Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.O>C(Cl)Cl.C(N(CC)CC)C>[Br:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:4]
Reactant: CNCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Reaction time: 0.08 h
Yield: 104.6 %

Procedure:
To a solution of bromoacetyl bromide (30 g) in methylene chloride (20 ml) at 0° was added a solution of N-methyl-4-nitrobenzenemethanamine (8.3 g; G. I. Wilson, J. Chem. Soc., 1926, 2461) in methylene chloride (10 ml) and triethylamine (12 ml). The reaction was stirred 5 min. at 0° and then water (20 ml) was added. The methylene chloride layer was dried and evaporated in vacuo. The residue was purified by column chromatography eluting with methylene chloride/methanol (97:3) to give the title compound (15 g) as an oil. NMR includes signals at d 3.1(3H,s,N--CH3); 3.9(2H,s,CH2Br); 4.55(2H,s,Ph--CH2 --N); 7.0-8.3(4H,m,aromatics).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[N:6][CH:7]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:18][CH:19]2[CH:20]3[CH2:28][CH:24]4[CH2:23][C:22]([OH:29])([CH2:27][CH:26]2[CH2:25]4)[CH2:21]3)=[O:14])=[N:6][CH:7]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(Oc2ccc(Cl)cn2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(Oc2ccc(Cl)cn2)c1

Procedure:
Prepared from 3-(5-chloro-pyridin-2-yloxy)-benzoic acid and 4-amino-1-hydroxyadamantane. 1H NMR (400 MHz, CDCl3): δ8.11 (s, 1H), 7.68 (d, 1H), 7.51-7.61 (m, 2H), 7.47 (t, 1H), 6.94 (d, 1H), 6.23-6.36 (m, 1H), 4.08-4.25 (m, 1H), 2.24 (t, 3H), 1.51-2.03 (m, 13H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=O)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl.NO.[N:27]1C=CC=CC=1.C(OCC)(=O)C>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:27])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (8.0 g), hydroxylamine hydrochloride (3.45 g) and pyridine (28 ml) are dissolved in ethanol (140 ml), and the mixture is stirred at 80° C. for 1 hour. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a 1N-hydrochloric acid, a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (100 ml), and thereto is added Raney nickel, and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes and at 50° C. overnight. The reaction solution is cooled to room temperature, and Raney nickel is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (5.50 g). MS (m/z): 324 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:33]#[N:34]>CN(C=O)C.N1C=CC=CC=1>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[NH:38][C:37]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=3[N:29]=2)[CH2:12][CH2:13]1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (15 g, 69.7 mmol) in DMF (50 mL) and pyridine (50 mL) was added CDI (11.3 g, 69.7 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 3,4-diamino-benzonitrile (9.27 g, 69.7 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (20 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 2-piperidin-4-yl-1H-benzoimidazole-5-carbonitrile (9 g, 70%) as pale solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46]C=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CO>CN(C=O)C>[C:43]([C:44]1([NH:49][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:7]=[C:8]3[C:31](=[CH:32][CH:33]=2)[C:12]2=[N:13][O:14][C:15]([C:16]4[C:20]([C:21]([F:22])([F:23])[F:24])=[C:19]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[O:18][N:17]=4)=[C:11]2[CH2:10][CH2:9]3)[CH2:46][CH2:45]1)#[N:48]
Reactant: O=C(O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CO
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C(O)c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
To 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Preparation 131B, Isomer 2, 25 mg, 0.055 mmol) in DMF (1 mL) was added 1-aminocyclopropanecarbonitrile, HCl (9.74 mg, 0.082 mmol), HATU (24.99 mg, 0.066 mmol), and N-methylmorpholine (0.036 mL, 0.329 mmol). The reaction mixture was stirred for 1 h at room temperature. Methanol was added and it was purified by prep HPLC (Phenomenex 21.2×250 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 30 min, 20 mL/min, 220 nM) to yield N-(1-cyanocyclopropyl)-2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (11 mg, 0.021 mmol, 38.2% yield) as a white solid: product HPLC ret. time=9.96 min (condition G); LC/MS M+1=521.06; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (1H, s), 7.89 (1H, d, J=7.92 Hz), 7.80 (2H, d, J=7.26 Hz), 7.63-7.76 (3H, m), 7.41-7.51 (2H, m), 6.43 (1H, d, J=4.18 Hz), 5.02 (1H, d, J=3.74 Hz), 3.05 (4H, s), 1.46 (2H, q, J=2.79 Hz), 1.07-1.24 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(O)C>C(COC)OC>[CH:13]([O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:1]=[C:2]2[CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Oc1cc(N)nc2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(OC(C)C)c3ccccc32)n1
Reaction time: 1 h

Procedure:
2.8 g of 2-amino-4-isopropoxyquinoline were dissolved in 50 ml of dimethoxyethane and 4 g of ethyl bromopyruvate were added thereto. The mixture obtained was allowed to stand at room temperature for 1 hour and then was reduced in volume under vacuum. 50 ml of ethanol were added thereto and the resultant mixture was refluxed for 90 minutes. The ethanol was evaporated off under vacuum and the residue was dissolved in 100 ml of 2 N HCl. The acid solution thus obtained was washed with 50 ml of ethyl acetate and then was made alkaline with sodium carbonate. The mixture was extracted three times with 50 ml of chloroform and the combined chloroform extracts were washed with 100 ml of water, dried over MgSO4 and then was evaporated to dryness under reduced pressure to obtain an orange oil. The oil was purified by column chromatography (silica gel-chloroform as eluant) and then was crystallized from diethyl ether to obtain colorless needles of ethyl 5-isopropoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 127°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24](=O)[CH3:25])=[CH:22][N:23]=4)[CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[N:28]([CH:30]=O)C.[NH2:32]N>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]5[CH:25]=[CH:30][NH:28][N:32]=5)=[CH:22][N:23]=4)[CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1cnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)cn12
Reactant: CN(C)C=O
Reactant: NN
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-c2ncccc2-c2ccc3ncc(-c4cc[nH]n4)n3c2)cc1Cl

Procedure:
1-(6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one (300 mg) and DMF.DMA (5 mL) were heated at 95° C. and stirred in a screw capped vial overnight. The reaction mixture was concentrated and the semi-solid residue was diluted with Et2O/hexanes (1:1). The solid was filtered and dried. The enamine (75 mg) and the hydrazine (1.2 eq) were heated in a screw capped vial at 100° C. for 12 h. The reaction mixture was concentrated and purified by preparative HPLC. 1H NMR (300 MHz, DMSO-d6): δ 13.02 (br s), 9.71 (dd, J=1.8, 1.0 Hz, 1H), 8.79 (dd, J=4.8, 1.6 Hz, 1H), 8.62 (s, 1H), 8.06 (dd, J=7.8, 1.7 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.89 (dd, J=9.3, 0.9 Hz, 1H), 7.74 (dd, J=7.3, 2.1 Hz, 1H), 7.62 (dd, J=7.8, 4.8 Hz, 1H), 7.50 (dd, J=9.3, 1.7 Hz, 1H), 7.37-7.14 (m, 2H), 6.95 (d, J=2.4 Hz, 1H). 19F NMR (282 MHz, DMSO-d6): δ −116.76 (q, J=7.3 Hz). LCMS: rt 4.98 min (A), purity 99%, MS (m/e) 390 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:33]([F:36])([F:35])[F:34])=[CH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:37](O)(=[S:39])[CH3:38]>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:37](=[S:39])[CH3:38])([C:33]([F:35])([F:34])[F:36])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=S)C(CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1)(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The starting material, tert-butyl 5′-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (3.0 g, 6.0 mmoL), was dissolved in dichloromethane (14 mL) and to this solution were added thioacetic acid (2.6 mL, 6.0 eq) and 2 drops of triethylamine and the resulting mixture was stirred at room temperature for 96 h under argon. Solvents were removed under reduced pressure and the crude product was purified via flash silica gel chromatography to yield 1.3 g of tert-butyl 5′-[3-(3,5-dichloro-4-fluorophenyl)-3-thioacetyl-4,4,4-trifluorobutanoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate. HNMR (400 MHz, CDCl3) δ ppm 8.01 (d, 1H, J=8.0 Hz), 7.82 (s, 1H), 7.60 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=5.8 Hz), 5.23 (d, 1H, J=18.5 Hz), 5.17 (s, 2H), 4.35 (d, 2H, J=9.7 Hz), 4.15 (d, 2H, J=9.7 Hz), 3.97 (d, 1H, J=18.5 Hz), 2.33 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11](=[O:19])[C:12]2[CH:18]=[CH:17][CH:16]=[N:15][C:13]=2[N:14]=1.[OH-].[NH4+:23]>>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:14][C:13]1[N:15]=[CH:16][CH:17]=[CH:18][C:12]=1[C:11]([NH2:23])=[O:19])=[O:10]
Reactant: O=c1oc(-c2ccccc2C(F)(F)F)nc2ncccc12
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cccnc1NC(=O)c1ccccc1C(F)(F)F
Yield: 33 %

Procedure:
2-(2-Trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.51 g) is stirred in 30% ammonium hydroxide (25 ml) at room temperature overnight. The resulting precipitate is filtered and rinsed with water and diethyl ether. The precipitate is dried under vacuum at 50 C overnight to give 2-(2-trifluoromethyl-benzoylamino)-nicotinamide (850 mg, 33% yield)
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH:25]([OH:27])[CH3:26])=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:5]([C:25](=[O:27])[CH3:26])=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCCCc1c(C(C)C)cc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)cc(C(C)C)c(C(C)=O)c1-c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
A mixture of 3,5-diisopropyl-2-(1-hydroxyethyl)-6-pentyl-4′-fluoro-1,1′-biphenyl (Example 192, 13.7 g, 37.1 mmol), Celite (26 g), and pyridinium chlorochromate (14.9 g, 69.3 mmol) in dichloromethane (750 mL) was stirred for 45 minutes. The mixture was diluted with ethyl acetate (750 mL) and hexane (1.5 L) and filtered through a plug of silica (100 mm×2″) topped with Celite (100 mm×0.5″). Elution was continued with ethyl acetate:hexanes (1:1 mixture, 3L×2). The combined filtrates were concentrated in vacuo to afford the desired product as a white solid (13.5 g, 99%). 1H NMR (300 MHz, CDCl3): δ 0.75-0.80 (m, 3H), 1.06-1.31 (m, 18H), 1.95 (s, 3H), 2.33-2.39 (m, 2H), 2.78 (septet, J=7.0 Hz, 1H), 3.18 (septet, J=7.0 Hz, 1H), 7.03-7.09 (m, 2H), 7.17-7.22 (m, 2H) 7.26 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 13.75, 22.02, 24.32, 24.37, 28.99, 29.10, 29.28, 30.60, 31.04, 32.06, 33.03, 114.85 (d, J=20.8 Hz, 2C), 122.06, 132.03 (d, J=7.3 Hz, 2C), 135.52 (d, J=2.4 Hz, 1C) 135.58, 135.76, 140.13, 140.85, 147.66 161.99 (d, J=246.6 Hz, 1C), 208.23. EI-MS: calculated for C25H33OF 368; found 368 (M+). Anal. calc for C25H33OF: C, 80.86; H, 8.96. Found: C, 81.04; H, 9.06. Rf=0.65 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05% aqueous trifluoroacetic add, B=CH3CN; linear gradient: 75%-100% B over 30 min; 254 nm, 1 mL/min): R.T. 22.7 min (94.0 area %). mp 123.0-124.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7].[Br:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:43]=[CH:42][C:25]([O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH2:35][C@@H:36]([OH:39])[CH2:37][OH:38])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>CC(=O)CC>[Br-:18].[NH2:14][C:13]1[C:8]([C:6]([NH:5][CH2:4][CH2:3][N+:2]([CH2:19][CH2:20][CH2:21][C:22]2[CH:43]=[CH:42][C:25]([O:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:34][CH2:35][C@@H:36]([OH:39])[CH2:37][OH:38])=[CH:40][CH:41]=3)=[CH:24][CH:23]=2)([CH3:17])[CH3:1])=[O:7])=[N:9][C:10]([Cl:16])=[C:11]([NH2:15])[N:12]=1
Reactant: CN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: OC[C@H](O)COc1ccc(CCCOc2ccc(CCCBr)cc2)cc1
Solvent: CCC(C)=O
Product: C[N+](C)(CCCc1ccc(OCCCc2ccc(OC[C@@H](O)CO)cc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Product: [Br-]

Procedure:
3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid (2-dimethylamino-ethyl)-amide (Intermediate H) (0.65 g, 2.52 mmol) and (S)-3-(4-{3-[4-(3-bromo-propyl)-phenoxy]-propyl}-phenoxy)-propane-1,2-diol (Intermediate J) (1.60 g, 3.78 mmol) in butan-2-one (25 mL) is heated at reflux overnight during which time precipitation of white solid is observed. The reaction mixture is filtered to collect the product, washed with warm acetone and dried under vacuum to afford the title compound. M+ 601. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (1H, t), 7.30 (1H, br), 7.12 (2H, d), 7.11 (2H, br), 7.07 (2H, d), 6.95 (1H, br), 6.84 (2H, d), 6.82 (2H, d), 4.89 (1H, d), 4.63 (1H, t), 3.94 (1H, dd), 3.89 (2H, t), 3.81 (1H, dd), 3.77 (1H, m), 3.59 (2H, m), 3.43 (2H, m), 3.42 (2H, m), 3.34 (2H, m), 3.08 (6H, s), 2.66 (2H, m), 2.47 (2H, m), 1.96 (2H, m), 1.93 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19](Br)=[C:18]([F:23])[N:17]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.C([Cu])#N.C(OC([N:40]1[C:44]2=[N:45][CH:46]=[C:47]([C:49]#[N:50])[CH:48]=[C:43]2[C:42]([CH2:51]Cl)=[CH:41]1)=O)(C)(C)C.N>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH2:51][C:42]2[C:43]3[C:44](=[N:45][CH:46]=[C:47]([C:49]#[N:50])[CH:48]=3)[NH:40][CH:41]=2)=[C:18]([F:23])[N:17]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cc(C#N)cnc21
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Br)c(F)n1
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Cc2c[nH]c3ncc(C#N)cc23)c(F)n1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (631, 0.600 g, 1.50 mmol, prepared as described in Example 60) in tetrahydrofuran (10.0 mL) at −25° C. under an atmosphere of nitrogen, was added a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.730 mL). The reaction was allowed to warm to 5° C. over 1 hour. The reaction was cooled to −35° C., followed by addition of a solution of CuCN.2LiCl (0.65 M in tetrahydrofuran, 2.4 mL). After 5 minutes, 3-chloromethyl-5-cyano-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (635, 0.086 g, 0.29 mmol) in tetrahydrofuran (4.0 mL) was added to the reaction. The reaction was allowed to warm to room temperature over 1 hour, then poured into a diluted ammonia solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (636, 0.13 g, 92%). MS (ESI) [M+H+]+=477.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 84.3 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 4.97 mg (0.0458 mMol) ethyl chloroformate, 11.1 mg (84%) of the title compound were recovered.
Reaction SMILES: [C:1]1([S:7]([CH2:9][Br:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[C:13]=1[CH3:20].[F:21][C:22]([F:35])([F:34])[S:23]([O:26]S(C(F)(F)F)(=O)=O)(=[O:25])=[O:24]>C(OCC)C>[O-:26][S:23]([C:22]([F:35])([F:34])[F:21])(=[O:25])=[O:24].[Br:10][CH2:9][S+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:16]=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]([CH3:20])[C:12]=1[CH3:11]
Reactant: Cc1ccc(C)c(C)c1C
Reactant: O=S(CBr)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: Cc1cc([S+](CBr)c2ccccc2)c(C)c(C)c1C
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Bromomethyl phenyl sulfoxide (500 mg, 2.29 mmol) of example 32 was dissolved in dry diethyl ether (15 mL) under an argon atmosphere. 1,2,3,4-Tetramethylbenzene (339 mg, 1.09 eq) was added to the previous solution and then the mixture cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.385 ml, 1.0 eq) was added slowly, maintaining the same temperature. The mixture was stirred until the reaction was complete. The precipitated triflate salt formed was isolated by filtration, washed with diethyl ether at 0° C. and dried under vacuum. 0.779 g (70%) of the desired product was obtained as a white solid. mp: 115-116° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([NH2:21])[CH:5]=1.[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:29][C:27]=2[N:28]=1.[C:38](N1C=CN=C1)(N1C=CN=C1)=S.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:38]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([O:33][C:34]([F:37])([F:35])[F:36])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[N:21][C:6]=2[CH:5]=1)=[O:22]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)c(N)c1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCNC(=O)OC(C)(C)C
Yield: 40 %

Procedure:
1-(2-tert-Butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (374.0 mg) was prepared by following General Procedure D starting from 3-amino-4-(2-tert-butoxycarbonylamino-ethylamino)-benzoic acid methyl ester (525.0 mg), 2-amino-6-(trifluoromethoxy)-benzothiazole (585.0 mg), 1,1′-thiocarbonyldiimidazole (445.0 mg), and EDC (480.0 mg) in DMF (2.0 mL).