Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:23]C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1

Procedure:
A solution of acetic acid 2,5-bis(benzyloxy)phenyl ester (1.85 g) and 5M sodium hydroxide solution (10.6 ml) in ethanol (11 ml) was heated under reflux for 6.5 hrs. After ethanol was evaporated under reduced pressure the clear solution was made acidic with diluted hydrochloric acid. The precipitated product was collected by filtration, washed with cold water and dried under reduced pressure. Yield is 0.56 g. 1H NMR (DMSO-d6) δ=4.97 (s, 2H), 5.01 (s, 2H), 6.34 (dd, J=3.1, 8.8 Hz, 1H), 6.49(d, J=3.1 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 7.28-7.46 (m, 10H), 9.1 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)Oc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)Oc1cccnc1

Procedure:
Ethyl 8-(p-chlorophenylsulfonamido)-5-(3-pyridyloxy)-octanoate is hydrolyzed with 1N aqueous sodium hydroxide and dioxane and the product is purified using preparative thin layer chromatography on silica gel using 4:1 ethyl acetate/hexane with 1% acetic acid as eluent to give 8-(p-chlorophenylsulfonamido)-5-(3-pyridyloxy)-octanoic acid; 1H-NMR (CDCl3): delta 8.16 (brs,1H), 8.08 (d,1H), 4.39 (m,1H), 2.86 (t,2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11](OC)=[CH:10][CH:9]=1>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:11]1[C:12]2[C:13](=[O:23])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:22])[C:21]=2[C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(OC)c2c1C(=O)c1ccccc1C2=O
Reactant: NCCCN
Solvent: ClCCl
Product: COc1ccc(NCCCN)c2c1C(=O)c1ccccc1C2=O

Procedure:
A solution of 1,3-diaminopropane (2.07 g, 28 mmol) and 1,4 dimethoxyanthraquinone (1.50 g, 5.6 mmol) in freshly distilled CH2Cl2 (1.5 l) was fitted with a reflux condenser, and irradiated with a sunlamp for 6 h. The solvent was distilled and the crude mixture was dried in vacuo overnight. The crude product was triturated with warm petroleum ether to remove excess amine. Chromatography (silica gel CCl4 and CH2Cl2, 1:1) was performed by slowly increasing the polarity of the solvent to CH2Cl2 to remove the unreacted 1,4-dimethoxyanthraquinone. Upon elution with methanol, a purple band slowly developed. A purple oil remained upon removal of the solvent. The oil was extracted with warm CCl4, and crystallized by adding petroleum ether to the combined CCl4 extracts. Crystallization afforded a purple solid, 0.48 g (28%) in three crops. Recrystallization from a mixture of CCl4 and petroleum ether afforded an analytical sample: mp 108°-110° C.; 1H NMR (CDCl3)δ9.95 (broad t, 1H), 8.21-8.25 (m, 2 H), 7.68-7.73 (m, 2 H), 7.37 (d, 1 H), 7.17 (d, 1H), 4.00(s, 3 H), 3.39-3.48 (m, 2 H), 2.94 (t,2 H), 1.86-1.98 (m, 2 H), 1.36 (broad s, 2H). Anal. Calcd. for C18H18N2O3 : C, 69.66; H, 5.85, N, 9.03. Found: C, 69.75; H 5.95; N, 8.95.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].CCN(CC)CC.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:5][C@@H:2]([CH3:1])[CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CC[C@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)OS(C)(=O)=O
Temperature: 0 °C

Procedure:
An ice cold solution of (S)-2-butanol (888 mg) in DCM (15 ml) was treated with Et3N (1.26 ml) and followed by dropwise addition of methanesulfonyl chloride (0.52 ml). After 1 h the solution was washed with saturated sodium hydrogen carbonate solution (5 ml), water (2×5 ml), brine (5 ml), dried (MgSO4) and evaporated to give the title compound (D32)(1.01 g). 1H NMR δ (CDCl3): 4.74 (1H, m), 3.00 (3H, s), 1.67 (2H, m), 1.41 (1H, d, J=6.5 Hz), 0.99 (3H, t, J=7.5 Hz).
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[C:18]([F:19])=[CH:17][C:12]2[NH:13][C:14](N)=[N:15][C:11]=2[CH:10]=1.[ClH:20]>CC(C)=O.[Cu](Cl)Cl>[Cl:20][C:14]1[NH:13][C:12]2[CH:17]=[C:18]([F:19])[C:9]([F:8])=[CH:10][C:11]=2[N:15]=1
Reactant: Cl
Reactant: Nc1nc2cc(F)c(F)cc2[nH]1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC(C)=O
Product: Fc1cc2nc(Cl)[nH]c2cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
The procedure used was similar to that reported in J. Med. Chem. 40:811-818, 1997. To a mixture of copper(II) chloride (795 mg, 5.91 mmol) in acetone (20 mL) was added tert-butyl nitrite (0.53 mL, 4.43 mmol). The reaction mixture was stirred at rt for 20 minutes, 5,6-difluoro-1H-benzimidazol-2-amine (500 mg, 2.96 mmol) was then added, and the mixture was heated at reflux for 2 h (with additional portions of tert-butyl nitrite added every 0.5 h). The reaction mixture was then cooled to rt, treated with 2 N HCl, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 2-chloro-5,6-difluoro-1H-benzimidazole (580 mg, 73%), which was used without further purification in the next step. LC-MS m/z 189.2 (MH+), ret. time 1.96 min; 1H NMR (300 M, DMSO-d6) δ 7.62 (t, 2H), 13.5 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:30]=[C:29]3[C:21]([C:22]4[CH:23]=[CH:24][C:25]([C:33]5[CH:34]=[CH:35][C:36]6[N:40]=[C:39]([C@@H:41]7[CH2:49][C:44]8([O:48][CH2:47][CH2:46][O:45]8)[CH2:43][N:42]7C(OCC7C=CC=CC=7)=O)[NH:38][C:37]=6[CH:60]=5)=[CH:26][C:27]=4[C:28]3([F:32])[F:31])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[O:48]1[C:44]2([CH2:49][C@@H:41]([C:39]3[NH:38][C:37]4[CH:60]=[C:33]([C:25]5[CH:26]=[C:27]6[C:22]([C:21]7[CH:20]=[CH:19][C:18]([C:15]8[NH:14][C:13]([C@@H:9]9[CH2:10][CH2:11][CH2:12][N:8]9[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=8)=[CH:30][C:29]=7[C:28]6([F:31])[F:32])=[CH:23][CH:24]=5)[CH:34]=[CH:35][C:36]=4[N:40]=3)[NH:42][CH2:43]2)[O:45][CH2:46][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CC7(CN6C(=O)OCc6ccccc6)OCCO7)[nH]c5c4)ccc2-3)[nH]1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CC7(CN6)OCCO7)[nH]c5c4)ccc2-3)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-Benzyl 8-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate (375 mg, 0.46 mmol) was dissolved in ethyl acetate (10 mL) and to it was added triethyl amine (140 mg, 1.38 mmol), followed by 10% Pd/C (Pearlman's catalyst) (196 mg, 0.09 mmol). The flask was purged with hydrogen gas three times by applying vacuum and purging hydrogen gas from a balloon and the mixture was stirred overnight at room temperature. The crude product was filtered through a 0.2 micron Nylon filter member and the filtrate was concentrated down on rotovap. (229 mg, 73%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[C:37]=[O:38]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:37]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[O:38])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-methoxyphenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (55 mg, 0.18 mmol) and 1-isocyanato-4-methoxybenzene (27.5 mg, 0.18 mmol) according to General Procedure G to give 20 mg (24.2%) of a white solid. Anal. Calcd. for C26H33N5O2 m/z 447.3, found: 448.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.41 (d, J=9 Hz, 2H), 7.29 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 6.82 (d, J=3 Hz, 2H), 5.95 (d, J=7.6 Hz, 1H), 3.89 (d, m, 1H), 3.77 (m, 1H), 3.70 (s, 3H), 3.26 (m, 1H), 2.79 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 1.89 (m, 3H), 1.68 (m, 1H), 1.60 (m, 2H), 1.45 (m, 1H), 1.23 (m, 6H), 1.10 (m, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:30][C:31]([CH:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:37])[C:32]([O:34]CC)=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO>[OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[CH:8][CH:9]=1)[CH2:3][N:40]1[CH2:41][CH2:42][CH2:43][CH:38]([C:31]([CH3:37])([CH3:30])[C:32]([OH:34])=[O:33])[CH2:39]1
Reactant: CCOC(=O)C(C)(C)C1CCCNC1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc([C@H]3CO3)cc2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CC(C)(C(=O)O)C1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C

Procedure:
To a mixture of (S)-3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C-peak 1 (30 mg, 0.075 mmol) and ethyl 2-methyl-2-(piperidin-3-yl)propanoate (14.97 mg, 0.075 mmol) in EtOH (10 mL) was added cesium carbonate (147 mg, 0.451 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Fractions with correct mass were isolated and concentrated in vacuo. This residue was heated in 6N HCl/dioxane (1:1) at 60° C. for 3 days. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Fractions with correct mass were isolated and freeze-dried overnight. Obtained 6 mg of 2-(1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)-2-methylpropanoic. 1H NMR (400 MHz, MeOD) δ ppm 8.14 (2H, d, J=8.36 Hz), 7.57-7.64 (4H, m), 7.44-7.55 (3H, m), 5.09-5.27 (1H, m), 3.70 (2H, d, J=10.34 Hz), 3.57 (1H, br. s.), 3.23-3.27 (2H, m), 2.79-2.97 (1H, m), 1.73-1.95 (2H, m), 1.24-1.42 (2H, m), 1.15 (3H, d, J=2.86 Hz), 1.11 (3H, s), 0.76 (1H, dd, J=11.44, 9.68 Hz). MS (m+1)=571 HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=92%.
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH2:15][OH:16])[C:9]([OH:11])=O.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH2:15][OH:16])[C:9]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=1)=[O:11]
Reactant: O=C(O)c1ccc(CO)c(Br)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CO)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
EDC (1.3 equiv.) was added to a solution of 3-bromo-4-(hydroxymethyl)benzoic acid (1.0 equiv), 3-(trifluoromethyl)aniline (1.1 equiv.), HOAt (1.3 equiv.) in DMF (0.43 M). The mixture was stirred at ambient temperature 3 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by ISCO(50% EtOAc/Heptane) to yield 3-bromo-4-(hydroxymethyl)-N-(3-(trifluoromethyl)phenyl)benzamide in 35% yield. LC/MS (m/z)=374.0 (MH+), Rt=0.93 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:33])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N#N>>[C:10]([O:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][O:5][C:10](=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(CO)(CO)CO
Agent: N#N
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)(CO)COC(=O)CCCCCCCCCCCCCCCCCCCCC
Temperature: 165 °C

Procedure:
A 1000 ml round bottomed flask was charge with 648.0 g (0.15 mol) PEG 105 pentaerythritol and 99.0 g. (0.30 mol) behenic acid. The mass was heated to 100° C. with a N2 sparge, 0.75 g methane sulfonic acid and 0.1 g hypophosphorus acid were charged. The batch was heated to 165° C. while collecting the water of reaction, and maintained until an acid value of 11.5 was reached. The finished material was a white waxy solid having an acid value of 11.5, and a hydroxyl value of 27.05.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Mg]Br.[CH:20](=[O:24])[CH2:21][CH2:22][CH3:23]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:20]([OH:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC=O
Reactant: Br[Mg]C#CCCCCCCCCOC1CCCCO1
Product: CCCC(O)C#CCCCCCCCCOC1CCCCO1

Procedure:
For example, according to the above-cited British patent, one starts from 10-(2-tetrahydropyranyloxy-)dec-1-ynyl magnesium bromide, which is reacted with butyraldehyde to obtain 14-(-2-tetrahydropyranyloxy-)-tetradec-5-yn-4-ol, which is then dehydrated to 2-(-tetradec-11-en-9-ynyloxy-)-tetrahydropyranyl(cis, trans mixture); the latter, after acetylation and reduction, provides a cis-cis and cis-trans mixture of 9,11-tetradecadienyl-acetate. To obtain the desired cis-trans compound, a difficult and expensive separation of the isomers is required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[N:7]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:5]2.CN.[CH2:20]([N:22](CC)CC)C.C(Cl)(Cl)Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:13])(=[O:12])[NH:22][CH3:20])[N:7]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:5]2
Reactant: CCN(CC)CC
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Agent: CN
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc2c(cc1Br)CCN2C(C)=O

Procedure:
To a suspension of 5-bromo-6-chlorosulfonyl-N-acetylindoline, 71.83 g (0.212 mol) in tetrahydrofuran was added a 40% aqueous solution of 2 equivalents of methylamine and 2 equivalents of triethylamine. The mixture was heated to reflux for 1.5 hours, then allowed to cool. Thin layer chromatography with chloroform showed that the reaction was complete. The cooled mixture was evaporated under reduced pressure, and the resulting white solid was suppended in hot methanol, filtered and washed with methanol and allowed to dry overnight. 65.12 g of 5-bromo-6-methylsulfamoyl-N-acetylindoline was obtained (92% by weight yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].CCN(CC)CC.[C:20](Cl)(Cl)=[O:21].C1(C)C=CC=CC=1>C1COCC1>[CH3:11][C:9]1([CH3:10])[O:12][C:20](=[O:21])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1=2
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(N)c(C(C)(C)O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Compound 14A (11.8 mmol, 1.95 g) in 200 mL THF was added Et3N (29.6 mmol, 4.06 mL) at 0° C. followed by a dropwise addition of a solution of phosgene in toluene (20% solution, 12.19 mmol, 7.9 mL). The reaction mixture was stirred at r.t. overnight It was extracted with Et2O, washed with water and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo to the desired product (2.14 g, expected wt.=2.25 g) which was used in the next step without further purification. MS (electrospray): mass calculated for C11H13NO2, 191.09, m/z found 192 (100%), [M+H]+.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[CH:15]1[CH:20]([OH:21])[CH2:19][CH2:18][CH2:17][CH:16]1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1.CO>[OH:21][CH:20]1[CH2:19][CH2:18][CH2:17][CH:16]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[CH2:15]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCC(O)C1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1C1CCCC(O)C1
Temperature: 80 °C
Reaction time: 64 h
Yield: 79.7 %

Procedure:
Tri-n-butyltin hydride (430 g, 1.48 mol) was added to a stirred solution of 2-(2-bromo-3-hydroxy-cyclohexyl)-isoindole-1,3-dione (400 g, 1.23 mol) and 2,2′-azobis(2-methylpropionitrile) (20 g) in toluene (4000 mL) and methanol (400 mL) and the reaction mixture was stirred at 80° C. for 64 h. The reaction mixture was concentrated to give the crude product. The crude product was washed with petroleum ether and ethyl acetate (1:1) to give 2-(3-hydroxy-cyclohexyl)-isoindole-1,3-dione (240 g, 0.98 mol) as a white solid. 1H NMR (CD3OD, 400 MHz): δ ppm 7.82 (m, 4H), 4.16 (m, 1H), 3.63 (m, 1H), 2.13 (m, 2H), 1.98 (d, 2H), 1.89 (m, 1H),1.68 (t, 1H), 1.46 (m, 1H),1.31 (m, 1H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[N:21]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[CH:25]=[C:24]([CH3:26])[CH:23]=2)=[CH:28][CH:29]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
To N-tert-butyl-3-{1-[6-(4-chloro-phenyl)-4-methyl-pyridin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (example 298) (0.028 g, 0.058 mmol) was added TFA (2 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as an off-white solid (0.025 g, 101%). MS (ISP) 425.1 [(M+H)+] and 427 [(M+2+H)+].
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH3:11])[O:8][C:7]=12.C([Li])CCC.[C:17](=[O:19])=[O:18]>C(OCC)C>[CH3:11][C:9]1[O:8][C:7]2=[C:2]([C:17]([OH:19])=[O:18])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1
Reactant: Cc1cc2ccnc(Br)c2o1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc2ccnc(C(=O)O)c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-bromo-2-methylfurano[2,3-c]pyridine (1.76 g) in dry diethyl ether (45 ml) under an atmosphere of nitrogen, was cooled to -78° C. and treated with n-butyllithium (1.6M in hexane) (5.8 ml). After stirring for 2 hours, the reaction mixture was poured onto a mixture of solid carbon dioxide pellets and diethyl ether (5 ml). After warming to room temperature, the solvent was removed under reduced pressure. The residue was triturated with diethyl ether and filtered to give the title compound as a pale pink powder 1.45 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([OH:17])[C:11](=[N:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[CH:10]=2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.[OH-].[Na+]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:11]2[CH:10]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[C:14]([OH:15])=[C:13]([CH3:16])[C:12]=2[OH:17])=[CH:24][CH:23]=1
Reactant: CC1=C(O)C(=Nc2ccc(N)cc2)C=C(Nc2ccc(N)cc2)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(O)c(Nc2ccc(N)cc2)cc(Nc2ccc(N)cc2)c1O

Procedure:
10 mg (0.04 mol) of 6-[(4-aminophenyl)amino]-4-[(4-aminophenyl)imino]-3-hydroxy-2-methylcyclohexa-2,5-dien-1-one are added to a solution containing 16 mg sodium hydrosulfite in 500 μl of methanol and 5 μl of aqueous sodium hydroxide solution. The reaction medium is stirred and the solution is then worked up according to the usual procedure and characterized. 4,6-Bis[(4-aminophenyl)amino]-2-methylbenzene-1,3-diol (2a) is obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2]1.C=O.[BH3-][C:16]#N.[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[CH3:16][N:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2]1
Reactant: [BH3-]C#N
Reactant: c1cncc(O[C@@H]2CCNC2)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To 164 mg (1 mmol) of 3-(3-(R)-pyrrolidinyloxy)-pyridine were added 300 mg (10 mmol) of paraformaldehyde, 314 mg (5 mmol) of NaCNBH3, and 5 mL of dry THF at room temperature. To the suspension was added 2 mL of trifluoroacetic acid dropwise. The suspension was allowed to stir at room temperature overnight. Next day, to the suspension was slowly added a mixture containing 20 mL of 4N NaOH and ice-chips. The mixture was then extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (15:1, CHCl3:MeOH) to obtain 9 mg (5%) of a clear oil: 1H NMR (300 MHz, CD3OD) δ 8.19 (1H, d, J=1.7 Hz), 8.12 (1H, m). 7.38 (2H, m), 4.99 (1H, m), 2.94-2.80 (3H, m), 2.52-1.93 (3H, m), 2.40 (3H, s); Mass spectrum (ESI) m/z 179.4 (M+H+).