Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([OH:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>ClCCl>[Br:21][C:17]1[CH:16]=[C:15]([CH:10]([S:7]([NH2:6])(=[O:8])=[O:9])[C:11]([OH:14])([CH3:12])[CH3:13])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(CNS(=O)(=O)C(c2cccc(Br)c2)C(C)(C)O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)C(c1cccc(Br)c1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A solution of 8.63 g of N-[2,4-dimethoxybenzyl]-1-(3-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide in 40 ml of dichloromethane was admixed with 10 ml of trifluoroacetic acid and stirred at room temperature for 30 minutes. The reaction solution was admixed with 40 ml of water, and gradually and cautiously with 150 ml of a saturated aqueous sodium hydrogencarbonate solution. The precipitate was filtered off with suction, washed with water and dried over P2O5 under reduced pressure. The crude product was purified by means of normal phase chromatography using a Flashmaster with a dichloromethane/methanol gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (4.11 g) with a molecular weight of 308.2 g/mol (C10H14BrNO3S); MS (ESI): m/e=325 (M+H2O+H+).
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C([O-])(=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+].C(OCC)(=O)CCCC>>[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:1])[CH3:14]
Reactant: O=C([O-])C=Cc1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCC(=O)OCC
Agent: [Na+]
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A total of 9 Fernbach flasks, each containing 500 ml. broth, were sterilized for 30 minutes at 121° C. After cooling to room temperature, 5.0 ml. of sterile 50% dextrose solution and 5.0 ml of the 24 hour grown inoculum were added to each flask. The flasks were incubated at 30° C. at 100 rpm for 24 hours. Sterile 10% sodium cinnamate, pH 7.0, was added to each flask as follows, 5 g/l at 24 hours, 9 g/l at 48 hours, and 6 g/l at 72 hours. Samples of broth were analyzed periodically, by GC using ethyl pentanoate as an internal standard. After 44 hours of incubation, all the flasks were combined and product was extracted 3 times with ethyl acetate (approximately 1/2 volume each time). The combined extracts were washed 2 times with 100 ml. saturated NaHCO3 each time, followed by 2 times 100 ml saturated NaCl washes. The solvent was removed under vacuum and the crude extract was fractionally distilled to recover product. A yield of 2.7 g/L having a purity of 99.4% was obtained.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:27]4[CH2:32][CH2:31][N:30](C(OCC5C=CC=CC=5)=O)[CH2:29][CH2:28]4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:43])(=[O:6])=[O:5])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)C>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:43])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C4CCN(C(=O)OCc5ccccc5)CC4)[nH]c3-c3ccccc3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C4CCNCC4)[nH]c3-c3ccccc3)cc21
Temperature: 25 °C

Procedure:
Vigorously stir a mixture of 1-isopropylsulfonyl-2-amino-6-(2-(1-(benzyloxycarbonyl)piperidin-4-yl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (0.74 g, 1.24 mmol), ammonium formate (4.94 mmol), and 10% palladium on carbon (0.12 mmol) in 30 mL absolute ethanol at reflux for 5 hours. Cool the reaction mixture to room temperature, filter through a bed of Celite®, and concentrate the filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 19:1 dichloromethane:methanol to provide the title compound. MS(ES+): m/z=465.2 (M+H)+
Reaction SMILES: ClC1C=C(OCCCN2CCN(C)CC2)C=CC=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[C:27]([CH3:28])[C:22]=2[N:21]=C1.[Cl:30][C:31]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:36]=[CH:35][C:32]=1[CH:33]=O.CC1C(C)=CC=C(N)C=1N>CN(C=O)C>[Cl:30][C:31]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:36]=[CH:35][C:32]=1[C:33]1[NH:19][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[C:27]([CH3:28])[C:22]=2[N:21]=1
Reactant: Cc1ccc2c(ncn2-c2ccc(OCCCN3CCN(C)CC3)cc2Cl)c1C
Reactant: CN1CCN(CCCOc2ccc(C=O)c(Cl)c2)CC1
Agent: Cc1ccc(N)c(N)c1C
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(-c3ccc(OCCCN4CCN(C)CC4)cc3Cl)nc2c1C
Yield: 76 %

Procedure:
2-{(2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole. 2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (91.5 mg, 0.31 mmol, 1.0 equiv) and 3,4-dimethyl-benzene-1,2-diamine (42 mg, 0.31 mmol, 1.0 equiv) were stirred with Na2S2O5 (76 mg, 0.40 mmol, 1.3 equiv) in DMF (0.25 M) at 90° C. for 12 h. The reaction mixture was loaded directly on silica gel and purified according to Method 2, which afforded 98 mg (76%) of the title compound. MS (electrospray): mass calculated for C23H29ClN4O, 412.20; m/z found, 413.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.68 (br s, 1H), 7.33 (br s, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.7, 2.5 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H), 2.60-2.39 (m, 13H), 2.39 (s, 3H), 2.30 (s, 3H), 2.05-1.95 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][N:2]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][CH:24]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc(CO)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Under ice-cooling, to a solution of methyl 4-[[methyl(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzoate (2.06 g, 6.1 mmol) in tetrahydrofuran (30 mL) was added 0.9 M diisobutylaluminum hydride-hexane solution (30 mL, 27 mmol). The reaction mixture was stirred at room temperature for 2 hrs, sodium sulfate 10 hydrate (8.7 g, 27 mmol) was added and the mixture was stirred at room temperature for 1 hr. Insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1) to give the title compound (1.9 g, yield 98%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1-n1nccn1
Product: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.45-6.50 (m, 9H), 4.65-2.70 (m, 5H), 2.10-0.75 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[C:7]([N+:24]([O-])=O)[CH:6]=1)=[O:4].C(O)(=O)C.O>O1CCOCC1.O.[Fe]>[NH2:24][C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of tert-butyl 4-[4-(methoxycarbonyl)-2-nitrophenyl]piperazine-1-carboxylate (200 mg, 0.547 mmol) in 1,4-dioxane-water (2:1) (6.0 mL), iron powder (76 mg, 1.37 mmol) and acetic acid (1 mL) were added under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water and a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions, filtered through a pad of celite, and extracted with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (83 mg (yield 45%)) was obtained as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)=[C:24]([CH3:40])[CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH3:40][C:24]1[CH:23]=[C:22]([O:21][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:41])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:27]=[C:26]([CH3:28])[C:25]=1[C:29]1[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:39])[F:38])=[CH:33][CH:34]=1
Reactant: CCCCCCC(Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC(Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 5 h
Yield: 111.2 %

Procedure:
To a mixture of 3-{4-[1-(2,6-Dimethyl-4′-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid methyl ester (105 mg) in methanol (2 mL) is added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h. The reaction mixture is concentrated and acidified by 5 N HCl (0.5 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (114 mg). MS (ES): 572.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:29]=[C:17]2[N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:30])[N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[CH2:10][O:11][C:13]1[CH:29]=[C:17]2[NH:18][CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:30])[N:14]=1
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Product: O=c1nc(OCc2cc(F)c(F)c(F)c2)cc2n1CCCN2

Procedure:
The title compound and/or its salt was prepared by a procedure similar to that described for E111 starting from (3,4,5-trifluorophenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([SiH2:27][O:28][C:29]([CH3:57])([CH3:56])[C:30]1([CH2:54][OH:55])[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:46]=[C:45]([CH3:53])[CH:44]=3)=[CH:37][CH:36]=2)[CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([SiH2:27][O:28][C:29]([CH3:57])([CH3:56])[C:30]1([CH:54]=[O:55])[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:46]=[C:45]([CH3:53])[CH:44]=3)=[CH:37][CH:36]=2)[CH2:31]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(COc2ccc(C3=NOC(CO)(C(C)(C)O[SiH2]C(C)(C)C)C3)cc2)c2ccccc2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(COc2ccc(C3=NOC(C=O)(C(C)(C)O[SiH2]C(C)(C)C)C3)cc2)c2ccccc2n1
Reaction time: 1 h

Procedure:
Dess-Martin Periodinate reagent (0.47 g, 1.1 mmol) was added to a solution of the product from step 24b, in methylene chloride (10 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred for 1 h and then partitioned between ethyl acetate and aqueous 10% NaHSO4. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to give 5-(tert-butyl-dimethyl-silanyloxymethyl)-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazole-5-carbaldehyde as a crude oil. MS found: (M+H)+=491.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)/[CH2:5]2.[CH3:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5]/[C:6](=[CH:14]\[C:15]3[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)/[C:7]2=[O:13])=[CH:3][C:2]=1[N:30]1[CH2:31][CH2:32][CH:27]([CH3:26])[CH2:28][CH2:29]1
Reactant: CC1CCNCC1
Reactant: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1cc2c(cc1N1CCC(C)CC1)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 110 °C

Procedure:
To a solution of 104 (150 mg, 0.348 mmol) and 4-methylpiperidine (69 mg, 0.696 mmol) in toluene and tBuOH (8:2, 10 mL) was added cesium carbonate 228 mg, 0.696). The reaction was degassed and purged with nitrogen for 10 min. Pd2(dba)3 (15.9 mg, 0.0174 mmol) and BINAP (32.4 mg, 0.15 m·mol) was added and again degassed and purged with nitrogen for another 10 min. The reaction was heated to 110° C. for overnight under sealed condition. The reaction was diluted with chloroform and filtered through celite bed. The organic layer was concentrated to get the crude compound 139 which was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound at 10% ethyl acetate in hexane as pale yellow coloured solid (E)-6-methoxy-5-(4-methylpiperidin-1-yl)-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one 139.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][CH2:7][C:4]1[N:3]=[C:2]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[O:10][CH3:9])[S:6][N:5]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(CCl)ns2)c(OC)c1
Reaction time: 8 h

Procedure:
5-Chloro-3-chloromethyl-[1,2,4]thiadiazole (10 mmol) is added to a solution of 2,4-dimethoxybenzylamine (10 mmol) in THF at room temperature followed by addition of DIEA (10 mmol). The mixture is stirred overnight. The white precipitate is filtered and washed with THF. The filtrate is concentrated to oil and dried under high vacuum.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>[Pd]>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:35]5[CH:34]=[N:33][N:32]([C:25]([CH3:24])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:36]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate were reacted under Suzuki palladium conditions to give ethyl 2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate. LC/MS (ESI+): m/z 476 (M+H)
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[C:25](Cl)=[CH:24][C:22]([NH2:23])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[C:25]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[CH:24][C:22]([NH2:23])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1
Reactant: Sc1cccc2cnccc12
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Sc2cccc3cnccc23)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
5-Isoquinolinethiol 500 mg (3.1 mmol) was dissolved in DMF 15 ml, potassium carbonate 830 mg (6.0 mmol) and 4,5-dichloro-2-nitroaniline 620 mg (3.0 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water, and the resulting precipitates were collected and washed with water to give 4-chloro-5-(5-isoquinolylsulfanyl)-2-nitroaniline 980 mg (98.4%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]([NH:20]C(=O)OC(C)(C)C)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:10]=[CH:11][CH:12]=1)#[N:2].[ClH:31]>O1CCOCC1>[ClH:31].[NH2:20][CH:14]([CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:28]=[CH:29][CH:30]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:8]=1)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16]
Reactant: CN(C)C(=O)C(Cc1cccc(Oc2cccc(C#N)c2)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)C(N)Cc1cccc(Oc2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 3-(3-(3-cyanophenoxy)phenyl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.045 g crude) was taken up in 4 M HCl in dioxane 2 ml and stirred at r.t. for 2 h. The reaction was complete, concentrated under reduced pressure in vacuo. The residue was taken up in acetonitrile and reconcentrated under reduced pressure two times to give crude 2-amino-3-[3-(3-cyanophenoxy)phenyl]-N,N-dimethylpropanamide-HCl salt (0.045 g) as a semisolid residue which was directly used in next step reaction without further purification. Analytical LCMS (M+H)+: m/z=310.0
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[Cl:29])=[CH:21][CH:20]=1>C1COCC1.CN(C=O)C.C1COCC1>[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][N:25]=[C:26]3[Cl:29])=[CH:21][CH:20]=2)[C:11]1=[O:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1nccc2ccc(CBr)cc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Reaction time: 0.03 h
Yield: 81.3 %

Procedure:
Sodium hydride (0.24 g, 6.05 mmol, 60% mineral oil dispersion) is added to a solution of [2-oxopyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (1.18 g, 5.89 mmol) in THF/DMF (62 mL, 9/1, v/v) at 0° C. The mixture is stirred for 2 minutes, then a solution of 7-bromomethyl-1-chloro-isoquinoline (1.4 g, 5.46 mmol) in THF (10 mL) is added dropwise via a cannula. The resulting yellow solution is stirred for 1 hour at 0° C. then at room temperature for 3 hours. The reaction mixture is quenched with saturated ammonium chloride solution, then diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 50% EtOAc/hexanes to 70% EtOAc/hexanes to give the product (1.67 g, 4.44 mmol) as a foamy white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][N:5]=[N:4][CH2:3]1.[CH2:8]([N:10]=[C:11]=[S:12])[CH3:9]>C(O)C>[CH2:8]([NH:10][C:11]([N:4]1[CH2:3][C:2]([CH3:7])([CH3:1])[CH:6]=[N:5]1)=[S:12])[CH3:9]
Reactant: CC1(C)CN=NC1
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)N1CC(C)(C)C=N1
Yield: 8.2 %

Procedure:
10 g (1 mol equiv.) 4,4-Dimethyl-4,5-dihydro-3H-pyrazole (synthesized as described in WO 2008/034863) and 11.6 mL (1.3 mol equiv.) ethyl isothiocyanate were added to 100 mL ethanol. The reaction mixture was refluxed for 1 hour. Silica gel was added and volatiles were removed in vacuo. Purification by flash chromatography on silica gel (Et2O:PA=1:2) afforded 15.2 g (80%) of 4,4-dimethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 1.19-1.30 (m, 9H), 3.63-3.72 (m, 2H), 3.93 (s, 2H), 6.74 (s, 1H), 7.14 (br.s., 1H).
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)[CH:24]=[N:25][C:11]2=3)(=O)=O)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[OH-].[K+].CO.O>[OH:19][C:18]1[C:13]2[C:12]3[CH:22]=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)[CH:24]=[N:25][C:11]=3[NH:10][C:14]=2[CH:15]=[N:16][C:17]=1[C:20]#[N:21]
Reactant: N#Cc1ncc2c(c1O)c1cc(-c3ccc(CN4CCCCC4)cc3)cnc1n2S(=O)(=O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ncc2[nH]c3ncc(-c4ccc(CN5CCCCC5)cc4)cc3c2c1O
Reaction time: 2.5 h

Procedure:
9-Benzenesulfonyl-5-hydroxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.01 mmol) was dissolved in 0.15N potassium hydroxide solution in methanol (7 mL). The reaction mixture was stirred for 2.5 h then treated with a solution of monobasic potassium phosphate (136 mg, 1.0 mmol) in water (2 mL). The resultant mixture was concentrated in vacuo and the resultant residue was diluted with water (5 mL). The pH of the aqueous phase was adjusted to 7 by the addition of 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate, DCM and THF. The combined organic phase was concentrated in vacuo and the residue purified by flash chromatography (silica, 500 mg column, Si-SPE, 10-20% methanol in DCM) to afford the title compound as its hydrochloride salt (25 mg, 63%). 1H NMR (DMSO-D6, 400 MHz): 12.91 (s, 1H), 11.86 (br. s, 1H), 10.41 (s, 1H), 9.13 (d, J=2.2 Hz, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.60 (s, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H), 4.33 (d, J=5.2 Hz, 2H), 3.39-3.29 (m, 2H), 2.92-2.83 (m, 2H), 1.85-1.63 (m, 5H), 1.45-1.31 (m, 1H). LCMS (Method A): RT=5.32 min, M+H+=384.