Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](OC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([N:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH3:2])[N:8]=3)[CH2:14][CH2:13]2)=[O:29])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1nccc(N2CCNCC2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccc(N2CCN(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 110 °C
Reaction time: 5 h
Yield: 71.7 %

Procedure:
2-Methyl-4-(1-piperazinyl)pyrimidine hydrochloride (18.80 g) and 1-(tert-butoxycarbonyl)-4-(4-nitrophenyloxycarbonyl) piperazine (25 g) were stirred in dry DMF (250 ml) and triethylamine (40 ml) under argon. The reaction mixture was stirred at 110° C. for 5 hours and then allowed to cool overnight. The solid was collected by filtration, washed with DMF and isohexane. The solid was purified by chromatography on silica gel using a gradient of dichloromethane to 5% methanol in dichloromethane as eluent to give 1-(tert-butoxycarbonyl)-4-(1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl)piperazine as a pale solid (19.92g); NMR (CDCl3): 8.15 (m, 1H), 6.35 (m, 1H), 3.7 (m, 4H), 3.45 (m, 4H), 3.35 (m, 4H), 3.3 (m, 4H), 2.5 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([NH:12][CH:11]=[CH:10]3)=[C:5]2[CH2:4]1.O>O1CCOCC1>[CH3:2][N:3]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([NH:12][CH2:11][CH2:10]3)=[C:5]2[CH2:4]1
Reactant: CN1Cc2c(ccc3cc[nH]c23)C(c2ccccc2)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN1Cc2c(ccc3c2NCC3)C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
12.5 ml (0.131 mol) of 10.5N hydrochloric acid are added dropwise to a mixture of 26 g (0.1 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole and 29.2 g (0.4 mol) of trimethylaminoborane in 150 ml of absolute dioxane at a temperature of 16° C., with stirring and in the absence of moisture. The mixture is then heated under reflux for 30 minutes and cooled to room temperature, 50 ml (0.3 mol) of 6N HCl are added and the mixture is heated under reflux once more for 15 minutes. After cooling to room temperature, 600 ml of H2O are added to the reaction mixture, the mixture is filtered over kieselguhr and, after addition of a further 600 ml of H2O, the filtrate is brought to pH 9 with 20% strength NaOH. The aqueous phase is now extracted several times with CH2Cl2 and, after drying over Na 2 SO4, the solvent is distilled off on a rotary evaporator. The oily residue is chromatographed on silica gel (silica gel 60 from E. Merck, Darmstadt) using ethyl acetate and MeOH (20:7) as the eluent.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][NH:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([C:31]2[CH:35]=[C:34]([C:36]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[NH:37])[S:33][C:32]=2[S:46][CH3:47])(=[O:30])=[O:29])[CH:23]=1)=[O:13])=[O:7].[OH-].[Na+]>CO.O>[C:42]([O:41][C:39]([NH:38][C:36](=[NH:37])[C:34]1[S:33][C:32]([S:46][CH3:47])=[C:31]([S:28]([C:24]2[CH:23]=[C:22]([C:16]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[NH:5][CH2:4][C:3]([OH:48])=[O:2])[CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])[CH:35]=1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)CNC(=O)NCCNC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCNC(=O)NCC(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
A solution of {3-[2-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-ethyl]-ureido}-acetic acid methyl ester ((Example 197: step a) 0.031 g, 0.042 mmol) in MeOH:water (2:1, 15 mL) was treated with NaOH (10 N, 0.042 mL, 0.420 mmol) and stirred at room temperature 18 h. MeOH was evaporated in vacuo and the remaining aqueous solution was acidified to pH 5 with glacial acetic acid. The solution was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to afford the product {3-[2-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-ethyl]-ureido}-acetic acid (0.025 g, 83%) as an off-white solid. The crude material was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:23])[C:19]([NH2:22])([CH3:21])[CH3:20])[CH3:16].C(N(CC)CC)C.O>CN(C)C=O>[CH2:15]([O:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[NH:22][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(C)(C)N
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(C)(C)NC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
1.28 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 12 ml of N,N-dimethylformamide; 1.16 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1.20 g of 2-aminoisobutyric acid ethyl ester hydrochloride and 1.00 ml of triethylamine were added, followed by stirring at room temperature for 16 hours. Water was added, the crystal precipitated was collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was combined with the above crystal collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fraction was collected and concentrated under reduced pressure to yield 1.20 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH2:13][OH:14])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>CS(C)=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH:13]=[O:14])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C=CCC(C=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 79.3 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-hydroxymethyl-3-butenyl]methylcarbamate (45 g) was dissolved in anhydrous dimethyl sulfoxide (320 mL), and triethylamine (87 mL) was added thereto. Under cooling with ice, sulfur trioxide-pyridine (31.7 g) was added, and the resultant mixture was stirred for 1 hour at room temperature. Ice-water (650 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (500 mL). The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby give the title compound (35.5 g, 77%).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH:18]=[CH2:19])[N:13]1[C:20](=[O:27])[C@@H:21]([NH:25]C)[CH2:22][CH:23]=[CH2:24])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH:18]=[CH2:19])[N:13]1[C:20](=[O:27])[C@@H:21]([NH2:25])[CH2:22][CH:23]=[CH2:24])=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1C(=O)[C@H](CC=C)NC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1C(=O)[C@@H](N)CC=C

Procedure:
Product 11F is reconstituted in dichloromethane (40 mL) and added trifluoroacetic acid (10 mL). Stirring until reaction complete by HPLC. Toluene is added and concentrated to an amber oil. The product is dissolved in dichloromethane and washed with saturated bicarb followed by drying over anhydrous magnesium sulfate, filtering and concentrating to an amber solid. LCMS characterization ES+356.1 (m+1).
Reaction SMILES: C(OC([N:6]=[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[C:20]([Br:25])=[CH:19][N:18]=2)[CH:11]=1)([CH3:9])=[O:8])=O)C.C(OC1C=CN=CN=1)C>>[Br:25][C:20]1[C:21]([O:23][CH3:24])=[N:22][C:17]([NH:16][C:12]2[CH:11]=[C:10]([S:7]([CH3:9])(=[NH:6])=[O:8])[CH:15]=[CH:14][CH:13]=2)=[N:18][CH:19]=1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(Nc2ncc(Br)c(OC)n2)c1
Agent: CCOc1ccncn1
Product: COc1nc(Nc2cccc(S(C)(=N)=O)c2)ncc1Br
Yield: 3 %

Procedure:
Intermediate 14a was prepared in analogy to GP 9 by reaction of Intermediate 14 (500 mg (1.16 mmol) to give, aside a larger quantity of the corresponding 4-ethoxypyrimidine, 14 mg (3%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[I:17]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:17])[C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: II
Reactant: Clc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cc(I)c(Cl)cn1
Reaction time: 2 h
Yield: 72 %

Procedure:
Under an argon atmosphere, 3 g of 2,5-dichloropyridine was added to 40 ml of tetrahydrofuran, and 11.15 ml of lithium diisopropylamide (2M heptane/tetrahydrofuran/ethylbenzene solution) was added at −78° C. After stirring for 2 hours, 5.66 g of iodine was added, and the mixture was further stirred for 3 hours. The reaction solution was poured into an aqueous saturated sodium thiosulfate solution, and the resultant solution was extracted with tert-butyl=methyl=ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4 g of 2,5-dichloro-4-iodopyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C[O-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Yield: 42 %

Procedure:
A mixture of 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (6.7 g, 10 mmol), a solution of NaOMe (0.5M in MeOH, 200 mL, 100 mmol) and THF (400 mL) was stirred at rt overnight. The resulting mixture was filtered through a pad of silica gel, which was rinsed with a solution of NH3 (2N in MeOH). The filtrate was concentrated. The residue was dissolved in THF and purified by silica gel chromatography using 0-10% MeOH (containing 0.2% NH3)/THF. The crude product was dissolved in a mixture of THF and MeOH (200 mL) and washed with a 2N NaOH solution (200 mL) and a saturated NaCl solution (100 mL). The organic layer was dried (Na2SO4), concentrated and triturated using Et2O to obtain 2.18 g of 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a beige solid. The impure fractions from the column were combined and concentrated. The residue was dissolved in THF. MeOH (100 mL) was added, followed by NaOMe (2.6 g). After 2 h the resulting mixture was diluted with EtOAc (100 mL) and a 2N NaOH solution (200 mL). The organic layer was washed with a saturated NaCl solution (200 mL), dried (Na2SO4) and concentrated down to about 20 mL volume. The resulting slurry was filtered and the solids were washed with Et2O to obtain 0.95 g of 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a light brown solid (combined yield 3.13 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.24 (s, 6 H), 3.11 (t, J=8.25 Hz, 2 H), 3.31 (s, 3 H), 3.76 (s, 2 H), 4.17 (t, J=8.25 Hz, 2 H), 6.21 (dd, J=3.48, 1.65 Hz, 1 H), 6.80-6.90 (m, 1 H), 6.90-7.01 (m, 2 H), 7.25-7.37 (m, 1 H), 7.59 (s, 1 H), 8.01 (s, 1 H), 8.09 (s, 1 H), 8.50 (d, J=8.43 Hz, 1 H), 8.60 (s, 1 H), 10.53 (s, 1 H), 11.28 (s, 1 H). ESIMS (M+H)=519.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][Mg]Cl.CON(C)[C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:17]=1)=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:34])[CH3:33])[CH:26]([CH3:27])[CH3:28])[CH:17]=2)=[O:15])[CH:8]=[CH:9][CH:10]=1
Reactant: CON(C)C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)Cc2cccc(Cl)c2)c2cccnc21
Yield: 94 %

Procedure:
This compound was prepared by the reaction of 3-chlorobenzylmagnesium chloride (0.25 M solution in diethyl ether) with N-methoxy-N-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide as described in General Method 1. The desired compound was obtained in 94% yield as a viscous clear oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][CH2:14][CH2:15]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH2:15]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:14]=[CH2:13]
Reactant: OCCCCc1ccccc1
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Product: C=CCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 250.3 %

Procedure:
To a solution of 4-phenylbutan-1-ol (0.60 g, 3.99 mmol) in 1,3-dibromopropane (2.14 mL, 10.60 mmol) was added tetrabutylammonium bromide (20 mg, 0.064 mmol) and 50% sodium hydroxide (1.5 mL). The mixture was stirred at room temperature overnight. The crude reaction was diluted with n-hexane (20 mL) and washed with water (2×10 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound (1.90 g, 92% purity) was obtained by distillation of the residue under reduced pressure and was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.Cl.Cl[CH2:24][CH2:25][N:26]([CH2:43][CH2:44]Cl)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:44][CH2:43][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)[CH2:25][CH2:24]1)=[O:20])[CH3:2]
Reactant: ClCCN(CCCl)Cc1ccc(OCCN2CCCCC2)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Yield: 48 %

Procedure:
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethylester was was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[4-(2-butynyloxy)phenyl]sulfonyl}acetate (2.9 g, 10.0 mmol) and bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine dihydrochloride (4.3 g, 10 mmol), 2.8 g of product (brown oil) was isolated. Yield 48%; MS: 583 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])/[C:4](/C)=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[CH2:15](OC(=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(=O)C1C(=CC=CC=1)O>>[CH2:1]([O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)/C(C)=C/c1ccccc1O
Solvent: O=Cc1ccccc1O
Product: CCOC(=O)/C=C/c1ccccc1O

Procedure:
According to the procedure of Example 1, (E)-3-(2-hydroxy-phenyl)-2-methyl-acrylic acid methyl ester was prepared from ethyl(triphenyl-phosphoranylidene)acetate and salicylaldehyde.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>Cl.CCO.[Pd]>[NH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])=[CH:10][C:11]=1[CH3:17]
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1CN
Reaction time: 2 h
Yield: 113.5 %

Procedure:
The reaction mixture of N-tert-butyl-4-cyano-3-methylbenzenesulfonamide (0.7176 g) and Pd/C (0.97 g) in 1N HCl/EtOH (1.5 ml 1N HCl in 15 ml EtOH) was stirred under H2 for 2 hours. Then 1N HCl (3 ml) was added to improve the reaction progress and it was stirred overnight. The reaction mixture was filtered through a pad of diatomaceous earth, washed with MeOH and concentrated to about 3 ml. The residue was diluted with H2O and lyophilized to give 0.8275 g 4-(aminomethyl)-N-tert-butyl-3-methylbenzenesulfonamide as white powder.
Reaction SMILES: [C:1]([O:6]C([O-])=O)(=O)[O:2][CH2:3][CH3:4].[NH2:10][C:11]([NH2:13])=[O:12]>C(Cl)(Cl)Cl>[C:1]([NH:10][C:11](=[O:12])[NH2:13])([O:2][CH2:3][CH3:4])=[O:6]
Reactant: NC(N)=O
Reactant: CCOC(=O)OC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(N)=O
Reaction time: 48 h

Procedure:
0.65 ml (0.72 g, 0.00443 moles) of ethyl pyrocarbonate are added to a solution of 1.0 g (0.00285 moles) of 1-(1',3'-bis/2",6"-dimethylphenyl/-4'-methyl-imidazolidine-2'-ylidene)-urea, prepared as described in Example 72, in 10 ml of dry chloroform, and the mixture is allowed to stand at room temperature for 48 hours. Thereafter the solvent and the excess of the reactant are distilled off under reduced pressure. The oily residue is dissolved in 10 ml of diethyl ether, the insolubles are filtered off, and the filtrate is concentrated to a final volume of about 2 ml. Next day the separated crystalline product is filtered off, washed with a small amount of diethyl ether and dried. 0.5 g (41.7%) of 1-(1',3'-bis/2",6"-dimethylphenyl/-4'-methyl-imidazolidine-2'-ylidene)-3-carbethoxy-urea are obtained; m.p.: 123°-125° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[Cl:27])[C:17]([NH2:20])=[N:18][N:19]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[NH:39]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:16]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=6[Cl:27])[C:17]([NH2:20])=[N:18][N:19]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH:41]=[N:40]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Nc1nnc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Product: Nc1nnc(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)n1-c1ccccc1Cl

Procedure:
Following the procedure in Example 93, 5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-(2-chlorophenyl)-4H-1,2,4-triazol-3-amine was coupled with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give 307. MS (ESI) 461.1
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[NH2:9])=O)(C)(C)C.O1CCOCC1.[ClH:24]>C(Cl)Cl>[ClH:24].[NH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)N(N)c1ccc(C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(NN)cc1

Procedure:
Title compound 52A, N-(4-cyano-phenyl)-hydrazinecarboxylic acid tert-butyl ester (0.23 g, 1.0 eq, 0.99 mmol) was suspended in a mixture of 4M HCl in Dioxane (4.2 ml, 17.0 eq, 16.8 mmol) and DCM (5 ml). The mixture was then stirred at room temperature for 18 hours The resultant precipitate was isolated by filtration and washed with DCM to yield the title compound as a cream solid. (0.14 g, 0.8 mmol, 85%). 1H NMR (DMSO) 400 MHz: Indicates product in >95% purity
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:23]=[C:22]([N:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[CH:21]=[CH:20][C:12]=3[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1>FC(F)(F)C(O)=O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:23]=[C:22]([N:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[CH:21]=[CH:20][C:12]=3[C:13]([OH:15])=[O:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc2sccc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-((benzothiophen-5-yl)amino)-4-(indolin-1-yl)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, methanol was added to the obtained residue, and solid matter was filtrated to give 2-((benzothiophen-5-yl)amino)-4-(indolin-1-yl)benzoic acid 67 mg of a brown solid.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([NH:26]C(=O)C(F)(F)F)[CH:9]=[CH:10][C:11]=1[S:12](=[O:25])(=[O:24])[NH:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:21][O:20][B:19]([OH:22])[C:18]=2[CH:23]=1)[CH3:2]>N.CO.[Pd]>[NH2:26][C:8]1[CH:9]=[CH:10][C:11]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:7]=1
Reactant: CCO/C=C/c1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Pd]
Agent: N
Solvent: CO
Product: CCOCCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Yield: 47.9 %

Procedure:
(E)-N-(3-(2-ethoxyvinyl)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2,2,2-trifluoroacetamide (47 mg) was hydrogenated with Pd/C (10%, 20 mg) in 7N NH3 in methanol (6 ml) at 50 psi for 4 hrs. The catalyst was filtered and filtrate was concentrated to dryness. The crude product was purified by prep-HPLC to give 4-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-ethoxyethyl)benzenesulfonamide (18 mg). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.97 (s, 1H), 9.15 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.10 (dd, J=2.2, 8.2 Hz, 1H), 6.42 (d, J=2.2 Hz, 1H), 6.34 (dd, J=2.0, 8.4 Hz, 1H), 5.84 (brs, 2H), 4.84 (s, 2H), 3.50 (t, J=7.2 Hz, 2H), 3.40 (q, J=7.1 Hz, 2H), 3.03 (t, J=7.1 Hz, 2H), 1.08 (t, J=7.0 Hz, 3H). MS (ESI) m/z=375 (M−1).