Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]([O:10][CH2:9][C@H:8]([NH2:7])[C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of [(R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (0.797 g, 1.7 mmol) in DCM (9 mL) was added TFA (5 mL) and the mixture was stirred at RT for 2 h. The volatiles were removed under reduced pressure and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min, then the organic fraction was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound (298 mg, 49%). LCMS (Method J): RT 2.02 min [M+H]+ 362.2.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][OH:28]>CC(=O)CC.O>[OH:28][CH2:27][CH2:26][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: OCCBr
Reactant: O=c1[nH]cc(C2CCNCC2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=c1[nH]cc(C2CCN(CCO)CC2)c2ccccc12
Yield: 55.9 %

Procedure:
4-(Piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (0.8 g) obtained in Example 31, potassium carbonate (2.0 g) and 2-bromoethanol (1.88 g) were dissolved in 2-butanone and water (1 mL), and the mixture was heated under reflux for 4 hrs. After the completion of the reaction, the solvent was evaporated, and water was added to the obtained residue. The mixture was extracted with chloroform, the organic layer dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1+triethylamine 2%) to give 4-(1-(2-hydroxyethyl)piperidin-4-yl)-2H-isoquinolin-1-one (0.46 g) as white crystals.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: CCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.4 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.310 g, 1.1 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (1.0 mL, 7 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Heptanoyl chloride (800 μm, 5.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in acetone and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and loaded onto preparative silica gel plates (20×20×0.2 cm). The plates were developed in a mixture of chloroform:acetone (80:20). The product was scraped from the preparative plate (Rf 0.5) and eluted from the silica gel with ethanol. After evaporation of the solvent the product was further purified on a Chromatotron (2 mm silica gel plate) with a mixture of hexane:acetone (80:20). Lyophilization afforded 0.227 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(heptanoyloxy)methyl]-tetrahydro-2-furyl]-9H-purine as an oil (51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 4-chloro-2-fluorobenzoic acid (1 eq) in CH2Cl2 (1.6 M) was added N,O-dimethylhydroxylamine hydrochloride (1.5 eq), EDCI (1.5 eq) and triethylamine (4 eq). The reaction mixture was stirred at rt for 16 hrs, concentrated and 0.5M aqueous citric acid was added. The mixture was extracted with 1:1 EtOAc:Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give 4-chloro-2-fluoro-N-methoxy-N-methylbenzamide, which was used as such for the next step.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:30].[Li+].[OH-]>C1COCC1.C(O)C>[CH3:30][C:7]1[CH:8]=[C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:31])=[O:2]
Reactant: COC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester (330 mg, 0.73 mmol) in THF (2.2 ml) and ethanol (2.2 ml) was treated at 0° C. with 1N LiOH (2.2 ml) and stirred for 1.25 h at RT. The reaction was extracted with aqueous 10% KHSO4/Et2O (3×). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. The product was crystallized from CH2Cl2/Et2O to give pure (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid, MS: 437.4 (MH)+, MP: 201-203° C., dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][C:11]([OH:13])=O)[CH:3]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][C:11]([Cl:17])=[O:13])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1OCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold suspension of 4-chloro-o-tolyloxyacetic acid (17.4 mmol) in 40 mL of dry dichloromethane was added oxalyl chloride (39.15 mmol) followed by one drop of N,N-dimethylformamide. Bubbling immediately began. After 30 minutes, the reaction mixture was warmed in a 45° oil bath for 1.5 hours. The solution was cooled to room temperature and all volatiles were removed by evaporation. Dry nitrogen gas was introduced into the evaporator and more dry dichloromethane was added. This was evaporated again in vacuo. Finally, dry toluene was added to the residue and this was evaporated at reduced pressure. The prepared acid chloride was used without further purification in the following step.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:16]#[CH:17]>>[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:3])[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
4-(nitro)benzyl chloroformate (5.00 g, 23.2 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (3.98 g, 17.4 mmol) according to general procedure 1. Yield=4.66 g, 86%. m/z MH+=302.98. HPLC rt=12.3 min.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([O:8][C:9](=[O:32])[CH2:10][CH2:11][NH:12][C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[NH2:30])[CH3:7]>C(Cl)Cl.O>[CH2:6]([O:8][C:9](=[O:32])[CH2:10][CH2:11][NH:12][C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)[CH:17]=[CH:16][C:15]=1[NH:30][C:3](=[O:4])[CH2:2][Br:1])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1NC(=O)CBr
Reaction time: 0.5 h

Procedure:
A solution of 1.44 g (7.15 mmol, 1.1 eq.) bromoacetyl bromide in 10 mL of methylene chloride was added over 10 mins. to a stirred biphasic solution of 2.38 g (6.5 mmol, 1.0 eq.) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyl)-β-alanine ethyl ester in 100 ml of methylene chloride and 30 mL of water cooled to 0° C. The reaction was complete in 1/2 hr. (TLC, 96 CH2Cl2 :4 MeOH, product Rf =0.71) and was partitioned between dilute aqueous sodium bicarbonate and methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated to give 3.11 g (98%) of off white crystals of N-(5-(4-cyanobenzyloxy)-2-(bromoacetyl)aminobenzoyl)-β-alanine ethyl ester which was used unpurified but may be recrystallized from ethyl acetate/hexane. 1H NMR (CDCl3, δTMS) 8.41(1H,d,ArH), 7.60 (4H,abq,ArH), 7.02(2H,d,ArH), 6.98(1H,t,NH), 5.12 (2H,s,ArCH2O),4.16 (2H,q,COOCH2), 3.97 (2H,s,CH2Br), 3.68 (2H,q,NCH2), 2.61 (2H,t,CH2COO), 1.25 (3H,t,CH3). IR (KBr): 3389(NH), 3355(NH), 2226(CN), 1735(ester), 1675,1642(amides), 1609,1523,1423,1244,1184,819. MS (FAB, M+H+) cald for C22H22N3O5Br 488.3, found (M+H+) 489.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][OH:10].Cl[C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[OH:10][CH2:9][CH:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][NH:1][C:19]1[C:18]2[C:17](=[O:27])[C:16]3[C:25](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:24](=[O:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: NCCN1CCCC1CO
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)c2c(NCCN3CCCC3CO)cccc21
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To [1-(2-aminoethyl)-pyrrolidin-2-yl-]methanol (1.63 g, 11.3 mmol) in pyridine (10 mL) was added 1-chloroanthraquinone (1.37 g, 5.646 mmol), and the mixture was stirred at 65° C. for 24 hours. Pyridine was removed in vacuo and the resulting mixture of oil and solid was dissolved in CH2Cl2 and washed with H2O (3×50 mL) to remove any unreacted amine. The separated organic layer was removed in vacuo and the crude product was chromatographed using CH2Cl2/CH3OH (97:3). The desired product was yielded as a red powder (0.21 g, 11%). M.p. 113-115° C.; δH(250 MHz; CDCl3); 1.75-2.0 (m, 4H), 2.25-2.35 (m, 1H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 3.35-3.55 (m, 4H), 3.75-3.85 (2×d, 1H), 7.0 (2×d, 1H), 7.45-7.6 (m, 2H), 7.65-7.8 (m, 2H), 8.2 (2×d, H), 8.45 (2×d), and 10.05 (s, 1H, C(1)NH); δC(62.9 MHz; CDCl3); 24.11, 27.15, 41.64, 52.99, 53.82, 62.61, 65.26, 113.15, 115.60, 126.57, 132.86, 133.81, 135.32, 151.49, 183.77, and 184.89; FAB MS, m/z(M+H)+ 351; Anal. calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 8.00. Found: C, 71.79; H, 6.13; N, 8.07.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=[O:16].[Br:18]Br>C(O)(=O)C>[Br:18][C:13]1[C:14]2[CH:1]=[C:2]([C:15]([OH:17])=[O:16])[CH:3]=[CH:4][C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=1
Reactant: O=C(O)c1ccc2c(ccc3ccccc32)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)c(Br)cc1ccccc12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Phenanthrene-2-carboxylic acid (1, 0.116 g, 0.5 mmol) was dissolved in acetic acid at 70° C. and then bromine (0.027 ml, 0.5 mmol) was added. The mixture was stirred at 70° C. overnight. The following day, bromine (0.027 ml, 0.5 mmol) was added and the mixture was refluxed for 6 h and then allowed to cool. The resulting precipitate was collected by filtration. 1H NMR (270 MHz, DMSO):—7.8 (m, 2H), 8.1 (d, 1H), 8.25 (d, 1H), 8.45 (s, 1H), 8.9 (s, 1H), 8.95 (m, 1H) and 9.05 (d, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([CH:37]=[CH:38][CH:39]=1)[CH2:15][N:16]1[CH2:36][CH2:35][C:19]2([O:24][CH2:23][CH2:22][N:21]([C:25]([C:27]3[N:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[S:30][CH:31]=3)=[O:26])[CH2:20]2)[CH2:18][CH2:17]1)[F:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:11][CH:10]([C:12]1[CH:13]=[C:14]([CH:37]=[CH:38][CH:39]=1)[CH2:15][N:16]1[CH2:36][CH2:35][C:19]2([O:24][CH2:23][CH2:22][N:21]([C:25]([C:27]3[N:28]=[C:29]([CH:32]([CH3:33])[CH3:34])[S:30][CH:31]=3)=[O:26])[CH2:20]2)[CH2:18][CH2:17]1)[CH2:9][OH:8]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(F)CO[Si](C)(C)C(C)(C)C)c4)CC3)C2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(F)CO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of (9-(3-(2-(tert-butyldimethylsilyloxy)-1-fluoroethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 39, step e) (0.33 g) in THF (5 mL) was treated with tetrabutylammonium fluoride (1M in THF, 0.69 mL) and stirred at room temperature for 50 minutes. More tetrabutylammonium fluoride (1M in THF, 0.69 mL) was added and the mixture was stirred for a further 80 minutes. The solution was then concentrated onto flash silica and the residue was purified by flash chromatography on silica eluted with 7.5% methanol in dichloromethane to afford the subtitled compound as a white foam. Yield 0.221 g.
Reaction SMILES: [C:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:19]1[CH2:24][CH2:23][CH:22]=[CH:21][C:20]1=[O:25].C(N(CC)CC)C>CN(C)C=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:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:22]3[CH2:23][CH2:24][O:19][C:20](=[O:25])[CH2:21]3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(I)ccc21
Reactant: O=C1C=CCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCc2cc(C3CCOC(=O)C3)ccc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline (2.0 g, Reference Example 12), 5,6-dihydro-pyran-2-one (1.1 g), tetrakis(triphenylphosphine)palladium(0) and triethylamine (2.2 g) in dimethylformamide (5 ml) was stirred at about 95° C. in a sealed vessel under an atmosphere of nitrogen overnight. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the layers separated, and the organic layer washed with sodium bicarbonate solution, then dried, and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:3,v/v) to give the title compound as a brown oil, 1.2 g.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCC(O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 28 using 5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1) and (6-methylpyridin-3-yl)boronic acid to afford an off-white solid. UPLC-MS (condition 1) tR=1.61 min, m/z=459.0 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.77 (m, 1H) 1.77-1.88 (m, 1H) 2.53 (s, 3H) 2.88 (d, J=11.49 Hz, 1H) 3.15-3.27 (m, 2H) 3.38 (td, J=9.96, 7.21 Hz, 1H) 4.15-4.22 (m, 1H) 4.84 (d, J=3.42 Hz, 1H) 7.34 (d, J=8.07 Hz, 3H) 7.68 (dd, J=7.95, 2.32 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 7.99 (d, J=2.45 Hz, 1H) 8.48 (d, J=2.20 Hz, 1H) 8.75 (d, J=2.45 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[CH:26]=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].S([CH2:44][N+:45]#[C-:46])(C1C=CC(C)=CC=1)(=O)=O>CO.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:8]=2[C:26]2[O:27][CH:46]=[N:45][CH:44]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(C=O)n(CC(=O)N(C)C)c2c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cnco3)n(CC(=O)N(C)C)c2c1

Procedure:
To a solution of methyl 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-formyl-1H-indole-6-carboxylate (from Step 4) in MeOH (0.05 M) was added K2CO3 (1.05 eq.) and tosylmethyl isocyanide (1.05 eq.). The resulting solution was refluxed under nitrogen for 1.5 h. The mixture was diluted with EtOAc and the organic phase was extracted with HCl (1N) and brine. The organic phase was then dried over Na2SO4 and evaporated in vacuo to give the clean product (quantitative).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=2/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1.CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([S:4][C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=2[CH:7]2[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCC/N=C/c1ccccc1SC1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCNC1c1ccccc1SC1CC1
Reaction time: 3 h

Procedure:
To 58C (15 mmol) in CH2Cl2 (100 mL) at −15° C. was added Et3N (2.1 mL, 15 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 30 mL, 30 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (100 mL) at 0° C. and stirred at rt for 1.0 h. The mixture was filtered through a pad of wet Celite®, extracted with CH2Cl2 (3×40 mL). The organic layer was washed with water, dried over Na2SO4. A small portion of the dried organic layer was concentrated to give crude ethyl 2-(2-(cyclopropylthio)phenyl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:1 ratio. LC-MS 292 (M+H). To the above ethyl 2-(2-(cyclopropylthio)phenyl)pyrrolidine-3-carboxylate in CH2Cl2 was added Et3N (2.1 mL, 15 mmol) and di-tert-butyl dicarbonate (1.0 M in THF, 15 mL, 15 mmol). The mixture was stirred at rt over night before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-30% ethyl acetate/hexanes) to provide 58D (3.3 g, 56%) as an oil. 1H NMR indicated a mixture of cis and trans isomer in 1:1 ratio. 1H NMR (400 MHz, CDCl3) δ ppm 0.66-0.75 (m, 2H) 0.87 (t, J=7.03 Hz, 3 H) 1.05-1.08 (m, 2H) 1.14-1.16 (s, 9H) 2.02-2.18 (m, 3H) 3.43-4.19 (m, 5H) 7.06-7.13 (m, 2H) 7.16-7.25 (m, 1H) 7.51-7.60 (m, 1H); LC-MS 292 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:11])[CH2:4][S:3]1(=[O:13])=[O:12].[I:14]I>C(Cl)(Cl)Cl>[I:14][C:9]1[S:8][C:7]2[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[CH2:4][C:5](=[O:11])[C:6]=2[CH:10]=1
Reactant: II
Reactant: CN1c2sccc2C(=O)CS1(=O)=O
Solvent: ClC(Cl)Cl
Product: CN1c2sc(I)cc2C(=O)CS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a stirring solution of 1-methyl-1H-thieno[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide (Preparation 33, 1.0 g) in CHCl3 (100 ml) at ambient temperature is added HgO (1.19 g) and iodine (1.17 g). The resulting mixture is stirred overnight at ambient temperature and the solids removed by filtration through diatomaceous earth. The solvent is removed in vacuo and the residue purified via flash column chromatography (4/1, hexanes/EtOAc) to afford 0.68 g (43%) of the title compound as a tan solid. Physical characteristics: 1H NMR (CDCl3) δ3.40, 4.20, 7.53; IR (diffuse reflectance) 2986, 1675, 1664, 1505, 1478, 1405, 1338, 1327, 1275, 1245, 1177, 1158, 1129, 818, 781 cm1; MS (EI) m/z 343 (M+). Anal. Found: C, 24.65; H, 1.82; N, 4.08.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.N#N.[NH:21](/[C:25](/[CH3:31])=[CH:26]\[C:27](OC)=[O:28])[C:22]([CH3:24])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:27](=[O:28])[CH:26]=[C:25]([CH3:31])[N:21]=[C:22]2[CH3:24])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (11.0 g, 56 mmol) in CH2Cl2 (200 mL) was added trimethylaluminium (168 mL, 168 mmol, 1 M in heptane) dropwise carefully under N2. The mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (10.57 g, 67 mmol) in CH2Cl2 (30 mL). The reaction was stirred at rt for 5 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The combined organic phases were washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized from EtOAc to give the title compound as a pale yellow solid (11.39 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([Cl:13])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)nc1
Product: O=C(Cl)c1ccc(F)nc1
Temperature: 80 °C

Procedure:
In a 100-mL round-bottom flask was placed a solution of 6-fluoropyridine-3-carboxylic acid (5.0 g, 35.4 mmol) in thionyl chloride (20 mL). The resulting solution was heated at 80° C. for 2 hours and concentrated under vacuum to give the title compound as a yellow oil.