Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](Cl)=[N:7][CH:8]=1)#[N:2].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(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:10]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2ccccc2)nc1
Yield: 93.8 %

Procedure:
5-Cyano-2-chloropyridine (5.0 g, 36.1 mmol), phenylboronic acid (6.6 g, 54 mmol), tetrakis(triphenylphosphine)palladium (0) (0.5 g), and aqueous Na2CO3 (7.6 g), in toluene (100 mL) were heated at 90° C. for 16 h. The mixture was diluted with EtOAc and washed with H2O. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc 2/1) to afford the title compound (6.1 g, 94%). MS (ESI) m/z 181 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11].[Cl:14][C:15]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3F)[O:21][C:17]=2[CH:16]=1>O>[Cl:14][C:15]1[C:30]([C:31]([F:34])([F:32])[F:33])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[O:11][CH2:10][C:9]([F:13])([F:12])[F:8])[O:21][C:17]=2[CH:16]=1
Reactant: OCC(F)(F)F
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
A mixture of 46 mg of 60% sodium hydride (in oil) and 2 ml of DMF was stirred at room temperature, to which a mixture solution of 0.12 g of 2,2,2-trifluoroethanol and 0.5 ml of DMF was added. After 15 minutes, 0.28 g of 6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole was added and stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 6-chloro-2-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 92”).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:16][O:17][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: O=S(c1ccccc1)c1ccc(Br)nc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)c2ccccc2)cn1

Procedure:
A solution of 2-bromo-5-phenylsulfinylpyridine (2.82 g., 0.01 mole) and 0.50 g. of sodium methoxide is heated in 50 ml. of refluxing methanol for 5 hours. The reaction mixture is evaporated in vacuo, and the residue is diluted with water. The solids are collected by filtration, washed with water and dried to yield 2-methoxy-5-phenylsulfinylpyridine.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)C=CC=CC=1.[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([CH:47]=O)=[N:43][C:44]=1[O:45][CH3:46].O>O1CCCC1>[Cl:38][C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42](/[CH:47]=[CH:19]\[CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:41][CH:40]=1
Reactant: COc1nc(C=O)ccc1Cl
Reactant: c1ccc([P+](CC2CCOCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C=C\C2CCOCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A solution of lithium hexamethyldisilazide in tetrahydrofuran (1 M, 10 mL) was added to a solution of triphenyl(tetrahydro-2H-pyran-4-ylmethyl)phosphonium iodide (5.51 g) in tetrahydrofuran (20 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (1.3 g) in tetrahydrofuran (20 mL) was slowly added to the reaction solution, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-chloro-2-methoxy-6-[(Z)-2-(tetrahydro-2H-pyran-4-yl)ethenyl]pyridine as a colorless powder (1.62 g, 60%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[N:16]([CH2:20][C:21](Cl)=[O:22])[C:15]=2[CH:24]=1>CC(C)=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[N:16]([CH2:20][C:21](=[O:22])[S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:15]=2[CH:24]=1
Reactant: O=C(Cl)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Cn1c(=O)sc2ccc(Cl)cc21)Sc1ccccc1

Procedure:
A charge containing 0.1 moles of benzenethiol, 0.1 moles of 85% potassium hydroxide and 250 ml of acetone is stirred as in Example 1. To this mixture, 0.1 moles of 5-chloro-2-oxo-3-benzothiazolineacetyl chloride is added in one portion. The remaining steps of Example 1 are then followed. Analytical data is summarized in Table I, below.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH3:11]>>[CH3:10][C:11]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9]
Reactant: CC(=O)O
Reactant: Cc1ccnc(N)c1N
Product: Cc1nc2nccc(C)c2[nH]1

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and acetic acid (0.15 ml) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (9:1) to give the pure product (0.25 g, 85%) as a light brown solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:25])[CH3:12])=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(=S)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 173 %

Procedure:
N-(4-(trifluoromethoxy)phenyl)acetamide (112 g, 0.511 mol) was dissolved in THF (400 ml) and Lawesson's Reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) (100 g, 0.247 mol) was added. The suspension was stirred at rt for 3 days, then filtered, filtrate evaporated and the residue was purified by chromatography (20% EtOAc in hexane) to give 100.5 g (84%) of N-(4-(trifluoromethoxy)phenyl)ethanethioamide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:42]C(N)C.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH:36]([CH3:42])[CH3:37])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: CC(C)N
Solvent: NCCO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNC(C)C)c4)cc23)CC1
Yield: 35 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (25 mg, 0.43 mmol) for the 2-aminoethanol to afford 9 mg of the title compound (35%).
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20](O)=O)[C@@H:12](O)[CH2:11][C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[C:15]1([C:14]2[CH:13]=[CH:9][C:10]([OH:24])=[CH:11][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2ccccc2)cc1

Procedure:
Following the procedure of Example 1 but using 0.535 g. of PGF2 α, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.385 g. of p-phenylphenol, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate followed by acetonitrile. The residue obtained by concentration of selected fractions, 0.270 g., is crystallized from ethyl acetate diluted with an equal volume of hexane as the title compound, white free-flowing crystals, m.p. 114.3°-116.8° C. having Rf 0.25 (TLC on silica gel in ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C)C=O>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([O:8][CH2:25][CH2:24][O:23][CH3:22])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: COCCBr
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 11) (305 mg) was dissolved in dimethylformamide (2 ml), potassium carbonate (622 mg) and 2-bromoethyl methyl ether (208 mg) were added. The reaction was stirred at room temperature for 1.5 hours and then at 50° C. for 12 hours. The solvent was removed under reduced pressure. The crude product was purified on silica (10 g) eluted with a solvent gradient of pentane:ethyl acetate (1:0 to 0:1) to yield the title compound as a white solid (201 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6](O)[CH2:5][C:4]1=[O:55])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]=[CH:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C=CC1=O)C(C)CC2OC
Yield: 87.7 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (210 mg) and a catalytic amount of p-toluenesulfonic acid in 40 ml of benzene was refluxed for 4 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the dark residue was purified by chromatography (silica gel, 7% i-propanol/CH2Cl2) to give 17-ethyl-1-hydroxy-12-[2'-(4",3"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (180mg) as a white solid. This material was dissolved in ethanol (20 ml) and treated with 5% Rh/C (40 mg). Hydrogen was introduced via balloon for 30 min. and the mixture was filtered through celite. Removal of solvent followed by chromatography (silica gel) gave 172 mg of the title compound. Mass, 1H and 13C NMR data were consistent with the title structure.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([C:14]1[CH:19]=[C:18]([C:20]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:24][CH2:23][CH2:22][O:21]2)[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:35])[CH3:34])=O>COCCOC>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2([C:18]3[CH:19]=[C:14]4[C:15](=[CH:16][CH:17]=3)[NH:32][C:33](=[O:35])[CH:34]=[C:12]4[C:11]3[CH:36]=[CH:37][CH:38]=[C:9]([O:8][CH3:7])[CH:10]=3)[O:21][CH2:22][CH2:23][O:24]2)=[CH:30][CH:29]=1
Reactant: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2NC(C)=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cccc(-c2cc(=O)[nH]c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Yield: 123 %

Procedure:
Potassium tert-butoxide (33 g) was added portionwise at room temperature to a solution of interm. (5-d) (36.4 g) in 1.2-dimethoxyethane (350 ml) and the mixture was stirred at room temperature overnight. The mixture was hydrolized and extracted with DCM. The organic layer was dried, filtered off and evaporated till dryness. The product was used without further purification, yielding 43 g of 6-[2-(4-chloro-phenyl)-1,3-dioxolan-2-yl]-4-(3-methoxyphenyl)-2(1H)-quinolinone (interm. 5-e).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)=[N+:19]=[N-:20]
Reactant: BrCc1ccc2c(cnn2C2CCCCO2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 90 °C
Yield: 99.5 %

Procedure:
To a solution of 5-(bromomethyl)-1-(2-tetrahydropyranyl)indazole (compound 108, 3.0 g, 10.2 mmol) in DMF (30 mL), was added with sodium azide (Aldrich, 2.64 g, 40.6 mmol) in one portion. The suspension was heated at 90° C. for 30 minutes and a yellow solution formed. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ether (2×150 mL). Combined organic layers were washed with brine, then dried (MgSO4). Evaporation of solvent gave the product (109) as a yellow oil (2.61 g, 99%). TLC Rf 0.63 (60:40 hexane-ethyl acetate); MS (electrospray) 258 (M+1); 1H NMR (CDCl3) δ2.03-2.15 (m, 2H), 2.55 (m, 1H), 3.72 (m, 1H), 4.02 (m, 1H), 4.52 (s, 1H), 5.71 (d, 1H, J=9.4 Hz), 7.32 (d, 1H, J=8.8 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.63 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH2:41][C:40]5[C:35](=[CH:36][C:37]([Cl:42])=[CH:38][CH:39]=5)[C:34]4=[O:43])[C:28]=2[CH3:44])=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([NH:17]C(=O)OCC[Si](C)(C)C)[CH:12]=3)(=[O:3])[NH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.CCOC(C)=O>O1CCCC1>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]3[C:7]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH2:41][C:40]6[C:35](=[CH:36][C:37]([Cl:42])=[CH:38][CH:39]=6)[C:34]5=[O:43])[C:28]=4[CH3:44])=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]=3[NH:10]2)=[CH:15][CH:14]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(NC(=O)OCC[Si](C)(C)C)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(N)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Reaction time: 4 h

Procedure:
To a burgundy, homogeneous solution of 2-(trimethylsilyl)ethyl 1-carbamoyl-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indol-7-ylcarbamate (0.126 g, 0.201 mmol) in tetrahydrofuran (0.2 mL) was added 1M TBAF/THF (0.402 mL, 0.402 mmol). After 4 hr, EtOAc (80 mL) was added, and the layer was washed with water (20 mL) and brine (20 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo to give a crude product as a light brown solid, which was used in the subsequent step.
Reaction SMILES: [Na].C[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][N:7]=1)=[O:5].Br[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:15]([O:17]C)=[O:16]>CO>[C:15]([CH:14]([S:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:3])=[O:5])=[N:7][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=1)([OH:17])=[O:16]
Reactant: COC(=O)C(Br)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(S)cn1
Agent: [Na]
Solvent: CO
Product: O=C(O)c1ccc(SC(C(=O)O)c2cccc(C(F)(F)F)c2)cn1
Reaction time: 8 h

Procedure:
To the solution prepared from 80 ml of methanol and 0.89 g of sodium, 6.53 g of 5-mercaptopyridine-2-carboxylic acid methyl ester are added, followed by the solution of 12.6 g of methyl α-bromo-m-trifluoromethylphenylacetate in 50 ml of methanol while stirring under nitrogen. The mixture is warmed for 1/2 hour on the steam bath and allowed to stand at room temperature overnight. It is evaporated, the residue taken up in water-diethyl ether, the organic phase washed with water, dried and evaporated. The residue is dissolved in the minimum amount of methanolisopropanol (1:1), the solution mixed with 85 ml of N aqueous sodium hydroxide, warmed for 1/2 hour on the steam bath, and stored at room temperature overnight. The mixture is evaporated, the residue taken up in 2 N hydrochloric acid and the mixture extracted with diethyl ether-ethyl acetate (1:1). The extract is washed with water, dried and evaporated and the residue recrystallized from diethyl ether-ethyl acetate, to yield the 5-(α-carboxy-m-trifluoromethylbenzylmercapto)-pyridine-2-carboxylic acid melting at 190°-195°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1ccc(SCC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
4-Bromothiophenol (37.8 g) in N,N-dimethylformamide (200 mL) was treated with potassium carbonate (30.4 g) and cyclopropylmethyl bromide (29.7 g). The suspension was stirred at ambient temperature for 16 hrs then diluted with diethyl ether (500 mL). The organic phase was washed with water (2×500 mL), dried (MgSO4) and concentrated to give the title compound as an oil (46.4 g). 1H NMR (360 MHz, CDCl3): δ 7.38 (2H, d, J=8.0 Hz), 7.21 (2H, d, J=8.0 Hz), 2.83 (2H, d, J=7.0 Hz), 1.08-0.98 (1H, m), 0.58 (2H, q, J=5.1 Hz), 0.24 (2H, q, J=5.1 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1>Cl>[Br:1][C:2]1[C:3]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)c(Br)cn1
Agent: Cl
Product: Nc1cc(NCC2CCNCC2)c(Br)cn1
Temperature: 105 °C
Yield: 92.2 %

Procedure:
A mixture of benzyl 4-((5-bromo-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate (0.695 g, 1.24 mmol) and 6M HCl (10 mL) was heated at 105° C. for 45 mins by microwave irradiation. After cooling the volatiles were removed in vacuo. The residue was redissolved in MeOH and adsorbed onto Isolute SCX-II acidic resin. The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated to give crude 5-bromo-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.326 g, 92%), LCMS (4) Rt=0.51 min; m/z (ESI+) 285/287 (MH+). A solution of di-tert-butyl dicarbonate (0.249 g, 1 eq.) in dichloromethane (1 mL) was added dropwise to an ice-cooled solution of 5-bromo-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.326 g, 1.14 mmol) and triethylamine (0.48 mL, 3 eq.) in dichloromethane (7.79 mL). The solution was stirred at 0° C. for 30 mins and then warmed to room temperature and stirred for a further 30 min. The mixture was concentrated. The crude product was purified by preparative TLC, eluting with 7% MeOH, 1% NH3, 92% dichloromethane, to give tert-butyl 4-((2-amino-5-bromopyridin-4-ylamino)methyl)piperidine-1-carboxylate (234 mg, 53%) as a white powder.
Reaction SMILES: [CH:1]1([C@H:4]2[C:8](=[O:9])[CH2:7][CH:6]([CH:10]3[CH2:12][CH2:11]3)[N:5]2C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.Cl.CCN(CC)CC.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>O1CCOCC1.CN(C1C=CN=CC=1)C>[CH:1]1([C@H:4]2[C:8](=[O:9])[CH2:7][CH:6]([CH:10]3[CH2:11][CH2:12]3)[N:5]2[S:36]([C:33]2[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:40])[F:41])=[CH:35][CH:34]=2)(=[O:38])=[O:37])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C(C2CC2)CC(=O)[C@@H]1C1CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1CC(C2CC2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@H]1C1CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
(2S)-tert-Butyl 2,5-dicyclopropyl-3-oxopyrrolidine-1-carboxylate (20) (127 mg, 0.480 mmol) was placed in dioxane (0.5 mL) and treated with 4N HCl in dioxane (2.0 mL). When reaction was done as indicated by TLC monitoring, it was concentrated in vacuo and used without further purification. This material was dissolved in CH2Cl2 (3 mL) and placed under nitrogen. DMAP (12 mg, 0.096 mmol) and Et3N (0.20 mL, 1.44 mmol) were added and the reaction cooled to 0° C. 4-(Trifluoromethyl)benzene-1-sulfonyl chloride (129 mg, 0.528 mmol) was added and the reaction stirred for 16 hr warming from 0° C. to rt. The reaction was concentrated in vacuo and the resulting crude product was purified by column chromatography using EtOAc/hexane gradients to yield (2S)-2,5-dicyclopropyl-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-one (21) (149 mg, 83% over two steps) as a 58:42 mixture of diastereomers. The product was a clear oil that solidified upon standing. MS (m/z) 374.1 (M+H)+; retention time (210 nM)=8.329 and 8.500 min, method [7].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:30])=[C:14]([C:26]([O:28][CH3:29])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[N:16]([S:38]([CH3:37])(=[O:40])=[O:39])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:14]([C:26]([O:28][CH3:29])=[O:27])=[C:13]([CH3:30])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(S(C)(=O)=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1, 4-dihydro-2-[[(4-methoxyphenyl)methyl]thio-]6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, methyl ester (1.14 g, 2.66 mmole) in 15 ml of dichloromethane under argon at 0°-5° C. was treated with pyridine (0.42 ml, 0.42 g, 5.32 mmole) and methanesulfonyl chloride (0.28 ml, 0.41 g, 3.57 mmole). The mixture was then allowed to stir at room temperature overnight.