Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([C:13](=[O:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]([CH3:11])[CH3:12])[CH2:25][CH2:24]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Clc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N-tert-butoxycarbonyl-L-valine (2.27 g, 10 mmol) and 1-(2-chlorophenyl)piperazine (2.00 g, 10 mmol) in N,N-dimethylformamide (50 ml) under ice-cooling was dropwise added a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.2 g, 11 mmol) and 1-hydroxybenzotriazole (1.5 g, 11 mmol) in dichloromethane (50 ml), and the reaction mixture was stirred at room temperature for 15 hours. The dichloromethane was then distilled off under reduced pressure and ethyl acetate (200 ml) was added to the residue. The ethyl acetate layer was washed successively with 10 w/v % aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine in the order mentioned and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was subjected to silica gel chromatography. Elution with ethyl acetate-n-hexane (1:2, v/v) gave 1,1-dimethylethyl 2-(4-(2-chlorophenyl)-piperazinyl)-2-oxo-(s)-1-(2-propyl)ethylcarbamate. This colorless oil was dissolved in ethyl acetate (50 ml), and 4N HCl/ethyl acetate (50 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction product was filtered and washed with ethyl acetate-n-hexane (1:1, v/v) to give 1-((s)-2-amino-3-methyl-1-oxobutyl)-4-(2-chlorophenyl)piperazine hydrochloride (3.32 g, 95.8%) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28]([NH:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2)=[O:29]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccc(Cl)c(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) in acetonitrile (10 mL), was added 3,4-dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and N,N-diisopropyl ethylamine (0.54 mL, 3.3 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as a white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.60 min (99.6%); mp, 271-273° C.; 1HNMR (DMSO-d6)2.17-2.22 (m, 1H, CHH), 2.58-2.90 (m, 6H, CHCH2, CH3), 4.97-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.34-8.17 (m, 6H, Ar), 9.14 (t, J=5 Hz, 1H, CH2NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.80, 23.29, 30.60, 42.30, 56.52, 117.66, 124.17, 125.56, 127.58, 129.28, 130.76, 131.31, 133.97, 134.11, 134.56, 140.39, 148.50, 154.86, 161.06, 164.10, 169.53, 172.62. LCMS MH=473, 475; Anal Calcd For C22H18N4O4Cl2+0.1 CH2Cl2: C, 55.09; H, 3.81; N, 11.63; Cl, 16.19. Found: C, 54.88; H, 3.60; N, 11.46; Cl, 16.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(C(F)(F)F)=O.[N+:30]([O-])([OH:32])=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:30]([O-:32])=[O:31])=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OCC2CCN(C)CC2)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, 89 mmol) in methylene chloride (75 ml) was cooled to 0-5° C. TFA (37.5 ml) was added followed by the dropwise addition over 15 minutes of a solution of fuming 24N nitric acid (7.42 ml, 178 mmol) in methylene chloride (15 ml). After completion of the addition, the solution was allowed to warm up and stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was dissolved in methylene chloride (50 ml). The solution was cooled to 0-5° C. and ether was added. The precipitate was collected by filtration, and dried under vacuum at 50° C. The solid was dissolved in methylene chloride (500 ml) and 3M hydrogen chloride in ether (30 ml) was added followed by ether (500 ml). The solid was collected by filtration and dried under vacuum at 50° C. to give ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4 g, 82%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH2:1]([NH:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 899.7 %

Procedure:
To a solution of benzylamine (5 g, 4.67 mmol) in pyridine (25 ml) was added (cautiously) p-toluenesulphonyl chloride (10 g, 5.25 mmol). The deep red coloured solution was stirred at room temperature for 1 hour before being poured into water (80-100 ml). The oily precipitate which solidified on scratching was filtered and recrystallised from ethanol to give the title compound (10.98 g, 90% yield, m.p. 115°-116° C., (Lit.1 114° C.)). δH (CDCl3): 7.80(2H,m); 7.25(7H,m); 4.95(1H,t); 4.05(2H,d); 2.35(3H,s)ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([B:9]2[O:16][C:15](=[O:17])[CH2:14][N:13]([CH3:18])[CH2:12][C:11](=[O:19])[O:10]2)[C:5]([F:8])=[N:6][CH:7]=1.[Cl-].[C:21]([O:25][C:26](=[O:29])[CH2:27][Zn+])([CH3:24])([CH3:23])[CH3:22].CCOCC>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[F:8][C:5]1[N:6]=[CH:7][C:2]([CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:29])=[CH:3][C:4]=1[B:9]1[O:16][C:15](=[O:17])[CH2:14][N:13]([CH3:18])[CH2:12][C:11](=[O:19])[O:10]1
Reactant: CN1CC(=O)OB(c2cc(Br)cnc2F)OC(=O)C1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1CC(=O)OB(c2cc(CC(=O)OC(C)(C)C)cnc2F)OC(=O)C1
Temperature: 80 °C
Yield: 62 %

Procedure:
To 2-(5-bromo-2-fluoropyridin-3-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (2.79 g, 8.43 mmol) was added dioxane (84 mL), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.299 g, 0.422 mmol) and (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in ether (25.3 mL, 12.65 mmol) (Rieke Metals), and the resulting mixture was sparged with nitrogen for 5 min at ambient temperature. The reaction mixture was then heated to 80° C. for 2 h. The reaction mixture was subsequently cooled to ambient temperature, adsorbed onto silica gel, and purified via flash chromatography (silica gel) with 100% DCM to 5% MeOH/DCM to give the title compound (62% yield) as a beige solid. m/z (ESI, +ve ion) 367.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6][CH2:5]2.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][N:4]4[C:10](=[N:1][CH:2]=[CH:3]4)[C:9]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: Nc1ccc2c(c1)-c1nccn1CCC2
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)-c2nccn2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-chloro-N-methyl-benzamide was converted to 2-[5-chloro-2-(5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-3-chloro-N-methyl-benzamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.17 (s, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.71 (d, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 4.16 (t, 2H), 2.81 (s, 3H), 2.70 (t, 2H), 2.46 (pent, 2H); MS (m/e) 494 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])=[O:3].N1CCCC1.[CH3:18][O:19][CH2:20][C:21](=O)[CH2:22][O:23][CH3:24]>C1(C)C=CC=CC=1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:12][C:21]([CH2:22][O:23][CH3:24])([CH2:20][O:19][CH3:18])[CH2:1][C:2](=[O:3])[C:4]=2[CH:9]=1)#[N:11]
Reactant: COCC(=O)COC
Reactant: CC(=O)c1cc(C#N)ccc1O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COCC1(COC)CC(=O)c2cc(C#N)ccc2O1

Procedure:
5-Cyano-2-hydroxyacetophenone (13.57 g) was dissolved in toluene (120 ml), and pyrrolidine (6 ml) and 1,3-dimethoxy-2-propanone (15 ml) were added. The mixture was refluxed under heating for 1 hour while removing the generated water. After cooling, the reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and brine in order, and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (ethyl acetate:hexane=2:8) to give 13.0 g of 6-cyano-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-4-one.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12](NCCCC)CCC.C(O)(=O)C.C=O>C1(C)C=CC=CC=1>[CH2:12]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: O=C1CCCc2ccccc21
Reactant: CCCCNCCCC
Agent: C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=C1CCc2ccccc2C1=O
Temperature: 90 °C

Procedure:
A 100-ml pressure-proof glass reaction vessel was charged with 2.92 g (0.02 mole) of 1-tetralone, 2.59 g (0.02 mole) of di-n-butylamine, 1.20 g (0.02 mole) of acetic acid and 15 ml of toluene. To the mixture 0.974 g (0.012 mole) of an 37% aqueous formaldehyde solution was added and the vessel was sealed and heated up to 90° C. After maintaining the temperature at 90° C. for 30 minutes, the vessel was cooled to room temperature. The contents were separated by addition of 5 ml of water, and the water layer was washed off with a 50% aqueous acetic acid solution. The toluene layer was further washed with a 10% aqueous hydrochloric acid, saturated aqueous NaHCO3 solution and saturated aqueous sodium chloride solution, to give a solution of 2-methylene-1-tetralone in toluene. The reaction mixture was analyzed by GLC and its composition was found to be 1.45 g of 2-methylene-1-tetralone and 1.16 g of unreacted 1-tetralone (the conversion of 1-tetralone: 60.2%; selectivity: 82.1%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32](O)=[O:33])[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[CH3:39][C:40]1([CH3:52])[CH2:45][CH2:44][N:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1.C(N(CC)CC)C>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)[C:32]([N:49]3[CH2:50][CH2:51][CH:46]([N:43]4[CH2:44][CH2:45][C:40]([CH3:52])([CH3:39])[CH2:41][CH2:42]4)[CH2:47][CH2:48]3)=[O:33])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: CC1(C)CCN(C2CCNCC2)CC1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Solvent: CCN(CC)CC
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCC(C)(C)CC4)CC3)cc(C)c2[nH]1

Procedure:
Prepared analogously to Example 7i from 90 mg (0.16 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 55 mg (0.20 mmol) 4,4-dimethyl-[1,4′]bipiperidinyl (used as the bis-hydrochloride salt), using 100 μL (0.72 mmol) triethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=1[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[CH3:26]
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC

Procedure:
M1 was prepared from 6,7-dimethoxyquinolin-4-ol and 1-fluoro-2-methyl-4-nitrobenzene following the general procedure reported in Preparative Example 1 Step 1-2. 1H NMR (400 MHz, d5-DMSO, 300K) δ 1.93 (s, 3H), 3.92 (s, 6H), 5.06 (br s, 2H), 6.24 (d, J=5.2 Hz, 1H), 6.48 (dd, J=8.4 Hz, J=2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.53 (s, 1H), 8.40 (d, J=5.2 Hz, 1H). MS (ES) C19H19N2O3 requires: 310. Found: 311 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(=O)C>[Br:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1c(C)cccc1C
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)Cc1c(C)ccc(Br)c1C
Temperature: 15 °C
Reaction time: 2.5 h

Procedure:
At about 15° C., a solution of 3.67 kg [23 mol] of bromine in 91 of glacial acetic acid is added dropwise to a solution of 3.175 kg [17.82 mol] of methyl 2,6-dimethylphenylacetate in 18 l of glacial acetic acid. The mixture is then stirred at 15° C. for another 2.5 hours, in order to warm to room temperature and stirred at room temperature for 48 hours. The reaction mixture is poured into 170 l of ice-water and extracted twice with in each case 60 l of methylene chloride. After removal of the solvent, 4 kg of a residue remain which, according to GC/MS, comprise 81.2% of methyl 3-bromo-2,6-dimethylphenylacetate (70.9% of theory),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([C:22]([F:23])([F:25])[F:24])[CH:11]=2)=[CH:14][CH:15]=1)(=[O:36])=[O:35]
Reactant: OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanol (2.72 g) and triethylamine (1.55 ml) in dichloromethane (30 ml) was added dropwise methanesulfonyl chloride (0.86 ml) under ice-cooling. The reaction mixture was allowed to warm to room temperature and stirred for 1 hr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=397.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH:35]=[C:34](OS(C(F)(F)F)(=O)=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH:33]=[C:34]([C:3]2[CH:4]=[C:5]([O:11][CH:12]([CH3:13])[CH3:14])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C

Procedure:
To a solution of 2-methyl-4-nitro-5-isopropoxy-phenylboronic acid pinacol ester (2.04 g, 6.4 mmol) and 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.2 g, 9.6 mmol) in 110 mL of DME/H2O (10:1 V/V) is added Pd(PPh3)4 (365 mg, 0.32 mmol) and Cs2CO3 (4.2 g, 12.8 mmol). The reaction mixture is heated under N2 at 80° C. overnight. After cooling to room temperature, the reaction is filtered through Celite and the filtrate is diluted with 100 mL of EtOAc, sequentially washed with H2O, brine, and finally concentrated in vacuo. The crude product is purified by silica gel flash chromatography (5%-15% EtOAc in Hexanes as eluent) to afford 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CD3OD, 400 Mz): 7.59 (s, 1H), 6.96 (s, 1H), 5.67 (broad s, 1H), 4.73 (m, 1H), 4.06 (m, 2H), 3.65 (m, 2H), 2.37 (m, 2H), 2.25 (s, 3H), 1.50 (s, 9H), 1.33 (d, J=6.0 Hz, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])(=[O:7])=[O:6].[OH-:26].[K+]>O1CCOCC1.O>[F:16][C:11]1[C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[C:9]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][OH:26])(=[O:7])=[O:6])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: O=S(=O)(CCCCl)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(CCCO)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
To a solution of 3-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-propane-1-sulfonamide (69.4 mg, 0.138 mmol) in a mixture of 8 ml 1,4-dioxane and 2 ml H2O was added KOH powder (0.674 g, 12.0 mmol) and the mixture was heated to the reflux temperature for 3 days. It was extracted using EtOAc/brine, the organic fraction was dried with Na2SO4 and the volatiles were removed. The residue was purified using flash-column chromatography (Si, DCM/MeOH 5:1, 0.3). Yield: 41 mg (62%). 1H-NMR (500 MHz, MeOH [d4]): δ=7.38-7.21 (d, 1H), 7.23-7.21 (d, 1H), 7.06-7.00 (q, 1H), 6.52-6.50 (m, 1H), 6.17-6.13 (t, 1H), 3.30-3.27 (t, 2H), 2.86-2.83 (t, 2H), 2.05-2.00 (m, 2H); m/z=485 [M−1]−.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.C1(P(=[CH:34][C:35](OCC)=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C.C(O)C>C([O-])(=O)C=C>[NH:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:34][C:35]1=[O:36]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CC(=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Synthesis of intermediates containing A2-77 (V═O) is shown in Scheme 54. Utilizing the procedure published by Doherty et. al (see WO 03/0999284), Wittig homologation of commercially available 2,4-dinitrobenzaldehyde (251) with ethyl (triphenylphosphoranylidene)-acetate results in propenoate 252. Catalytic hydrogenation in the presence of glacial acetic acid and ethanol results in the target 1H-quinolin-2-one 253 which, utilizing the same oxidation/reduction sequence as shown in Scheme 53 results in hydrazine 254 (R15, V═O) and iodide (255). At the conclusion of the synthesis that utilizes 254 or 255, reduction of the amide with LAH under standard conditions provides an optional synthesis of intermediates containing A2-77 (V═H2).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].[BH3-]C#N.[Na+].CC(O)=O>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=3)=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: NCc1ccccc1-c1cccc(O)c1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(Cn2cncc2CNCc2ccccc2-c2cccc(O)c2)cc1F
Reaction time: 72 h

Procedure:
2-Aminomethyl-3′-hydroxybiphenyl hydrochloride from Step H (129 mg, 0.548 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde from Example 3, Step G (132 mg, 0.576 mmol) were stirred in MeOH (2 mL) for 30 min, then NaCNBH3 (38 mg, 0.60 mmol) was added. The reaction mixture was adjusted to pH 5 with AcOH, as judged from wetted pH paper, and stirring was continued at ambient temperature for 3 days. The reaction was quenched with 10% aq. citric acid and stirred for 20 min. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The titled product was crystallized from CH2Cl2-hexane and the first crop of white needles used for the next reaction.