Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[C:13](=[O:15])[N:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:30][C@@H:31]([CH2:44][NH2:45])[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[OH:30][C@@H:31]([CH2:44][NH:45][CH:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([CH:16]=[C:12]3[S:11][C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:14][C:13]3=[O:15])=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(C=C3SC(NCCN4CCOCC4)=NC3=O)cc2)CC1
Product: O=C1N=C(NCCN2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(2-morpholin-4-ylethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 20) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.43 (t, J=4.7 Hz, 2 H), 2.50-3.70 (m, 13 H), 3.59 (t, J=4.7 Hz, 2 H), 3.75-4.15 (m, 5 H), 4.86 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.62 (d, J=7.5 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.38 (d, J=9.0 Hz, 2 H), 7.47 (s, 1 H), 9.47 (s, 1 H), 10.57 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 311.5 ((M+2H)2+, 100%); 621.9 (MH+, 15%); HRMS Calcd. for C31H40N7O5S (MH+): 622.2812. Found: 622.2811.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5](=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5](=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a stirred solution of 1,1-dimethylethyl(2E)-3-{4-[(4,4-dimethylcyclohexylidene)(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (21) (0.24 g, 0.57 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 1 h and concentrated in vacuo to give an oil. The oil was dissolved in CH2Cl2 and the solvent was removed in vacuo to give a solid which was dried under vacuum at 90° C. to give 0.170 g (82%) of compound 22 as a pale tan solid. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6 H), 1.31 (m, 4 H), 2.16 (m, 4 H), 6.44 (d, J=15.9 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.84 (d, J=8.3 Hz, 2 H), 7.05 (d, J=7.9 Hz, 2 H), 7.52 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.32 (s, 1 H), 12.33 (br s, 1 H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C30H42O3Si2: 506.2673 (M+). Found: 506.2669.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
10.7 gm (0.035 mol of 4-hydroxy-2H-naphtho[2,1-e]1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 15.0 gm (0.0875 mol) of freshly distilled benzyl bromide were added to a mixture of 33 ml of water and 120ml of ethanol, and then 38.5 ml of 1 N sodium hydroxide were added dropwise. After stirring for 24 hours at room temperature, the crystals which had formed were suction-filtered off, washed with water and dried. Recrystallization from ethylene chloride/petroleum ether yielded 11.9 gm (86% of theory) of 2-benzyl-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide, m.p. 254°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:5].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[CH:27][CH:26]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[CH2:7][CH2:8][CH2:9][C:10]([N:31]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:28]1[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=1)=[O:12])=[O:5]
Reactant: CCC(C)(C)N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C)(C)N(CCCC(=O)N(CCCC(=O)O)c1ccc(OC)cc1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(2,4-dichlorobenzoyl)-4-[(1,1dimethylpropyl)amino]butyric acid and methyl γ-(p-anisidino)butyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(2,4-dichlorobenzoyl)-4-(1,1-dimethylpropylamino)butyryl]-4-(p-anisidino)butyric acid.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:21])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:25][NH2:26])[CH:23]=[CH2:24]>C(O)C>[CH2:22]([O:25][N:26]=[C:1]([C:6]1[C:7](=[O:21])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH:23]=[CH2:24]
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Reactant: C=CCON
Solvent: CCO
Product: C=CCON=C(CCC)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 20 ml of ethanol was dissolved 1.5 g of 2-butyryl-3-hydroxy-5-(4-methylthiophenyl)-2-cyclohexen-1-one and to the solution was added 0.5 g of allyloxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water. The crystal sedimented was collected with a filtering step and recrystallized with methanol. Thus, 1.4 g of colorless objective crystals having a melting point of 72°-74° C. was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:19]2[C@H:20]3[C@H:25]([CH2:26][CH2:27][C:18]=2[CH:17]=[CH:16][CH:15]=1)[NH:24][CH2:23][CH2:22][CH2:21]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@H:20]([C:19]5[C:14]([F:13])=[CH:15][CH:16]=[CH:17][C:18]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Fc1cccc2c1[C@@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3c(F)cccc3CC[C@@H]21
Yield: 41 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10-fluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 41% of theory; LC (method 1): tR=2.76 min; Mass spectrum (ESI+): m/z=350 [M+H]+.
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4]1)#N.[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H]([OH:40])C1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[C:10]([O:9][CH2:8][C@H:7]1[O:6][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4][C@@H:3]1[CH:1]=[O:40])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#C[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a stirred solution of 3'-cyano-2',3'-dideoxy-5' -O-trityl uridine (0.96 g, 2 mmol), (see Tetrahedron Letters 29: 2995 (1988) for synthesis of the thymidine analog) in dry THF (20 ml) under argon was added a solution of DIBAL-H in toluene (Aldrich) (1M, 4 ml) at -10° C. over a period of 10 min. After 30 mins the reaction was quenched with MeOH (5 ml) at -10° C. The mixture was further stirred at ambient temperature for 30 mins and diluted with CH2Cl2 (25 ml) before concentrating under vacuum. This process was repeated with CH2Cl2 (3×25 ml) in order to remove the residual THF. The residue was purified by flash chromatography on silica gel (25 g). Elution with CH2Cl2 (9:1, v/v) and crystallization from CH2Cl2 /MeOH gave 5' -O-trityl-3'-C-formyl-2',3'-dideoxyuridine (0.53 g, 53%); mp 100° C.; 1H NMR (CDCl3) δ2.25-2.8 (m, 2, CH2), 3.4 (m, 1, C3,H), 3.45-3.6 (m, 2, C5,CH2), 4.37 (m, 1, C4, H), 5.4 (d, 1, C5H), 6.1 (m, 1, C1,H), 7.2-7.4 (m, 15, C6H5), 7.81 (d, 1, C6H), 7.95 (brs, 1, NH), 9.61 (s, 1, HC=O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=CN=[CH:24]1)=[O:22].Cl.CNC.C(N(CC)CC)C>ClCCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([NH:20][C:21]([N:23]([CH3:27])[CH3:24])=[O:22])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)N(C)C)nc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Following the procedure of Example 11, 3.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine and 2.0 g of carbonyldiimidazole are reacted at reflux in 50 ml of 1,2-dichloroethane for 24 hours. The mixture is cooled, treated sequentially with 1.5 g of dimethylamine hydrochloride and 2 ml of triethylamine, and stirred at room temperature for 1.5 hours. It is then washed with water prior to chromatography over 150 g of silica gel. The product is eluted with a 99/1 chloroform/methanol mixture and recrystallized from ethyl acetate to give N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-yl]-N',N'-dimethylurea, mp 177°-181° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OC)=O.[NH2:28][CH:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[N:32]([CH:41]([CH3:43])[CH3:42])[N:31]([CH3:44])[C:30]1=[O:45]>ClCCl>[CH3:44][N:31]1[C:30](=[O:45])[CH:29]([NH:28][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[N:32]1[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)N1C(=O)c2ccccc2C(N)C(=O)N1C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of N-boc-(L)-valine (IV, 1.04 g, 4.8 mmol) in dichloromethane (100 mL) was added the N-methyl morpholine (0.56 g, 5.6 mmol) and methyl chloroformate (0.37 mL, 4.8 mmol) at 0° C. The resulting solution was stirred for 10 minutes before the addition of a solution of 5(R,S)-amino-2,3,4,5-tetrahydro-3-methyl-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione (IIIA, 1.0 g, 4.04 mmol) in dichloromethane (5 mL) and it was further stirred for another 1 h. The resulting mixture was washed with 1N hydrochloric acid (50 mL), sodium bicarbonate (50 mL), brine (50 mL) and dried over MgSO4, filtered and concentrated to afford the crude product. This product was purified further on flash (silica gel) chromatography (hexane/ethyl acetate, 3/2) to afford 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-3-methyl-1-oxobutyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione(1.5 g, 83%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7])(=[O:19])=[O:18]
Reactant: CC(O)CCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(O)CCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
(±)-Heptan-1,6-diol (1.06 g, 8 mmol) and pyridine (1.36 ml, 1.33 g, 16.8 mmol) were dissolved in dichloromethane (20 ml) and the mixture was cooled in ice. Methanesulfonyl chloride (0.65 ml, 0.96 g, 8.4 mmol) was added dropwise and the mixture was stirred at room temperature for 18 hours. Dichloromethane (50 ml) was added and the mixture was washed with aqueous HCl (1M, 50 ml) and brine (30 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/20% hexane, to give the alcohol as an oil (1.01 g, 60%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>CO>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:29][CH:30]=1)[CH3:32]
Reactant: CCNCC
Reactant: O=C(c1ccc(OCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: CO
Product: CCN(CC)CC(O)COc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[1-(4-Glycidoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (200 mg) is dissolved in methanol (4 ml) and thereto is added diethylamine (0.26 ml) and the mixture is stirred at room temperature overnight, and then refluxed with heating for 3 hours. The solvent is concentrated and the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1→dichloromethane:methanol=10:1) to give 1-{1-[4-(3-diethylamino-2-hydroxypropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.18 g)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[CH:8]1.[C:16](=O)(O)[O-:17].[Na+]>CN(C=O)C>[CH3:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]=[O:17])=[CH:8]1
Reactant: Cn1ccc2cccnc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cc(C=O)c2cccnc21
Temperature: 0 °C
Yield: 83 %

Procedure:
Phosphoryl chloride (5.15 ml, 55.3 mmol) was added dropwise to DMF (70 ml) under stirring at 0° C. After the reaction mixture was stirred at 0° C. for 10 minutes, a solution of 1-methyl-1H-pyrrolo(2,3-b)pyridine (4.87 g, 36.8 mmol) in DMF (5 ml) was added dropwise at the same temperature. After completion of the dropwise addition, the reaction mixture was stirred at 0° C. for 4 hours and at 60° C. for 3.5 hours. The reaction mixture was poured in ice water—a saturated aqueous solution of sodium bicarbonate to neutralize the mixture therewith, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 1-methyl-1H-pyrrolo(2,3-b)pyridine-3-carbaldehyde (4.87 g, 83%) was obtained as a yellow solid.
Reaction SMILES: [CH:1]([C@H:4]1[C:9](=O)[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[C:6]=2[O:5]1)([CH3:3])[CH3:2].C[S:24]P1(=S)SP(=S)(SC)S1>C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[C:9](=[S:24])[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: CSP1(=S)SP(=S)(SC)S1
Reactant: COC(=O)CN1C(=O)[C@H](C(C)C)Oc2c(C(C)C)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=S)[C@H](C(C)C)Oc2c(C(C)C)cccc21
Temperature: 50 °C
Reaction time: 64 h
Yield: 93.5 %

Procedure:
A mixture of (S)-methyl 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetate (3.05 g), 2,4-bis (methylthio)-1,3,2,4-dithiadiphosphetan-2,4-disulfide (Davy reagent methyl)(2.84 g) and toluene (60 ml) was stirred at 50° C. for 64 hours. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (100 g) using hexane-ethyl ether (85:15, v/v) as the eluent to yield (S)-methyl 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetate as an oil (3.00 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2].CN(C)C1C=CC=CC=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>C(#N)C>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([NH:10][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a mixture of 2-nitro-benzene-1,4-diamine (10 g, 65.30 mmol) and N,N-dimethylaniline (8.7 g, 71.83 mmol) in acetonitrile (310 ml) at 0° C. 4-isopropyl-benzenesulfonylchloride (13.85 g, 63.34 mmol) was added over a period of 1 h. The mixture was stirred at 0° C. for 1 h and for 16 h at room temperature. After concentrating the mixture in vacuo the obtained oil was triturated with water. The precipitate was collected, washed with ethanol and dried in vacuo to give the product as a yellow powder (11.76 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[F:26][C:27]([F:40])([F:39])[C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]=[C:35]=[O:36])=O)=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:35](=[O:36])[NH:34][C:32]([C:31]2[CH:37]=[CH:38][C:28]([C:27]([F:40])([F:39])[F:26])=[CH:29][CH:30]=2)=[N:9]1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3)[nH]c2=O)c1F
Yield: 73.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.050 g, 0.13 mmol), 4-(trifluoromethyl)benzoyl isocyanate (Intermediate-59, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.045 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=4.4 Hz, 2H), 7.41 (t, J=8 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.2 Hz, 2H), 8.17 (t, J=5.8 Hz, 1H), 12.9 (br s, 1H); MS (m/z): 471.10 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12]Cl.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][O:15][CH3:14]
Reactant: O=[N+]([O-])c1cc(CCl)c(Cl)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 21 h
Yield: 27 %

Procedure:
To a solution of 1,5-dichloro-2-(chloromethyl)-4-nitrobenzene (Hagmann, William K.; Dorn, Conrad P.; Frankshun, Robert A.; O'Grady, Laura A.; Bailey, Philip J.; et al.; JMCMAR; J. Med. Chem.; EN; 29; 8; 1986; 1436-1441, 10.6 g, 44 mmol) in methanol (30 ml) was added sodium methoxide (44 ml, 66 mmol) at room temperature. The mixture was stirred at 80° C. for 21 h. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (6:1/4:1) to afford 2.8 g (27%) of the title compound as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C1COCC1>[C:42]([O:41][C:39]([CH2:38][N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 40 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.11 g) in THF (5 mL) was added DIEA (0.1 mL) and tert-butyl bromoacetate (0.06 mL). Additional tert-butyl bromoacetate (0.040 mL) was added after 16 hours. After 40 hours, the reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water, NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/5, Chromatotron) afforded the titled compound (0.124 g). MS (m/z) 582 (MH+). mp 74.7° C.