Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[I:8][C:7]1[C:2]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[S:9][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)=[CH:24][CH:23]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1I
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-3-iodopyridine (4.93 g, 22.11 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (6.16 g, 25.4 mmol), and cesium carbonate (10.81 g, 33.2 mmol) in DMSO (50 mL) was heated at 80° C. overnight. The reaction was cooled to rt and poured into water (200 mL). The solution was extracted with EtOAc (3×) and the combined organic layers were washed with brine, evaporated onto silica gel and purified by flash chromatography (Isco (240 gram)) eluting with EtOAc:hexanes (0:1→1:1) to give a white crystalline solid. MS (ESI, pos. ion) m/z: 445.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][O:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:8]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][O:6][C:7]1[N:12]=[C:11]([NH:13][C:33](=[O:35])[CH3:34])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:8]=1
Reactant: Nc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)Nc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
The title compound was obtained by treating 2-(3,4-difluorobenzyloxy)-4-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Example 33) with acetic anhydride and catalytic DMAP by the same general procedure described in Example 34. Workup and flash column chromatography on silica gel (eluted with 80/20 hexanes/ethyl acetate) afforded the desired product. HPLC/MS: m/e=536 (M++1); Rt=4.5 min. 1H-NMR 500 MHz (CDCl3): δ 2.56 (s, 3H), 5.45 (s, 2H), 7.03-7.27 (m, 9H), 7.38 (d, J=2 Hz, 1H), 8.05 (bs, 1H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=3)=[O:24])[CH2:18][CH2:19]2)=[O:46])=[CH:40][CH:39]=1
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: O=C=Nc1ccc(F)cc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)Nc3ccc(F)cc3)CC2)c2ccccc21
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) was stirred in 8 mL tetrahydrofuran and cooled in an ice bath to 10° C. To the mixture was added dropwise 4-fluorophenyl isocyanate (0.11 mL, 1 mmol) and the resulting mixture was stirred 1.5 h at room temperature and filtered, and the filtrate was evaporated to an oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.147 g colorless crystals. Mp 158° C. Mass spectrum, m+ =466. Anal (C27H33 FN6O6) theory C, 58.27; H, 5.98; N, 15.10; found C, 58.48; H, 6.23; N, 14.94.
Reaction SMILES: [CH2:1]1[O:18][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[CH2:25]([NH:26][CH2:1][CH:2]([OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:1][CH:2]([OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCC1CO1
Reactant: NCCCCCCN
Product: CCCCCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCCCCC

Procedure:
Condensation of 1-heptadecene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxyheptadecylamine] (I: R = CH3 (CH2)14, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:15][N:13]([CH3:14])[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=3)=[O:29])=[CH:3][CH:4]=2)=[O:7])[CH2:9]1
Reactant: CN(C)C1CCN(C(=O)c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)c2ccc(NC(=O)c3ccc4ccccc4n3)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
A mixture of 1-(4-aminobenzoyl)-3-dimethylamino-pyrrolidine (46 mg, 0.2 mmol), quinoline-2-carbonyl chloride (38 mg, 0.2 mg) and diisopropyl ethyl amine (0.1 mL, 0.6 mmol) in CH2Cl2 is stirred at room temperature for 5 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by reverse-phase semi-preparative HPLC, using the same HPLC conditions described in Example 1, to give the title compound as a white powder (10mg), identified by HPLC and mass spectral analyses. Retention Time, MS [366.2 m/e (M+H)].
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccccc1

Procedure:
To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethylamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent: hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:12][S-:13].[Na+].O>CN(C=O)C>[CH3:12][S:13][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5]
Reactant: C[S-]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cccc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
[step 1] Commercially available 3-chloro-2-nitroaniline (3.0 g, 17 mmol) was dissolved in DMF (87 mL), sodium thiomethoxide (1.54 g, 21 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was discontinued with water, and the mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give 3-(methylthio)-2-nitroaniline (2.5 g, 78%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O[CH2:13][C:14]1[CH:39]=[CH:38][C:17]([O:18][CH2:19][C:20]2[O:24][N:23]=[C:22]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:21]=2)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]2[O:24][N:23]=[C:22]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:21]=2)=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COc2ccc(CO)cc2)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
Phthalimide (480 mg) was added to a solution of tert-butyl (2S)-2-(5-[4-(hydroxymethyl)phenoxymethyl]-1,2,4-oxadiazol-3-yl)-1-piperidinecarboxylate [see Preparation 13] (1.06 g) in tetrahydrofuran (10 ml). The mixture was cooled to 0° C. and triphenylphosphine (1.07 g) was added followed by diethylazodicarboxylate (0.642 ml). The resulting yellow solution was stirred at 0° C. for 10 mins. and then at room temperature for 1 hour. The mixture was evaporated to a low volume under reduced pressure and partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by volume, hexane:ethyl acetate to afford tert-butyl (2S)-2-[5-(4-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]phenoxymethyl)-1,2,4-oxadiazol-3-yl]-1-piperidinecarboxylate (1.09 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]([NH:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[S:8])=[O:5].[C:16](=O)([O-])[O-].[Na+].[Na+].IC>O1CCCC1>[CH3:16][S:8]/[C:7](=[N:6]\[C:4](=[O:5])[CH:3]=[C:2]([CH3:15])[CH3:1])/[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)=CC(=O)NC(=S)N1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CS/C(=N\C(=O)C=C(C)C)N1CCCCC1
Reaction time: 60 h
Yield: 150.5 %

Procedure:
A mixture of 3-methyl-N-(piperidine-1-carbonothioyl)but-2-enamide (3.21 g, 14.2 mmol, Eq: 1.00), sodium carbonate (1.58 g, 14.9 mmol, Eq: 1.05) and iodomethane (10.1 g, 4.43 ml, 70.9 mmol, Eq: 5) in tetrahydrofuran (100 ml) was stirred for 2.5 days under reflux. The mixture was evaporated, 30 ml of ethyl acetate was added and the mixture was filtrated, the filtrate was evaporated affording 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-piperidin-1-yl-meth-(Z)-ylideneamide (5.137 g, 151%) as an orange-brown semi-solid. MS: m/z=241.2 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:6][CH:5]=1)([O-])=O.C(O)C>C(OCC)(=O)C.[Pt](=O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
1.39 g (5.0 mmol) of the product prepared in step 15.2 are dissolved in 25 mL of hot ethyl acetate. After cooling to room temperature, 25 mL of absolute ethanol and 0.057 g (0.25 mmol) of platinum (IV) oxide are successively added. The reaction mixture is placed under a hydrogen pressure of 2.75 bar for 2 hours, and is filtered through thin glass fibre paper. The filtrate is concentrated under vacuum and purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (from 70/30 to 55/45). 1.05 g of the expected product are obtained. Yield=85%.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[C:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3](=[O:19])[CH:2]([NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][CH:28]=3)[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(-c2ccccc2)cc1

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-phenylbenzoyl chloride (33.8 mg, 0.156 mmole) in place of p-trifluoromethylbenzoyl chloride. The product was chromatographed on silica gel (15% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from Et2O to give the title compound which was dried in vacuo at 82° C.: (m.p. 274°-276° C.).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([C:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[C:36](O)=[O:37])[CH:18]=1)#[N:16].C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:36]([C@H:26]2[CH2:25][CH2:24][C@H:23]3[C@H:22]4[C@H:31]([CH2:30][CH2:29][C@:27]23[CH3:28])[C@:32]2([CH3:35])[C:19]([CH:18]=[C:17]([C:15]#[N:16])[CH2:34][CH2:33]2)=[CH:20][CH2:21]4)=[O:37])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
0.106 ml of benzhydrylamine were added to a solution of 100 mg of 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)], a catalytic amount of 4-dimethylaminopyridine and 0.131 ml of triethylamine in 4 ml of methylene chloride. 88.0 mg of tosyl chloride were then divided into three portions and added to this reaction mixture at 30 minute intervals at room temperature, whilst stirring. One hour after finishing the addition of the tosyl chloride, the reaction mixture was diluted with methylene chloride, and washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate, and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized from acetone, to give 138 mg (yield 92%) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10]2[CH:22]=[CH:23][S:24][C:9]=2[C:8]=1Cl)=[O:6])([CH3:3])[CH3:2].C(OC(C1C(=O)N(CC2C=CC=C(F)C=2)C2C=CSC=2C=1[N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=O)C>>[CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:10]2[CH:22]=[CH:23][S:24][C:9]=2[C:8]=1[N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Reactant: CC(C)OC(=O)c1c(Cl)c2sccc2n(Cc2cccc(F)c2)c1=O
Product: CC(C)OC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 7-chloro-4-(3-fluoro-benzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid isopropyl ester (18) by applying the same procedure as described for 4-(3-fluoro-benzyl)-5-oxo-7-piperazin-1-yl-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (19). 1H-NMR (DMSO-d6) δ 1.28 (d, J=6.0 Hz, 6H), 2.81 (m, 4H), 3.22 (m, 4H), 5.07 (m, 1H), 5.36 (s, 2H), 7.10 (m, 3H), 7.29 (m, 1H), 7.35 (m, 1H), 7.98 (m, 1H); EIMS m/z 430 (M+1).
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH2:7].[OH-].[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C@H:6]1[O:1][CH2:7]1
Reactant: O
Reactant: C=Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc([C@@H]2CO2)c1
Temperature: 0 °C
Yield: 92 %

Procedure:
A 2-necked round-bottom flask equipped with a water-cooled overhead stirrer was charged with 3-chlorostyrene (5.01 g, 3.61×10-2 mol), CH2Cl2 (45 mL), (R,R)-3 (0.578 g, 9.10×10−4 mol), and 4-PPNO (0.924 g, 5.40×10−3 mol). The solution was cooled to 0° C., and precooled buffered bleach (0.6 M, 75 mL, 4.50×10−2 mol, Clorox®, buffered to pH=11.3 with 0.05 M Na2HPO4 and IM NaOH) was added. The two phase system was stirred vigorously, and the course of the reaction was monitored by GC. Upon complete consumption of starting olefin (<6 h), the reaction mixture was filtered through a plug of Celite on a coarse glass frit and washed with CH2Cl2 (75 mL). The organic layer of the filtrate was washed with distilled water (2×25 mL), and the aqueous layers were extracted with CH2Cl2 (2×25 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Removal of the catalyst was effected by elution through a pad of SiO2 (30 g) using pentane and CH2Cl2 (1:1). The eluent was concentrated in vacuo, and subsequent bulb-to-bulb distillation (70° C., 0.6 mm Hg) from CaH2 afforded (R)-3-chlorostyrene oxide (5.15 g, 92%) as a pale yellow liquid in 32% ee.
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH2:4]1)#[N:2].[N:25]1([CH2:30][C:31](O)=[O:32])[CH:29]=[N:28][CH:27]=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:25]1([CH2:30][C:31]([N:6]2[CH2:7][C@H:3]([C:1]#[N:2])[CH2:4][C@H:5]2[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)=[O:9])=[O:32])[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: N#C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Reactant: O=C(O)Cn1cncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
A flask was charged with (2S,4R)-4-cyano-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.88 g, 2.69 mmol), prepared as in Reference 8, 2-(1H-1,2,4-triazol-1-yl)acetic acid (340 mg, 2.69 mmol), DIEA (3.0 mL, 17 mmol), HATU (1.12 g, 2.96 mmol) and DMF (10 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by chromatography (EtOAc to EtOAc/MeOH (9:1)+1% NEt3) to give (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-cyano-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.72 g, 1.66 mmol, 62% yield) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.20 (s, 1H), 8.46 (s, 1H), 7.97 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.22-7.17 (m, 2H), 7.03-6.95 (m, 4H), 5.38-5.26 (m, 2H), 4.59-4.55 (m, 1H), 4.08-3.94 (m, 2H), 3.84-3.50 (m, 2H), 2.39-2.32 (m, 1H). MS (EI) for C22H19FN6O3. found 517.3 (MH+).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11](Br)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1.[C:36]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:41]=[CH:40][C:39]([N:42]([C:58]2[CH:63]=[CH:62][C:61]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:60][CH:59]=2)[C:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11]([C:46]4[CH:45]=[CH:44][C:43]([N:42]([C:58]5[CH:59]=[CH:60][C:61]([C:64]6[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=6)=[CH:62][CH:63]=5)[C:39]5[CH:40]=[CH:41][C:36]([C:70]6[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=6)=[CH:37][CH:38]=5)=[CH:48][CH:47]=4)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc1)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Temperature: 73 °C
Reaction time: 10 h
Yield: 63.8 %

Procedure:
10-(biphenyl-4-yl)-7-bromo-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole synthesized in Example 6 (13.0 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amine (15.9 g) a toluene/ethanol (4/1, v/v) mixed solvent (250 ml), and a 2M potassium carbonate aqueous solution (51 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (2.1 g), and stirred at 73° C. for 10 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-Dichlorobenzene (1.7 L) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was cooled to a room temperature. A precipitated solid was collected by filtration and purified by recrystallization using 1,2-dichlorobenzene (1.7 L) to obtain a white powder of 10-(biphenyl-4-yl)-7-[4-bis(biphenyl-4-yl)amino-phenyl]-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (13.4 g; yield 63.8%).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:20][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1noc(N2CCC(=O)CC2)n1
Reactant: NC1CC1
Product: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared from 1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. LC (method 8): tR=0.95 min, Mass spectrum (ESI+): m/z=265 [M+H]+.