Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:2]3[S:3][CH:4]=[CH:5][CH:6]=3)=[C:18]([F:25])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: Brc1cccs1
Reactant: CCCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(-c2ccc(-c3cccs3)c(F)c2)cc1

Procedure:
A mixture of 25.3 g (0.16 mol) of 2-bromothiophene, 40.0 g (0.16 mol) of 4′-propyl-3-fluoro-4-biphenylboronic acid, 8.5 g (7.4 mmol) of tetrakis(triphenylphosphine)palladium(0) and 170 ml of 2 N sodium carbonate solution in 420 ml of toluene/ethanol (1:2) is refluxed for 18 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-(4′-propyl-3-fluorobiphenyl-4-yl)thiophene as a colourless solid (m.p. 88° C.).
Reaction SMILES: [OH-].[K+].[N+:3]([CH3:6])([O-:5])=[O:4].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>>[N+:3]([CH:6]=[CH:12][C:8]1[O:7][CH:11]=[CH:10][CH:9]=1)([O-:5])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccco1
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])C=Cc1ccco1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a 20% potassium hydroxide solution (25 mL) at 0° C. was added nitromethane (2.7 mL, 50 mmol) over 5 min followed by the slow addition via syringe pump of 2-furaldehyde (4.1 mL, 50 mM). The resulting brown solution was stirred vigorously for an additional 10 min at 0° C. then poured into an ice cold 50% HCl solution. The precipitate was collected via filtration, thoroughly washed with water, taken up in MeOH, solvents removed under reduced pressure, taken up in CHCl3 and filtered to remove any material that did not dissolve to give 2-(2-nitrovinyl)furan (10% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccccc1
Product: Clc1cccc(-c2nc3c(c(Nc4ccccc4)n2)CCC3)c1
Yield: 95.4 %

Procedure:
Following general procedure A1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.185 g, 0.70 mmol) was reacted with aniline (0.130 g, 1.4 mmol) to afford the title compound (0.215 g, 95%) as an orange solid. MW=321.80. 1H NMR (DMSO-d6, 500 MHz) δ 8.25 (s, 1H), 8.30-8.22 (m, 2H), 7.79 (d, J=8.5 Hz, 2H), 7.55-7.49 (m, 2H), 7.41-7.35 (m, 2H), 7.10-7.05 (m, 1H), 2.93-2.86 (m, 4H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 322 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH3:18])([CH:15]([CH3:17])[CH3:16])[CH2:12][CH:13]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:13]/[CH2:12][C:11]([CH3:18])([CH3:10])[CH:15]([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)C(C)(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 80.7 %

Procedure:
Step D In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1 g, 7.7 mmol) was reacted with 3,3,4-trimethyl-pentanal (1.1 g, 8 mmol) in CH2Cl2 at room temperature for 5 h to give [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.5 g, 80%).
Reaction SMILES: C([NH:4][C:5]([CH2:16][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][CH3:31])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:34]>CO>[ClH:34].[NH2:4][C:5]([CH2:16][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][CH3:31])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-l,3-diacetoxy-2-hexadecylpropane (1.75 g) was dissolved in 100 ml of methanol and 23.8 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane =1:1 in order to give 892 mg of 2-amino-2-hexadecyl-1,3-propanediol hydrochloride.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:17][C@H:16]2[CH3:31])(=[O:14])=[O:13])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1C=C(C([O-])=[O:41])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[F:33][C:2]([F:1])([F:32])[C:3]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N+:24]([O-:41])=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[CH2:17][C@H:16]2[CH3:31])(=[O:13])=[O:14])=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: C[C@@H]1CN(c2ccncc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1CN(c2cc[n+]([O-])cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a flask containing 1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-4-yl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol (60 mg, 0.12 mmol) and 1.5 mL of DCM/MeOH (9/1, v/v) was added MMPP (74.6 mg, 0.15 mmol). The resulting slurry was stirred at room temperature over night. Reaction was complete as determined by TLC. This was filtered, washed with DCM. The filtrate was concentrated under reduced pressure. Purification by flash column chromatography to yield 1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[1-oxido-3-(trifluoromethyl)pyridin-4-yl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white solid (13.5 mg, 21.9 yield). HRMS: calcd for C20H21F6N3O4S+H+, 514.12297. found (ESI-FTMS, [M+H]1+), 514.12174.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH4-].[Na+]>>[CH2:24]([NH:17][CH2:16][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:14][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[C:10]([CH3:13])[CH:9]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc2c(NC(CN)c3ccccc3)cc(C)nc12
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1cccc2c(NC(CNCc3ccccc3)c3ccccc3)cc(C)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
N*1*-(8-Methoxy-2-methylquinolin-4-yl)-1-phenylethane-1,2-diamine (Example 75, 150 mg, 0.488 mmole) and benzaldehyde were stirred at RT for 20 hrs. Molecular sieve (4A) was added and the mixture was heated to 60° C. within 2 hrs. NaBH4 was added and the mixture was stirred for 1 h at RT. The resulting mixture was filtered and extracted with dichloromethane. The organic phases were dried and concentrated. The residue was purified using preparative HPLC (RP-18, water/acetonitrile) to obtain the product (21 mg, 11%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:35])=[O:34])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3].Cl[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48]>O1CCCC1.O>[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:34])=[O:35])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[N:26][C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:48])=[CH:28][CH:29]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3]
Reactant: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCc3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and benzyl chloroformate in tetrahydrofuran/water.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]#[C:26][C:27](O)=[O:28].ClCCl.C(O)C.N>>[CH2:15]([N:3]([CH2:1][CH3:2])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:27](=[O:28])[C:26]#[C:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[CH:11][CH:12]=1)[CH3:16]
Reactant: O=C(O)C#Cc1ccc(Cl)cc1Cl
Reactant: CCN(CC)C(C)COc1ccc(N)cc1
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: CCN(CC)C(C)COc1ccc(NC(=O)C#Cc2ccc(Cl)cc2Cl)cc1

Procedure:
Prepared analogously to Example 3.4.c. from 4-(2-diethylaminopropoxy)phenylamine and (2,4-dichlorophenyl)propynoic acid. Yield: 0.41 g (65.2% of theory); melting point: 70° C.-72° C.; C22H24Cl2N2O2 (M=419.35); calc.: molecular ion peak (M+H)+: 419/421/423; found: molecular ion peak (M+H)+: 419/421/423; Rf value: 0.4 (silica gel, dichloromethane/ethanol/ammonia (5:1:0.01)).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[OH:26])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[C:29](OCC)(=O)C>CN(C=O)C>[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[O:26][CH3:29])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.04 g, 1.0 mmol) is suspended in DMF (10 ml), and thereto is added 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62 mmo) obtained in Example 30 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added methyl iodide (0.06 ml, 1.0 mmol) under ice-cooling, and the mixture is stirred for 1 0 minutes. To the reaction solution is added ethyl acetate (50 ml), and the mixture is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol), and recrystallized from isopropyl ether to give the title compound (0.09 g) as colorless crystals, m.p. 101-102° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH2:8][CH:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[N:6][CH:7]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCC1CN2C=NC=C(Br)C2=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCc1cn2cncc(Br)c2n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
8-Bromo-2-ethyl-2,3-dihydroimidazo[1,2-c]pyrimidine (3.0 g) was dissolved in toluene (60 mL), then activated manganese(IV) dioxide (3.5 g) was added thereto, and the mixture was heated under stirring at 90° C. for 1 day. Manganese(IV) oxide was filtered off through Celite, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (1.3 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[C:4]([CH:23]2[CH2:26][N:25](C(OCC3C=CC=CC=3)=O)[CH2:24]2)[C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.Cl.O>CO.[Pd]>[NH:25]1[CH2:26][CH:23]([C:4]2[C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:8]([NH:10][C:11]3[N:19]=[CH:18][N:17]=[C:16]4[C:12]=3[N:13]=[CH:14][NH:15]4)[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:37])[CH2:24]1
Reactant: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reaction time: 8 h

Procedure:
Benzyl 3-{3-chloro-6-ethoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate (83 mg, 0.16 mmol) and 5% palladium (74 mg) was combined in methanol (5 mL), to which was added 0.25 M HCl in water (1.6 mL, 0.40 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature overnight. The suspension was filtered and concentrated to give N-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-9H-purin-6-amine. LCMS calculated for C19H24ClN6O (M+H)+: m/z=387.2. found: 387.1. The azetidine made above was combined with DIPEA (0.1 mL, 0.6 mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by the addition of 37% formaldehyde (0.1 mL, 2 mmol). The mixture was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (0.17 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with MeOH and purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2. found: 401.1.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].C(O)(=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CN(C)C=O>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1NCc1ccccc1

Procedure:
The title compound was prepared by method D using 3 -amino-4 -hydroxy-6-phenyl-2H-pyran-2 -one hydrochloride (0.500 g, 2.08 mmol), 1% acetic acid in dimethylformamide (20 mL), benzaldehyde (0.233 mL, 2.29 mmol), sodium cyanoborohydride (0.144 g, 2.29 mmol). m.p. dec. 205° C., 1H NMR (250 MHZ, DMSO-d6) δ4.37 (s, 2 H), 6.56 (s, 1 H), 7.27 (m, 5 H), 7.45 (m, 3 H), 7.67 (m, 2 H).
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7](F)(F)F)=O.[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=C2)([O-:16])=[O:15].O>CN(C)C=O>[N+:14]([C:17]1[CH:25]=[C:24]2[C:23](=[CH:19][CH:18]=1)[NH:22][CH:21]=[C:7]2[C:6]([OH:5])=[O:11])([O-:16])=[O:15]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
Trifluoroacetic anhydride (21.37 g) was added dropwise to a chilled solution of 5-nitro-1H-indole (15.0 g) in dry dimethylformamide (150 ml) under a dry N2 atmosphere. The solution was allowed to warm to room temperature, and was then heated at reflux for 24 hours. The reaction mixture was cooled and poured into water (500 ml) and the resulting dark brown precipitate was filtered, suspended in water (200 ml) containing sodium hydroxide (50.0 g), and heated at reflux for 3 hours. The dark brown solution was cooled to room temperature, extracted with ether (4×100 ml), acidified to pH2 and the title compound filtered and dried (19 g), m.p. 256°-258° C. δH (360 MHz, DMSO-d6) 7.71 (1H, d, J=7.2 Hz, H-7), 8.9 (1H, dd, J=7.2, 1.0 Hz), 8.27 (1H, s, H-2), 8.89 (1H, d, J= 1.0 Hz, H-4); m/z 206 (M+, 70), 163 (10), 138 (20), 123 (100, 106 (15), 81 (10%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:26]
Reactant: COc1cc(N)c(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: COc1cc(NC(=O)CBr)c(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
1-(2-Amino-4,5-dimethoxy-phenyl)-2-(3,4-dichloro-phenyl)-ethanone (5.52 g, 16.24 mmol) was dissolved in dichloromethane (20 ml), distilled water was then added (2 ml) and the resulting solution was cooled at −5° C. under nitrogen. Bromoacetylbromide (1.63 ml, 18.68 mmol) was dissolved in dichloromethane (10 ml) and added dropwise to the previous solution; the temperature was not allowed to exceed +5° C. The reaction mixture was stirred at 0° C. for 15 min and then allowed to reach the RT before further stirring for 2.5 h. Dichloromethane was added (30 ml) and the organic layer was washed with distilled water, saturated NaHCO3 solution, and brine. It was dried over magnesium sulfate, filtered and the solvent was removed under vacuum. This crude mixture was purified by flash chromatography (dichloromethane/methanol, 360/1) to give the product as a yellow solid (5.25 g, 70%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:26])(=[O:25])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[CH3:36])[CH2:31][NH2:32]>>[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[CH3:36])[CH2:31][NH:32][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:25])(=[O:26])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: CCOC(=O)c1nc(-c2ccccc2S(=O)(=O)N(C)C)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1C
Product: Cc1ccc(CNC(=O)c2nc(-c3ccccc3S(=O)(=O)N(C)C)n(C)c(=O)c2O)cc1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3,4-dimethylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as white needles (0.0560 g, 60% yield). 1HNMR (500 MHz, CDCl3) δ: 12.19 (1H, s), 7.91 (1H, dd, J=7.48, 1.68 Hz), 7.71–7.65 (2H, m), 7.61 (1H, m), 7.36 (1H, dd, J=7.48, 1.68 Hz), 7.07 (1H, d, J=7.33 Hz) 7.00 (1H, s), 6.96 (1H, d, J=7.63 Hz), 4.57 (1H, dd, J=14.65, 7.02 Hz), 4.37 (1H, dd, J=14.65 Hz), 3.23 (3H, s), 2.63 (6H, s), 2.22 (6H, s). HRMS (ESI) calcd for C23H27SN4O5 (M+H): 471.1702; found 471.1708.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH:29]1([CH2:32][NH:33][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:31][CH2:30]1
Reactant: NCC1CC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC3CC3)ccc21
Yield: 23.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid cyclopropylmethyl-amide (24 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (90 mg), cyclopropane-methylamine (16 mg), DPPA (48 uL), and DIEA (39 uL). LC/MS: m/z 462.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.16 (bs, 1H), 8.30 (s, 1H), 7.87 (s, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.50 (d, 1H), 7.26 (d, 1H), 7.12 (d, 1H), 3.40 (bs, 3H), 2.94 (t, 2H), 0.89-0.78 (m, 1H), 0.21 (d, 2H), 0.02 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Cl:13])=[CH:4][CH:3]=1.Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:13][C:5]1[C:6]2[CH2:7][C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[C:2]([N:1]=[C:15]=[O:16])=[CH:3][CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)Cc2c(Cl)ccc(N)c2O1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(Cl)ccc(N=C=O)c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1.97 g (0.010 mole) of 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran in 60 mL of toluene was added slowly 1.2 mL (0.010 mole) of trichloromethyl chloroformate. This mixture was stirred at ambient temperature for one hour and then was heated at reflux for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 2.23 g of 4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl isocyanate as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:20][OH:21])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[H-].[Na+].[CH2:46]1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:20][O:21][CH3:46])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC[C@H](O[C@@H]1CC[C@H]2[C@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 156; 0.3 g, 0.5 mmol), methyl iodide (0.04 g, 0.02 ml, 0.3 mmol), sodium hydride (0.04 g, 1.6 mmol) and 18-crown-6 (0.3 g, 1 mmol) in N,N-dimethylformamide (3 ml) was heated at 60° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 30% ethyl acetate/hexane. The title compound was isolated as a white crystalline solid (285 mg, 97%).