Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:7][S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[CH2:19][C:20](O)=[O:21])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([C@H]1C(C2C=CC=CC=2)(C2C=CC=CC=2)OC(=S)N1)(C)C.Cl.C(N=C=NCCCN(C)C)C.P([O-])(O)(O)=O.[Na+]>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([NH:7][S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH:20]=[O:21])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNS(=O)(=O)CCCCCC/C=C/CC(=O)O
Agent: CC(C)[C@@H]1NC(=S)OC1(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCNS(=O)(=O)CCCCCCC=CCC=O
Temperature: 0 °C
Reaction time: 13 h
Yield: 101.6 %

Procedure:
Under a nitrogen atmosphere, (E)-10-hexylsulfamoyl-dec-3-enoic acid (100 mg, 0.30 mmol) obtained in Step C-3 and (S)-4-isopropyl-5,5-diphenyl-oxazolidine-2-thione (89.2 mg, 0.30 mmol) were dissolved in dichloromethane (3.5 mL), and the mixture was cooled to 0° C. While maintaining the temperature at 0° C., N,N-dimethyl-4-aminopyridine (3.7 mg, 0.03 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74.7 mg, 0.39 mmol) were added in order, and the mixture was stirred at 0° C. for 2 minutes and at room temperature for 13 hours. To the reaction solution was added an aqueous solution (4.2 mL) of 10% sodium dihydrogen phosphate and ethyl acetate and the mixture was extracted. The organic layer was washed with water and a saturated brine in order, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was then purified with SP1 (SiO2 cartridge, 20% ethyl acetate/n-hexane, Rf=0.25) to obtain the target compound, (E)-104(S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-10-oxo-dec-7-ene-1-sulfonic acid hexylamide (ESI (LC/MS positive mode) m/z 613 (M+H); Rt 2.60 min.; 65% purity, 96.8 mg, 53% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].Cl.[CH3:13][O:14][CH:15]1[CH2:18][NH:17][CH2:16]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]2[CH2:18][CH:15]([O:14][CH3:13])[CH2:16]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: COC1CNC1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: Cl
Product: COC1CN(C(=O)c2ccc(N)c(Cl)c2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 25 using 4-amino-3-chlorobenzoic acid and 3-methoxyazetidine hydrochloride.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)[CH3:2].[H-].[Na+].[CH3:29]I>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:29])[C:20]=2[CH:26]=1)[CH3:2]
Reactant: CCn1c(-c2ccc3c(c2)NC(=O)CO3)c(C#N)c2ccc(OC)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(-c2ccc3c(c2)N(C)C(=O)CO3)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
1-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo [1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (20 mg, 0.058 mmol), prepared as in example 1BH, was combined with NaH (14 mg, 60% suspension in oil, 0.35 mmol). THF (300 μL) was added. This was stirred at room temperature for 5 minutes. A solution of methyl iodide (4.4 μL) in THF (100 μL) was added. This was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc and aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yielded 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (16 mg, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([NH2:23])=O>>[C:20]1([C@H:9]2[C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:10](=[O:11])[NH:12][C:10]2=[O:11])[C:15]2=[C:16]3[C:17](=[CH:18][CH:19]=[CH:14]2)[CH2:7][CH2:2][CH2:3][N:23]3[CH:21]=1
Reactant: NC(=O)Cc1ccccc1Cl
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccccc1Cl

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(2-chlorophenyl)-pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 2-chlorophenylacetamide. 1H NMR (DMSO-d6) 400 MHz δ: 11.655(s, 1H), 7.41-7.48(m, 2H), 7.27-7.35(m, 3H, J=7.2), 7.87(d, 1H, J=7.6), 6.81-6.88(m, 2H), 4.632 (d, 1H, J=7.6 Hz), 4.494(d, 1H, J=7.2), 4.07-4.10 (m, 2H), 2.884(m, 2H), 2.09(m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=O)[CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1>O1CCCC1>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1
Reactant: CN(C)C(=O)CCc1c[nH]c2c1CCCC2
Solvent: C1CCOC1
Product: CN(C)CCCc1c[nH]c2c1CCCC2
Yield: 27.7 %

Procedure:
3-(4,5,6,7-Tetrahydro-1H-indol-3-yl)-propionic acid dimethyl amide (7.7 g) and 13 g of borane-tetrahydrofuran complex in 50 mL of tetrahydrofuran was refluxed for 3 hours. The reaction was quenched with acetone and then water and evaporated to dryness. The residue was chromatographed on silica gel to give 2 g (20% yield) of 3-(3-dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indole as a yellow oil.
Reaction SMILES: N1C2C(=CC=CC=2)C[CH2:2]1.[CH2:10]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:31]([OH:33])=[O:32])=[C:24]([CH3:30])[C:25]=2[N+:27]([O-:29])=[O:28])[CH2:20][CH2:19]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].S(=O)(=O)(O)O>CO>[CH2:10]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:31]([O:33][CH3:2])=[O:32])=[C:24]([CH3:30])[C:25]=2[N+:27]([O-:29])=[O:28])[CH2:20][CH2:19]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCN1CCc2cc(C(=O)O)c(C)c([N+](=O)[O-])c21
Reactant: c1ccc2c(c1)CCN2
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCCCCCN1CCc2cc(C(=O)OC)c(C)c([N+](=O)[O-])c21

Procedure:
0.88 (3H, br-t, J=7 Hz, —(CH2)7CH3), 1.00˜1.70 (121H, m, —H2(CH2)f—), 2.47 (3H, s, indoline C6—CH3), 3.02 (2H, t, J=8 Hz, indoline C3—H2), 3.03 (2H, t, J=7 Hz, >NCH2—), 3.69 (2H, t, J=8 Hz, indoline C2—H2), 5.00 (IH, br, -2H), 7.73 (1H, s, indoline C4—H). (4) 1-Octyl-5-carboxy-6-methyl-7-nitroindoline (1.4 g) was dissolved in methanol (30 ml), and conc. sulfuric acid (4.1 g) was added, which was followed by refluxing for 4 hr. Methanol was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/ methanol=1/10−10/1) to give 750 mg of 1-octyl-5-methoxycarbonyl-6-methyl-7-nitroindoline as crystals.
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][CH:11]([OH:25])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>CN(C=O)C>[N+:7]([C:5]1[N:6]=[C:2]2[N:3]([CH:4]=1)[CH2:10][CH:11]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[O:25]2)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cn(CC(O)COc2ccc(OC(F)(F)F)cc2)c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(OC(F)(F)F)cc1)C2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
A solution of alcohol 82 (242 mg, 0.568 mmol) in anhydrous DMF (5 mL) under N2 at 0° C. was treated with 60% NaH (36 mg, 0.90 mmol), then quickly degassed and resealed under N2. After stirring at 0° C. for 45 min, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (15 mL), added to brine (40 mL), and extracted with CH2Cl2 (6×50 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with CH2Cl2, to give 1 (171 mg, 87%) as a cream solid: mp (MeOH/CH2Cl2/hexane) 170-172° C.; 1H NMR [(CD3)2SO] δ 8.16 (s, 1H), 7.31 (br dd, J=9.1, 0.8 Hz, 2H), 7.05 (dt, J=9.2, 3.1 Hz, 2H), 5.74 (m, 1H), 4.50 (dd, J=10.8, 8.9 Hz, 1H), 4.46 (dd, J=11.5, 2.8 Hz, 1H), 4.39 (dd, J=11.5, 5.2 Hz, 1H), 4.22 (dd, J=10.8, 6.5 Hz, 1H). Anal. (C13H10F3N3O5) C, H, N.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[NH2:37]>COCCO>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:37][C:36]4[CH:38]=[C:39]([O:43][CH3:44])[C:40]([O:41][CH3:42])=[C:34]([O:33][CH3:32])[CH:35]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1cc(Nc2ncc3ccc(-c4ccc(S(C)(=O)=O)cc4)n3n2)cc(OC)c1OC
Temperature: 180 °C
Yield: 14.4 %

Procedure:
2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125 mg, 0.000373 mol), N,N-Diisopropylethylamine (0.0974 mL, 0.000559 mol) and 3,4,5-Trimethoxyaniline (81.9 mg, 0.000447 mol) were dissolved in 2-Methoxyethanol (2.2 mL) and the reaction was heated at 180° C. under 300 W microwave conditions until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 24.45 mg of [7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine as a lyophilated powder. (M+H)=455.14. 1H NMR (400 MHz, CDCl3) δ 9.11 (m, 1H), 8.73 (s, 1H), 8.34 (d, 2H, J=8.59 Hz), 8.05 (d, 2H, J=8.34 Hz), 7.23 (m, 1H), 7.18 (d, 1H, J=5.05 Hz), 6.87 (s, 2H), 3.86 (s, 3H), 3.77 (s, 6H), 3.25 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[F:15][C:16]([F:21])([F:20])C([O-])=O.[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[F:15][C:16]([F:21])([F:20])[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1=Cc2cc(C(F)(F)F)ccc2OC1(C)C
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A suspension containing 6-bromo-2,2,3-trimethyl-2H-1-benzopyran (38.0 g, 0.15 mol), potassium trifluoroacetate (62.0 g, 0.408 mol) and cuprous iodide (57.0 g, 0.30 mol) in dimethylformamide (530 ml) and toluene (225 ml) was heated under nitrogen until a total of 70 ml of toluene was collected by distillation. Toluene was distilled off until the temperature of the reaction mixture reached 149° C. After a further four hours at this temperature the mixture was cooled to room temperature, water and diethyl ether were added, and the organic phase separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with heptane to give 18.82 g of 6-trifluoromethyl-2,2,3-trimethyl-2H-1-benzopyran as an oil, ms 242 (M+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:36])[C:10]1[N:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29][C:28](C)(C)C(C)(C)[O:26]3)=[C:21](C=O)[CH:20]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13])(C)(C)C.[BH4-].[Na+].Cl>CO>[OH:26][B:25]1[C:22]2[CH:23]=[CH:24][C:19]([O:18][C:16]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([N:9]([CH2:8][CH2:7][OH:6])[CH3:36])[N:17]=3)=[CH:20][C:21]=2[CH2:28][O:29]1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)c1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCO)c1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To a clear solution of 11 (5.2 g, 9.7 mmol) in MeOH (anhydrous, 150 mL) was slowly added NaBH4 (2.2 g, 58 mmol). The reaction was stirred at room temperature for 4 hours, before the addition of HCl solution (1 M, 150 mL). The stirring was kept at room temperature overnight. Then the solution was slowly evaporated in vacuo. Purification was accomplished by reverse phase Biotage with 5%-100% MeOH/H2O gradient to afford 786 mg (25% yield) of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:31])([CH3:30])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:20]([C:21]3[C:22](=[O:28])[NH:23][C:24](=[O:27])[NH:25][CH:26]=3)[C:15]3[N:16]=[C:17]([CH3:19])[O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH:29]=1)([CH3:4])[CH3:3].[Cl:32][C:33]1[N:38]=[C:37](Cl)[CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:32][C:33]1[N:38]=[C:37]([N:25]2[CH:26]=[C:21]([CH:20]3[C:15]4[N:16]=[C:17]([CH3:19])[O:18][C:14]=4[CH:13]=[CH:12][C:11]4[CH:29]=[C:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:30])[CH3:31])[CH:8]=[CH:9][C:10]3=4)[C:22](=[O:28])[NH:23][C:24]2=[O:27])[CH:36]=[CH:35][N:34]=1
Reactant: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step (viii) (0.35 g), 2,4-dichloropyrimidine (0.18 g) and cesium carbonate (0.26 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 4 hours. The mixture was partitioned between water and ethyl acetate, the organic phase washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50-80% ethyl acetate in isohexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([O:21][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of trans-N-t-butoxycarbonyl-4-(3-methylphenyl)-3 hydroxy piperidine (131 mg, 0.449 mmol), in DMF (2 ml) at 0° C. was added sodium hydride (27 mg of a 60% dispersion in mineral oil, 0.890 mmol). After 10 min, benzyl bromide (0.107 ml, 0.890 mmol) was added and the reaction allowed to warm to room temperature over 16 hrs. The reaction was quenched by the addition of saturated NH4Cl solution (5 ml) and extraction with EtOAc. The organic extracts were washed with brine and dried (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, gradient elution, 10-15% EtOAc in hexanes) afforded the title compound as an oil.
Reaction SMILES: C(O)C.[CH2:4]([N:6]([CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=2)[C:12]([N:20]2C(=O)C3=CC=CC=C3C2=O)=[N:11]1)[CH3:5].O.NN>O>[CH2:31]([N:6]([CH2:4][CH3:5])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:20])=[N:11]1)[CH3:32]
Reactant: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2c(Cl)cccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To 70 ml of ethyl alcohol was added 3.50 g of 1-(3-diethylaminopropyl)-3-phthalimido-4-chloroindazole. The mixture was added with 2.50 g of 85% hydrazine hydrate under cooling with ice and stirred for 3 hours under cooling with ice. The reaction mixture was filtered and the filtrate was condensed under reduced pressure. The condensed residue was added with 20 ml of water and extracted with chloroform. The chloroform layer was extracted with 2N-hydrochloric acid and the pH of the hydrochloric acid layer was adjusted to 10 with potassium carbonate. The alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure to give 2.03 g of 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole having the following analytical values in a yield of 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[C-]#N.[CH2:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:9][C:10](=[O:11])[N:18]([CH2:16][CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:8])[CH3:7])=[CH:12][CH:13]=1
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Reactant: CCNc1ccccc1
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: CCN(C(=O)NC(C)(C)c1ccc(Cl)cc1)c1ccccc1
Yield: 98.2 %

Procedure:
A solution of 3.9 g of p-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 20 ml of toluene was added to 2.7 g of N-ethylaniline and the mixture was heated under reflux for 3 hours. After allowing the reaction mixture to cool, the mixture was washed successively with 2N hydrochloric acid, 2N aqueous sodium hydroxide and water. The organic layer was dried over anhydrous sulfate and the solvent was removed by distillation under reduced pressure to obtain 6.2 g of the title compound as a light brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](C)(C(OCC)=O)[C:9](OCC)=O)[C:5]([F:20])=[CH:4][N:3]=1.CC(O)=O.Cl.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[C:5]([F:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1nc(Cl)ncc1F
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCc1nc(Cl)ncc1F
Temperature: 100 °C
Yield: 20.7 %

Procedure:
Diethyl 2-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylmalonate (3.00 g, 9.85 mmol) was treated with glacial HOAc (25 mL) and 5N HCl (10 mL) and fitted with a reflux condenser and heated to 100° C. for 18 h. The reaction was cooled to RT and treated with H2O (30 mL) and DCM (45 mL) and the DCM layer separated and dried over MgSO4, filtered and concentrated. The crude residue was purified with flash chromatography (eluting with 100% DCM) affording 2-chloro-4-ethyl-5-fluoropyrimidine (328 mg, 21%) as a viscous pale yellow oil. MS (ESI, pos. ion) m/z: 161.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (1H, s), 2.87 (2H, qd, J=7.6, 2.0 Hz), 1.29-1.37 (3H, t).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([N:5]=[C:6]1[N-:10][N:9]=[C:8]([S:11][CH3:12])[S:7]1)=[O:4].[Na].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(#N)C>[CH2:19]([O:18][C:16]([N:10]1[N:9]=[C:8]([S:11][CH3:12])[S:7][C:6]1=[N:5][C:3](=[O:4])[N:2]([CH3:13])[CH3:1])=[O:17])[CH3:20]
Reactant: CSc1n[n-]c(=NC(=O)N(C)C)s1
Reactant: CCOC(=O)Cl
Agent: [Na]
Solvent: CC#N
Product: CCOC(=O)n1nc(SC)sc1=NC(=O)N(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
80.5 g of 2-(dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazol-3-id, sodium salt, were suspended in 300 ml of acetonitrile and treated dropwise with stirring with 36.5 g of ethyl chloroformate at room temperature. The mixture was further stirred for 2 hours, treated with ice water, the precipitated substance separated by suction filtration, and recrystallized from acetonitrile. There is obtained 84.5 g (86.9% of theory) of 2-(dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid ethyl ester of m. pt. 129° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH2:23])[CH2:13][CH2:12]1)=[O:10])[CH3:7].[CH3:25][C:26]([CH3:28])=O.C(O)(=O)C>CO.[OH-].[Na+].ClCCl>[CH3:7][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:23][CH:26]([CH3:28])[CH3:25])[CH2:15][CH2:16]1)=[O:10])[CH3:5]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncncc2N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Nc1cncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h

Procedure:
A solution of sodium cyanoborohydride (0.13 g) in methanol (4 ml) is added to a mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[5-amino-6-pyrimidinyl]piperazine (PREPARATION 10, 0.44 g), acetone (3 ml), and glacial acetic acid (0.4 ml) in methanol (7 ml) at 0°. The mixture is stirred at 20°-25° for 72h. The reaction is diluted with an aqueous sodium hydroxide solution (10%) and dichloromethane. The phases are separated and the organic phase is washed with water and the concentrated to a colorless liquid which is flash chromatographed on silica gel eluting with methanol/chloroform (1/99). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.26, 1.49, 3.2, 3.44, 3.5-3.62, 7.89 and 8.33 δ.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([NH:23][C@H:24]([C:32]([OH:34])=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[NH:35]([CH3:54])[C@H:36]([C:38]([NH:40][C@H:41]([C:50]([O:52][CH3:53])=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH3:37]>C(OC(=O)C)C>[NH:23]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:24]([C:32]([N:35]([CH3:54])[C@H:36]([C:38]([NH:40][C@H:41]([C:50]([O:52][CH3:53])=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH3:37])=[O:34])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CN[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
The procedure of Example 1 is followed using 1 liter of ethylacetate, 30.68 ml of isobutyl chloroformate, 26.00 ml of N-methylmorpholine, 62.72 grams of BOC-phenylalanine and 68 grams of N-Me-Ala-Tyr-OMe affording 3 crops of product as follows:
Reaction SMILES: [ClH:1].N[N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][CH2:5][CH2:4]1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[ClH:1].[CH3:14][N:15]1[CH2:20][CH2:19][C:18]2[N:3]3[C:9]4[C:10](=[CH:11][CH:12]=[CH:13][C:8]=4[CH2:7][O:6][CH2:5][CH2:4]3)[C:17]=2[CH2:16]1
Reactant: NN1CCOCc2ccccc21
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: CN1CCc2c(c3cccc4c3n2CCOC4)C1

Procedure:
By a procedure similar to that described in Example 110, 1-amino-1,2,3,5-tetrahydro-4,1-benzoxazepine hydrochloride is reacted with 1-methyl-4-piperidone to yield the title compound, m.p. 286°-288° .