Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[CH2:3][CH2:4]O.[S:9]1C=CC=C1CC([O-])=O.[K+].[CH3:19][C:20](C)=[O:21]>>[C:20]([O:21][C:2]1[CH2:3][CH2:4][O:8][C:6]=1[CH3:7])(=[S:9])[CH3:19]
Reactant: CC(=O)C(Cl)CCO
Reactant: O=C([O-])Cc1cccs1
Reactant: CC(C)=O
Agent: [K+]
Product: CC(=S)OC1=C(C)OCC1

Procedure:
13.65 g (0.1 m) of 3-chloro-3-acetylpropanol (b.p. 90°-110° C/2mmHg; nD20 1.4740) prepared according to the method described by J. R. Stevens and G. A. Stein, J.Am.Chem.Soc. 62, 1045 (1940), were refluxed with 18.6 g (0.15 m) potassium thiolacetate in 100 ml of acetone for about 2 hours. After cooling the reaction mixture was filtered and the filtrate evaporated to dryness and the residue dissolved in water. The aqueous solution was extracted five times with chloroform and the combined extracts washed, dried and evaporated. Distillation of the residue yielded 3-thioacetoxy-2-methyl-4,5-dihydrofuran, b.p. 57°-59° C/0.6 mmHg.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:17]1[C:18]2[N:19](C=NN=2)[C:20]2C(N=1)=CC=C[CH:21]=2.C(NCC)C.C(NCCC)CC>>[CH2:18]([N:19]([CH2:20][CH3:21])[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:17]
Reactant: Cc1nnc2c(Cl)nc3ccccc3n12
Reactant: Clc1nc2ccccc2n2cnnc12
Solvent: CCNCC
Solvent: CCCNCCC
Product: CCN(CC)c1nc2ccccc2n2c(C)nnc12
Yield: 54 %

Procedure:
This compound was prepared by the method of Example 11, utilizing 4-chloro-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 3) as starting material in place of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 2) and diethylamine as reagent in place of di-n-propylamine. The crude product obtained was recrystallized from chloroform and then from cyclohexane to afford 7.2 g. (54% yield) of pure 4-diethylamino-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 123°-125° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:6]=1)=[O:4].O.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>CO>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]([NH:14][CH2:13][CH2:12][N:7]2[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]2)=[O:16])[CH:18]=1
Reactant: COC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1

Procedure:
1,6-dihydro-1-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.39 g, 1.3 mmol) was hydrolysed in a mixture of methanol (3.9 ml), water (3.9 ml), and 15% aqueous sodium carbonate (3.9 ml) at 65°-70° C. for 1.5 hours. The solution was acidified (to pH 5.5 with acetic acid). The precipitated product was recovered by filtration, washed with water, and dried, MP: >295 ° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:9][S:8][CH2:7][CH:6]([OH:10])[CH2:5][S:4][CH2:3]1.[CH3:11][CH:12]([CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][N:21]=[C:22]=[O:23])[CH2:13]N=C=O.CC[O:28][CH2:29][CH3:30].C(Cl)Cl>O1CCCC1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:22](=[O:23])([OH:10])[NH2:21].[C:22](=[O:23])([OH:28])[NH2:21].[CH2:1]=[C:2]1[CH2:9][S:8][CH2:7][CH:6]([CH2:11][CH:12]([CH3:13])[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][CH:2]2[CH2:9][S:8][CH2:7][C:29](=[CH2:30])[CH2:5][S:4][CH2:3]2)[CH2:5][S:4][CH2:3]1
Reactant: C=C1CSCC(O)CSC1
Reactant: CC(CN=C=O)CC(C)(C)CCN=C=O
Reactant: CCOCC
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1CSCC(CCC(C)(C)CC(C)CC2CSCC(=C)CSC2)CSC1
Product: NC(=O)O
Yield: 96 %

Procedure:
7-Methylene-1,5-dithiacyclooctan-3-ol (C-8 Alcohol; 2.9 g, 16 mmole) and dibutyl tin dilaurate (10 mg; Sigma-Aldrich) were dissolved in dry tetrahydrofuran (THF, 10 ml) under nitrogen. The resulting solution was heated to reflux and a solution of 2,4,4-trimethyl-1,6-diisocyanatohexane (1.76 g, 8.2 mmole) in dry THF (10 ml) was added dropwise. The reaction was monitored by thin layer chromatography (ether:methylene chloride 1:1) until the starting C8-Alcohol was consumed. (About 12 hours reaction time.) The solvent was then evaporated to give a viscous clear oil/gum. The oil/gum was purified by dissolving in methanol (15 ml per gram) to give a slightly milky solution. A small quantity of the gum separated. The solution was filtered into another flask and water (3 ml per gram) was added slowly to the filtrate with stirring. During the addition, a white residual material separated from the solution. The liquid solvent was decanted and the residue was washed with methanol:water 3.5:1. The washed residue was dissolved in methylene chloride, BHT inhibitor was added (1 mg per gram), and the solution dried with sodium sulfate. The solvent was evaporated to give a slightly cloudy viscous liquid (4.36 g, 96% yield). The product structure of C-8 Diurethane was confirmed by 1H and 13C NMR.
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.N>[Br-].[Zn+2].[Br-].CO.O>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of 7-ACA, 8 g of zinc bromide and 0.9 g of methanol. The mixture was heated at 60° C. for 80 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture were added 10 ml of water and 5 ml of methanol. Then, the mixture was adjusted to pH 7.5 with aqueous ammonia at a temperature of from 0° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.71 g. The yield of the desired product was 29 %.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:11]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(CC)CC)C.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cccc(C2CCCCC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(Cl)cc1C1CCCCC1
Temperature: 100 °C

Procedure:
21 g (61.3 mmol) of 7, 25.8 ml (183.8 mmol) of trimethylsilylacetylene, 2.15 g (3 mmol) of bis(triphenylphosphine)palladium(II) chloride and 21.2 ml (153.2 mmol) of triethylamine are dissolved in 60 ml of N,N-dimethylformamide under nitrogen, and the mixture is heated at 100° C. overnight. 100 ml of water are added to the cooled solution, and the mixture is extracted twice with methyl t-butyl ether (100 ml). The combined organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography, giving the product 8, which is employed in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH:31]1C1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:18]3[CH:19]=[N:20][C:21]([N:33]4[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]4)=[CH:22][CH:23]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: CN1CCNCC1c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for the above example from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (90 mg, 0.202 mmol) and 1-methyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (92 mg, 0.303 mmol). The final product was collected as a light brown solid (54 mg, 49%). 1H NMR (400 MHz, DMSO-d6)™ ppm 1H NMR (400 MHz, DMSO-d6)™ ppm 11.54 (br. s., 1H) 8.65 (d, J=2.27 Hz, 1H) 8.61 (t, J=4.80 Hz, 1H) 8.36 (s, 1H) 8.04-8.08 (m, 2H) 7.83 (s, 1H) 6.96 (d, J=9.09 Hz, 1H) 5.92 (s, 1H) 5.14 (quin, J=6.57 Hz, 1H) 4.42 (d, J=4.80 Hz, 2H) 3.53-3.59 (m, 4H) 2.53-2.61 (m, 2H) 2.40-2.45 (m, 4H) 2.23 (s, 3H) 2.14 (s, 3H) 1.51-1.58 (m, 2H) 1.50 (s, 3H) 1.49 (s, 3H) 0.88 (t, J=7-7.33 Hz, 3H). LC-MS (ES) m/z=542.2 [M+H]+
Reaction SMILES: CN.Cl[C:4]1[C:13]([C:14]([C:16](=[CH:22][N:23]([CH3:25])C)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:12][C:11]2[C:6](=[C:7]([F:28])[C:8]([F:27])=[C:9]([F:26])[CH:10]=2)[N:5]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:20]([O:19][C:17]([C:16]1[C:14](=[O:15])[C:13]2[CH:12]=[C:11]3[CH:10]=[C:9]([F:26])[C:8]([F:27])=[C:7]([F:28])[C:6]3=[N:5][C:4]=2[N:23]([CH3:25])[CH:22]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Agent: CN
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A solution, at about 5° C., of 10 g of methylamine in 50 cm3 of ethanol is added in the course of 10 minutes, at between 5° and 10° C., to a stirred suspension of 19.3 g of ethyl 2-(2-chloro-6,7,8-trifluoro-quinoline-3-carbonyl)-3-dimethylaminoacrylate in 150 cm3 of ethanol kept at a temperature close to 5° C., the mixture is stirred for 1 hour at between 5° and 10° C. and the temperature is allowed to rise to about 20° C. 7.6 g of DBU are added to the solution obtained and the mixture is heated at about 30° C. for 1 hour. After cooling to a temperature close to 20° C., the product is drained and washed with twice 100 cm3 of ethanol and twice 100 cm, of diisopropyl ether. 13.4 g of 3-ethoxycarbonyl-7,8,9 -trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 320° C., which is used for the subsequent steps without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[CH3:12][S-:13].[Na+]>CN(C=O)C.C(C1C(O)=CC(C)=C(SC2C=C(C(C)(C)C)C(O)=CC=2C)C=1)(C)(C)C>[Cl:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: C[S-]
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])cc1Cl
Reaction time: 6 h
Yield: 52.3 %

Procedure:
To a solution of 4-fluoro-3-chloronitrobenzene (27 g, 156 mmol) in DMF (150 mL) at room temperature was added 5-tert-butyl-4-hydroxy-2-methylphenyl sulfide (100 mg) followed by sodium thiomethoxide (NaSMe) (10 g, 143 mmol) and the reaction was stirred for 6 h. The DMF was removed in vacuo and the residue was partitioned between ether (1 L) and water (1 L). The ether layer was washed with water (1 L) and brine (1 L), dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2; DCM: pentane 1:5 increasing polarity to 3:7) to give the title compound (15.22 g, 49%) as a yellow solid; δH (400 MHz, CDCl3) 2.53 (3H, s), 7.20 (1H, d), 8.09 (1H, dd), 8.20 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])[CH:18]=[C:17]([Cl:29])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.CN1CCOCC1>O1CCCC1>[CH:30]1([NH:33][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:20][C:19]([CH2:21][CH:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:18][C:17]=3[Cl:29])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])(=[O:13])=[O:12])[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To the title compound of Step E (38 mg, 0.08 mmol) in dry tetrahydrofuran (1 ml) at room temperature was added cyclopropylamine (8.0 mL, 0.12 mmol) and N-methylmorpholine (17 ml, 0.15 mmol). The reaction mixture was stirred at room temperature for two hours, quenched with 1N HCl (15 ml), and extracted with ethyl acetate (3×15 ml). The combined extracts were washed with 1N HCl (2×15 ml), brine (15 ml), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (8% methanol in dichloromethane) to afford the title compound (16 mg, 41% yield). MS (APCI+) Calc: 516.0, Found: 516.9 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.[C:56]([O:59][BH-](OC(=O)C)OC(=O)C)(=[O:58])C.[Na+].O>C(Cl)Cl>[CH:56]([OH:59])=[O:58].[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:53]3[CH2:54][CH2:55][CH:50]([F:49])[CH2:51][CH2:52]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCC(F)CC5)cc4)c4ccccc43)cn12
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 176b (0.188 mmol) and 4-fluoropiperidine (38.8 mg, 0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg, 0.28 mmol) was added. The mixture was stirred at RT for 1 h. Water was added and the mixture extracted with DCM. The combined organics were passed through a phase separator and concentrated to dryness. The resulting residue was purified by RP-HPLC (C, 18, 18 mL/min, 20-85% MeCN in H2O+0.1% HCO2H) and the relevant fractions combined and concentrated to dryness. The title product was isolated as an off white solid (31 mg). LCMS (Method 5): Rt 3.71 min, m/z 734.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.1 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.67 (4H, m), 1.76-1.96 (6H, m), 1.98-2.17 (2H, m), 2.31 (2H, m), 2.54 (m, obscured by solvent), 2.90 (1H, m), 3.16 (1H, m, obscured by solvent), 3.51 (2H, s, obscured by solvent), 4.66 (1H, dm, J=48 Hz), 4.82 (1H, m), 5.51 (1H, t, J=4.2 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.7 Hz), 7.19 (1H, dd, J=9.8, 2.3 Hz), 7.24-7.50 (8H, m), 7.63 (1H, d, J=10.2 Hz), 7.69 (1H, d, J=1.4 Hz), 8.10 (1H, s), 8.16 (1H, s).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1[C:21]2[N:20]3[CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][NH:17][CH2:16][C:15]=2[S:14][CH:13]=1>N1C=CC=CC=1.O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([N:17]2[CH2:16][C:15]3[S:14][CH:13]=[CH:12][C:21]=3[N:20]3[CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: c1cc2n(c1)-c1ccsc1CNC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2Cc3sccc3-n3cccc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
An excess of para-toluenesulfonyl chloride is added to a solution of 1 g (0.0053 mol) of 5,6-dihydro -4H-pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine in 10 ml of pyridine, and the reaction mixture is then stirred at room temperature for one hour. The pyridine is then removed under reduced pressure and the oil residue obtained is ground in 100 ml of water. The emulsion formed is extracted with 3 times 100 ml of ethyl ether. The organic phases are separated after settling has taken place, combined, dried, washed with acidulated water, dried over magnesium sulfate and evaporated under vacuum. The solid residue is recrystallized. 0.4 g of 5-(p-tolylsulfonyl)-5,6-dihydro-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine is thereby obtained in the form of yellow crystals, melting point 165° C. (ethyl ether).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[SH:19][C:20]1[N:24]([CH3:25])[CH:23]=[N:22][N:21]=1>>[CH3:25][N:24]1[CH:23]=[N:22][N:21]=[C:20]1[S:19][C:10]1[CH:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:13][C:14]3[S:15][CH:16]=[CH:17][N:18]=3)[C:3]=2[N:11]=1
Reactant: Cn1cnnc1S
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Nc1nccs1
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3nccs3)c2n1

Procedure:
The compound of Example 33 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 4,6-dichloro-pyrido[3,2-d]pyrimidine, 2-aminothiazole and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 78.4 %

Procedure:
Following general procedure II, (S)-tert-butyl (1-(5-((6-chloro-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (85 mg, 0.30 mmol) to afford the product (100 mg) which was carried forward without any purification: ESI MS m/z 637 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30]>>[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:27][CH2:28][C:29](=[O:30])[C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH2:20][CH2:19]2)[CH:13]=1)=[O:10]
Reactant: O=C(CCCCl)c1cccs1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3cccs3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(2-thienyl)-1-butanone: ESMS m/e: 399.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[NH:8][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH2:21]>COCCOCCOC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[C:9]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:19])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2ccc(Cl)cc2[nH]1
Reactant: O=C(Cl)c1ccccc1
Reactant: O
Solvent: COCCOCCOC
Product: O=C(C(C(=O)c1ccccc1)=C1Nc2ccc(Cl)cc2N1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
5-Chloro-2-methylbenzimidazole (833 mg) was dissolved in Diglyme (4 ml), and TEA (2.43 ml) was added thereto. Benzoyl chloride (2.0 ml) was further added thereto, followed by 15 minutes of stirring at about 100° C. Water (0.1 ml) was added dropwise to the reaction solution and the whole was heated under stirring at 175° C. for 10 minutes. After the reaction solution was cooled with air, water (15 ml) was added and the mixture was stirred, then the supernatant was decanted. Methanol (5 ml) was added to the residue and the precipitated crystals were collected by filtration, washed with cold methanol, and dried to obtain 2-(5-chloro-1,3-dihydro-2H-benzimidazol-2-yliden)-1,3-diphenylpropan-1,3-dione (706 mg, 38%) as pale yellow powdery crystals. Hereinafter, the compounds of Examples 2 to 25, 119 and 126 were obtained similarly.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:11])[O:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
4-Chloroaniline (2.3531 g) was dissolved in pyridine (20 ml), and to the solution was added dropwise ethyl chloroformate (2.116 ml) under ice-cooling. After the mixture was stirred for 1.5 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (3.6875 g, quantitative yield).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].Cl.Cl.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:18]([C:20]3[CH:21]=[C:22]([Cl:33])[C:23]([C:31]#[N:32])=[C:24]4[C:30]=3[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)[CH3:19])[N:15]=[C:16]([CH3:17])[C:9]=12.C(N(CC)CC)C>CN(C)C=O>[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:18]([C:20]3[CH:21]=[C:22]([Cl:33])[C:23]([C:31]#[N:32])=[C:24]4[C:30]=3[O:29][CH2:28][CH2:27][N:26]([CH2:2][CH2:3][OH:4])[CH2:25]4)[CH3:19])[N:15]=[C:16]([CH3:17])[C:9]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCNC3)c2ncnc(N)c12
Reactant: OCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(CCO)C3)c2ncnc(N)c12
Temperature: 80 °C
Yield: 479.4 %

Procedure:
2-Bromoethanol (4.7 μL, 0.066 mmol) was added to a mixture of 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (15 mg, 0.039 mmol) (from Example 46, step 13) and triethylamine (10 μL, 0.09 mmol) in N,N-dimethylformamide (2 mL). The reaction was heated at 80° C. for 3 h and then allowed to cool. The product was purified without workup by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the desired compound as white amorphous solid (0.08 g, 50%). LCMS calculated for C20H23ClN7O2 (M+H)+: m/z=428.1; found: 428.2.