Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)=[CH:10][C:3]=12.[OH-].[Na+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>O1CCCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[C:9]([CH:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)ccnc3[nH]2)C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C3CCN(C(=O)OC(C)(C)C)C3)cc3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 59C (0.5 g, 1.554 mmol) in 20 mL tetrahydrofuran, was added sodium hydroxide (0.249 g, 6.22 mmol) and the mixture was stirred at room temperature for 1 hour. p-Toluenesulfonyl chloride (0.355 g, 1.865 mmol) and benzyltriethylammonium chloride (0.018 g, 0.078 mmol) were added and the mixture was stirred for 12 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford the crude product which was purified by column chromatography (100-200 silica-gel in hexane and eluted with 15% ethyl acetate-hexane) to afford the title compound. LCMS: 475.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:50]=[CH:49][C:24]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH:35]([C:46]([O-:48])=[O:47])[CH2:34]4)=[O:32])=[CH:27][CH:26]=3)=[CH:23][CH:22]=2)=[CH:10][CH:9]=1>ClCCl>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:22]=[CH:23][C:24]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]4[CH2:38][CH2:37][NH:36][CH:35]([C:46]([OH:48])=[O:47])[CH2:34]4)=[O:32])=[CH:29][CH:30]=3)=[CH:49][CH:50]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CC1C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(C(=O)c2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-(4′-Dibenzofuran-4-ylbiphen-4-yl-carbonyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester (135 mg) in anhydrous dichloromethane. The reaction was stirred at room temperature for 2 hours (TLC control). The resultant brown oil was reconstituted and concentrated from methanol (3×10 mL) and then from dichloromethane (2×10 mL) to give the title compound as a white solid (112 mg, 100%): Rf 0.10 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.18 (2H, t, J=9 Hz, Ar—H), 8.04 (2H, d, J=9 Hz, Ar—H), 7.92 (2H, d, J=9 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.75 (2H, t, J=8 Hz, Ar—H), 7.61 (2H, m, Ar—H), 7.53 (2H, t, q, J=8 Hz, Ar—H), 7.43 (1H, t, J=8 Hz, Ar—H), 4.34 (1H, m, CHN), 3.40 (4H, m), 3.18 (2H, m); ESI-LCMS e/z calcd for C30H24N2O4 476.530, found 477 (M+H)+, 499 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6](CC=CC1C=CC=CC=1)[CH2:5]2.C(O)C>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CN(CC=Cc1ccccc1)C2=O
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)CNC2=O

Procedure:
5-Methyl-2-(phenyl-allyl)-2,3-dihydro-isoindol-1-one (3.64 g, 14.61 mmol) was taken up in a 50/50 mixture of ethanol-3M HCl (100 mL) and heated to 80EC for 12 h. The reaction mixture was cooled and the ethanol was removed under reduced pressure. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (1:1 hexane/ethyl acetate) Yield 1.40 g. 1H NMR (CDCl3, 300 MHz): δ 2.51 (s, 3H), 4.48 9s, 2H), 7.27-7.36 (m, 2H), 7.75 (d, J=8 Hz, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:23]2[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: OCC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(CO)CC1
Temperature: 65 °C
Yield: 27.7 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 4-piperidinemethanol (0.047 g, 0.41 mmol), palladium acetate (1.5 mg, 0068 mmol), (S)-(−)-2,2′-bs(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4, evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (30 mg, 28%). LCMS calculated for C17H20ClN2O2 (M+H)+: m/z=319.1; Found: 319.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C>[CH:23]1([CH2:22][N:8]([C:6]2[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH3:1])[N:7]=2)[C:9](=[O:11])[CH3:10])[CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(C)n1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CC1CCC1)c1ccc([N+](=O)[O-])c(C)n1
Temperature: 80 °C

Procedure:
N-(6-Methyl-5-nitro-pyridin-2-yl)-acetamide (0.5 g) was taken in 5 mL anhydrous DMF. 3 eq of K2CO3 and 3 eq of bromomethyl-cyclobutane were added and heated at 80° C. for 24 h. Water was added to the reaction and the mixture extracted with EtOAc (2X10 mL). The organic layer was washed with water and brine and dried over Na2SO4. Solvent was concentrated and the residue was purified over silica to give N-Cyclobutylmethyl-N-(6-methyl-5-nitro-pyridin-2-yl)-acetamide LCMS (m/z): 264.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>ClCCl>[CH3:1][CH:2]1[CH2:4][N:3]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CBr
Reactant: CC1CN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of 2-methylaziridine (5.6 g, 99 mmol) and N,N-diisopropylethylamine (18.8 mL, 108 mmol) in dichloromethane (250 mL) under an atmosphere of nitrogen, ethyl bromoacetate (10 mL, 90 mmol) was added over a period of 1 h. The resultant mixture was allowed to slowly warm up and stirred at room temperature overnight. The resultant mixture was concentrated under vacuum, and the residue was suspended in chloroform. A stream of anhydrous ammonia gas was bubbled into the mixture with stirring for a period of 15 min. The resultant suspension was filtered, and the filtrate concentrated under vacuum. The residue was further treated with anhydrous diethyl ether and the milky solution filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue subjected to distillation under reduced pressure (bp ˜60° C., 18 torr) to provide the title compound as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:24]([O:26]CC)=[O:25])([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P([O-])([O-])([O-])=O.C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:24]([OH:26])=[O:25])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C[C@@](NC(=O)OCc1ccccc1)(C(=O)O)C(=O)OCC
Temperature: 30 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
4.0 g of pig liver esterase produced by Sigma [PLE (27 kU/g), lyophilized product, product number: E3019] was dissolved in a 0.05 mol/L phosphate buffer adjusted to pH 6.5 (360 mL), and the solution was added with a solution of diethyl 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinate (4.0 g) dissolved in ethanol (40 mL). The mixture was stirred at 30° C. for 20 hours to obtain (R)-1-ethyl hydrogen 3-benzyloxycarbonylamino-3-ethoxycarbonylsuccinate at a yield of 84% and optical purity of 93.6% ee.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:24]1([S:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[CH:11]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cn2cc(Oc3cccc(NS(=O)(=O)c4ccccc4)c3)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (18.6 mg, 0.060 mmol), benzenesulfonyl chloride (12.8 μL, 0.100 mmol), tetrahydrofuran (3 mL) and aqueous sodium hydrogen carbonate solution (2 mL) was stirred at room temperature for 4 hr. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (10.9 mg, 41%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].[C:14](Cl)(=[O:19])[CH2:15][C:16](Cl)=[O:17]>O1CCOCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:13][C:14](=[O:19])[CH2:15][C:16]([NH:13][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:17])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: C1COCCO1
Product: O=C(CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reaction time: 8 h
Yield: 58 %

Procedure:
4-Nitroanthranilic acid (5.0 g, 26.6 mmol) was dissolved in dry dioxane (130 ml). To this solution, a solution of malonyl dichloride (1.45 g)in dry dioxane (5 ml)was added dropwise at room temperature. After stirring the mixture overnight, the precipitated crystals were collected by filtration, and washed with water and ether to give a pale yellow crystals of the title compound (2.58 g, 89.8%). m.p., 269°-270.5° C.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:28])[CH:11]=[C:12]([CH3:27])[N:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)C1C=CC=CC=1>Cl>[C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=[C:15]([N:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:28])[CH:11]=[C:12]2[CH3:27])[CH:16]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Agent: Cl
Product: Cc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Temperature: 140 °C

Procedure:
6.0 g (1.3 mmol) 5-(benzyloxy)-1-biphenyl-3-yl-2-methyipyridin-4(1H)-one was suspended 150 ml 4 N aq HCl. The reaction mixture was heated at 140° C. for 18 h, then cooled to rt, concentrated in vacuo, suspended in CH2C 2, and collected by filtration to give 1-biphenyl-3-yl-5-hydroxy-2-methylpyridin-4(1/-/)-one. LCMS (M+H)+=278.2.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](C1C=CC=CC=1CS(Cl)(=O)=O)#[N:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=1[C:49]#[N:50])(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccccc1CS(=O)(=O)Cl
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: N#Cc1ccccc1CS(=O)(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 72 %

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (2-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7 as a white solid in 72% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:31][C:30]=1B1OC(=O)CN(C)CC(=O)O1.C(=O)([O-])[O-].[K+].[K+].O>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>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]=[N:34][C:29]=3[F:28])[N:3]=2)=[CH:12][CH:13]=1
Reactant: CN1CC(=O)OB(c2cc(CC(=O)OC(C)(C)C)cnc2F)OC(=O)C1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC(=O)OC(C)(C)C)cnc3F)n2)cc1
Temperature: 80 °C
Yield: 37 %

Procedure:
To 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.783 g, 2.035 mmol) (Example 51), tert-butyl 2-(6-fluoro-5-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)pyridin-3-yl)acetate (1.49 g, 4.07 mmol), and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.072 g, 0.102 mmol) was added dioxane (20 mL) and potassium carbonate in water (3.05 mL, 6.10 mmol), and the resulting mixture was heated at 80° C. for 1 h. The reaction mixture was then added to a separatory funnel and partitioned between EtOAc (100 mL) and sodium bicarbonate (saturated, aqueous). The organic layer was separated, washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel; 0% to 40% EtOAc/hexanes) gave the title compound (37% yield). m/z (ESI, +ve ion) 560.4 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([NH:12][C:13]3[C:14]([NH2:23])=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=3)=[O:11])[CH:8]=2)[CH:3]=[N:2]1.COC(C1C=C(N[C:36](=[O:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)C(N)=CC=1)=O.N1C2C(=CC=C(C(O)=O)C=2)C=N1>>[C:43]([C:40]1[CH:39]=[CH:38][C:37]([C:36]([NH:23][C:14]2[C:13]([NH:12][C:10]([C:7]3[CH:8]=[C:9]4[C:4]([CH:3]=[N:2][NH:1]4)=[CH:5][CH:6]=3)=[O:11])=[CH:18][CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)=[O:47])=[CH:42][CH:41]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3cn[nH]c3c2)c(N)c1
Agent: O=C(O)c1ccc2cn[nH]c2c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3cn[nH]c3c2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
By methods substantially equivalent to those described in Example 9-C, N2-(4-t-butylbenzoyl)]-N1-(6-indazolylcarbonyl)-4-methoxycarbonyl-1,2-benzenediamine (0.1 g, 5%) was prepared from 4-methoxycarbonyl-N2-(4-t-butylbenzoyl)-1,2-benzenediamine and 6-indazolecarboxylic acid.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Cl:9][C:10]1[C:11]2[S:18][CH:17]=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1.[Br:19]C(F)(F)C(Br)(F)F.O>O1CCCC1>[Br:19][C:17]1[S:18][C:11]2[C:10]([Cl:9])=[N:15][CH:14]=[N:13][C:12]=2[CH:16]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Clc1ncnc2ccsc12
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Clc1ncnc2cc(Br)sc12
Temperature: -78 °C
Yield: 99.5 %

Procedure:
In a 250 mL round-bottomed flask 65 mL of tetrahydrofuran and lithium diisopropylamine (18.5 mL, 37 mmol, 2M in tetrahydrofuran) were cooled to −78° C. 4-chloro-thieno[3,2-d]pyrimidine (5.26 g, 31 mmol) was dissolved in 37 mL of tetrahydrofuran and slowly added to the reaction mixture over 5 minutes, After 20 minutes 1,2-dibromo-1,1,2,2-tetrafluoroethane (4.05 mL, 34 mmol) was added slowly to the solution of the anion. The temperature was maintained at −78° C. for 20 minutes then warmed to room temperature for 2 hours. The reaction mixture was poured into water and extracted with chloroform (3×100 mL), dried over sodium sulfate, and dried in vacuo to afford 7.70 g (99%) of 6-bromo-4-chloro-thieno[3,2-d]pyrimidine. 1H NMR (400 MHz, DMSO) d 8.97 (s, 1H), 8.01 (s, 1H). LC-MS: 249, 251 (MH+); HPLC RT: 4.04 minutes.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)[CH:7]([OH:27])[CH2:8][N:9](CC1C=CC=CC=1)[CH:10]([CH3:19])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:2]>[C].[Pd].C(O)C>[CH:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[OH:31])[CH:7]([OH:27])[CH2:8][NH:9][CH:10]([CH3:19])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:2]
Reactant: Cc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(NC=O)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CC(C)NCC(O)c2ccc(O)c(NC=O)c2)cc1

Procedure:
In 50 ml. of ethanol there was dissolved 1.62 g. of 3-formylamino-4-benzyloxy-α-[N-benzyl-N-(1-methyl-2-p-tolylethyl)aminomethyl]benzyl alcohol prepared by the procedure in Reference Example 10 and after adding to the solution 0.3 g. of 10% palladium carbon, the catalytic reduction was conducted at normal temperature and pressure until 154 ml. of hydrogen was absorbed. The catalyst was filtered off and after adding to the remaining ethanol solution 8 ml. of water, and 186 mg. of fumaric acid, the solvent was removed from the resultant solution under a reduced pressure. The residue was dissolved in ethanol and benzene was added to the solution until the solution became slightly turbid. When the system was allowed to stand in a refrigerator, 550 mg. of a white crystalline material was formed. The crystals were recovered and recrystallized from ethanol-benzene to give 3-formylamino-4-hydroxy-α-[N-(1-methyl-2-p-tolylethyl)aminomethyl]benzyl alcohol . 1/2 fumarate . 1/2 hydrate melting at 132°-133° C. (decomposed).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH:1]1([CH2:6][C@H:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: ClCCN1CCOCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SC#N)s2)cc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCCN3CCOCC3)s2)cc1

Procedure:
The title compound was prepared from (R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide and 4-(2-chloroethyl)morpholine as described in Example 10. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.55 (1H), 3.96 (t, 1H), 4.00-3.37 (broad m, 8H), 3.34 (m, 2H), 3.10 (s, 3H), 3.09-3.05 (m, 2H), 2.26-2.29 (m, 1H), 1.89-1.47 (m, 8H), 1.18 (m, 2H); HPLC-MS: m/z: 524 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:35][CH2:36][CH3:37])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[C:13](=[C:24]3[N:28]([CH2:29]C)[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[S:25]3)[S:12]2)[CH:9]=1)(=O)[CH3:2].Cl.[NH2:39][OH:40]>N1C=CC=CC=1>[CH2:16]([N:15]1[C:14](=[O:23])[C:13](=[C:24]2[N:28]([CH3:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[S:25]2)[S:12][C:11]1=[N:10][C:8]1[CH:9]=[C:4]([C:1](=[N:39][OH:40])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:35][CH2:36][CH3:37])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2CC)C(=O)N1Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCNc1ccc(C(C)=NO)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
To the product of Example 38 was added hydroxylamine hydrochloride (2 equiv) and pyridine. The resulting mixture was heated at 80° C. for 24 h, cooled, concentrated and chromatographed (TEA-washed silica gel, 0-50% EtOAc/Hex) to give the title compound. 1H-NMR (DMSO-d6): δ 11.07 (1H, s), 7.88 (1H, s), 7.67 (2H, m), 7.53 (1H, d), 7.39 (2H, m), 7.21-7.33 (5H, m), 7.09-7.14 (1H, m), 5.05 (2H, s), 3.92 (2H, q), 3.27 (3H, s), 2.23 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH+).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].ClCCCl.C(=O)=O.[O:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[O:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:26].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: CC(=O)CCCCC(=O)Cl
Agent: [Fe+2]
Agent: O=C=O
Agent: [Al+3]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)CCCCC(=O)[c-]1cccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ferrocene (26g; 0.14 mole) was dissolved in dichloromethane (500 ml) and stirred at -35° (1,2-dichloroethane/dry ice bath). 6-Oxo-heptanoyl chloride from step (a) was added followed by aluminium chloride (18.7g; 0.14 moles) over 30 minutes. Stirring at -35° was continued for another 2 hours and the mixture was poured into ice/water (1 kg). The dichloromethane layer was separated, washed with water (3 × 600 ml), dried over sodium sulphate and concentrated under vacuum, giving a red oil. The desired product was isolated by column chromatography using 9:1 toluene:ethyl acetate as eluent on silica. Recrystallisation of the orange solid from petroleum ether (bp 60-80) afforded the pure compound (3.2g; 73%) mp 70°-71°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:4]([C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[NH:15][S:12]([CH3:11])(=[O:14])=[O:13])#[N:5]
Reactant: CS(N)(=O)=O
Reactant: N#Cc1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1ccc(F)cc1C#N
Temperature: 120 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
(Step 1) A suspension of 2,5-difluorobenzonitrile (12.4 g), methanesulfonamide (9.3 g) and potassium carbonate (13.6 g) in DMSO (360 ml) was stirred overnight at 120° C. The reaction solution was poured into 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give N-(2-cyano-4-fluorophenyl]methanesulfonamide (6.57 g) as a white solid.