Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[F:18])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To Ethyl 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoate (1.0 g, 3.32 mmol) in N,N-dimethylacetamide (5 mL) was added 2-fluoroaniline (1.48 g, 13.28 mmol) dropwise over 30 seconds at room temperature. The mixture was stirred at room temperature for 2 hours, and then it was diluted with ethyl acetate (33 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (8 mL) was added, and the mixture concentrated to give ethyl 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22].[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>>[Cl:22][C:21]1[C:6]2[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:1][C:26]([NH:25][CH2:23][CH3:24])=[O:27]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N)c2Cl
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C

Procedure:
5 g (0.016 M) of 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are heated at reflux with 15 ml of ethylisocyanate under nitrogen for 7 hours. The mixture is poured on to methanol/ice-water and extracted with methylene chloride. The organic phase is separated, dried with sodium sulphate, filtered and concentrated. The residue is purified on a 300 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethyl acetate/ether. There is obtained 1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-ethylurea which melts at 155°-160° C. with decomposition.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[CH:9][C:10]=1[F:11])([CH3:4])([CH3:3])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:12][Br:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)ccc1F
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 3-tert-butyl-4-fluorotoluene (5.92 g, 34.4 mmol) in carbon tetrachloride (60 ml), N-bromosuccinimide (6.1 g, 34.4 mmol) and benzoyl peroxide (containing 25% of water) (1.1 g, 3.44 mmol) were added, followed by stirring for 30 min. while heating under reflux. The mixture was evaporated to remove the solvent; the thus obtained residue was mixed with n-hexane and filtered to remove the insoluble matter. The filtrate was evaporated to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane) to give the titled compound (7.01 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:34][CH3:35])[C:28]=1[O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:34][CH3:35])[C:28]=1[O:29][S:30]([CH3:33])(=[O:31])=[O:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:53][CH2:52][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:56][CH2:55]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OS(C)(=O)=O
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OS(C)(=O)=O)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) (Example 11b) in chloroform (2 mL) was added pyridine (0.099 mL, 1.226 mmol) followed by benzenesulfonyl chloride (0.059 mL, 0.460 mmol). The reaction mixture was stirred at room temperature for 1 hr. The saturated solution of NH4Cl was added, and layers were separated. Organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at the room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. trans-2-phenyl-N-((1-(phenylsulfonyl)piperidin-4-yl)methyl)cyclopropanamine (10 mg, 0.026 mmol, 8.37% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.76-7.85 (m, 2H), 7.65-7.73 (m, 1H), 7.52-7.66 (m, 2H), 7.15-7.28 (m, 2H), 7.06-7.16 (m, 1H), 6.97-7.05 (m, 2H), 3.77 (d, J=12.13 Hz, 2H), 2.57 (dd, J=1.26, 6.82 Hz, 2H), 2.13-2.35 (m, 3H), 1.72-1.97 (m, 3H), 1.36-1.54 (m, J=3.73, 3.73, 7.33, 7.33, 14.78 Hz, 1H), 1.14-1.35 (m, 2H), 0.90-1.10 (m, 2H); LC-MS Rt=0.76 min; MS (ESI): 370.9 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:10][CH:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([O:28]C)[CH:21]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[NH4+].O>C(Cl)Cl>[CH:5]1([CH2:10][CH:11]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:28])[CH:21]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1OC
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A 1.0M solution of boron tribromide in methylene chloride (7.43 mL, 7.43 mmol) at 25° C. was treated with a solution of 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 113, 0.27 g, 0.74 mmol) in methylene chloride (7.43 mL). This solution was stirred at 25° C. for 1 h. At this time, the reaction was cooled to 0° C. and treated with a dilute aqueous ammonium hydroxide solution. This mixture was stirred at 0° C. for 20 min. At this time, the reaction was poured into water and was extracted with chloroform (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide (38.8 mg, 15.7%) as a white solid: mp 170–173° C.; EI-HRMS m/e calcd for C17H20N2O3S (M+) 332.1194 found 332.1192.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=2)=[N:31]\[OH:32])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 2-{5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-2-oxo-2H-pyridin-1-yl}-acetamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=466.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:8]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[H-].[Na+].CN(C=O)C.Cl[CH2:37][O:38][CH:39]=[O:40]>O>[CH3:37][O:38][C:39]([NH:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:12]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)=[O:40]
Reactant: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: O=COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Yield: 45.4 %

Procedure:
0.19 g (0.50 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine synthesized in (1) of the Example 6 and 60% sodium hydride (24 mg, 0.60 mmol) added to DMF (2 ml) were reacted at room temperature for 1 hour. The reaction mixture was added and reacted with 0.040 ml (0.55 mmol) of chloromethylformate at room temperature for 16 hours. The reaction solution was poured into water and extracted with methyl acetate. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 100 mg (yield: 46%) of the titled compound as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>CC(C)=O.C(N(CC)CC)C>[CH:13]1([NH:18][C:19]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C=NC1CCCC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccccc12)NC1CCCC1
Yield: 34.7 %

Procedure:
Tryptamine (1.04 g, 6.5 mmol) was dissolved in a mixture of acetone (20 ml) and triethylamine (1 ml) under a nitrogen atmosphere. Cyclopentyl isocyanate (795 mg, 7.15 mmol, 0.81 ml) was swiftly added dropwise at 0° C. and the mixture was then subsequently stirred for 2H, while cooling with ice, and at RT overnight. A white solid had precipitated out of the solution, and was filtered off with suction and rinsed with acetone. It was 641 mg of pure product. The filtrate was concentrated i. vac. and the residue was then stirred thoroughly with acetone (10 ml). The undissolved white solid was filtered off with suction and rinsed with acetone, and a further 612 mg of pure product were obtained in this way.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:18]([CH3:20])[CH3:19])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)I
Reactant: N#Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)c(C#N)c1
Temperature: 60 °C
Yield: 78.4 %

Procedure:
2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL, 20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with ether (100 mL), filtered over celite and the filtrate was washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, evaporated and purified by column chromatography (5-45% EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrile as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=9.0 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0. found 240.1 (M+1)+. Retention time: 1.81 minutes (3 min run).
Reaction SMILES: [Cl-:1].[OH:2][CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12].C(O)C.[CH2:38]=[C:39]1[O:43][C:41](=[O:42])[CH2:40]1>N1C=CC=CC=1>[Cl-:1].[C:41]([O:2][CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N+:11]([CH3:12])([CH3:13])[CH3:14])(=[O:42])[CH2:40][C:39]([CH3:38])=[O:43]
Reactant: C=C1CC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCOCC[N+](C)(C)C
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCOCC[N+](C)(C)C)OC(=O)CC(C)=O
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
1.5 g (2.94 millimole) of 2-[2-[2-hydroxy-3-(octadecyloxy)propyloxy]ethoxy]ethyltrimethylammonium chloride was dissolved in 80 ml of pyridine, to which 2 ml of diketene was added, and the mixture was stirred at 45° C. for 5 minutes. 10 ml of ethanol was added thereto, and the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (Merck Co., Art.7734, 38 g, Eluant; chloroform-methanol=4:1-2:1), to give 1.5 g (86%) of the above-captioned compound.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]#[N:13])[CH2:3][CH2:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].C([O-])(=O)C.[Na+]>[Ni]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC1CCOc2ccccc21
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)NCCC1CCOc2ccccc21
Temperature: 50 °C

Procedure:
The saturated cyano compound obtained in Step B is solubilised in the reactor of a Parr apparatus with acetic anhydride. Sodium acetate (1.5 eq.) and also Raney nickel (6 mg per 50 mg of product) are then introduced into the reaction medium. The whole is heated at 50° C. under hydrogen pressure of 40 psi for 12 hours. Once the solvent has been removed after returning to normal temperature and pressure conditions, extraction is carried out with ethyl acetate. Purification of the concentrated organic phase by flash chromatography (CHCl3/AcOEt 7/3) results in the desired amide. Colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:10])[N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: Nc1cc(Cl)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(Cl)cc(N)n1
Temperature: 120 °C
Yield: 23 %

Procedure:
To a 10% aqueous solution of dioxane (0.1 M) was added 4,6-dichloropyridin-2-amine (1.0 equiv.), trimethylboroxine (1.5 equiv.), Pd(PPh3)4 (0.10 equiv.) and K2CO3 (3.0 equiv.). The solution was heated in an oil bath to 120° C. for 18 hrs, cooled to room temperature (not all of starting material was consumed), extracted with EtOAc, dried with Na2SO4, and concentrated. The crude material was purified via SiO2 column chromatography eluting with 5% MeOH/DCM to yield an off-white solid in 23% yield. LCMS (m/z): 143 (MH+); LC Rt=1.11 min.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[Cl:25])[CH2:18][N:19]=[N+:20]=[N-:21])=[O:14])=[CH:11][CH:10]=1>C(O)C>[NH2:3][C:2]1[N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:15]([C:13](=[O:14])[C:12]3[CH:26]=[CH:27][C:9]([Cl:8])=[CH:10][CH:11]=3)[CH:16]=2)[N:20]=[N:21][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(C(=O)c2ccc(Cl)cc2)c1
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(Cl)c(C(=O)c3ccc(Cl)cc3)c2)c1N
Temperature: 0 °C
Yield: 60.3 %

Procedure:
To a stirred solution of sodium (0.147 g, 6.41 mmol) in ethanol (20 ml) under nitrogen atmosphere was added 2-cyanoacetamide (539 mg, 6.41 mmol) and the mixture was refluxed 10 minutes. The mixture was cooled slightly, 3-(4-chlorobenzoyl)-4-chlorobenzyl azide (1.51 g, 4.93 mmol) was added, and the mixture was refluxed 1 hour. The mixture was cooled to 0° C. and filtered. The product was washed with ice cold ethanol (2×5 ml), water (3×5 ml), ice cold ethanol (2×5 ml), and diethyl ether (10 ml), and dried at 50° C. for 3 hours under vacuum to provide 1.16 g (60%) of 5-amino-1-(3-[4-chlorobenzoyl]-4-chlorobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 189°-192° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:24])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>CN(C=O)C.O>[CH:1]([O:4][C:5](=[O:24])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[Cl:25])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2cc(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)c(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To [4-(6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.3 g, 34.9 mmol) in DMF (50 mL) was added a solution of N-chlorosuccinimide (5 g, 37.4 mmol) dropwise over 20 minutes and the mixture stirred at room temperature for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and triturated with ether to provide [4-(3-chloro-6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (10.65 g, 85%) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]([CH3:22])[CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]([CH3:22])[CH2:11][C:7]=3[N:8]([CH3:25])[C:9]=2[CH:10]=1
Reactant: CI
Reactant: CC1Cc2[nH]c3cc(Br)ccc3c2CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2c(c3ccc(Br)cc3n2C)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
tert-Butyl 7-bromo-3-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (enantiomer A) (1.00 g, 2.73 mmol) was dissolved in DMF (10 mL), and NaH (60% disp, 131 mg, 3.28 mmol) was added. After stirring for 30 minutes, MeI (386 mg, 0.170 ml, 3.28 mmol) was added, and the reaction continued for 1 h. The mixture was poured into water (250 ml), and the solid was filtered off to provide the title compound (180 mg, 17%) as a yellow solid: ESI MS m/z 379 [M+H]+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: CC[C@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(=O)OC
Agent: Cl
Product: CC[C@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[CH:4]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:6]1[C:7]([OH:9])=[N:8][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][C:5]=1[OH:10])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)nc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(O)cc(C(F)(F)F)nc1O
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
6-Trifluoromethyl-pyridine-2,4-diol (56 g, 310 mmol) was added in 3-5 gm portions to concentrated sulphuric acid (140 mL) with stirring to give a pale brown solution. The temperature increased to −50° C. during the addition. Nitric acid (21.1 mL 328 mmol, 70% HNO3 d=1.4 gm/ml) was added drop wise at such a rate as to maintain a reaction temperature of between 45° and 50° C. which took approximately 90 minutes. Once all the nitric acid had been added the reaction was allowed to cool to ambient temperature over 3 hours. Poured into ice/water (˜1.3 kg) with stirring, after a few minutes a pale yellow precipitate formed which was filtered off, dissolved in ethyl acetate and dried over sodium sulphate, filtered and evaporated. A second crop of material was obtained by extraction of the aqueous filtrate with ethyl acetate. Combined batches and purified by crystallization from ethyl acetate/n-heptane gave 3-nitro-6-trifluoromethyl-pyridine-2,4-diol as a white ‘fluffy’ solid (49.5 gm 71% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.CCOC(C)=O.[Cl:26][C:27]1[CH:32]=[C:31](CCl)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[C:31]([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:18])[N:15]([CH3:16])[CH3:17])[CH2:12][CH2:13]2)[CH:30]=[CH:29][N:28]=1
Reactant: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCc1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1-Boc-4-(N,N-dimethylcarbamoyl)piperazine was treated with 8 M HCl/EtOAc to afford a salt, then the salt (1.0 equiv) was mixed with 2-chloro-4-(chloromethyl)pyridine (1.0 equiv) (Preparation B-11) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜90% yield).