Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11](OC)=[O:12])[CH3:10])[C:5]([N+:15]([O-])=O)=[CH:4][N:3]=1.Cl>C(O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:15][C:11](=[O:12])[C@@H:9]([CH3:10])[NH:8][C:6]=2[N:7]=1
Reactant: COC(=O)[C@@H](C)Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: C[C@H]1Nc2nc(Cl)ncc2NC1=O
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirred solution of methyl N-(2-chloro-5-nitropyrimidin-4-yl)-D-alaninate (5 g, 19.2 mmol) in ethanol (400 mL) was added iron powder (7.14 g, 127 mmol). The resulted mixture was heated to reflux, followed by addition of 1M aqueous hydrochloric acid (15 ml) in small portions. The mixture was refluxed for 2 h. Then it was cooled to rt, the insoluble material was filtered off to give a clear solution. The solvent was evaporated to give a crude residue, which was then purified by silica gel flash chromatography (eluent: 5% methanol in dichloromethane) to give desired product (Yield: 81%). 1HNMR (300 MHz, DMSO d6): δ 1.34 (d, J=6.9 Hz, 3H), 4.22 (q, J=1.2 Hz, 1H), 7.50 (s, 1H), 8.45 (s, 1H) and 10.59 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:27]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3Br)c2)CC1
Reaction time: 0.08 h
Yield: 49.6 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in methylene chloride (1 mL) was allowed to stand for 5 min. To this mixture was added 2-bromobenzoyl chloride (151 mg, 0.687 mmol). The reaction mixture was mixed for 2 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. The filtrate solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column (Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360). The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 45.6 mg (50%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1.Cl.O1CCOCC1>CC(O)C>[CH3:1][N:2]([CH3:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH:16][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28](=[O:29])[NH:30][CH3:31])[C:22]([Cl:36])=[CH:21][N:20]=3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)N(C)C)CC3)ncc1Cl
Temperature: 120 °C
Yield: 80.9 %

Procedure:
7-Amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-carboxylic acid dimethylamide (80 mg, 0.343 mmol, 1.0 eq) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (112 mg, 0.378 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (94.5 μL, 0.378 mmol, 1.1 eq) was added and the reaction was heated at 120° C. in a microwave for 10 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 7-[5-chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid dimethylamide as a yellow foam (137 mg, 81%). LCMS (m/e) 494 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.08 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.11 (s, 1H), 7.51 (d, 1H, J=7.8 Hz), 7.50-7.40 (m, 1H), 7.40 (s, 1H), 7.30-7.25 (m, 1H), 7.14-7.02 (m, 2H), 6.93 (s, 1H), 6.32-6.21 (m, 1H), 3.46-3.38 (m, 4H), 3.05 (d, 3H, J=4.8 Hz), 2.98-2.90 (m, 4H), 2.87 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:22](I)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5].[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[OH:1][C:2]1[CH:24]=[CH:23][C:22]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5]
Reactant: OB(O)c1ccsc1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccsc2)ccc1O
Yield: 38.7 %

Procedure:
Using 2-hydroxy-5-iodo-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide(compound of Example 81(1)) and 3-thiopheneboronic acid as the raw materials, the same operation as the Example 81(2) gave the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:20]=1>>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[O:12])=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
(4-Acetyl-3-hydroxy-2-propylphenoxy)acetic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by chromatography on silica gel to give (4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]acetamide, the title compound, mp 95°-97° (from methylene chloride-ether) in 57% yield.
Reaction SMILES: CCCCCCCCCCCCCCC[C:16]([O:18][CH2:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[C:30]1[C:35]([CH3:37])([CH3:36])[CH2:34][CH2:33][CH2:32][C:31]=1[CH3:38])\[CH3:27])\[CH3:22])=[O:17].O.C[O-].[Na+].B(F)(F)F>C1(C)C=CC=CC=1>[CH3:38][C:31]1[CH2:32][CH2:33][CH2:34][C:35]([CH3:36])([CH3:37])[C:30]=1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH2:19][O:18][CH:16]=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Agent: *CC(*)C
Agent: C[O-]
Agent: FB(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CCOC=O

Procedure:
Sunflower oil (7.5 g) and retinyl palmitate (2.5 g) were mixed and water (0.03 g) and immobilised Lipase D (Rhizopus oryzae (Amano) immobilised on Accurel® EP100 macroporous polypropylene (Acordis) 0.1 g) or Candida rugosa AY (Amano) on Accurel® EP100 (Acordis) (CR; 0.1 g) added. The mixtures were placed in a shaking water bath at 55° C. for 20 or 23 hours. The immobilised lipase was then removed by simple filtration to directly yield the product, a solution of retinol esters in triglyceride oil. The composition of the retinyl esters was separated from the triglycerides by thin layer chromatography (0.5 mm silica G plates, Analtech Ltd.) using toluene as eluting solvent and visualised by spraying with 1% 2,7-dichlorofluorescein in ethanol. The ester band was scraped off and FAMEs were produced using 3 mL sodium methoxide and 1 mL toluene at 80° C. for 20 minutes followed by 5 minutes at 80° C. with boron trifluoride (2 mL volumes of reagent). The fatty acid content was then analysed by Fatty acid methyl ester Gas Chromatography (FAME-GC). GC conditions: Column—30 m/0.53 mm/0.5 um restek famewax, Helium carrier gas 15 kpa, flame ionisation detection, 260° C. PTV injection (Run: 3 min @ 260° C., 80° C. hold 1 min, +20/min to 180° C., +2/min to 220° C., +1/min to 230° C., +4 min hold at 230° C.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=C(O)C=CC=1Cl.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Oc1ccc(Cl)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution N-BOC-4-hydroxypiperidine(2.0 g, 0.01 mol), triphenylphosphine (3.68 g, 0.014 mol) and 3,4-dichlorophenol (1.96 g, 0.012 mol) in dry toluene (75 ml) [with molecular sieves, at 0° C. and under Argon] was added diethyl azodicarboxylate (2.52 ml, 0.016 mol), dropwise. The mixture was stirred for 1.5 hrs at 0° C. Filtered the solution and removed the toluene before vigorously stirring in isohexane (100 ml) and filtered the resulting suspension. The filtrate was washed with 2M aqueous NaOH (×8), dried with Na2SO4 and evaporated in vacuo. Purification of the residue on silica (eluant: 20% EtOAc/isohexane) afforded N-Boc-Piperidine, 4-(3,4-dichloropkenoxy)-(9Cl) as a yellow solid (1.96 g). 1H NMR (DMSO): 7.52 (d, 1H), 7.31 (d, 1H), 7.01 (dd, 1H), 4.62 (m, 1H), 3.65 (m, 2H), 3.15 (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H), 1.40 (s, 9H), MS (ES+): 346.3 (MH+), 368.4 (MNa+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[C:18](Cl)(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][CH2:2][CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(O)CCCC=CC1C2CCC(C2)C1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCCC=CC1C2CCC(C2)C1CO
Reaction time: 16 h
Yield: 95 %

Procedure:
65.7 g (0.28 mole) of 6-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-hex-5-enoic acid are heated under reflux in 220 ml of methanol and 600 ml of carbon tetrachloride with the addition of 6.0 g (0.03 mole) of p-toluenesulphonic acid, for 16 hours. The mixture is then washed 3 times with 500 ml of saturated aqueous sodium bicarbonate solution and twice with 500 ml of saturated aqueous sodium chloride solution. The mixture is dried over sodium sulphate and the solvents are then evaporated off in vacuo. 66.4 g (yield: 95%) of methyl 6-(3-hydroxymethyl-bicyclo-[2.2.1]hept-2-yl)-hex-5-enoate are obtained.
Reaction SMILES: BrC1C=C(C=CC=1Cl)C(OC)=O.CC1C=CC=C(C)C=1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][C:33]1[C:38]([C:39]2[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:46])=[CH:37][C:36]([C:47](OC)=[O:48])=[CH:35][CH:34]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>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.C1COCC1.C(COC)OC.C(O)C.O>[Cl:32][C:33]1[C:38]([C:39]2[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:46])=[CH:37][C:36]([CH2:47][OH:48])=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(Cl)c(-c2c(C)cccc2C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1ccc(Cl)c(Br)c1
Agent: Cc1cccc(C)c1B(O)O
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1cc(CO)ccc1Cl
Temperature: 90 °C
Reaction time: 15 h

Procedure:
In an atmosphere of nitrogen, a mixture of methyl 3-bromo-4-chlorobenzoate, (2,6-dimethylphenyl)boronic acid, lithium chloride, sodium carbonate, water, ethanol, dimethoxyethane and tetrakis(triphenylphosphine)palladium was stirred at 90° C. for 15 hours, thereby obtaining methyl 6-chloro-2′,6′-dimethylbiphenyl-3-carboxylate. Lithium aluminum hydride was added under ice-cooling to a THF solution of the resulting methyl 6-chloro-2′,6′-dimethylbiphenyl-3-carboxylate, followed by warming up to room temperature and stirring for 2 hours to obtain (6-chloro-2′,6′-dimethylbiphenyl-3-yl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]=1[OH:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:22][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:23]
Reactant: COC(=O)c1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1cccc2nc(-c3cccc([N+](=O)[O-])c3)oc12

Procedure:
Prepared by the method of Example 15c), from 3-(3-nitrobenzamido)-2-hydroxybenzoic acid methyl ester (1.00 mg, 3.16 mmol) and p-toluenesulfonic acid monohydrate (1.26 mg, 6.64 mmol) the subtitle compound was obtained (600 mg, 64%). 1H NMR (DMSO) δ 8.95(m, 1H), 8.7(m, 1H), 8.59(dd, 1H), 8.23(d, 1H), 8.05(m, 2H), 7.70(t, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([O-:16])=O)[C:11]([C:17]3[S:18][CH:19]=[CH:20][N:21]=3)=[CH:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.[K+].[CH3:23][O:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([CH2:33][NH2:34])[N:26]=1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:33][NH:34][C:14]([C:12]2[C:11]([C:17]3[S:18][CH:19]=[CH:20][N:21]=3)=[CH:10][N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:13]=2)=[O:16])=[N:26][C:25]=1[O:24][CH3:23]
Reactant: COc1ccc(CN)nc1OC
Reactant: Cc1cncc(-c2cc(C(=O)[O-])c(-c3nccs3)cn2)c1
Agent: On1nnc2cccnc21
Agent: [K+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(-c3cncc(C)c3)ncc2-c2nccs2)nc1OC
Temperature: 65 °C
Yield: 74.7 %

Procedure:
Potassium 5′-methyl-5-(1,3-thiazol-2-yl)-2,3′-bipyridine-4-carboxylate (7-4, 980 mg, 2.9 mmol, 1 equiv), 1-(5,6-dimethoxypyridin-2-yl)methanamine (3-6, 490 mg, 2.9 mmol, 1 equiv), EDC (670 mg, 3.5 mmol, 1.2 equiv), 1-hydroxy-7-azabenzotriazole (480 mg, 3.5 mmol, 1.2 equiv) and diisopropylethylamine (2.0 mL, 12 mmol, 4 equiv) were suspended in DMF (14.6 mL) and the reaction mixture was heated for 2 hours at 65° C. The reaction mixture was then partitioned between DCM (50 mL) and water (50 mL). The layers were separated and the organic layer was dried over MgSO4 and concentrated. The residue was purified by normal phase column chromatography (0-20% MeOH in EtOAc) to afford a white solid that was recrystallized from chloroform/hexanes to give the title compound (7-5) as a crystalline solid (970 mg, 75% yield). 1H NMR (CDCl3, 300 MHz) δ 9.08 (s, 2H), 8.53 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.81 (dd, J=3.1 and 1.1 Hz, 1H), 7.78 (t, J=4.8 Hz, 1H), 7.43 (dd, J=3.3 and 1.1 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 4.58 (d, J=5.3 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 2.45 (s, 3H). HRMS (M+H)C23H21N5O3S calc'd 448.1438. found 448.1443
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[S:10][C:9]([CH:11]([N:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)[CH3:12])=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([NH2:29])=[N:31][CH:32]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Product: CC(c1cc2nc(-c3ccc(N)nc3)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in General Procedure A. Purification on silica yielded 299. NMR: (CDCl3): 1.43 (3H, d, J 7.2, Me), 2.56-2.68 (4H, m, CH2), 2.73 (3H, s, Me), 3.18-3.29 (4H, m, CH2), 3.80-3.83 (4H, m, CH2), 3.94-3.99 (5H, m), 4.58 (2H, br s, NH2), 6.48 (1H, d, J 8.1, Ar), 7.19 (1H, s, Ar), 8.38 (1H, dd, J 8.1 and 2.0, Ar) and 9.07 (1H, d, J 2.0, Ar). MS: (ESI+): MH+=504.26
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Nc1ccccc1
Product: C=Nc1ccccc1
Temperature: 160 °C

Procedure:
The procedure was the same as for Example 1 with the exception that aniline was omitted from the initial reaction solution. As the reactor contents heated to 160° C., approximately 30% of the nitrobenzene was converted. Complete nitrobenzene conversion required 5.5 hours at 160° C. and yielded 0.068 mole methyl N-phenyl carbamate (68% selectivity), 0.022 mole aniline, 0.007 mole N-methylene aniline, and 0.001 mole (N-methylaniline (summed to 30% selectivity to aniline).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](Cl)=[O:10].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@H:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][CH:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)C1CC2CCC1CC2
Product: O=C(NC1CCN(CCc2ccc(F)cc2)C1)[C@H]1CC2CCC1CC2

Procedure:
2-Bicyclo[2.2.2]octanecarbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-2-bicyclo[2.2.2]octanecarboxamide.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](I)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1COCC1.O.CC(OC)(C)C>[C:24]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:23])=[CH:5][CH:6]=3)(=[O:11])=[O:12])[CH:14]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1

Procedure:
Add to a 2 L 3-neck flask equipped with reflux condenser, thermometer and nitrogen inlet, 4-(3-iodo-indole-1-sulfonyl)-benzoic acid methyl ester (0.1 mol, 44.1 g), phenylboronic acid (0.12 mol, 22.35 g), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (0.0025 mol, 2.04 g), 2M sodium carbonate (140 ml) and 0.5 L THF. Heat the mixture to reflux under nitrogen for 2 hours. Remove THF under vacuum, and add MTBE (500 ml) and DI water (200 ml) to the residue. Filter the solution through a pad of Celite, and wash with MTBE (500 ml). Separate the organic layer and concentrate under vacuum to give a brown solid. Dissolve the solid in THF (250 ml). Add to this solution 5N NaOH (35 ml) dropwise over a 30 minute period. Stir the reaction at ambient temperature for 3 hours, and quench with DI water (250 ml) and MTBE (250 ml). Separate the water layer and back extract the organic layer with DI water (250 ml). Combine the aqueous layers and wash with MTBE (500 ml). Stir the aqueous layer at ambient temperature and adjust the pH is to 1 with concentrated HCl. Stir the slurry at ambient temperature for 2 hours, filter and wash with DI water (500 ml). Dry the off-white, gray solid in vacuum oven at 65° C. for 16 hours to obtain 25.44 g. 1H NMR (DMSO) 8.2 (d, 2H), 8.1 (m, 3H), 7.9 (d, 1H), 7.7 (d, 2H), 7.4 (m, 5H). MS (ES−)=376.2 (M−1). Anal. Calcd. For C21H15NO4S: C, 66.8308; H, 4.0060; N, 3.7112. found C, 66.54; H, 4.07; N, 3.20.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH:29]3[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCC1CCNCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(piperidin-4-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-d6) δ ppm 9.89 (brs, 2 H), 7.875 (t, J=8.0 Hz, 2 H), 7.76 (s, 1 H), 7.625 (t, J=6.8 Hz, 1 H), 7.48 (d, J=7.6 Hz, 1 H), 7.30 (d, J=8.4 Hz, 1 H), 7.226 (d, J=1.6 Hz, 1 H), 6.73 (t, J=5.43 Hz, 1 H), 5.07 (brs, 2 H), 4.42 (brs, 2 H), 4.10 (d, J=12.63 Hz, 2 H), 3.63 (m, 2 H), 3.23-3.05 (m, 2 H), 2.50 (s, 2 H), 2.05 (s, 3 H), 1.76-1.66 (m, 3 H), 1.15-0.98 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[CH:6][CH:5]=1.[CH2:20]=[C:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C.C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH2:20][C:21]12[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19]
Reactant: COC(=O)c1ccc(/N=C/c2cccc(Br)c2)cc1
Reactant: C=C1CCCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)C1(CCCC1)CC(c1cccc(Br)c1)N2
Temperature: 80 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a stirred solution 4-{[1-(3-bromo-phenyl)-meth-(E)-ylidene]amino}-benzoic acid methyl ester (3.2 g, 10.0 mmol) in acetonitrile (16.0 mL) were added methylene-cyclopentane (4.0 mL, 40.0 mol) and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) (980.0 mg, 2.0 mmol). The resulting mixture solution was stirred at 80° C. for 16 h in sealed tube. The mixture solution was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2′-(3-bromo-phenyl)-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-quinoline]-6′-carboxylic acid methyl ester (1.6 g, 40%) as a light yellow solid: MS (ESI) M+1=400.0.