Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C@@H:16]3[C@@H:12]([CH2:13][O:14][CH2:15]3)[O:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[CH:20]1([CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=2)[CH2:22][CH2:21]1>>[NH2:17][C:10]1[O:11][C@H:12]2[C@@H:16]([C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH:20]5[CH2:22][CH2:21]5)=[CH:30][N:29]=4)=[O:32])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=1)[CH2:15][O:14][CH2:13]2
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21
Reactant: O=C(O)c1ccc(OCC2CC2)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC4CC4)cn3)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21

Procedure:
The coupling of (3aS,7S,7aS)-7-(5-amino-2-fluoro-phenyl)-7-methyl-3,3a,7,7a-tetrahydro-1H-2,4-dioxa-6-aza-inden-5-ylamine and 5-cyclopropylmethoxy-pyridine-2-carboxylic acid (prepared as described in Scott, J. et al., WO 2011/044181) following procedure G yielded the title compound as a colorless solid. MS: m/z=441.3 [M+H]+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH:49][C:50]([CH3:54])([CH3:53])[CH2:51][OH:52])(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1>[OH:52][CH2:51][C:50]([NH:49][S:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)[CH:41]=1)(=[O:48])=[O:47])([CH3:54])[CH3:53]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(CO)NS(=O)(=O)c1cccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (Example H.4) (0.237 g, 0.77 mmol), tetrakis(triphenyl-phosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (268 mg, 66%). MS (ISP) 585.2 [(M+H)+]; mp 150° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[F:33])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C1COCC1>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[CH2:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:4]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:6])=[O:7])[CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)N(CCN)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCNC(C)=O)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 48 h
Yield: 46.4 %

Procedure:
To 1 g of N-(2-aminoethyl)N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxybenzenesulfonamide (compound 215) dissolved in 25 ml of THF are added 0.167 ml of pyridine and 0.22 g of acetic anhydride. After 48 hours at room temperature, the reaction medium is concentrated. The residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture to give 0.505 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[C:4]([O:13][CH3:14])[CH:3]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: ClCCl
Product: COc1cc(NC(=O)Nc2cccc([N+](=O)[O-])c2)ccc1-c1cnco1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 600 mg (3.2 mmol) of 1D in 20 ml of methylene chloride was added, as a solid, 525 mg (3.2 mmol) of m-nitrophenylisocyanate. A voluminous precipitate was obtained. Stirring was continued overnight. The precipitate was filtered and washed with methylene chloride to afford 1.1 g (3.1 mmol, 97%) of 49A as a yellow solid.
Reaction SMILES: [OH:1]S(O)(=O)=O.[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[CH:7]=[CH2:8]>O>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[O:9][CH2:6][CH:7]([OH:1])[CH2:8]2
Reactant: O=S(=O)(O)O
Reactant: C=CCOc1ccccc1Br
Solvent: O
Product: OC1COc2c(Br)cccc2C1
Reaction time: 0.5 h

Procedure:
Tl2O3 (2.38 g, 5.2 mmol) was added at room temperature to a mixture of H2SO4 (6.9 ml) and water (6.1 ml) and this mixture was stirred for 30 min and added to o-allyloxy-bromo-benzene (1.9 g, 8.92 mmol) and water was added (37 ml). The reaction mixture was stirred in 60° C. under Argon. The product was extracted with CH2Cl2 and the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give 1.34 g of a raw oil, which was chromatographed (SiO2 and ether as eluant). The fractions containing at least 85% purity of the product were pooled and the solvent was removed, yielding 310 mg of an oil. GC/MS showed M+ /M+2 at m/e=228.00(100%)/230.00(88%).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH2:6][NH2:7])[CH2:4][NH2:5].C[O-].[Na+].Cl.[NH2:12][C:13](N)=N>CO>[ClH:1].[CH3:2][CH:3]1[CH2:6][NH:7][C:13]([NH2:12])=[N:5][CH2:4]1
Reactant: CC(CN)CN
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1CN=C(N)NC1

Procedure:
To a solution containing 6.7 g (41.6 mmol) of 2-methyl-1,3-propandiamine hydrochloride (Tetrahedron (1994) 50(29), 8617-8632) in 50 ml of methanol was added 83 ml of a solution of sodium methylate in methanol (1 mmol/ml) and the resulting mixture treated with 3.97 g (41.6 mmol) of guanidine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:26])([CH3:25])[C:20](OCC)=[O:21].O>CS(C)=O>[CH3:25][C:19]1([CH3:26])[C:20](=[O:21])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 30 °C
Yield: 120.9 %

Procedure:
To a solution of 2-amino-5-nitrophenol (200 g) in dimethylsulfoxide (1000 mL) was added anhydrous potassium carbonate (269 g) under stirring at 30° C. or lower, then to the mixture was added ethyl 2-bromo-2-methylpropionate (278.4 g) at 30° C. or lower, and the mixture was stirred at 26° C. for 24 hours. To the reaction mixture was added water (2000 mL) at 40° C. or lower, and then stirred at room temperature for 3 hours. The reaction product was collected by filtration, and successively washed with dimethylsulfoxide/water (2:1, 800 mL) and water (3200 mL) to obtain the title compound (348.6 g) as a yellow solid (wet material) (yield: 121%, purity: 96%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1>ClCCl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][S:8]([NH:11][C:12]([NH:18][C:19]1[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[N:24]=1)=[O:13])(=[O:10])=[O:9]
Reactant: O=C=NS(=O)(=O)Oc1ccccc1OCCCl
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2OCCCl)n1
Reaction time: 24 h
Yield: 88.9 %

Procedure:
A solution of 5.6 g (0.02 mol) of the product of Example 1 in 20 ml of dichloromethane is added dropwise at 0° C. to 3.1 g (0.02 mol) of 2-amino-4,6-dimethoxypyrimidine in 30 ml of dichloromethane. The reaction mixture is allowed to reach room temperature, and stirring is continued for 24 hours. The reaction solution is diluted using 100 ml of dichloromethane and washed with 50 ml of 1N hydrochloric acid and 50 ml of water. The organic phase is dried using sodium sulfate, and the solvent is removed on a rotary evaporator. The viscous oil which remains is crystallized by trituration with diethyl ether. 7.7 g (89% of theory) of 1-[2-(2-chloroethoxy)phenoxy-sulfonyl]-3-(4,6-dimethoxypyrimidin-2-yl)urea of melting point 132°-134° C. are obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:7](=[S:8])[CH2:6][CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].C1CCCCC1>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][S:8][C:7]1[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:10][C:9]=1[O:11][CH3:12]
Reactant: COC1=CC(C(C)=O)=CCC1=S
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1SCCCCl
Temperature: 25 °C

Procedure:
A mixture of 1-(4-thio-3-methoxyphenyl)ethanone (10.0 g, 54.9 mmol), potassium carbonate (9.0 g, 65.1 mmol), and acetone (100 ml) was stirred at reflux under nitrogen for 30 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3chloropropane (6.5 ml, 9.5 g, 60.4 mmol) dissolved in acetone (25 ml) was dripped into the reaction. After complete addition, the reaction was heated to reflux and stirred under nitrogen for 17 hours. After the reaction was carried to substantial completion, the reaction mixture was filtered and the resulting filter cake was washed with acetone. The filtrate was concentrated to provide an amber oil. A small sample was solidified by trituration with hot cyclohexane to provide 1-[4-[(3chloropropyl)thio]-3-methoxyphenyl]ethanone as a yellow solid, 11.7 g, m.p.=53°-55° C.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1>CN1CCCC1=O.O>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([NH:2][NH2:3])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(NN)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
4.5 ml of hydrazine hydrate were added dropwise to the solution of 3.2 g of 4-fluoro-2-methoxynitrobenzene in 15 ml of N-methylpyrolidone and the mixture was stirred for 2 hours, which initially resulted in gentle heating. The mixture was then diluted with 50 ml of water and stirred, and a precipitate formed which was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]1[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:5]2=1.C(Cl)(=O)C(Cl)=O.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)=[O:14])[C:6]1[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:5]2=1
Reactant: Nc1ccc(F)cc1
Reactant: CN1CCc2c(n(CC(=O)O)c3ccc(Cl)cc23)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCc2c(n(CC(=O)Nc3ccc(F)cc3)c3ccc(Cl)cc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid (0.1 g, 0.39 mmol) was dissolved in dichloromethane (4 mL) and was cooled to 0° C., using an ice-bath; oxalyl chloride (0.04 mL, 0.43 mmol) was added drop-wise to the reaction mixture. Catalytic amount (1 drop) of dimethyl formamide was added and the reaction mixture was stirred for 1 h at room temperature. Excess oxalyl chloride was distilled away under reduced pressure. A solution of 4-fluoroaniline (0.042 g, 0.43 mmol) in dichloromethane (2 mL) and 4-dimethylaminopyridine (0.017 g, 0.143 mmol) was added to the residue under nitrogen at room temperature and the reaction mass was stirred for 30 min. The reaction mixture was quenched with water and neutralized with 10% NaHCO3, extracted with dichloromethane (2×10 mL). The combined organic layer was dried over sodium sulfate and concentrated by rotary evaporation to obtain 2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-(4-fluorophenyl)acetamide (6 mg) after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5 mL). 1H NMR (DMSO): 11.4 (s, 1H), 10.6 (s, 1H), 7.6 (m, 3H), 7.4 (d, 1H), 7.3-7.1 (m, 3H), 5.1 and 4.9 (d, 2H), 4.4 (q, 2H), 4.1-3.9 (bs, 2H), 3.5 (s, 3H), 3.2-3.1 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@@H:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:3]=1.Cl.[NH2:20][C@@H:21]1[CH2:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]1[OH:29].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@@H:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:3]=[C:2]([NH:20][C@@H:21]2[CH2:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]2[OH:29])[N:7]=1
Reactant: Clc1nc(Cl)nc(N[C@H]2CCc3ccccc32)n1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OC[C@H]1C[C@@H](Nc2nc(Cl)nc(N[C@H]3CCc4ccccc43)n2)[C@H](O)[C@@H]1O
Temperature: 150 °C
Yield: 88 %

Procedure:
A mixture of 4,6-dichloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (735 mg, 2.61 mmol), (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (400. mg, 218 mmol), potassium carbonate (602 mg, 4.36 mmol) and 1,4-dioxane (3.60 mL) in a sealed tube was heated to 150° C. for 20 mins using MWI. Silica gel chromatography eluting with a gradient of 2 to 7% MeOH in DCM afforded the title compound as a white solid (750. mg, 88%). LC/MS: Rt=1.42 min, ES+ 392 (FA standard).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:11](OC)(OC)(OC)[CH3:12]>O>[Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[N:6]([C:11]([CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ncc(Br)nc1Cl
Reactant: COC(C)(OC)OC
Solvent: O
Product: Cc1nnc2c(Cl)nc(Br)cn12
Temperature: 130 °C

Procedure:
5-bromo-3-chloro-2-hydrazinylpyrazine 1′-1 (945 mg; 3.51 mmol) is dissolved in 12 ml trimethyl orthoacetate and heated up to 130° C. for 1 hour. The solution is diluted with water and extracted with EtOAc. The organic phase is then purified with flash chromatography: cHex/EtOAc=70%/30% to 55%/45% within 10 column volumes.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:26][CH2:25][CH2:24][S:23]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:6]2([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=3)[S:26][CH2:25][CH2:24][S:23]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Reactant: COc1cc(OC)cc(C(=O)C2CCCC2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(OC)cc(C2(C3CCCC3)SCCS2)c1

Procedure:
Compound 10 was prepared from Compound 6 using the same procedure as described above for Compound 9. Yield 2.92 g (87%) as an oil. Rf=0.52 (hexane:ethyl acetate 92:8); IR (neat) 2955, 1206, 1066, 694 cm−1; 1H NMR δ 6.98 (d, J=2.19 Hz, 2H), 6.34 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.35–3.09 (m, 4H), 2.82–2.71 (m, 1H), 1.80–1.43 (m, 8H). 13C NMR δ 160.03, 149.37, 106.37, 98.35, 79.474, 55.35, 52.14, 38.79, 31.17, 25.73; MS: (ESI, Pos.) m/z 333 ([M+23]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][S:23][CH3:24])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][S:23][CH3:24])[CH:5]=1
Reactant: CSCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CSCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The mixture of 3.0 g of N-(4-nitro-2-methylmercaptomethylphenyl)-4-chlorophthalimide, 1.5 g of Raney nickel and 250 ml of ethyl acetate is hydrogenated at room temperature and atmospheric pressure until the hydrogen uptake ceases. It is filtered, the filtrate evaporated and the residue recrystallized from benzene, to yield the N-(4-amino-2-methylmercaptomethylphenyl)-4-chlorophthalimide melting at 134°-137°. Analogously the N-(4-amino-2-methylsulfonylmethylphenyl)-4-chlorophthalimide is prepared, m.p. 253°-257° (acetonitrile); as well as the N-(4-amino-2-hydroxymethylphenyl)-4-chlorophthalimide, m.p. 228°-230° (ethyl acetatediethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[N:13]=1
Reactant: CN1CCC(N)CC1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NC3CCN(C)CC3)nc21

Procedure:
The product of Example 44, and 1-methylpiperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=440 (MH+). Rt=1.67 min.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CS(C)=O>[CH3:20][O:19][C:17]([C:16]1[S:15][C:4]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:18]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C

Procedure:
24.8 g (126.7 mmol) of 2,4-dinitrobenzaldehyde, 13.4 g (126.7 mmol) of methyl mercaptoacetate and 35.3 ml (253.3 mmol) of triethylamine in 74.5 ml of DMSO are heated at 80° C. for 1 h. The reaction solution is poured into 250 ml of ice-water. The resulting precipitate is filtered off with suction, washed with water and dried at 50° C. under reduced pressure overnight. This gives 16.1 g (53.6% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9]([Cl:18])=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9]([Cl:18])=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1c2cc(Cl)cc(Cl)c2nn1CC(C)(N)C#N
Product: COc1c2cc(Cl)cc(Cl)c2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (181 mg, described in Example 125) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (161 mg, 51%). MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.42 (s, 3H), 4.53 (d, J=14.2 Hz, 1H), 4.88 (d, J=14.2 Hz, 1H), 7.35 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 8.02-8.09 (m, 2H) and 9.21 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.4 (s, 3F).
Reaction SMILES: CN(C)C[CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C([Li])CCC.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29]CCl>CCOCC.CCCCCC>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2
Reactant: CN(C)CCCCl
Reactant: CN(C)CCC1Sc2ccccc2Sc2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)CCCC1Sc2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.10 g 11H-dibenzo(b,e)-1,4-dithiepin (of example 14, reference given) in 50 ml of ether was stirred and treated dropwise with 10 ml of 15% n-butyllithium solution in hexane for 15 minutes in a nitrogen atmosphere. The mixture was stirred for another 30 minutes at room temperature. It was then treated dropwise with 10 ml of 3-dimethylaminopropyl chloride, the mixture stirred for 4 hours and washed with water. The basic product was then extracted with dilute hydrochloric acid, the acid layer made alkaline with aqueous ammonia and the base extracted with ether. Processing of the extract yielded 3.7 g for oily base which was chromatographed on a column of 200 g neutral of aluminium oxide (activity II). A small amount of less polar impurities was initially eluted with benzene which then eluted 2.89 g of a homogeneous oily base which was converted by neutralization with oxalic acid to the hydrogen oxalate, m.p. 181°-182° C. (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][O:19][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Yield: 98.7 %

Procedure:
Into a 200 cc glass reactor equipped with a stirrer, 26.3 g of ethyl 2-chloro-4,5-difluorobenzoylacetate, 23.7 g of ethyl ortho-formate and-. 40 ml of acetic anhydride were charged, and reacted at a reaction temperature of from 120° to 135° C. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure to obtain 31.5 g of the desired compound as the residue.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]1([CH3:36])[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:36][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N=C=S)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: S=C=Nc1ccc(CBr)cc1
Yield: 63.2 %

Procedure:
N-bromosuccinimide (6.26 g) (supplied from Tokyo Chemical Industry) and 1.13 g of 70% benzoyl peroxide (supplied from Aldrich) were added to a solution of 5.02 g of p-tolyl isothiocyanate (supplied from Tokyo Chemical Industry) in 100 mL of carbon tetrachloride, and stirred with heating reflux for 19 hours. The reaction suspension was filtrated and the filtrate was concentrated. The residue was applied onto the silica gel column and eluted with hexane, to yield 4.85 g of the title compound.