Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@H:28](Cl)[CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24]>CN(C=O)C>[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@@H:28]([S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24]
Reactant: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 2 °C
Reaction time: 2.5 h
Yield: 87.2 %

Procedure:
A solution of 76 g (0.68 mol) potassium-tert.-butylate in 1.5 l DMF was cooled (−3° C.) and treated slowly (1.5 h) with 202 g (0.73 mol) triphenylmethanethiol in 0.8 l DMF (at max 1° C.). After 2.5 h at 0° C., a solution of 161 g (0.61 mol) of (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 0.35 l DMF was added. The reaction was stirred over night at 2° C., evaporated, dissolved in 1.5 l EtOAc, poured into 2.7 l aqueous saturated NH4Cl solution and extracted with EtOAc (2×). The organic phase was washed with aqueous saturated NaHCO3, dried over Na2SO4 and evaporated. Colum chromatographyon silica gel with hexane/EtOAc (95:5 to 7:3) gave 268 g (87%) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 504 (MH30 ).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH2:18])[N:12]=1.[N:19]([O-])=[O:20].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH2:18])[C:14]([N:19]=[O:20])=[C:15]([NH2:17])[N:16]=1
Reactant: Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 153.7 %

Procedure:
The product of step (a) (2.5 g) was dissolved in acetic acid (150 ml) and the solution cooled to 5° C. A solution of sodium nitrite (625 mg) in water (50 ml) was added dropwise resulting in a dark blue colouration. The reaction was stirred at room temperature for 30 minutes during which time a pink solid precipitated from solution. This was isolated by filtration and washed with water, then dried at 50° C. to give the sub-titled product as a blue solid (4.14 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=C(C=CC=1OC)C[N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][C:35](=[CH:38][C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[F:46])[CH2:34][CH2:33]2)=[O:31])[CH2:25][CH2:24]1.O>CN(C=O)C>[F:46][C:40]1[CH:41]=[CH:42][C:43]([F:45])=[CH:44][C:39]=1[CH:38]=[C:35]1[CH2:36][CH2:37][N:32]([C:30]([NH:29][CH:26]2[CH2:25][CH2:24][N:23]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=3)[CH2:28][CH2:27]2)=[O:31])[CH2:33][CH2:34]1
Reactant: COc1ccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1Cl
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 4.4 %

Procedure:
4-Fluorobenzoic acid methyl ester (125 mg, 0.807 mmol) was dissolved in DMF (3.0 mL), and potassium carbonate (150 mg, 1.08 mmol) and the compound (200 mg, 0.538 mmol) obtained in Example 36 (1) were added thereto, followed by stirring overnight while heating at 120° C. After the reaction mixture was cooled to room temperature, water was added thereto. After extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:100), thereby giving the title compound (11.0 mg, 4%) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].CS(O[CH2:10][CH2:11][CH2:12][N:13]([C:15]([O:17][CH:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:16])[CH3:14])(=O)=O>CCO.C(Cl)Cl>[CH2:1]([N:3]([CH3:4])[CH2:10][CH2:11][CH2:12][N:13]([CH3:14])[C:15](=[O:16])[O:17][CH:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH3:2]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCOS(C)(=O)=O
Reactant: CCNC
Solvent: ClCCl
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCN(C)CC
Reaction time: 50 h
Yield: 64 %

Procedure:
A solution of ethylmethylamine (2 mL) in EtOH (10 mL) was treated with 3-((((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)carbonyl)(methyl)amino)propyl methanesulfonate (500 mg, 0.7 mmol) in CH2Cl2 (2.5 mL). The solution was stirred (50 h), concentrated and subjected to chromatography (EtOAc) to yield (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (3-(ethyl(methyl)amino)propyl)(methyl)carbamate (305 mg, 64%) as a pale yellow oil. Rf 0.41 (10% CH3OH—CH2Cl2), 1H NMR (400 MHz, CDCl3, δH) 5.47-5.34 (m, 8H, C═CH×8), 4.81-4.75 (m, 1H, CHO2CNR2), 3.33 (br. s, 2H, CH2NCH3), 2.94 (br. s, 3H, CO2NCH3), 2.83 (app. t, 4H), 2.45 (q, 2H, N(CH3)CH2CH3), 2.37 (t, 2H, CH2N(CH3)CH2CH3), 2.25 (s, 3H, N(CH3)CH2CH3), 2.14-2.07 (m, 8H, CH2HC═C×4), 1.81-1.70 (m, 4H, CH2×2), 1.62-1.50 (m, 4H, CH2×2), 1.46-1.25 (m, 34H, CH2×17), 1.09 (t, 3H, CH3NCH2CH3), 0.93 (t, 6H, H3×2), FW 685.16, C45H84N2O2.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[N+:10]([O-:21])=[C:9]([NH:22][C:23](OCC(C)C)=[O:24])[N:8]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH-].[Na+]>O>[N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[N:10]3[O:21][C:23](=[O:24])[N:22]=[C:9]3[N:8]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(=O)Nc1nc(N2CC=CCC2)nc(NC(=O)OCC(C)C)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1nc(N2CC=CCC2)nc2nc(=O)on12
Reaction time: 1.25 h

Procedure:
8 g. of diisobutyl 6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine-2,4-dicarbamate-3-oxide are dissolved in 300 ml. of methylene chloride and 1000 ml. of water and adjusted to pH 12.7 with concentrated sodium hydroxide. The mixture is stirred for 75 minutes, the organic phase is separated and the aqueous phase is adjusted to pH 4 with 3-N hydrochloric acid solution. The thus-obtained acidic aqueous solution is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated, there being obtained pure isobutyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazine-7-carbamate having a melting point of 210°-215° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][F:5].[CH2:6]([O:13][C:14](=[O:43])[C@@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)(=[O:35])=[O:34])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([O:13][C:14](=[O:43])[C@@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)(=[O:35])=[O:34])=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][F:5])=[CH:19][CH:18]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
3-Bromo-1-fluoro propane (1.6 g, 11 mmol) was added to a mixture of (S)-2-{[(S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (compound 17c) (2.0 g, 3.7 mmol) and cesium carbonate (3.6 g, 11 mmol) in DMF (60 mL). The suspension was stirred overnight at room temperature. The reaction mixture was diluted in ethyl acetate and washed with water, dried over magnesium sulfate and concentrated. The resulting oil was chromatographed (dichloromethane/methanol, 9/1) on silica gel to produce 1.89 g (85.1%) of the title compound.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.C(N(CC)CC)C.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[NH2:32])([O-:22])=[O:21].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C1COCC1>[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[NH:32][C:1](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
Di-tert-butyl carbonate (1.76 g), triethylamine (1.13 ml), and DMAP (10 mg) were added to a THF (8.2 ml) solution containing 5-nitro-1H-indazol-3-amine (1.45 g) under ice cooling, followed by stirring for 20 minutes. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were extracted with water and saturated saline and dried over sodium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0 to 3:2) and a yellow solid of tert-butyl (5-nitro-1H-indazol-3-yl)carbamate (1.8 g) was thus obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[CH:33]=[C:32]([C:34](O)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:37])[CH:30]=2)[N:25]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:34]([C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH3:37])[CH:30]=4)[N:25]=[C:24]([CH3:23])[CH:33]=3)=[O:35])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: Cc1ccc2nc(C)cc(C(=O)O)c2c1
Agent: Cl
Product: Cc1ccc2nc(C)cc(C(=O)N3CCCC[C@@H]3COc3cccc4c3C(N)=NS(=O)(=O)N4)c2c1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2,6-dimethylquinoline-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.12-1.53 (m, 2H), 1.58-1.84 (m, 4H), 1.98 (s, 3H), 2.64 (s, 3H), 3.02 (m, 1H), 3.19 (m, 1H), 4.18 (dd, 1H, J=9.9, 3.1 Hz), 4.95 (t, 1H, J=10.2 Hz), 5.45 (m, 1H), 6.66 (m, 1H), 7.01 (d, 1H, J=8.2 Hz), 7.27 (s, 1H), 7.38 (s, 1H), 7.46-7.61 (m, 2H), 7.81 (d, 1H, J=8.6 Hz), 7.98 (br s, 1H), 8.26 (br s, 1H), 10.94 (s, 1H). MS 494 (MH+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:18]=[CH:17][C:10]2[O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:9]=2[CH:8]=1)[OH:6])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]([C:7]1[CH:18]=[CH:17][C:10]2[O:11][C:12]([CH3:15])([CH3:16])[O:13][CH2:14][C:9]=2[CH:8]=1)[OH:6]
Reactant: CC1(C)OCc2cc([C@@H](O)CN=[N+]=[N-])ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Yield: 38.5 %

Procedure:
(1R)-2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (16.99 g) was hydrogenated over 10% Pd-C (1 g) in ethanol (300 ml). The catalyst was collected by filtration, and washed with ethanol. The combined washings were evaporated under reduced pressure and the residue was triturated in diethyl ether to give the title compound (5.86 g). The mother liquors were chromatographed on a Biotage column eluting with toluene:ethanol:aqueous ammonia (85:14:1) to give a further batch of the title compound (5.99 g). LCMS RT=1.68 min, ES+ve 206 (MH-H2O)+.
Reaction SMILES: [Na].[CH2:2]([C:4]1[C:9]([NH:10][C:11]([C:13]2[N:14](CC3C=CC=CC=3)[CH:15]=[CH:16][N:17]=2)=[O:12])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:3].N>>[CH2:2]([C:4]1[C:9]([NH:10][C:11]([C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:3]
Reactant: CCc1ncncc1NC(=O)c1nccn1Cc1ccccc1
Agent: N
Agent: [Na]
Product: CCc1ncncc1NC(=O)c1ncc[nH]1

Procedure:
Small pieces of sodium (~230 mg) are added to a solution of Example 1 (2 g, 6.5 mmol) in freshly distilled ammonia until the blue color persists. The reaction mixture is quenched with a small amount of solid ammonium chloride and allowed to evaporate off excess ammonia. The residue is taken up in 25 mL of water and the pH is adjusted to 7.0 with 18% HCl. This is extracted with methylene chloride (3×50 mL). The organic extracts are combined, dried over MgSO4 and concentrated in vacuo. Recrystallization from methanol and ether (1+19) affords the title compound.
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:6]([C:26]([O:28][CH3:29])=[O:27])[CH2:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[C:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:6]([C:26]([O:28][CH3:29])=[O:27])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CN(C(C)=O)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(C)=O)c2ccccc2CN1S(=O)(=O)c1ccc(O)cc1
Yield: 33.8 %

Procedure:
To a 0° C. solution of methyl 1-acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate (9.8 g, 23.42 mmol) in methylene chloride (50 ml) was added, dropwise, a 1.0 molar solution of boron tribromide (51.52 ml, 51.52 mmol) in methylene chloride and the mixture was stirred overnight at room temperature. Ice and water were added to the reaction mixture and the insolubles filtered off. The filtrate was diluted with methylene chloride and water. The organic layer was separated, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by chromatography on silica gel (hexane:ethyl acetate (I:1)) to give 3.2 g of product as a white foam.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:37][C:17]=1[C:18]([NH:20][C:21]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1>[C:1]([N:47]1[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][O:41][C:38]2[CH:39]=[CH:40][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:17]([CH:37]=2)[C:18]([NH:20][C:21]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[O:19])[CH2:45][CH2:46]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCNCC2)ccc1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(C(C)=O)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, acetic anhydride (0.025 mL) was added to a solution mixture of methyl 2-(2-(benzyloxy)-5-(2-(piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.12 g) in methylene chloride (2.4 mL) and pyridine (0.027 mL), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain methyl 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate as a colorless oily substance.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[O:9])=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Adipoyl chloride (45.8 g, 0.25 mol) was added over a 30-45 minute period to a mechanically stirred suspension of aluminum chloride (83.3 g, 0.625 mol) in fluorobenzene (235 ml, 2.5 mol) maintained at 5°-10° C. The yellow slurry was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured onto approximately 1000 g of ice containing 100 ml of concentrated hydrochloric acid. The resulting suspension was separated by decantation and washed several times with water. The organic layer was distilled to remove excess fluorobenzene and the solid residue collected by filtration, washed with water, and dried at 110° C. The crude solid was recrystallized from approximately 1000 ml of toluene to afford 57.0 g (76% yield) of 1,4-bis(4-fluorobenzoyl) butane; mp 165°-167° C.; 'H NMR (CDCl3) δ1.2-2.1 (m, 4H, CH2), 3.00 (t, 4H, O=CCH2 , J=7.0 Hz), 7.0-8.2 (m, 8H, aromatic). Anal. Calcd. for C18H16F2O2 : C, 71.51%; H, 5.33%; F, 12.57%. Found: C, 71.68%; H, 5.38%; F, 12.78%.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:27]1[C:31]2[CH:32]=[CH:33][C:34]([NH2:36])=[CH:35][C:30]=2[NH:29][CH:28]=1>>[N:27]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:10]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=5)[N:23]4[N:22]=3)=[CH:35][C:30]=2[NH:29][CH:28]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: Nc1ccc2nc[nH]c2c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5nc[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (103 mg, 0.262 mmol) was coupled with 3H-benzimidazol-5-ylamine (60 mg, 0.45 mmol) at 105° C. for 120 h to afford the title compound. Yield of TFA salt: 24 mg (16%) of brown powder; LC/MS: 462 (M+H); HPLC: 97% pure, RT=2.65 min; 1H NMR: (DMSO, δ) 9.91 (s, 1H), 9.40 (s, 1H), 9.11 (s, 1H), 8.59 (s, 1H), 8.42 (d, J=8.0, 1H), 8.09 (s, 1H), 8.01 (d, J=8.0, 1H), 7.85 (m, 2H), 7.77 (t, J=7.7, 1H), 7.65 (s, 1H), 7.28 (d, J=4.9, 1H), 7.06 (d, J=4.9, 1H), 1.10 (s, 9H)— benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1.C([BH3-])#N.[Na+].C=O.C(O)(=O)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(Cl)n[nH]c12
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2c(Cl)n[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(3,5-dichloro-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (120 mg, 0.23 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (72 mg, 1.15 mmol) and formalin (0.84 mL). After 5 min, the reaction was treated with a drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by preparative HPLC to afford 30 mg (30%) as a clear oil. 1H-NMR (CD3OD, 500 MHz) δ 7.53 (d, J=1.8 Hz, 1H), 7.33-7.45 (m, 2H), 6.99-7.14 (m, 3H), 4.66 (q, J=6.7 Hz, 1H), 3.41-3.52 (m, 2H), 3.38 (qAB, JAB=9.2 Hz, 2H), 2.81-2.90 (m, 2H), 2.77(s, 3H), 2.61-2.69(m, 2H), 2.07-2.18 (m, 2H), 1.48 (m, 3H). Mass spec.: 442.44 (MH)+.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21].[CH2:23](O)[CH3:24]>>[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]([O:18][CH2:23][CH3:24])=[O:17])=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21]
Reactant: Cc1cc2oc(C(=O)O)cc(=O)c2c(C)c1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)c2c(C)c(Cl)c(C)cc2o1

Procedure:
10 Parts of concentrated sulphuric acid were added to a suspension of 66.1 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid in 600 parts of ethanol, and the mixture was heated at reflux for 24 hr. Most of the ethanol was removed by evaporation under reduced pressure, and 1500 parts of water were added to the reaction mixture. The precipitated solid was filtered, dissolved in chloroform and the solution, dried and evaporated, leaving 58.5 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester as a colourless solid. On recrystallisation from ethanol, the product had melting point 114.5°-115.5°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(O)(=O)C.[H][H]>C1COCC1.[Pd].C([O-])([O-])=O.[Ca+2]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH2:16]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C=CN(c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc(N2C=CC(=O)CC2)c(F)c1

Procedure:
In a 500 ml Parr bottle, 1-(2-fluoro-4-nitrophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 3, 35 g, 148.3 mmol), Pd/CaCO3 (3.5 g, 10 wt %) and acetic acid (17 ml, 297 mmol) are combined in THF (350 ml). The mixture is hydrogenated at 40° C. under 15 psi hydrogen for 6 h at which time the reaction is complete by HPLC. The reaction mixture is filtered through a GF/F filter and the catalyst cake washed with THF (350 ml). The filtrate is partitioned between 500 ml of NaHCO3 and 500 ml of ethyl acetate. The organic layer is washed again with 500 ml of NaHCO3. The organic layer is separated and dried over MgSO4. The mixture is filtered, and the filtrate is concentrated under reduced pressure to afford 29.0 g (95% recovery) of the title compound, MS (ESI−) for C11H11FN2O m/z 205.0 (M−H)−; 1H NMR (MeOD) δ 7.37 (d, 1 H), 7.02 (t, 1 H), 6.47 (m, 3 H), 5.07 (d, 1 H), 3.84 (t, 2 H), 2.58 (t, 1H).