Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.CN([CH:32]=[O:33])C>C1COCC1>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:32]([OH:33])[N:7]([C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CC(C)(NC(=O)c1ccc(F)c(Cl)c1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2ccc(F)c(Cl)c2C1O
Yield: 45.5 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-chloro-4-fluoro-N-(1-methyl-1-phenylethyl)benzamide (3.00 g, 10.3 mmol) was dissolved in THF (120 mL), and the solution was treated with TMEDA (5.00 mL, 32.9 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 32.6 mL, 32.9 mmol) and DMF (1.80 mL, 22.6 mmol), followed by purification by flash column chromatography (chloroform) and by slurry (chloroform) to obtain 4-chloro-3-hydroxy-5-fluoro-2-(1-methyl-1-phenylethyl)isoindolinone (1.50 g, yield 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9](=[NH:11])[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1.[CH2:19]1[CH:26]2[C:22]3([C:28](O)=[O:29])[CH2:23][CH:24]([CH2:27][CH:20]1[CH2:21]3)[CH2:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9](=[N:11][C:28]([C:22]23[CH2:23][CH:24]4[CH2:27][CH:20]([CH2:19][CH:26]2[CH2:25]4)[CH2:21]3)=[O:29])[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: COCCn1cc(Cc2cccc(F)c2)sc1=N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1cc(Cc2cccc(F)c2)sc1=NC(=O)C12CC3CC(CC1C3)C2

Procedure:
A mixture of the product of Example 45A (342 mg, 1.29 mmol), hexahydro-2,5-methano-pentalene-3a-carboxylic acid (256 mg, 1.54 mmol), HATU (737 mg, 1.24 mmol) and triethylamine (1.08 mL, 7.74 mmol) in 20 mL of DMF was processed according to the method of Example 43B to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.50-1.61 (m, 4 H), 1.65-1.76 (m, 4 H), 2.03-2.11 (m, 2 H), 2.21-2.26 (m, 2 H), 2.48-2.55 (m, 1 H), 3.25 (s, 3 H), 3.68 (t, J=5.4 Hz, 2 H), 3.99 (s, 2 H), 4.25 (t, J=5.4 Hz, 2 H), 7.03-7.13 (m, 3 H), 7.26 (s, 1 H), 7.33-7.41 (m, 1 H); MS (DCI/NH3) m/z 415 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([O:20][C:21]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[O:38])[CH:32]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:20][C:21]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:38])[CH:32]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)c1cccc(-c2cccc(C=O)c2)c1OCc1ccccc1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(-c2cccc(C(O)c3ccccn3)c2)c1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 2-bromopyridine (1.51 g, 9.58 mmol) in dry tetrahydrofuran (20 mL) was stirred under nitrogen at −78° C. and 2.5M n-butyllithium in hexanes (3.8 mL, 9.5 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 30 min. when a solution of 9 (2.1 g, 6.1 mmol) in tetrahydrofuran (15 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 20 min., then for 2 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried over sodium sulfate and stripped. The crude 10 was used as such in the next step.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][C:19]([CH:22]=O)=[CH:20][CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].C(O)(=O)C.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[O:18][C:19]([CH2:22][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)o3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)o3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(5-formyl-2-furanyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 21) (18 mg, 0.047 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with acetic acid (8.04 μL, 0.140 mmol) and piperidine (9.27 μL, 0.094 mmol) and stirred under nitrogen for 30 minutes. sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added and the reaction was stirred again under nitrogen. After 17 hours reaction time a second quantity of sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added. 1 hour after this another sample of sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added. After 2 further hours the reaction was loaded onto a 2 g Flash SCX-column, eluting with MeOH (60 mL) followed by 2M MeOH/NH3 (60 mL). The product-containing fraction was evaporated to dryness to give a brown solid which was purified by MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (3 mg).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[CH2:18]([S:22]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCS(=O)(=O)Cl
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCS(=O)(=O)On1nnc2ccccc21
Reaction time: 4 h
Yield: 96.7 %

Procedure:
In benzene (50 ml) are dissolved 1-hydroxy-1,2,3-benzotriazole (6.8 g) and triethylamine (7.0 ml) and thereto is added dropwise a solution of n-butanesulfonyl chloride (7.8 g) in benzene (10 ml) at room temperature and the mixture is stirred for 4 hours. After the reaction, the benzene layer is separated, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 1-(n-butanesulfonyloxy)-1,2,3-benzotriazole (12.3 g) as an oily substance. Infrared spectrum (film): 1395, 1175 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][C:28]1([C:31]#[N:32])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:23](=[O:25])[NH:27][C:28]2([C:31]#[N:32])[CH2:30][CH2:29]2)[CH2:10]1)(=[O:14])=[O:15]
Reactant: N#CC1(N)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
The carboxylic acid 5A (195 mg, 0.5 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (65.2 mg, 550 μmol), HATU (380 mg, 1.00 mmol) and ethyldiisopropyl amine (262 μL, 1.5 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature over night. The reaction was concentrated under reduced pressure. The residue was diluted with 5% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with 1M aqueous hydrogen chloride solution and with saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure to yield (2S,4R)-tert-butyl 4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)-pyrrolidine-1-carboxylate 6H as a yellow oil (66%). MS ISP (m/e): 354.2 (100) [(M−BOC+H)]+, 398.1 (25) [(M-Isobutylene+H)]+, 454.1 (12) [(M+H)]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH:19][CH2:20][CH:21]([F:23])[F:22])=[CH:14][C:13]=2[N:24]2[CH2:28][CH2:27][C@@H:26]([F:29])[CH2:25]2)=[CH:6][CH:5]=1.[Cl:33][C:34]1[C:47]([N:48]=[C:49]=S)=[C:46]([Cl:51])[CH:45]=[CH:44][C:35]=1[CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].CC(C)N=C=NC(C)C>C1COCC1>[F:32][C:2]([F:31])([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:12]2[C:13]([N:24]3[CH2:28][CH2:27][C@@H:26]([F:29])[CH2:25]3)=[CH:14][C:15]3[N:19]([CH2:20][CH:21]([F:23])[F:22])[C:49]([NH:48][C:47]4[C:46]([Cl:51])=[CH:45][CH:44]=[C:35]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42])[C:34]=4[Cl:33])=[N:18][C:16]=3[CH:17]=2)=[O:30])=[CH:6][CH:5]=1
Reactant: Nc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)c(N2CC[C@@H](F)C2)cc1NCC(F)F
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)Nc4ccc(OC(F)(F)F)cc4)c(N4CC[C@@H](F)C4)cc3n2CC(F)F)c1Cl

Procedure:
The title compound is prepared in analogy to 6c from (R)—N-(4-trifluoromethoxyphenyl)-2-[3-fluoro-pyrrolidinyl]-4-(2,2-difluoro-ethylamino)-5-amino-benzoic acid amide (94 mg, 0.20 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (64 mg, 0.20 mmol), DIC (62 μL, 0.40 mmol) and THF (10 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1CCCc2c1[nH]c1ccc(Br)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg, 0.19 mmol) in dichloromethane (1 mL) was added phenyl isocyanate (23 μL, 0.21 mmol). The mixture was stirred at room temperature 15 hours and the resulting precipitate collected by filtration to give a gray solid (62% yield). 1H-NMR (DMSO-d6): δ 11.01 (s, 1H), 7.60 (d, 1H), 7.45 (m, 2H), 7.33-7.23 (m, 4H), 7.17 (dd, 1H), 6.94 (m, 1H), 6.63 (d, 1H), 5.02 (m, 1H), 2.68 (m, 2H), 2.06 (m, 1H), 1.95-1.70 (m, 3H); MS m/z 384 (M−1).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[C:5]([S:14][CH2:15][CH2:16][CH3:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1>C(O)(=O)C>[Cl:3][C:4]1[C:5]([S:14]([CH2:15][CH2:16][CH3:17])=[O:1])=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: OO
Reactant: CCCSc1ncc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Product: CCCS(=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 27 °C
Reaction time: 14 h

Procedure:
At 15-20° C., 8.4 g (0.124 mol) of 50% strength hydrogen peroxide were added over a period of 15 min with stirring to a mixture of 31 g (0.1213 mol) of 3-chloro-2-n-propylthio-5-trifluoromethylpyridine in 150 ml of acetic acid, the temperature increasing to 27° C. over a period of 6 h. The reaction mixture was stirred at 25° C. for 14 h and then poured into ice-water and extracted 3 times with methylene chloride. The organic phase was washed with water and saturated sodium bicarbonate solution, dried and concentrated under reduced pressure, giving 32 g (97.2% of theory) of the title compound of mp. 51-53° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([OH:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[N-:67]=[N+:68]=[N-:69].[Na+].O>CN(C)C=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:67]=[N+:68]=[N-:69])[CH:46]([OH:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(S(=O)(=O)c4ccccc4[N+](=O)[O-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 80 °C

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-{2'-[4"-(o-nitrobenzenesulfonyl)-3"-hydroxycyclohexyl]-1'-methylvinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (87 mg) in dry dimethylformamide (1 ml) is added sodium azide (16.7 mg) in one portion. The reaction is heated at 80° C. under nitrogen atmosphere for 3 hr. The reaction mixture is cooled, poured into water (5 ml) and extracted with ethyl acetate. Normal work-up followed by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62](O)=[O:63]>>[CH3:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:63]
Reactant: COCCOCC(=O)O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: COCCOCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 4.1 %

Procedure:
The crude product obtained using Compound 18 (200 mg, 0.602 mmol), N-methylmorpholine (0.132 mL, 1.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.842 mmol), 1-hydroxybenzotriazole monohydrate (106 mg, 0.783 mmol) and 2-methoxyethoxyacetic acid (0.0674 mL, 0.722 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (chloroform/methanol=80/20) to obtain Compound 127 (0.011 g, 4%).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=1>CS(C)=O>[CH3:1][C@H:2]1[CH2:3][O:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][N:7]1[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=1
Reactant: C[C@H]1COC(c2ccccn2)CN1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COC(c2ccccn2)CN1c1ccc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a solution of (5S)-5-methyl-2-(pyridin-2-yl)morpholine (0.7 g, 3.93 mmol) in dimethylsulfoxide (20 mL) was added triethylamine (0.68 g, 7.86 mmol). After 10 min, 6-chloro-3-nitropyridin-2-amine (0.68 g, 3.93 mmol) was added. After 4 h at 110° C., the mixture was cooled to room temperature, and then was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (80% ethyl acetate in petroleum ether) to afford 6-((5S)-5-methyl-2-(pyridin-2-yl)morpholino)-3-nitropyridin-2-amine (0.5 g, 41%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:40])=[CH:19][C:20]([CH3:39])=[C:21]([C:23]4[NH:38][C:26]5[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:25]=5[N:24]=4)[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:40][C:18]1[CH:19]=[C:20]([CH3:39])[C:21]([C:23]2[NH:38][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:25]=3[N:24]=2)=[CH:22][C:17]=1[C:15]([N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 133.8 %

Procedure:
To a solution of tert-butyl 2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 2.8, 100 mg, 0.17 mmol, 1.00 equiv, 90%) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature. After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane and washed with sodium bicarbonate (aq., sat.). The organic phase was dried (Na2SO4) and concentrated under reduced pressure to yield 0.1 g (68%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:14][NH:13][C:12](=[O:21])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[N:14][N:13]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[N:31][CH:30]=4)[C:12](=[O:21])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: CN(C)C(=O)c1n[nH]c(=O)c2c1c1ccc(F)cc1n2C
Reactant: COc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N(C)C)c3c4ccc(F)cc4n(C)c3c2=O)cn1

Procedure:
A solution of 0.3 g (1.04 mmol) of 7-fluoro-N,N,5-trimethyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-carboxamide (obtained in stage 3.2.), of 0.120 g (0.63 mmol) of cuprous iodide, of 0.20 g (1.45 mmol) of potassium carbonate and of 0.60 g (3.19 mmol) of 3-bromo-6-methoxypyridine in 50 ml of N,N-dimethylformamide is heated at 150° C. for 20 h. The reaction mixture is cooled and concentrated under reduced pressure. Dichloromethane, water and a sodium hydroxide solution (1M) are added. The organic phase is separated by settling, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate: 100/0 to 0/100; then ethyl acetate/methanol: 95/5). The white solid obtained is recrystallized from a dichloromethane/ethyl acetate mixture and washed with diethyl ether. A white solid (0.26 g; 0.66 mmol) is isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[CH3:5][C:6]([CH:8]([CH3:10])[CH3:9])=O.C1C=CC=CC=1>O>[CH:8]([C:6]1([CH3:5])[NH:1][CH2:2][CH2:3][S:4]1)([CH3:10])[CH3:9]
Reactant: NCCS
Reactant: CC(=O)C(C)C
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C1(C)NCCS1
Yield: 77.5 %

Procedure:
15.43 g (0.2 mol) of cysteamine and 29.0 g (0.2 mol) of isopropyl methyl ketone were treated with 200 ml of benzene and boiled under an inert gas atmosphere for 14 hours on a water-separator. The solution was concentrated on a rotary evaporator and filtered over 25 g of neutral aluminium oxide (activity I). The aluminium oxide was then flushed with ether. The filtrate was again concentrated and subsequently distilled under a high vacuum through a Widmer column. 22.51 g (yield 77% of theory) of 2-isopropyl-2-methyl-thiazolidine (nD20 = 1.5085) passed over in a boiling range of 40°-42° C and at a pressure of 0.009 mm Hg. IR: νmax = 1440, 1370, 790 cm-1. Odour: camphorous, woody; flavour: greenish.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:11]1[CH:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4ccccc4C3)c(F)cc2c1=O
Yield: 35.6 %

Procedure:
133 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 83 mg of isoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 65 mg of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[NH:29][C:30](=[O:35])[C:31]([OH:34])([CH3:33])[CH3:32])[NH:25][C:24](=[O:36])[CH2:23]2>>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:23]3[C:22]4[C:26](=[CH:27][C:28]([NH:29][C:30](=[O:35])[C:31]([OH:34])([CH3:32])[CH3:33])=[C:20]([F:19])[CH:21]=4)[NH:25][C:24]3=[O:36])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17]
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 41.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 112 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide as starting materials to give N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide (40 mg, 41.8%) as a yellow solid.
Reaction SMILES: [C:1]1([Si:7]2([CH2:20][CH2:21][CH3:22])[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Cl)=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:16]2[CH2:17][CH2:18][CH:13]([CH:10]3[CH2:11][CH2:12][Si:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH2:20][CH2:21][CH3:22])[CH2:8][CH2:9]3)[CH2:14][CH:15]=2)=[CH:26][CH:25]=1
Reactant: CCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: Fc1ccc([Mg]Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[Si]1(c2ccccc2)CCC(C2CC=C(c3ccc(F)cc3)CC2)CC1
Reaction time: 2 h

Procedure:
31.5 g of 4-(4-phenyl-4-n-propyl-4-silacyclohexyl)cyclohexanone was dropped in 120 ml of a solution of 1.0 mole of p-fluorophenylmagnesium chloride in tetrahydrofuran at a temperature of 40° to 50° C. After agitation at 50° C. for 2 hours, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, followed by extraction with benzene. 1.0 g of p-toluenesulfonic acid monohydrate was added to the benzene phase, followed by distilling off the resultant water under reflux. When the distilling of water stopped, the benzene solution was washed with a sodium hydrogencarbonate aqueous solution, dried and concentrated to obtain crude 4-(4-(4-fluorophenyl)-3-cyclohexenyl)-1-phenyl-1-n-propyl-1-silacyclohexane. This product was dissolved in 100 ml of ethanol and hydrogenated in the presence of 1.0 g of a palladium-carbon catalyst, followed by separation of the catalyst by filtration and concentration to obtain 35.0 g (yield: 88%) of 4-(4-(4-fluorophenyl)cyclohexyl)-1-phenyl-1-n-propyl-1-silacyclohexane. The results of IR analysis are shown below.