Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: Cn1c(Nc2nc3ccc(F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(F)cc3s1)n2C

Procedure:
2-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (29 mg) was prepared by following General Procedure F using 2-(6-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 401; and 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (m, 1H), 8.06 (br, 1H), 7.76-7.70 (m, 2H), 7.66 (br, 1H), 7.45 (d, 1H), 7.20 (t, 1H), 3.61 (s, 3H), 3.44 (m, 4H), and 3.26 (s, 3H), —NH proton signal was not observed.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[F:13].[CH3:14][C@@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:14][C@H:15]([OH:16])[CH3:17])=[CH:6][C:5]=1[F:13]
Reactant: Fc1cc2cc[nH]c2cc1Cl
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ccc2cc(F)c(Cl)cc21
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 6-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.42 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 85 hours and subsequently treated with is water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene/ethyl acetate (19:1). There was obtained 0.51 g (74.6%) of (R)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as white crystals (m.p. 104°-105°.)
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[C:12]([C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(COC)OC.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[O:1]([CH2:8][C:9]1[N:14]=[C:13]2[C:15]([O:20][C:18](=[O:19])[C:12]2=[CH:11][CH:10]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(COc2ccccc2)nc1C(=O)O
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1OC(=O)c2nc(COc3ccccc3)ccc21

Procedure:
30 g of 6-phenoxymethylpyridine-2,3-dicarboxylic acid are added to a mixture of 100 ml of dimethoxyethane, 28 ml of acetic anhydride and 15 ml of pyridine while stirring and the reaction mixture is further stirred for one hour at room temperature. The whole is then concentrated by evaporation under a high vacuum. The above anhydride remains in the form of a light-coloured oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][C:21]1[S:22][C:23]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][C:25]=1[CH3:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl.CN(C)C=O>[CH2:27]([C:23]1[S:22][C:21]([CH3:20])=[C:25]([CH3:26])[C:24]=1[C:5]([C:4]1[CH:8]=[C:9]([CH3:13])[C:10]([O:11][CH3:12])=[C:2]([CH3:1])[CH:3]=1)=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1c(C)cc(C(=O)O)cc1C
Reactant: Cc1cc(Cc2ccccc2)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a suspension of 3,5-dimethyl-p-anisic acid (15.2 g, 84.4 mmol, RN-21553-46-8) in anhydrous methylene chloride (200 mL) at room temperature under nitrogen was added oxalyl chloride (9.6 mL, 110 mmol) and N,N-dimethylformamide (5 drops). After two hours the solvent was removed. The resulting residue was dissolved in anhydrous methylene chloride (200 mL), and added to 2,3-dimethyl-5-benzylthiophene (17.1 g, 84.4 mmol) under nitrogen. The resulting mixture was, cooled to −78° C., and tin(IV) chloride (10.8 mL, 92.8 mmol) was added quickly. The −78° C. bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then poured onto ice water (1 L), and the resulting mixture was extracted once with diethyl ether (700 mL), and a second time with diethyl ether (400 mL). The combined diethyl ether extracts were washed with ice water (500 mL), dilute sodium bicarbonate (500 mL), water (500 mL), brine (1 L), and then dried (Na2SO4). Concentration under reduced pressure gave the title compound as a yellow oil (25.2 g, 82%): NMR (DMSO-d6): δ7.40 (s, 2H), 7.24-7.15 (m, 3H), 7.06 (d, 2H), 3.83 (s, 2H), 3.70 (s, 3H), 2.28 (s, 3H), 2.26 (s, 6H), 1.83 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=O)=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C[Al](C)C.C(Cl)Cl.CCOCC>C1(C)C=CC=CC=1>[CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:39][C:36]4[NH:37][N:38]=[C:34]([CH2:33][CH2:32][C:26]5[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:24]([O:23][CH3:22])[CH:25]=5)[CH:35]=4)=[O:17])=[CH:20][CH:21]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(N2CCCN(C3CC3)CC2)cc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C5CC5)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 33.7 %

Procedure:
4-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared using the same procedure as for Example 159, but starting from ethyl 4-(4-cyclopropyl-1,4-diazepan-1-yl)benzoate (0.288 g, 1 mmol, 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol) and a 2M solution of trimethylaluminium (1.250 mL, 2.50 mmol) in toluene. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford a gum which solidified on trituration with DCM/Ether to afford the title compound (0.165 g, 33.7%).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6]([CH2:9][CH2:10][C:11]3[N:12]=[C:13]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[O:14][C:15]=3[CH:16]([CH3:18])[CH3:17])=[N:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH:36]=[CH2:37]>CC(C)=O>[CH2:37]([O:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6]([CH2:9][CH2:10][C:11]3[N:12]=[C:13]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[O:14][C:15]=3[CH:16]([CH3:18])[CH3:17])=[N:7][O:8][C:4]=2[CH:3]=1)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: CC(C)c1oc(-c2ccc(Cl)cc2Cl)nc1CCc1noc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc2c1
Reaction time: 20 h
Yield: 76.5 %

Procedure:
The obtained 6-hydroxy-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazole (500 mg, 1.20 mmol) and potassium carbonate (249 mg, 1.80 mmol) were suspended in acetone (30 mL). Allyl bromide (217 mg, 1.80 mmol) was dropwise added to the suspension for 1 minute while cooling with ice. The mixture was allowed to room temperature, and stirred for 20 hours. After insoluble was filtered off, the filter cake was washed with acetone. The filtrate and washings were combined, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (4/1) to give the desired compound (420 mg) as colorless oil (yield 77%).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:23]([CH:22]([CH2:25][CH3:26])[CH2:21][O:20][C:14]1[CH:15]=[CH:16][C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][C:13]=1[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[N:7]1)[CH3:24]
Reactant: OB(O)c1ccccc1
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1nc(CCC(=O)OC)cc1C
Product: CCC(CC)COc1ccc(-c2ccccc2)cc1Cn1nc(CCC(=O)O)cc1C

Procedure:
The title compound was prepared from 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester and benzeneboronic acid using Suzuki chemistry and following the method in Example 1, Step 8.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.[N:19]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)=[C:20]=[O:21]>ClCCl>[C:15]([O:14][C:12]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([NH:11][C:20]([NH:19][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)=[O:21])=[CH:7][CH:6]=2)[C:2]([NH2:1])=[N:3]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1cccc(CCN=C=O)c1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)Nc2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)c1
Yield: 54.8 %

Procedure:
6.1 700 mg of tert-butyl 3,5-diaminoindazole-1-carboxylate (3.1 mmol) and 532 mg of 1-(2-isocyanatoethyl)-3-methoxybenzene (3.0 mmol) are stirred at RT for 24 hours in 10 ml of dichloromethane. The reaction mixture is washed with water, the organic phase is separated off, dried and evaporated. Purification of the residue by column chromatography (eluent:ethyl acetate) gives 700 mg of tert-butyl-3-amino-5-{3-[2-(3-methoxyphenyl)ethyl]ureido}indazole-1-carboxylate (53%), MS-FAB (M+H+)=426.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.C(O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:1][O:2][C:3](=[O:23])[C@@H:4]([CH3:22])[N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[N:12]=[C:13]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](C)Nc1ncccc1NC(=O)c1ccc(Cl)cc1
Reactant: OCCO
Solvent: O
Product: C[C@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 96 %

Procedure:
A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alanine methyl ester (27.4 g, 0.0822 mole) in ethylene glycol (150 ml) was refluxed under nitrogen for 1.75 hours and then cooled. One-third of this solution was added to water (1 liter), extracted with ethyl acetate twice and the combined organic layers were washed three times with water and once with a saturated sodium chloride solution. The organic layers was dried over magnesium sulfate, treated with charcoal, filtered, and evaporated to give 8.3 g of a yellow solid (96% yield). The solid was dissolved in hot isopropyl ether (with a little isopropyl alcohol) and filtered hot. Upon cooling to room temperature, solid precipitated, which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at room temperature to give 3.29 g of title compound, mp 110°-113° C.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=4[Cl:26])[N:12]=[CH:11][C:10]=3[N:9]3[CH:27]=[N:28][N:29]=[C:8]3[C@H:7]2[CH2:30][CH3:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1NC=CN=1)([C:34]1[NH:35]C=CN=1)=O>CN(C=O)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21]([NH:35][CH3:34])=[O:22])=[CH:19][C:18]=4[Cl:26])[N:12]=[CH:11][C:10]=3[N:9]3[CH:27]=[N:28][N:29]=[C:8]3[C@H:7]2[CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)O)cc3Cl)nc2N1C1CCCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)NC)cc3Cl)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
4-((R)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-ylamino)-3-chlorobenzoic acid (I-3) (27 mg) was dissolved in DMF (0.4 ml) and treated with carbonyl diimidazole (12 mg, 0.077 mmol) and the mixture stirred at RT for 90 min. The solution was cooled in an ice bath and methylamine gas bubbled in for 2 min. The mixture was stirred at RT for 2 hours, evaporated under reduced pressure and purified by chromatography to give 4-((R)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-ylamino)-3-chloro-N-methylbenzamide (15 mg) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11](#[N:13])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[C:11]#[N:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC#N
Solvent: Cc1ccccc1
Product: N#CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Metachlorobenzoyl chloride (43.8 g, 0.1 mol), cuprous cyanide (29.1 g, 0.13 mol), and acetonitrile (20 mL) in toluene (37 mL) were refluxed for 3 hours, and were cooled to room temperature. Then, insoluble substances were removed through filtration, and the residue was washed with toluene. Solvent in the resulting filtrate was evaporated under reduced pressure, and the residue was distilled to give metachlorophenyloxoacetonitrile (28 g, 68% yield).
Reaction SMILES: [C:1]([C:9]1[C:17]([NH:18][C:19](=[O:22])[CH2:20][Cl:21])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>>[ClH:21].[C:1]([C:9]1[C:17]([NH:18][C:19](=[O:22])[CH2:20][N:32]([CH3:33])[CH3:31])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1cc(C(=O)O)cc(OCc2ccccc2)c1C(=O)c1ccccc1
Reactant: CNC
Product: CN(C)CC(=O)Nc1cc(C(=O)O)cc(OCc2ccccc2)c1C(=O)c1ccccc1
Product: Cl
Reaction time: 20 h

Procedure:
A mixture of 4-benzoyl-3-benzyloxy-5-chloroacetamidobenzoic acid (0.85 g) and 20% w/w aqueous dimethylamine (10 ml) is left at room temperature for 20 hours and is then evaporated in vacuo. The residue is triturated with conc. hydrochloric acid (about 5 ml) and the resulting precipitate is collected by filtration and dried. After recrystallization from methyl cellosolve, 4-benzoyl-3-benzyloxy-5-dimethylaminoacetamidobenzoic acid hydrochloride is obtained with a melting point of 264.5°-265.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(N)cc2s1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirring solution of 6-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (3.9 g, 15.8 mmol) in DMF (120 mL) was added 10% Pd/C (700 mg, 10 wt %). The reaction was charged with H2, degassed and refilled with hydrogen three times. The slurry was stirred at RT for 4 days at balloon pressure, then filtered through a plug of Celite, and solvent was removed under reduced pressure. The solid was washed with EtOAc, and filtered to yield the desired amine. 1H NMR (CDCl3) δ 7.92 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.08 (s, 1H), 6.78 (d, J=8.4 Hz, 1H), 3.92 (s, 3H). MS (EI): cal'd (ME) 208.04, exp (MH+) 208.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[N:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(F)nc1
Product: N#Cc1cc(-c2ccc(F)nc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (55 mg, 69%), MS (ISP) m/z=321.5 [(M+H)+], mp 264.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1)=[O:9])=[O:4].C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.O>ClCCl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=2[NH:5][C:3]([CH2:2][N:37]2[CH2:38][CH2:39][N:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)[CH2:35][CH2:36]2)=[O:4])=[N:12][CH:13]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CN1CCN(c2ccncc2)CC1)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 2-(bromoacetyl)amino-N-(5-chloropyridin-2-yl)benzamide (0.369 g, 1 mmol) in dichloromethane (10 ml) was added potassium carbonate (0.169 g, 1.22 mmol) and 1-(4-pyridyl)piperazine (0.171 mg, 1.05 mmol). The reaction was stirred overnight at room temperature. Water (2 mL) was added and the mixture was passed through a column of flux-calcined, high purity, inert diatomaceous earth packed into a polypropylene tube (article number CE 1103 from Varian) to remove water. The solvent was removed and the residue was purified by RPHPLC (CH2Cl2/5% 2 N ammonia in methanol) to give 0.08 g of pure title product.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:23][CH2:22][C:21](=[N:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:42](Br)[CH:43]=[CH2:44].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O.[Zn]>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])([CH2:44][CH:43]=[CH2:42])[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1CC(=NS(=O)C(C)(C)C)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC[C@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Reaction time: 16 h

Procedure:
To a suspension of (2R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-4-{[(1,1-dimethylethyl)sulfinyl]imino}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide (Intermediate 1, 50 mg, 0.082 mmol) and Zinc powder (16.14 mg, 0.247 mmol, Aldrich) in THF (1.5 mL) was added at 25° C. allyl bromide (0.021 mL, 0.247 mmol, Aldrich) and the reaction mixture was stirred at this temperature for 16 hrs. Brine and EtOAc were added and the resulting mixture was filtrated over Celite® and the two phases were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic phases were dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc; 25M Si cartridge) to give two different products:
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:57])([F:56])[C:9]1[CH:10]=[C:11]([CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1)[CH2:12][N:13]1[C@H:17]([CH3:18])[C@@H:16]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[C:29]2[CH:30]=[C:31]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([O:45]C)=[O:44])=[CH:39][C:38]=3[Cl:47])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[O:15][C:14]1=[O:48].O.[OH-].[Li+].Cl>O.ClCCl>[F:57][C:8]([F:7])([F:56])[C:9]1[CH:10]=[C:11]([CH:49]=[C:50]([C:52]([F:54])([F:55])[F:53])[CH:51]=1)[CH2:12][N:13]1[C@H:17]([CH3:18])[C@@H:16]([C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:20]=2[C:29]2[CH:30]=[C:31]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([OH:45])=[O:44])=[CH:39][C:38]=3[Cl:47])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[O:15][C:14]1=[O:48]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(=O)O)cc2Cl)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a 1,4-dioxane solution (2 mL) of starting methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (65 mg, 0.087 mmol) was added a solution of lithium hydroxide monohydrate (36.5 mg, 0.87 mmol) in water (1 mL). The resulting mixture turned to a cloudy, slightly purple mixture (from a light yellow solution). Aliquot at reaction time=22 min indicated completion of reaction. Reaction crude was acidified (1N HCl, aq.). Volatiles were removed from the crude mixture. The resulting mixture was purified by a preparative reverse phase HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/ a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Related fractions were pooled & evaporated in vacuo to afford a colorless glass. The glass was dissolved in dichloromethane and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to afford 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=731.11; found=732.08 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) 8.22, 8.13 (d, J=1.5 Hz, 1H), 8.05-7.99 (m, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.70-7.64 (m, 1H), 7.60 (s, 0.6H), 7.54-7.51 (m, 1.8H), 7.50-7.44 (m, 1H), 7.42-7.30 (m, 2H), 7.13 (d, J=2.5 Hz, 0.6H), 7.10 (d, J=9.0 Hz, 0.6H), 7.17 (d, J=8.5 Hz, 0.4H), 5.22 (d, J=4.5 Hz, 1H), 4.82, 4.77 (d, J=16 Hz, 1H), 4.27, 4.22 (d, J=16 Hz, 1H), 3.87 (s, 1.8H), 3.59 (s, 1.2H), 3.49-3.43 (m, 0.4H), 3.32-3.25 (m, 0.6H), 0.86 (d, J=6.0 Hz, 1.2H), 0.73 (d, J=6.5 Hz, 1.8H).
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][NH2:14]>C(O)C>[NH3:4].[CH3:13][NH:14][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Solvent: CCO
Product: CNC1CN(C(=O)OC(C)(C)C)C1
Product: N
Temperature: 100 °C

Procedure:
tert-Butyl 3-iodoazetidine-1-carboxylate (EP 1176142, pg. 23, ex. 2 (i)) (2.0 g, 7.07 mmol) was added to 33% methylamine in ethanol (45 mL) and the reaction mixture heated in a sealed vessel at 100° C. for 24 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and 1M aqueous sodium hydroxide. The organic layer was separated and washed with brine, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.880 ammonia 96:3.5:0.5 to yield the title product.