Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].O1CCOCC1.[C:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O:20][CH:21](OC)[CH2:22][C:23](OC)=O>C(O)(=O)C>[C:9]1([N:15]2[CH:23]=[CH:22][C:21](=[O:20])[NH:18][C:16]2=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)CC(OC)OC
Reactant: NC(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=c1ccn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.05 g NaH (41 mmol as 50% suspension in mineral oil) was added to 55 ml dry dioxane. 3.87 g (28.4 mmol) phenylurea was then added portionwise while keeping the reaction mixture under an argon atmosphere and then was heated for a few minutes to 50° C. After cooling the resulting mixture to room temperature, 6.31 g (42.6 mmol) of methyl 3,3-dimethoxypropionate was added, the mixture then refluxed for 2 hours, after which the resulting mixture was allowed to cool to room temperature. The cooled mixture was then poured into 280 ml 40% acetic acid, stored overnight in a refrigerator and then extracted twice with 140 ml chloroform. The collected chloroform fractions were dried over MgSO4 and evaporated under reduced pressure. The residue was crystallized from methanol using after treatment with activated carbon yielding 0.88 g (16%) of 1-phenyluracil (m.p. 244–245° C., Lit. 244–255° C. (Winckelmann et al., Synthesis 1986, 1041)).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[S:13].[OH-].[Na+]>O>[NH2:10][C:8](=[N:9][C:12](=[S:13])[O:14][CH3:15])[S:7][CH3:6]
Reactant: COC(=S)Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=S)N=C(N)SC
Reaction time: 1 h

Procedure:
To 69.5 parts 2-methyl-2-thiopseudourea sulfate and 110 parts methyl chlorothioformate in 500 ml. of water is added dropwise at 0°-5°C. 120 parts 50% sodium hydroxide. The reaction mixture is stirred at 0°-5°C. for 1 hour and then at room temperature for 2 hours. The solution is extracted with methylene chloride. The methylene chloride extract is then dried and the solvent evaporated on a rotary evaporator to give 47 parts of methyl N-(1-amino-1-methylthiomethylene)thiocarbamate melting at 75°-76°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[O:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:26]([C:24]3[CH:25]=[N:20][CH:21]=[N:22][CH:23]=3)=[O:27])[CH:11]=[N:10][C:9]=2[O:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1cncnc1
Product: O=C(Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 42g, using 6-(4-chloro-phenyl)-5-cyclobutoxy-pyrazin-2-ylamine (example 50c) and 5-pyrimidinecarboxylic acid (CAN 4595-61-3) as starting materials; LC-MS (UV peak area/ESI) 96.3%, 482.1073 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH3:13][O:14][CH2:15][C:16]([NH:12][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([NH:11][C:16](=[O:17])[CH2:15][O:14][CH3:13])[C:2]=1[Cl:1])[C:6]([NH2:8])=[O:7])=[O:17]
Reactant: COCC(=O)Cl
Reactant: NC(=O)c1cc(N)c(Cl)c(N)c1
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(C(N)=O)cc(NC(=O)COC)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzamide (2.8 g) in pyridine (40 ml) is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanolethyl acetate-hexane to give the title compound (4.0 g) having the following physical properties.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10](O)=[O:11].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[F:6][C:7]1[C:15]([F:16])=[CH:14][CH:13]=[C:9]([C:10]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:11])[C:8]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)cc1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
This material was then coupled directly with 2-(aminooxy)ethanol as follows: The crude 3,4-difluoro-2-[[4-(methoxycarbonyl)-phenyl]amino]benzoic acid was dissolved in dry THF (20 mL) to which was added CDI (1.63 g, 10.0 mmol). This reaction mixture was stirred at room temperature for 2 hours, then a solution of 2-(aminooxy)ethanol (1.55 g, 20.1 mmol) in dry THF (10 mL) was added and the reaction allowed to stir at room temperature overnight. The reaction solvent was removed under reduced pressure and the resulting oil dissolved in EtOAc (200 mL) which was washed sequentially with 1 M HCl (100 mL), water (100 mL), and brine (100 mL). The solution was dried (Na2SO4), the solvent removed under reduced pressure and the crude oil purified by chromatography on flash silica (10% EtOAc as eluant) to give methyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]amino]benzoate (0.889 g, 48%) as a white solid; mp (EtOAc/hexanes) 158-160° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.64 (br s, 1 H), 8.76 (br s, 1 H), 7.78 (d, J=8.8 Hz, 2 H), 7.41-7.27 (m, 2 H), 6.80 (dd, J=8.8, 1.8 Hz, 2 H), 4.67 (br s, 1 H), 3.78 (s, 3 H), 3.76 (t, J=4.8 Hz, 2 H), 3.50 (t, J=4.6 Hz, 2 H). Anal Calcd for C17H16F2N2O5: C, 55.7; H, 4.4; N, 7.7. Found C, 55.7; H, 4.4; N, 7.6.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=O>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Reactant: COc1cc(C=O)cc(OC)c1
Product: COc1cc(C=Cc2cc(OC)c(C(C)C)c(OC)c2)cc(OC)c1
Yield: 25 %

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 3,5-dimethoxybenzaldehyde in 25% yield as the same procedure as described in example 5(b)
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:21][CH2:22][OH:23].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:30][C:27]1[N:26]=[CH:25][C:24]([C@H:20]([NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:22][OH:23])=[CH:29][CH:28]=1
Reactant: Cc1ccc([C@H](N)CCO)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C)nc4)c3C2)nc1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (35 mg, 0.14 mmol) and (R)-3-amino-3-(6-methylpyridin-3-yl)propan-1-ol (15 mg, 0.090 mmol) in acetonitrile (1.5 mL) and N,N-diisopropylethylamine (31 μL, 0.18 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was concentrated and purified by semi-prep HPLC ((100×20.2 mm, C18 column; 30-60% CH3CN-water [10 mM Et2NH]) to give a light yellow foam. LC-MS: 391.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([C:16]3[C:17](=O)[NH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:5]=2[N:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:5]=2[N:6]=1
Reactant: Cc1nc2c(o1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1nc2c(o1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A mixture of the product from step (iii), (0.075 g) and Lawesson's reagent (0.094 g) in 1,4-dioxane (5 ml) under nitrogen was heated at reflux 16 h. The reaction mixture was partitioned between ethyl acetate and saturated brine. The organic phase was collected, dried over magnesium sulphate and solvent evaporated under reduced pressure. Purification was by flash chromatogaphy eluting with 0 to 2% ethanol in dichloromethane followed by a second column eluting with 40% ethyl acetate in toluene to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: COc1cccc(O)c1
Product: COc1cccc(Oc2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-methoxy-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-Methoxy-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23](O)=[O:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:11].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.CC1C=CC(C)=CC=1CC(N1CCC(C2SC=C([C:67]([N:69](C)[C@@H:70]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[CH2:71][CH3:72])=O)N=2)CC1)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([N:69]([CH3:67])[C@@H:70]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[CH2:71][CH3:72])=[O:24])[N:22]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(C(=O)O)co3)CC2)c1
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1coc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-[1-[(2,5-dimethylphenyl)acetyl]-4-piperidinyl]-4-oxazolecarboxylic acid (i.e. the product of Example 9, Step F) (245 mg, 0.72 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 80 mmol) and 4-methylmorpholine (88 μL) in 3 mL of dichloromethane were stirred at room temperature for 15 minutes. (α,R)-α-Ethyl-N-methylbenzenemethanamine (i.e. the product of Example 1, Step C) (0.80 mmol, 119 mg) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloromethane, washed with 1 N aqueous hydrochloric acid and water, dried over MgSO4 and concentrated under reduced pressure. The products were purified by silica gel chromatography using 50-100% ethyl acetate in hexanes as eluant to give 90 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].Cl.C(N(CC)CC)C>C(O)C>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:26][CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)CN
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Temperature: 75 °C

Procedure:
A mixture of 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (170 mg, 0.58 mmol, Example 7, Step 1), glycine ethyl ester•HCl (97 mg, 0.69 mmol), triethylamine (0.2 mL, 1.4 mmol), and ethanol (2 mL) was heated at 75° C. in a sealed vial for 30 h. The reaction was allowed to cool to rt, concentrated, and purified by silica gel chromatography (3:2→1:4; hexanes:ethyl acetate) to give ethyl 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)acetate: 1H NMR (400 MHz, DMSO-d6): δ 7.93 (t, 1H), 7.68 (d, 1H), 7.08 (d, 1H), 4.92 (s, 1H), 4.80 (m, 1H), 4.13 (q, 2H), 4.10 (d, 2H), 3.86 (s, 3H), 1.90-1.45 (m, 8H), 1.20 (t, 3H); MS (ESI): 361.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][S:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35])(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[S:29]([CH3:28])(=[O:31])=[O:30])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccccc1CN
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3S(C)(=O)=O)ncc2[N+](=O)[O-])CC1
Reaction time: 24 h
Yield: 69.1 %

Procedure:
{4-[(2-Chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) was dissolved in DMF (3 mL). 2-Methanesulfonyl-benzylamine hydrochloride (115 mg, 0.52 mmol) and diisopropylethylamine (0.14 mL, 0.78 mmol) were added sequentially. After 24 h, the reaction was partitioned between water (10 mL) and DCM (10 mL). The organic layer was washed with 5% AcOH (aq), saturated Na2CO3 and water, dried over MgSO4, filtered and concentrated. Chromatography (silica, 0-15% MeOH in DCM; Rf=0.3 10% MeOH in DCM) yielded 96 mg of (4-{[2-(2-methanesulfonyl-benzylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester as a pale yellow solid, m/z 535.7 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([C:20](=O)[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=1.[CH:23]([NH2:25])=[O:24]>C(O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]([NH:25][CH:23]=[O:24])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=1
Reactant: CC(=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Reactant: NC=O
Solvent: O=CO
Product: CC(NC=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1

Procedure:
A mixture of 2.9 g of 1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone, 40 ml of formamide and 13 ml of concentrated formic acid was refluxed for 15 hours, then cooled and evaporated. The residue was partitioned between unsaturated aqueous potassium bicarbonate and chloroform. The organic phase was separated, dried, filtered and evaporated. The residue was chormatographed on silica gel, eluting 125 ml fractions, fractions 1-4 with chloroform and fractions 5-7 with 2% methanol in chloroform. Fractions 5-7 were combined and evaporated, giving 1.25 g of the desired product as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:23]([NH:22][CH2:21][CH2:20][Cl:19])=[O:24])[CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1
Reactant: O=C=NCCCl
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCCN2
Solvent: ClCCl
Product: O=C(NCCCl)N1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 48 h

Procedure:
10 parts of 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine is dissolved in 75 parts by volume of methylene chloride. To this solution is added 6 parts of 2-chloroethylisocyanate and the resultant mixture left standing at ambient temperature for about 48 hours. Then, additional 2 parts of 2-chloroethylisocyanate is added to the mixture, the mixture heated on a steam bath for about 4 hours and the solvent removed to give a solid. The solid is washed with ether and crystallized from a mixture of methylene chloride and hexane to give 7-chloro-N-(2-chloroethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-1-carboxamide, as yellow crystals melting at about 160°-161° C. This compound is represented by the following formula ##STR17##
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[CH2:36]([O:38][CH2:39]CCN)[CH3:37]>>[CH2:36]([O:38][CH2:39][CH2:2][CH2:1][NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:37]
Reactant: CCOCCCN
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCCCOCC)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 3-ethoxypropylamine.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]=O>C([O-])(O)=O.[Na+]>[CH2:1]([N:8]([CH3:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccccc1
Reactant: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(CCNC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a mixture of tert-butyl 2-(benzylamino)ethylcarbamate (2.8 g, 11.2 mmol) and 37% aqueous CH2O (1.0 mL, 11.2 mmol) in 1,2-dicholoroethane (35 mL) at RT was added NaHB(AcO)3 (3.7 g, 11.2 mmol). The mixture was stirred (RT, 16 h), diluted with saturated aqueous NaHCO3 (400 ml) and extracted with EA (3×300 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford tert-butyl 2-(benzyl(methyl)amino)ethylcarbamate (1.38 g, 46.8%). 1HNMR (CDCl3): δ7.25 (m, 5H, CH), 3.5 (s, 2H, CH2), 3.3 (m, 2H, CH2), 2.48 (m, 2H, CH2), 2.2 (s, 3H, CH3), 1.4 (s, 9H, CH3).
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:25])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[C:26]([O-])(=O)[CH3:27].[Na+].C(O)(=O)C.[BH4-].[Na+]>>[CH2:1]([N:3]([CH2:26][CH3:27])[CH:4]([CH3:25])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3c(OC)c(OC)ccc23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3c(OC)c(OC)ccc23)C1
Yield: 21.2 %

Procedure:
Prepared by the method described in Example 73 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (10.0 g, 0.029 moles), sodium acetate (4.7 g, 0.058 moles), acetic acid (43.2 g, 0.72 moles), and sodium borohydride (5.9 g, 0.16 moles). Several recrystallizations from ethyl acetate/hexane yielded the product as the free base (2.3 g), mp 99°-100° C.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br>CN(C=O)C.O>[O:15]1[CH2:14][CH:13]1[CH2:11][O:8][CH2:7][C:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1=CC=CCC1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=CCCC(COCC2CO2)=C1
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
(Compound No. 229) 1,3-Cyclohexadiene-1-methanol (2 g, 0.0182 mol) synthesized in Example 21 was dissolved in DMF (10 ml) and 60% sodium hydride (775 mg, 0.0194 mol) was added at 0° C. The mixture was stirred for 10 minutes and a solution of epibromohydrin (3 g, 0.022 mol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour and at 40° C. for 1 hour and the reaction mixture was poured in water, extracted with ethyl acetate and the combined ethyl acetate layer was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography (silica gel 60 g, ethyl acetate:hexane=1:10) to obtain 1-(2,3-epoxypropoxymethyl)-cyclohexa-1,3-diene (2.31 g, 76%). This compound has the following NMR spectrum.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][C:16](=[O:22])[CH2:15]2)=O.FC(F)(F)C(O)=O>>[Cl:8][CH2:9][CH2:10][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][C:16](=[O:22])[CH2:15]2
Reactant: O=C1Cc2cc(C(=O)CCl)c(Cl)cc2N1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Temperature: 42.5 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Triethylsilane (57.2 gm) was added slowly to the reaction mixture of 5-(2-Chloro acetyl) -6-chloro oxindole (50.0 gm) and trifluoroacetic acid (175 mL) below the temperature of 45° C. The reaction was maintained at 40-45° C. for 6 hours. The reaction mass was cooled to 0° C. to -5° C. and maintained stirring for 90 minutes. The separated solid was filtered and washed with water (50 mL). Then the wet compound was further slurred in water (250 mL) for 90 minutes. The resultant solid was filtered, washed with water (50 mL) and dried at a temperature of 70-75° C. to afford 5-(2-chloroethyl) -6-chloro oxindole (43.5 gm).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13].[CH3:14][N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28](O)=[O:29])[CH:24]=[N:25][C:19]=2[NH:18][C:17](=[O:31])[CH2:16]1>>[CH3:1][N:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13])[C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[N:25][C:19]2[NH:18][C:17](=[O:31])[CH2:16][N:15]([CH3:14])[CH2:21][C:20]=2[CH:22]=1
Reactant: CNCc1c(C)[nH]c2ccccc12
Reactant: CN1CC(=O)Nc2ncc(C=CC(=O)O)cc2C1
Product: Cc1[nH]c2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(C)CC(=O)N2
Yield: 9.9 %

Procedure:
According to the method of example 35g, methyl-(2-methyl-1H-indol-3-ylmethyl)amine (115 mg, 0.66 mmol) and 3-(4-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid (192 mg, 0.6 mmol) were coupled to give crude product. Purification by column chromatography (silica gel, CH2Cl2/MeOH/NH3, 9:4.55:0.05) gave title compound (24 mg, 9%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.95-8.01 (m, 2H), 7.56-7.60 (m, 2H), 7.47-7.50 (m, 1H), 7.16-7.26 (m, 2H), 6.92-7.05 (m, 2H), 3.90 (s, 2H), 3.56 (s, 2H), 3.02 (s, 2H), 2.93 (s, 3H), 2.83 (s, 3H), 2.46 (s, 3H); MS (EST) m/e 404 (C23H25N5O2+H)+.