0.5 g). The mixture was stirred for another hour and filtered. The filtrate was washed with water and brine, dried over Na2SO4, concentrated and purified on silica gel (CH2Cl2/EtOAc) to provide [4-(3-cyano-1-cyclobutyl-6-pyridin-2-yl-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (82 mg, 47%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: O=C(Cc1c[nH]cn1)N1CCN(c2ccc(OC(F)F)c(OC3CCC3)c2)C[C@@H]1Cc1ccccc1

Procedure:
Prepared by the method outlined for Example 189 using (1H-imidazol-4-yl)-acetic acid and (S)-3-benzyl-1-(3-cyclobutoxy-4-difluoromethoxy-phenyl)-piperazine (Example 4, Compound 92) as starting materials. Product as an oil. LC/MS (Method B) 2.54 min, [M+1]+ 497. Potency class A.
Reaction SMILES: C(#N)C.N(OC(C)(C)C)=O.N[C:12]1[C:13]2[N:14]([N:19]=[C:20]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=2)[C:15]([Cl:18])=[CH:16][CH:17]=1.[Cl:30]CCl>Cl.[Cu]Cl>[CH2:23]([S:22][C:20]1[N:21]=[C:13]2[C:12]([Cl:30])=[CH:17][CH:16]=[C:15]([Cl:18])[N:14]2[N:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCCl
Reactant: Nc1ccc(Cl)n2nc(SCc3ccccc3)nc12
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: Clc1ccc(Cl)n2nc(SCc3ccccc3)nc12

Procedure:
A mixture of 9.9 g (0.10 mol) of copper (I) chloride with 300 mL of acetonitrile was prepared and 8.7 mL (6.8 g, 0.066 mol) of 90 percent t-butyl nitrite was added with stirring. After 10 minutes 9.5 g (0.033 mol) of 8-amino-2-benzylthio-5-chloro[1,2,4]triazolo[1,5-a]pyridine was added and the reaction mixture was allowed to react with stirring for 3 days. The mixture was then diluted with dichloromethane and 2N aqueous hydrochloric acid, and after mixing this well, the phases were separated. The organic layer was washed with 2N aqueous hydrochloric acid and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane to obtain 6.5 g (63 percent of theory) of the title compound as a yellow powder melting at 103°-104° C.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)OC1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.C(O)(=O)C>CO>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][CH:4]3[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]3)=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
1,4-Cyclohexanedione monoethylene ketal (3.90 g), 5-aminoindazole (2.66 g), and acetic acid (0.5 ml) were dissolved in methanol (50 ml), and a borane-pyridine complex (2.50 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr, was then cooled to room temperature, and was concentrated. The residue was dissolved in acetic acid-water (1:1, 50 ml), and the mixture was then stirred at 80° C. for 3 hr. The reaction mixture was concentrated to remove a major part of acetic acid. A saturated aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (3.21 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH3:16]>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:16][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: N
Reactant: FC(F)(F)c1cc(Cl)cc(C(F)(F)F)n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
A mixture of 4-chloro-2,6-bis(trifluoromethyl)pyridine (50 g, 0.20 mole) in concentrated ammonia (250 ml, density 0.88) and ethanol (250 ml) containing copper sulphate (ca. 0.5 g) was stirred and heated in a pressure vessel at 100°-120° C. for 5 hours. The mixture was cooled, extracted with methylene chloride and dried over MgSO4. The solvent was removed under reduced pressure leaving the title compound as a cream solid. The product was recovered in a yield of 26 g, (56% of theoretical), m.p. 147°-149° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([B:13]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=2[CH3:31])[C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[CH:10]=[C:9]([B:32]([C:42]2[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:43]=2[CH3:50])[C:33]2[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=2[CH3:41])[CH:8]=1.[CH3:51][Si:52](I)([CH3:54])[CH3:53]>CCCCCC.C1COCC1.O>[C:15]1([CH3:22])[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[B:13]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])[C:11]1[CH:12]=[C:7]([Si:52]([CH3:54])([CH3:53])[CH3:51])[CH:8]=[C:9]([B:32]([C:42]2[C:43]([CH3:50])=[CH:44][C:45]([CH3:49])=[CH:46][C:47]=2[CH3:48])[C:33]2[C:34]([CH3:41])=[CH:35][C:36]([CH3:40])=[CH:37][C:38]=2[CH3:39])[CH:10]=1
Reactant: Cc1cc(C)c(B(c2cc(Br)cc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)c2)c2c(C)cc(C)cc2C)c(C)c1
Reactant: C[Si](C)(C)I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(c2cc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)cc([Si](C)(C)C)c2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 110.6 %

Procedure:
6.25 ml (0.01 mol) of a 1.6 M solution of butyllithium in hexane are added at -78° C. to a solution of 6.53 g of (0.01 mol) of 1-bromo-3,5-bis(dimesitylboryl)benzene in 50 ml of THF. The mixture is stirred at -78° C. for 1.5 h, and then 2.0 ml (3.0 g; 0.015 mol) of trimethylsilyl iodide are added over the course of 10 minutes. After the mixture has been stirred again at -78° C. for one hour, it is allowed to warm up to room temperature and stirred for about 12 hours. It is then diluted with water and subjected twice to extraction with 50 ml of ethyl acetate each time. Drying over magnesium sulfate and concentration gives 7.15 g of a viscous oil. Following purification by chromatography (hexane, SiO2), 3.7 g (0.0058 mol, i.e. 58% of theory) of the title compound are obtained as a white solid. Physical data are given in Table 1.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7]>[Pd].CO>[CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7]
Reactant: COP(=O)(CC(=O)C(C)CC#Cc1ccccc1)OC
Agent: [Pd]
Solvent: CO
Product: COP(=O)(CC(=O)C(C)CCCc1ccccc1)OC
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A mixture consisting of (±)-dimethyl (3-methyl-2-oxo-6-phenylhex-5-yn-1-yl)phosphonate (15db(i)/15dc(i)), (1.0 g, 3.4 mmol) and 10% palladium on activated carbon (15 mg) in methanol (30 mL) was stirred under an atmosphere of hydrogen overnight. The hydrogen was evacuated and the mixture was filtered through a micropore filter. The filtrate was concentrated in vacuo to afford the title compound (1.0 g, quantitative yield) as a clear oil; 1H-NMR (CDCl3) δ 7.3-7.25 (m, 2H), 7.2-7.1 (m, 3H), 3.8-3.7 (m, 6H), 3.1 (d, 2H), 2.8-2.75 (m, 1H), 2.7-2.5 (m, 2H), 1.8-1.65 (m, 1H), 1.65-1.5 (m, 2H), 1.4-1.3 (m, 1H), 1.1 (d, 3H); MS (ESI−) m/z 299 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])/[CH:21]=[CH:22]/[C:23]([O-])=[O:24].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:28]([O:27][C:20](=[O:26])[CH:21]=[CH:22][C:23](=[O:24])[NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[CH3:29]
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 23.5 %

Procedure:
To an ice cold solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline and 0.216 g of monoethyl fumarate in 3 mL of dry dimethylformamide was added 0.288 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl (EDAC). 7-Amino-4-(3-bromoanilino)-quinazoline can be made by methods well-known to those skilled in the art. See, for example, J Med Chem, 1995:3482, which is hereby incorporated by reference. After stirring at 50° C. for 5 minutes, the ice bath was removed, and the reaction was permitted to warm to room temperature where it stirred for 15 hours. The reaction was poured into cold water, and the suspension was made basic with the addition of a saturated sodium bicarbonate solution. The resulting solid was collected by filtration, washed with water, and then recrystallized from 50 mL of ethanol to afford 0.052 g of the desired product, mp >260° C.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](Cl)=[CH:26][N:25]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C>CC(O)C.[Pd]>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Oc4ccc(Cl)cn4)c3c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Oc4ccccn4)c3c12

Procedure:
A suspension of 124 mg of 5-(5-chloro-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester in 15 ml of 2-propanol is combined with 50 mg of triethylamine and 120 mg of Pd-C (10%) and hydrogenated at room temperature and under normal pressure. After absorption of the stoichiometric quantity of hydrogen the mixture is filtered, the filtrate is concentrated, and the residue is recrystallized from 2-propanol, thus obtaining 96 mg (84%), mp 188°-189° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]([NH2:14])=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.S.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12](=[S:17])[NH2:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cnc2c(c1)CCCC2C(N)=O
Agent: S
Solvent: c1ccncc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 0 °C
Yield: 180.7 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (27.9 g. 0.14 m) in dry pyridine (300 ml.), saturated with H2S gas, was treated with P2S5 (26 g., 0.14 m) and heated at reflux for 45 min. whilst maintaining a slow stream of H2S gas. The reaction mixture was evaporated to dryness in vacuo and cooled to 0° C, made alkaline with 10% sodium hydroxide and the solution extracted with chloroform (3 × 100 ml.). The combined extracts were washed with brine, dried and evaporated in vacuo. The residual oil was triturated with benzene and the solid filtered and recrystallised from benzene to give the title compound as pale yellow needles m.p. 149° (21.8 g., 87%). The hydrochloride was prepared as already described in Example 18 and isolated as colourless needles m.p. 219° C.