Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[O:10]=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[C:13](=O)[O:12]1.O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[C:13](=[O:12])[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=2)[C:11]1=[O:10]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1cccc(C)c1N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N1C(=O)c2ccc(C(=O)O)cc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-dimethylaniline (1.21 g) in DMF (15 mL) was added 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (1.92 g) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and the resulting precipitate was filtered, washed with water and dried under reduced pressure. The solid was suspended in HOAc (25 mL) and the mixture was heated at 110° C. for 4 h. The resulting solution was cooled and the solvent was removed under reduced pressure to give 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid as an off-white solid, mp=210-213° C.; MS (m/z) 294 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[C:21]([Cl:34])[CH:20]=1)=[O:4].[C:35](O)(=[O:38])[CH:36]=[CH2:37].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:34][C:21]1[CH:20]=[C:19]([NH:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([NH:5][C:3]([CH2:2][NH:1][C:35](=[O:38])[CH:36]=[CH2:37])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)CN
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)NCC(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OC
Temperature: 0 °C
Yield: 27 %

Procedure:
170 mg of 2-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-acetamide as a starting material was dissolved in 5 ml of THF, and cooled to 0° C. The solution was reacted with 0.04 ml of acrylic acid, 0.06 ml of pyridine and 134 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 1 hour and at room temperature for 5 hours. The reacted solution was extracted with chloroform after adding saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate methanol=10:1) to obtain the title compound (51 mg, 27%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][NH2:35]>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:35][CH2:34][CH:30]4[CH2:31][CH2:32][CH2:33][N:29]4[CH3:28])=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: CN1CCCC1CN
Product: CN1CCCC1CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with (1-methylpyrrolidin-2-yl)methylamine similar to as described in Example 2 to afford 7.6 mg of (±) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-[(1-methylpyrrolidin-2-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 470 (M)+. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 7.27 (s, 1H), 7.01 (d, J=10.4, 4.6 Hz, 1H), 4.67-4.44 (m, 2H), 4.44-4.14 (m, 2H), 2.96 (s, 2H), 2.36 (s, 1H), 2.02-1.86 (m, 2H), 1.83 (s, 1H), 1.78-1.62 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([C:7]1[CH:8]=[C:9](O)[CH:10]=[CH:11][CH:12]=1)#[N:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:4][C:11]1[CH:12]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:5]#[N:6]
Reactant: OCCBr
Reactant: N#Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cccc(OCCBr)c1
Reaction time: 8 h

Procedure:
0.71 ml (10.0 mmol) of 2-bromoethanol, 1.43 g (12.0 mmol) of 3-cyanophenol and 3.15 g (12.0 mmol) of triphenylphosphine were dissolved in 100 ml of tetrahydrofuran. 5.22 g (12.0 mmol) of diethyl azodicarboxylate (40% solution in toluene) was added to the solution at room temperature, and they were stirred overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained. This product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([N:15]5[CH2:16][CH2:17][O:18][CH2:19][CH2:20]5)[CH:10]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 75.6 %

Procedure:
Using 1.18 g of t-butyl N-{2-amino-5-[3-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate, 0.92 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.53 g of diethyl cyanophosphonate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to Example (2-1), whereby 1.48 g of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=O)[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]3[CH:25]=[CH:26][N:27]=[C:15]23)=[C:4]([F:28])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[S:30])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]3[CH:25]=[CH:26][N:27]=[C:15]23)=[C:4]([F:28])[CH:3]=1
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)Nc1cc(-n2c(=S)cc(C(F)(F)F)n3ccnc23)c(F)cc1Cl

Procedure:
A mixture of 8-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (0.6 g), diphosphorus pentasulfide (0.5 g) and toluene (30 ml) was heated to reflux for 3 hours. The solid matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography of silica gel (developing solvent: ethyl acetate) to give the compound of interest (0.5 g) as a yellow crystal.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26]1=[O:36])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:5][CH:4]=2)[C:26]1=[O:36])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O

Procedure:
Prepared from 4'-bromomethyl-1,1'-biphenyl-2-nitrile (prepared by the method of M. Fisher, et al, U.S. Pat. No. 5,206,235) and 3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) by the procedure described in Example 1, Step Q. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H), 1.90 (m, 1H), 2.40-2.60 (m, 3H), 4.28 (m, 1H), 4.94 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 5.43 (d, 7 Hz, 1H), 7.1-7.3 (m, 4H), 7.33 (d, 8 Hz, 2H), 7.35-7.50 (m, 4H), 7.60 (t, 8 Hz, 1H), 7.72 (d, 8 Hz, 1H). FAB-MS: calculated for C29H29N3 O3 467; found 468 (M+H, 15%), 368 (M-BOC, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[O:16])[C@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][OH:11])=[CH:4][CH:3]=1.[Si]([N:23]=[N+:24]=[N-])(C)(C)C>CC#N>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:16])[C@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][OH:11])=[CH:17][CH:18]=1)=[N+:23]=[N-:24]
Reactant: CC(=O)N[C@H](CO)C(=O)NCc1ccc(N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC#N
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a cooled (0° C.) CH3CN solution (70 mL) of (R)—N-(4-aminobenzyl)-2-acetamido-3-hydroxypropanamide (2.40 g, 9.56 mmol) maintained under Ar, t-BuONO (3.41 mL, 28.68 mmol) followed by TMSN3 (3.02 mL, 22.94 mmol) were slowly added. The resulting solution was allowed to stir at room temperature (16 h) under Ar. The solvent was removed in vacuo, and the product was purified by column chromatography (SiO2; 1/9 MeOH/CHCl3) to give 2.10 g (79%) of (R)—N-(4-azidobenzyl)-2-acetamido-3-hydroxypropanamide as a white solid: mp 161-163° C.; [α]26D +13.2° (c 1.0, MeOH); Rf=0.35 (1/9 MeOH/CHCl3); IR (nujol mull) 3268, 2924, 2128, 1649, 1553, 1459 cm−1; 1H NMR (DMSO-d6) δ 1.87 (s, CH3C(O)), 3.58 (t, J=5.7 Hz, CH2OH), 4.26-4.32 (m, CH2Ar and CH), 4.91 (t, J=5.7 Hz, OH), 7.03-7.08 (m, 2 ArH), 7.28-7.31 (m, 2 ArH), 7.94 (d, J=8.1 Hz, NHCH), 8.40 (1, J=6.0 Hz, NHCH2); 13C NMR (DMSO-d6) δ 22.7 (CH3C(O)), 41.5 (CH2Ph), 55.3 (CH), 61.7 (CH2OH), 118.9, 128.7, 136.5, 137.7 (C6H5), 169.4, 170.3 (2C(O)); HRMS (ESI) 278.1249 [M+H+] (calcd. for C12H16N6O3 278.1253); Anal. (C12H15N5O3) Calcd.: C, 51.98%; H, 5.45%; N, 25.26%. Found: C, 51.93%; H, 5.47%; N, 24.98%.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[CH3:14][C:15]1[O:21]C(C)(C)O[C:17](=[O:18])[CH:16]=1>C1(C)C=CC=CC=1>[C:17]([O:1][CH2:2][N:3]1[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]2[C:7]1=[O:8])(=[O:18])[CH2:16][C:15]([CH3:14])=[O:21]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1CO
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCN1C(=O)c2ccccc2C1=O
Yield: 97.8 %

Procedure:
A solution of 10.0 g (0.056 mol) of N-(hydroxymethyl)phthalimide and 8.02 g (0.056 mol) of 2,2,6-trimethyl-1,3-dioxen-4-one in 100 ml of toluene was refluxed for 24 hours under nitrogen. Recrystallization in ethyl acetate gives 14.3 g (97%) of an off-white solid: mp 106°-109° C.; NMR (CDCl3) 7.6 (4H,m), 5.6 (2H,s), 3.4 (2H,s), 2.18 (3H,s);
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][C:7]2([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)C.C(=O)([O-])[O-].[Na+].[Na+].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH:24]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][O:6][CH:7]3[C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)[CH2:26][CH2:25]1
Reactant: CC1(C2=NCCN2)OCCc2c(Br)cccc21
Reactant: OB(O)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: c1cc(C2CC2)c2c(c1)C(C1=NCCN1)OCC2
Temperature: 120 °C

Procedure:
The mixture of 2-(5-bromo-1-methylisochroman-1-yl)-4,5-dihydro-1H-imidazole (Example 11, 0.15 g), sodium carbonate (0.27 g), bis(triphenylphosphine)palladium(II) chloride (0.02 g), cyclopropylboronic acid (0.09 g), water (1 ml), and acetonitrile (2 ml) was heated in a microwave oven at 120° C. for 15 min. The title compound was purified with separation methods A and G. (Yield 8 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[S:25]([CH3:24])(=[O:27])=[O:26])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2cccc(CNCCc3ccccn3)c2)n1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N(CCc1ccccn1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 16 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])(O)[CH3:12])[CH:3]=1.OS(O)(=O)=O>>[CH3:12][C:11]1([CH3:14])[CH2:10][C:9]([CH3:16])([CH3:15])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[S:8]1
Reactant: CC(C)(O)CC(C)(C)c1cc(Br)ccc1S
Agent: O=S(=O)(O)O
Product: CC1(C)CC(C)(C)c2cc(Br)ccc2S1

Procedure:
A mixture of 500 mg (1.49 mmol) of 4-bromo-2-(1,1,3-trimethyl-3-hydroxybutyl) thiophenol (Compound 71) and 8 ml of 20 percent aqueous H2SO4 was heated at reflux for 24 h. The mixture was extracted with hexanes the organic extracts were combined and washed successively with water, saturated NaHCO3, water again, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): δ 1.35 (6H, s), 1.40 (6H, s) 1.93 (2H, s), 7.17 (1H, dd, J-8.4 Hz, 2.1 Hz), 7.23 (1H, d, J~8.4 Hz), 7.26 (1H, d, J~2.1 Hz). MS exact mass, m/e 284.0221 (calcd. for C13H17 S Br, 284.0234).
Reaction SMILES: Cl[Sn]Cl.[F:4][C:5]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]1[CH:17]=[CH:16][C:12]([N:13]([CH3:15])[CH3:14])=[CH:11][C:10]=1[N+:18]([O-])=O>Cl.C(O)(=O)C>[F:4][C:5]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]1[CH:17]=[CH:16][C:12]([N:13]([CH3:14])[CH3:15])=[CH:11][C:10]=1[NH2:18]
Reactant: CN(C)c1ccc(/C=C/c2c(F)cccc2F)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Product: CN(C)c1ccc(/C=C/c2c(F)cccc2F)c(N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
A solution of 5 g (26.4 mmol, 8.5 equiv) of SnCl2 in 7 mL of conc HCl was added dropwise to a solution of 0.95 g (3.1 mmol) of 6 in 100 mL of glacial acetic acid. The mixture was stirred for ca. 12 h at 25° C. A precipitate was collected by filtration, washed with 5 mL of glacial acetic acid, and suspended in 200 mL of water. The aqueous suspension was adjusted to pH 9-10 with NaOH and was extracted with Et2O. The combined ethereal extracts were washed with water, dried over anhydrous MgSO4 and concentrated. The residue was recrystallized from ethanol to afford 590 mg (69%) of 7 as yellow crystals: mp 97-98° C. 1H NMR (DMSO-d6): δ 7.41 (d, 1H, J=16.4 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.24-7.18 (m, 1H), 7.12-7.05 (m, 2H), 6.61 (d, 1H, J=16.4 Hz), 6.10 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 6.03 (d, 1H, J=2.8 Hz), 5.05 (br.s, 2H), 2.87 (s, 6H). 13C NMR (DMSO-d6): δ 160.25 (dd, J1=246.0 Hz, J2=7.9 Hz, two C), 151.95, 147.98, 132.39 (t, J=7.1 Hz), 127.45 (t, J=11.1 Hz), 127.06, 116.11 (t, J=15.1 Hz), 112.20 (dd, J1=18.7 Hz, J2=6.8 Hz, two C), 111.39, 108.21, 103.52, 99.07, 40.28 (two C). MS: m/z (%) 275 (21), 274 (100), 273 (33), 257 (15), 211 (16). Anal. Calcd for C16H16F2N2: C, 70.06; H, 5.88. Found: C, 70.18; H, 5.94.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>CCOC(C)=O.CC(O)C>[CH:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[C:5]([O:4][CH2:3][C@@H:2]([OH:1])[CH2:18][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)c(OC)c1
Temperature: 85 °C
Yield: 47.6 %

Procedure:
To a solution of (S)-(+)-4-(2,3-Epoxypropoxy)-carbazole (7.56 g, 0.031 mole) in EtOAc/IPA (40/80 mL) was added 2,4-dimethoxybenzylamine (9.48 mL, 0.063 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was cooled to room temperature and purified following the procedure similar to one described in step 11 for the synthesis of example 23, to afford the desired compound as colorless solid (6 g, 48%) with m.p: 152-154° C. 1H NMR (400 MHz, CDCl3): δ 2.17 (s 1H), 2.88-2.92 (m, 1H), 2.98-3.00 (m, 1H), 3.74-3.87 (m, 8H), 4.18-4.32 (m, 3H), 6.38-6.45 (m, 2H), 6.67 (d, 1H, J=8.0 Hz), 7.05 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.18-7.40 (m, 4H), 8.08 (s, 1H), 8.21 (d, 1H, J=8.0 Hz). MS m/z: 407.1 (M+1). Chiral purity: 99.96%
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].[OH-].[Na+].[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH:31]2[O:34][CH:32]2[CH3:33])=[CH:28][CH:27]=1)[CH3:21]>C(O)C>[OH:34][CH:32]([CH2:31][O:30][C:29]1[CH:35]=[CH:36][C:26]([O:25][CH2:24][CH2:23][O:22][CH2:20][CH3:21])=[CH:27][CH:28]=1)[CH2:33][NH:6][CH2:7][CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CCOCCOc1ccc(OC2OC2C)cc1
Reactant: NCCNC(=O)N1CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCCOc1ccc(OCC(O)CNCCNC(=O)N2CCOCC2)cc1

Procedure:
12.0 g of the neutral sulphate of N-2-aminoethyl-4-morpholinecarboxamide, 2.16 g NaOH and 100 ml of absolute ethanol were refluxed 1 h. During continuing reflux 8.6 g of 3-(4-(2-ethoxyethoxy)phenoxy-1,2-epoxypropane in 50 ml of abs. ethanol was added little by little. The resulting mixture was refluxed over night, filtered and evaporated. The residue was dissolved in 200 ml of ethyl acetate and extracted twice with water. The water phase was treated with NaCl and extracted twice with ethyl acetate. The ethyl acetate phase was dried, filtered and evaporated. The residue was crystallized from ether, and recrystallized from ethyl acetate. Yield 1.1 g. Melting point 75°-77° C. (base). The structure was determined using NMR analysis.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26]I)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOCC>[C:11]([N:18]1[CH2:19][CH2:20][CH:21]([CH2:24][CH2:25][CH2:26][O:1][C:2]2[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COC(=O)c1cc(O)no1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-hydroxy-5-isoxazolecarboxylate (Aldrich) (3-5) (286 mg, 2.0 mmol), 3-4 (706 mg, 2.0 mmol), Cs2CO3 (650 mg, 2.0 mmol), and DMF (10 mL) was stirred at ambient temperature. After 72 hours the reaction mixture was diluted with ether and then washed with H2O and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 4% acetone/CH2Cl2) gave 3-6 as a colorless solid. Rf 0.54 (silica, 40 %EtOAc/hexanes).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[S:30]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31]1>ClCCCl>[F:22][C:2]([F:1])([F:21])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:35]([C:32]3[CH:33]=[CH:34][S:30][CH:31]=3)(=[O:37])=[O:36])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=S(=O)(c1ccsc1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (50 mg, 0.152 mmol, published PCT patent application no. WO 2006/094842) and triethylamine (63.6 μL, 0.457 mmol) in 1,2-dichloroethane (1.5 mL) was added 3-thiophenesulfonyl chloride (1M in dichloroethane, 168 μL, 0.168 mmol, ASDI, Newark, Del.). The reaction was shaken on an orbital shaker for 18 h. The reaction solvent was removed under reduced pressure and the crude product was purified by reverse-phase preparative HPLC using a Sunfire Prep C18 OBD (100×19 mm, 5 μm) column, 0.1% TFA in MeOH/H2O, gradient (65% to 95% over 4.5 min) to provide 1,1,1,3,3,3-hexafluoro-2-(4-(4-(3-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.27 (m, 1H), 7.85 (dd, J=5.1, 2.9 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.37 (d, J=5.1 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.33-3.28 (m, 4H), 3.07-3.01 (m, 4H). m/z (ESI, +ve ion) 475.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.597 μM; GK-GKRP EC50 (LC MS/MS)=0.964 μM.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([CH3:14])=[C:12]([Cl:15])[CH:11]=[C:10]([C:16](=O)[CH3:17])[C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)C(=O)C)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+]>CO.C(#N)C>[NH2:32][CH:16]([C:10]1[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:8]([NH:4][C:1](=[O:3])[CH3:2])[C:13]([CH3:14])=[C:12]([Cl:15])[CH:11]=1)[CH3:17]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(N(C(C)=O)C(C)=O)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(=O)Nc1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of N-acetyl-N-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)acetamide (57 mg, 0.16 mmol), ammonium acetate (120 mg, 1.6 mmol) and sodium cyanoborohydride (20 mg, 0.32 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step. LCMS calculated for C17H19ClFN2O (M+H)+: m/z=321.1. found: 321.0.