Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)(Cl)Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[N+:4]([O-:18])[C:5]2[CH:6]=[CH:7][C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=c1ccc2c(cc(F)c[n+]2[O-])[nH]1

Procedure:
7-Fluoro-1,5-naphthyridin-2(1H)-one (1.280 g, 7.798 mmol) and m-chloroperoxybenzoic acid (2.123 g, ca. 1.2 eq. based on an mCPBA content of 75%) were stirred in chloroform (60 mL) at reflux overnight. Further mCPBA (0.420 g) was added and the mixture was stirred at reflux for an additional 6 hours. The mixture was diluted with DCM to a total volume of ca. 100 ml and filtered with suction. The solid collected was washed with DCM (2×20 mL) and air-dried to give 7-fluoro-1,5-naphthyridin-2(1H)-one 5-oxide as a tan solid (1.045 g, contaminated with ca. 12% starting material).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[N:16][C:17]([S:19][CH3:20])=[N:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.CS(C)=O>O>[CH3:20][S:19][C:17]1[N:16]=[C:15]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=2)[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[N:18]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1nc2c(c(OS(=O)(=O)C(F)(F)F)n1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNCC2
Temperature: 100 °C
Yield: 55.4 %

Procedure:
A solution containing methylsulfanyl-4-trifluoromethanesulfonyloxy-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylic acid tert-butyl ester (950 mg, 2.15 mmol), 4-trifluoromethylaniline (0.6 mL, 4.74 mmol) and DMSO (8 mL) was heated at 100° C. for 24 h. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified (FCC; MeOH/CH2Cl2) to give the title compound (422 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[NH3:25]>C(O)C>[NH2:25][CH:12]=[C:6]([C:4](=[O:5])[C:3]1[CH:16]=[C:17]([F:24])[C:18]([Cl:23])=[C:19]([N+:20]([O-:22])=[O:21])[C:2]=1[Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCO
Product: CCOC(=O)C(=CN)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
38 g of the product from Example 1 are intitially introduced into 40 ml of ethanol. A mixture of 8 ml of concentrated NH3 solution in 25 ml of ethanol is added dropwise with ice cooling. The mixture is stirred for 2 hours at room temperature and the phases are then separated. The organic phase is washed with water and dried. 38.3 g of the title compound remain on concentration.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][C:13]([CH3:15])=O.C(OC(=O)C)(=O)C>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[C:13](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([CH3:15])[CH3:12]
Reactant: CC(C)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)=C(C)C
Yield: 41 %

Procedure:
There were placed diethyl malonate (133 g, 0.83 mol), acetone (72 g, 1.24 mol), acetic anhydride (106 g, 1.05 mol) and zinc chloride (17.0 g, 0.125 mmol in a 500 ml three neck flask. After 24 hour reflux, benzene (200 ml) was added and the reaction mixture was washed with water (100 ml×4). The aqueous layer was further extracted with benzene (50 ml×2). The organic layers were combined and concentrated. The residue was distilled under reduced pressure to give oily product, diethyl isopropylidenemalonate (68.0 g, 0.34 mol, 41.0%, b.p.: 112° C./9 mmHg). The structure was confirmed by the following data.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1)#[N:2].[C:19](O)([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2]
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC2(CCCCC2)O1
Temperature: 0 °C

Procedure:
(±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid 3.32 g (13.12 mmol), is dissolved in 15 mL of dichloromethane, cooled to 0° C. and 0.1 g of 4-dimethylaminopyridine (DMAP) added, followed by t-butyl alcohol, and followed by 3.25 g of dicyclohexylcarbodiimide (DCC). This solution is stirred and allowed to slowly warm to room temperature over a 16.5-hour period. TLC shows mainly product, and some slightly lower Rf by-product. The mixture is stirred one hour and 50 mL of dichloromethane is added and stirring continued four hours. One hundred mL of diethyl ether is added and then filtered. The filtrate is concentrated at reduced pressure. This crude concentrate is chromatographed on silica gel and eluted with 4:1 hexane:ethyl acetate to yield (±)-cis-1,1-dimethylethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5 ]undecane-2-acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[C:24]([O:40][CH3:41])[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CN(C=O)C>[F:39][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([C:28]([C:26]1[CH:25]=[C:24]([O:40][CH3:41])[N:23]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:27]=1)=[O:29])[CH2:31][CH2:32]2
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)cc(OC)n3)CC1)C(=O)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 0.633 g (2.30 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.700 mg (2.28 mmol) (2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone and 954 mg (6.90 mmol) potassium carbonate in 5.0 mL NMP was stirred for 8 h at 130° C. After cooling the reaction mixture to RT the precipitate formed was filtered off and purified by preparative HPLC. The fractions containing the product were combined and evaporated down i. vac. The residue obtained was digested in DMF and the product remaining as a solid was suction filtered and dried i. vac. The mother liquor was again purified by preparative HPLC, the fractions containing product were combined and evaporated down i. vac. The residue was triturated with ethanol, the solid product was suction filtered and dried i. vac.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:20])=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 99 %

Procedure:
As described for example 162b, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24 mmol) was converted using 4-aminotetrahydropyran instead of ethanolamine to the title compound (SiO2, heptane:ethyl acetate=50:50 to 0:100, 89 mg, 99%) which was obtained as a white solid. MS: m/e=381.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: CN
Product: CNC(=O)c1cnc(CCc2c(-c3ccc(F)cn3)noc2C)s1
Yield: 48 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using methylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (33 mg, 48%) which was obtained as a white solid. MS: m/e=347.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[O:5][CH2:6][C:7]#[N:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:3]=1)#[N:8]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(OCC#N)cc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(OCC#N)cc1NS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
(3-Amino-4-methylphenoxy)-acetonitrile (2.6 g) was dissolved in 10 ml of pyridine, cooled in an ice bath; 2.29 g of methanesulfonyl chloride was added; and the reaction mixture was stirred at 5° C. for 1 hour. The mixture was poured into ethyl acetate, washed with hydrochloric acid, then water, dried, and evaporated giving 3.5 g of N-(5-cyanomethoxy-2-methylphenyl)-methanesulfonamide. ##STR66##
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:22][N:23](/[CH:25]=[N:1]/[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2nc1/N=C/N(C)C
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A mixture of methyl 2-amino-6,7-dimethoxy-3-quinolinecarboxylate (3.60 g, 13.04 mmol) and 4.10 g of dimethylformamide dimethylacetal in 60 mL of toluene containing 40 mg of p-toluenesulfonic acid is heated at reflux for 2 hours. Upon cooling to room temperature a solid formed and is collected by filtration to provide 736 mg of methyl 2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarboxylate as an off-white solid, mp 166–168° C. MS 318.1, 319.0 (M+H)+ Analysis for C16H19N3O4 Calcd: C, 60.56; H, 6.03; N, 13.24. Found: C, 60.63; H, 6.08; N, 13.32.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:28][O:29][C:30]([CH:32]1[NH:37][CH2:36][C:35]2[N:38]=[CH:39][N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[C:44]([CH3:51])[CH:43]=3)[C:34]=2[CH2:33]1)=[O:31]>C(#N)C>[CH3:28][O:29][C:30]([CH:32]1[N:37]([C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:36][C:35]2[N:38]=[CH:39][N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[C:44]([CH3:51])[CH:43]=3)[C:34]=2[CH2:33]1)=[O:31]
Reactant: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CC#N
Product: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 16.7 g dicyclohexycarbodiimide, 10.9 g hydroxybenzotriazole hydrate, 17.2 g diphenylacetic acid and 150 mL acetonitrile is stirred at 25° C. for 15 min then treated with a solution of 25.4 g methyl-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate in 125 mL acetonitrile. The resulting suspension is stirred 48 hr at 25° C., filtered and the filtrate is evaporated, dissolved in dichloromethane, washed with 10% Na2CO3, dried and evaporated. Chromatography on silica gel (chloroform-methanol, 99:1) gives a crisp foam which crystallizes when triturated with methanol. MS (FAB) 525 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5](O)=[S:6].Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:31][CH2:30]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][CH:29]([NH:28][C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:30][CH2:31]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[S:6]
Reactant: COc1ccc(C)cc1C(O)=S
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=S)c4cc(C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-methylthiobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC4CC4)C4CCCC4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2cc[nH]c2n1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
4-[1-(1-Cyclopentyl-2-cyclopropylethyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (13 mg, 0.023 mol) was stirred at room temperature in a solution of DCM (2 mL) containing TFA (1.5 mL) for two hours. The solvent was removed in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stilling for one hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (9 mg, 90%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:3]=1[CH3:27].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]3[CH:13]=[CH:14][C:15]([S:18]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)(=[O:19])=[O:20])=[CH:16][CH:17]=3)[C:3]=2[CH3:27])=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1sc(Br)c(C)c1-c1ccc(S(=O)(=O)N2CCCCC2)cc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared by following process provided in example 3 step 4, using 48b and (4-chlorophenyl)boronic acid as reactants.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[C:7]=1[CH2:8]O>C1C=CC=CC=1.O>[CH3:5][C:6]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[C:7]=1[CH2:8][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(C)C)cc(C)c1CO
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C(C)C)cc(C)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Thionyl chloride (0.63 g, 5.28 mmol) was added to a solution of 2,6-dimethyl-4-isopropylbenzyl alcohol (Example 2a) (0.47 g, 2.64 mmol) in dry benzene (20 mL). The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under reduced pressure to give a yellow oil. The crude oil was suspended in water (10 mL) and extracted with ether (3×10 mL). The solvent was removed under reduced pressure to give 0.51 g (98%) of the title compound as a white liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH2:67][NH2:68])[CH:62]=1>CN(C)C=O>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:68][CH2:67][C:63]3[CH:62]=[N:61][CH:66]=[CH:65][CH:64]=3)=[CH:26][CH:25]=2)=[N:19][C:18]=1[CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CCCOC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CCCOC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 66.5 %

Procedure:
A solution of 4-[4-[3-([1-[(tert-butoxy)carbonyl]piperidin-4-yl]oxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoic acid (1.0 g, 2.25 mmol, 1.00 equiv), EDCI (560 mg, 2.92 mmol, 1.30 equiv), HOBt (400 mg, 2.96 mmol, 1.32 equiv), triethylamine (800 mg, 7.91 mmol, 3.51 equiv) and pyridin-3-ylmethanamine (480 mg, 4.44 mmol, 1.97 equiv) in N,N-dimethylformamide (30 mL) was stirred at 35° C. overnight. The product was precipitated by the addition of 50 mL of ice/water. The solid was collected by filtration, washed with 3×30 mL of water and dried in a vacuum oven to give 0.8 g (67%) of tert-butyl 4-[3-(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)propoxy]piperidine-1-carboxylate as a white solid LC-MS-PH: (ES, m/z): 535 [M+H]+, 435, 367, 352, 239, 102.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Yield: 93.9 %

Procedure:
Beginning with 1.00 gm (7.4 mMol) 5-fluoro-1H-indole and 1.82 mL (14.8 mMol) 1-methyl-4-piperidone, 1.60 gm (94%) of the title compound were recovered as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:17])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (148 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [Prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (245 mg, 0.39 mmol, 75% yield) as a yellow oil: LCMS (ES) m/e 615, 617 (M, M+2)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)c(Cl)ccc3c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3ccc(Cl)c(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 7,8-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate (0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2.5 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed by crystallization from MeOH/EtOAc to give 1.5 g (81%) of a white solid: mp 132.5-135.0° C.; IR (diffuse reflectance) 2974, 1747, 1683, 1465, 1450, 1416, 1365, 1303, 1255, 1216, 1195, 1170, 1155, 1115, 803 cm−1; MS (EI) m/z 440 (M+), 442, 440, 386, 385, 384, 311, 300, 298, 57, 56; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.13; H, 5.98; N, 6.36.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccccc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-phenylindole-3-carboxylic acid ethyl ester (170 mg, 0.46 mmol, see step (b) Example 3) and 4-trifluoromethylphenylboronic acid (129 mg, 0.68 mmol). Yield 150 mg (64%).