Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[CH3:11][NH2:12]>C1COCC1>[CH3:11][NH:12][C:7]([CH:3]1[C:2]([CH3:10])([CH3:1])[C:4]1([CH3:6])[CH3:5])=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)C1C(C)(C)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
A solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (16.05 g, 0.1 mole) in the THF (50 ml) was added slowly to 35% aqueous methyl amine (200 ml). The reaction mixture was stirred for 24 hours at room temperature, and, after removal of THF under reduced pressure, was extracted with CH2Cl2 (2×50 ml). The CH2Cl2 extract was washed successively with H2O (2×100 ml), 0.3 N HCl (200 ml), 0.1 NaHCO3 (100 ml) and saturated NaCl (150 ml), dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was treated with hexane (100 ml) at room temperature for 30 minutes, filtered and dried to afford 10.5 g (68 mmole, 68%) of a white solid, m.p.: 98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH:8]([CH3:10])[CH3:9])[S:5][CH:6]=1.O.NN.Cl>C(O)CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH:8]([CH3:10])[CH3:9])[S:5][CH:6]=1
Reactant: CC(C)C(=O)c1cc(Br)cs1
Agent: Cl
Agent: NN
Solvent: O
Solvent: OCCO
Product: CC(C)Cc1cc(Br)cs1
Temperature: 160 °C
Yield: 24.9 %

Procedure:
1-(4-bromo-2-thienyl)-2-methyl-1-propanone (816 mg, 3.52 mmol) was diluted in ethylene glycol (3 mL). Hydrazine monohydrate (0.46 mL, 9.5 mmol, 2.7 eq) was added, and the mixture was heated to 160° C. for 1.5 h behind a blast shield. The mixture was cooled to rt, and diluted with water. 6 M aqueous HCl was added until pH was acidic (pH paper), and the mixture was extracted three times with hexanes. The combined organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by biotage, 25M+ column, eluting with 5% ethyl acetate in hexanes. Fractions containing the desired product were concentrated in vacuo to afford the title compound as light yellow oil (192 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.BrN1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:34][C:35]1[N:40]=[C:39]([SH:41])[N:38]=[C:37]([OH:42])[CH:36]=1>C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[CH3:34][C:35]1[N:40]=[C:39]([S:41][CH2:1][C:2]2[S:3][C:4]([CH3:7])=[CH:5][N:6]=2)[N:38]=[C:37]([OH:42])[CH:36]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1cnc(C)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ncc(C)s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To CCl4 (100 mL) in a 250 mL round bottom flask were added 2,5-dimethyl-1,3-thiazole (1.7 g, 15 mmol), 1-bromopyrrolidine-2,5-dione (2.94 g, 16.5 mmol), and benzoyl benzenecarboperoxoate (180 mg, 0.75 mmol). The reaction mixture was heated at 80° C. for 4 hours. The solvent was then removed under vacuum. The crude product was dissolved in ethanol (30 mL). 6-methyl-2-sulfanylpyrimidin-4-ol (700 mg, 5 mmol) and triethylamine (1.4 mL) were added, and the mixture was stirred at room temperature for 2 hours. After removal of the solvent, the crude product was purified by column chromatography (0-8% methanol in DCM) to provide the title compound as a white solid (480 mg, 40% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 2.50 (s, 3H), 4.56 (s, 2H), 6.03 (br, 1H), 7.55 (s, 1H); M+ 254.
Reaction SMILES: CO[C:3](=[O:16])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:17]1([CH2:29][C:30]([NH2:32])=[O:31])[C:27]2=[C:28]3[C:23](=[CH:24][CH:25]=[CH:26]2)[CH2:22][CH2:21][CH2:20][N:19]3[CH:18]=1>>[C:17]1([C:29]2[C:30](=[O:31])[NH:32][C:3](=[O:16])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:27]2=[C:28]3[C:23](=[CH:24][CH:25]=[CH:26]2)[CH2:22][CH2:21][CH2:20][N:19]3[CH:18]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2cc(Cl)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(Cl)ccc12

Procedure:
Beginning with 6-chloroindole-3-glyoxylic acid methyl ester and 2-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetamide, the title compound was prepared as a dark red foam essentially as described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([CH3:15])[CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])=[C:4]([CH2:15][Br:16])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Br)cc1CBr)C(F)(F)F
Yield: 67.5 %

Procedure:
A solution of Example 478A (2.5 g, 8.9 mmol) and N-bromosuccinimide (1.58 g, 8.9 mmol) in carbon tetrachloride (25 mL) was irradiated with a 100-watt incandescent bulb overnight. The solution was filtered and the filtrate was concentrated. The concentrate was purified by flash chromatography on silica gel using 3–4% ethyl acetate/hexanes to give 2.17 g (68% yield) of the desired product. MS (ESI(−)) m/e 360, 362 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)=[O:27])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])[CH:32]=[CH:31]3)=[O:27])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(-n2ccc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a mixture of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.150 g, 0.6376 mmol) and N-(4-chlorophenethyl)-1H-indole-5carboxamide (0.2095 g, 0.7014 mmol) in DMSO (3 mL) was added K2CO3 (0.1322 g, 0.9564 mmol), and the reaction mixture was heated at 120° C. for 30 minutes, then at 130° C. for 1 hour. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 5% to 100% ethyl acetate/hexanes to provide tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indol-1-yl)-3cyanophenyl)acetate (0.160 g, 48.82% yield) as a waxy solid. MS (APCI)=514.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[CH2:26]([O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:8][C:5]2[C:4]([C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Yield: 21.7 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (100 mg, 0.38 mmol, 1 eq) and ethyl 3-cyclopropyl-3-oxopropanoate (89.4 mg, 0.57 mmol, 1.5 eq) in anhydrous EtOH (5 ml), was added p-TsOH.H2O (72.6 mg, 0.38 mmol, 1 eq) and the mixture was refluxed for 16 h. After cooling, the reaction mixture was concentrated in vacuo and then diluted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (elution with 3% ethyl acetate in hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (33 mg, 22%) as a pale yellow solid. MS (ESI): 400.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].Br>C(O)(=O)C>[CH3:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)c1ccc(-c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
A mixture containing α-methyl-4'-(methoxy)[1,1'-biphenyl]-4-acetic acid, ethyl ester (22.0 g, 77.4 mmol), acetic acid (400 mL) and 48% hydrobromic acid (80 mL) is refluxed for 18 hours. The solution is concentrated under reduced pressure to one-third the volume and the product crystallizes from the solution. The solid is filtered and dried to give a quantitative yield. A portion of this material is recrystallized from acetonitrile and a white solid is obtained, m.p. 205°-206° C. MS (EI m/z): 242 (M)+, (b.p., M-CO2H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[CH:17][C:10]3[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:34])(=O)=O)=CC=1>C1COCC1>[F:34][C:13]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:18]=[CH:17][C:10]=2[S:11][C:12]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cc2cc(-c3ccccc3)ccc2s1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1sc2ccc(-c3ccccc3)cc2c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of compound 52c (507 mg, 1.99 mmol) in THF (8 mL) at −70° C. was added n-BuLi (1.6 M in hexane, 2.62 mL, 4.19 mmol). The mixture was stirred at −70° C. for 1 h; then a solution of N-fluorobenzenesulfonimide (817.3 mg, 2.59 mmol) in THF (2 mL) was slowly added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The resulting mixture was partitioned between dilute aqueous HCl and EtOAc. The organic solution was washed with water and brine, dried over Na2SO4, and concentrated. The residue was tritrated from CH2Cl2, filtered and dried the solid to give compound 52d (391.9 mg). MS m/z (M+H+) 273.0.
Reaction SMILES: [CH2:1]([NH:4][C:5](=S)[NH:6][NH2:7])[CH:2]=[CH2:3].[Cl:9][CH:10]([C:16]([CH3:18])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>C(O)C>[ClH:9].[CH3:18][C:16]1[NH:7][N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: C=CCNC(=S)NN
Agent: Cl
Solvent: CCO
Product: C=CCNc1n[nH]c(C)c1C(=O)OCC
Reaction time: 1.5 h
Yield: 59 %

Procedure:
A mixture of 26.24 g (0.2 mole) of 4-(2-propenyl)-3-thiosemicarbazide and 32.9 g (0.2 mole) of ethyl 2-chloroacetoacetate in 150 mL of absolute ethanol was stirred under nitrogen atmosphere for 1.5 hr, treated with 100 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1.5 hr. The reaction mixture was stirred at ambient temperature for ~72 hr, heated to reflux and filtered to remove the amorphous sulfur. The filtrate was concentrated in vacuo to give a deep red oil which crystallized on trituration with acetone to give 29 g of product. Recrystallization from acetone gave 21 g of needle-like crystals tinted with yellow. A second recrystallization from benzene gave 15.8 g of fine white needles, mp 133°-134° C. A rework of the filtrates from both recrystallizations gave an additional 7 g of crude product.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[CH:18][C:19]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:20]([CH:30]=1)[C:21]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22].[CH3:39][N:40]1[CH2:45][CH2:44][CH:43](O)[CH2:42][CH2:41]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:39][N:40]1[CH2:45][CH2:44][CH:43]([O:15][C:16]2[CH:17]=[CH:18][C:19]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:20]([CH:30]=2)[C:21]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH2:42][CH2:41]1
Reactant: CN1CCC(O)CC1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN1CCC(Oc2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)CC1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A solution of DIAD (0.30 ml, 1.56 mmol) in toluene (1 ml) was added dropwise to a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 200 mg, 0.624 mmol), 1-methyl-4-piperidinol (79 mg, 0.687 mmol) and Ph3P (409 mg, 1.561 mmol) in toluene under nitrogen at 0° C. The reaction mixture was stirred at 115° C. overnight. The mixture was then cooled and concentrated. The residue was added to water and extracted with ethyl acetate (3×60 ml). The organic phase was washed with saturated brine (30 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product. The crude product was purified by Pre-TCL (DCM:methanol=8:1) to yield the title compound as a yellow solid. 36 mg.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH:8]([C:9]([O:11]CC)=[O:10])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][NH:5]1.Cl>CO>[O:3]=[C:4]1[CH:8]([C:9]([OH:11])=[O:10])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][NH:5]1
Reactant: CCOC(=O)C1C(=O)NCC1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1C(=O)NCC1c1ccccc1

Procedure:
1 M sodium hydroxide aqueous solution was added at room temperature to a methanol solution of ethyl 2-oxo-4-phenylpyrrolidine-3-carboxylate (Wako Pure Chemical Industries (Wako), Japan) and stirred for 13Hours. The reaction solution was acidified by adding 1 M hydrochloric acid, and the thus precipitated solid was collected by filtration and dried to obtain 2-oxo-4-phenylpyrrolidine-3-carboxylic acid. FP: 206.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[C:13]([CH2:17][CH2:18][OH:19])=[N:12][C:11]=2[CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:25]([N:27]=C=O)=[O:26]>O1CCCC1.O>[C:25]([O:19][CH2:18][CH2:17][C:13]1[N:14]([CH2:15][CH3:16])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:20]([CH3:21])[CH3:22])[N:12]=1)(=[O:26])[NH2:27]
Reactant: CCn1c(CCO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(CCOC(N)=O)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
In 15 ml of dry tetrahydrofuran was dissolved 1.5 g (4.2 mmol) of the alcohol compound (123a), and the mixture was cooled to -30° C., followed by addition of 1.2 g (6.4 mmol) of trichloroacetylisocyanate. After 5 minutes, the mixture was warmed to 0° C., and stirred for 10 minutes. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water, and ethyl acetate was distilled off. To the residue was added 15 ml of methanol, 0.26 g of triethylamine and 0.72 ml of water, and the mixture was heated at 50° C. for 0.5 hours. The mixture was diluted with ice-water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% methanol:ethyl acetate), and recrystallized from ethyl acetate-n-hexane to give 1.5 g of Compound I-137 as crystals (yield 89%). mp 161-162° C.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[N:17]=1)=[O:15])[CH3:12]>CCN(CC)CC.C(Cl)Cl>[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:19]=[C:18]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:35][CH:36]=2)[N:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 23.7 %

Procedure:
Phenyl sulfonyl chloride (0.02 ml, 1.3 eq.), Et3N (1 drop) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (40 mg, 1 eq.) in CH2Cl2 (2 ml) and the mixture was reacted overnight at r.t. The reaction mixture was extracted with EA and washed with brine. The crude was purified by chromatography to give a product (13 mg, 23.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[F:28][C:29]([F:43])([F:44])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=1)[C:33]([O:20][C@@H:10]1[C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(F)cc2)[C@@H](O)C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with septa, magnetic stir bar thermocouple and nitrogen line was added 5.0 g (17.77 mmol) (3R,4S) tert-butyl-3-hydroxy-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (Example 2, Step B, Rt 13.686 min) and 100 mL methylene chloride. To the resulting solution was added 5.0 mL (35.54 mmol) triethylamine by syringe. The reaction mixture was cooled to 0° C. and 3.80 mL (19.55 mmol) 3,5-bis(trifluoromethyl)benzoyl chloride was added slowly by syringe over 10 min. A white precipitate formed after the addition was complete and the resulting mixture stirred for 1 hr at 0° C. when the cooling bath was removed. The reaction mixture was stirred an additional 2 hr at which time TLC (EtOAc/hex; 3:7) showed no starting material remained. The reaction mixture was poured into a separatory funnel which contained sat. aq. NaHCO3. The layers were separated, the organic layer dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to give the title compound as a yellow oil which was used without further purification in the next reaction. 1H-NMR (CDCl3): δ: 1.55 (s, 9H), 3.4-4.09 (br. m, 6H), 5.41 (s, 1H), 7.06 (m, 2H), 7.30 (m, 2H), 8.12 (s, 1H), 8.44 (s, 2H)ppm.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:26]3[C:31]4[S:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[C:30]=4[CH:29]=[CH:28][CH:27]=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3.C[O:40][B:41](OC)[O:42]C.Cl>O1CCCC1>[CH:29]1[C:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:26]([N:17]2[C:16]3[CH:15]=[CH:14][C:13]([B:41]([OH:42])[OH:40])=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:27][CH:28]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
An excess of 1.6M n-BuLi in hexane (14 mL, 22.3 mmol) was added to a solution of 3-bromo-9-(diberizo[b,d]thiophen-4-yl)-9H-carbazole (8.7 g, 20.3 mmol) in 100 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C. Trimethylborate (2.8 g, 26.4 mmol) was added dropwise; the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (50 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum, and the residue was crystallized from n-hexane to give the 9-(dibenzo[b,d]thiophen-4-yl)-9H-carbazol-3-ylboronic acid 4.7 g (59%)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:23]=[CH:22][C:16](/[CH:17]=[CH:18]/B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd]Cl>[F:12][C:13]1[CH:23]=[CH:22][C:16](/[CH:17]=[CH:18]/[C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccnc(/C=C/c2ccc(F)cc2)c1
Temperature: 100 °C
Yield: 47.1 %

Procedure:
Methyl 2-chloroisonicotinate (5.5 g, 32.05 mmol), (E)-4-fluorostyrylboronic acid (7.98 g, 48.08 mmol), potassium phosphate (3.93 mL, 48.08 mmol) and PdCl2 (dppf) (0.464 g, 0.64 mmol) were split into 5 equal portions and each portion was placed in a microwave reaction vessel. The vessels were evacuated and backfilled with nitrogen. Methanol (15 mL) was added to each vessel, the vessels were sealed and heated in a single node microwave reactor at 100° C. for 10 min each. The contents of the vessels was pooled and water and DCM were added, the phases separated and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 6:1 to 4:1 of EtOAc in heptane over 15 CV was used as mobile phase. (E)-Methyl 2-(4-fluorostyryl)isonicotinate (3.88 g, 47%) was isolated. 1H NMR (400 MHz, cdcl3) δ 3.98 (s, 3H), 7.04-7.18 (m, 3H), 7.52-7.62 (m, 2H), 7.63-7.71 (m, 2H), 7.93 (s, 1H), 8.74 (d, 1H). MS m/z 258 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28].[C:29](O)(=[O:31])[CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28])(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2N)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2NC(C)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 19.6 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.1 mmol), acetic acid (9 mg, 0.15 mmol), EDCI.HCl (29 mg, 0.15 mmol), and HOBt (20 mg, 0.15 mmol) in acetonitrile (5 mL) was added DIPEA (0.052 mL, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep HPLC to give the title compound as a white solid (Yield: 9 mg).