Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH:18]([CH:20]1[O:24][C:23]([NH:25][CH3:26])=[N:22][C:21]1=[O:27])[CH3:19])=[CH:12][NH:13]2)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH:18]([CH:20]1[O:24][C:23]([NH:25][CH3:26])=[N:22][C:21]1=[O:27])[CH3:19])=[CH:12][NH:13]2
Reactant: CNC1=NC(=O)C(C(C)c2c[nH]c3cccc(OCc4ccccc4)c23)O1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC1=NC(=O)C(C(C)c2c[nH]c3cccc(O)c23)O1
Reaction time: 24 h
Yield: 64.3 %

Procedure:
5-[1-(4-benzyloxyindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one (149 mg) was dissolved in a mixture of ethanol and tetrahydrofuran (5:1.6 ml). 10% palladium-carbon (45 mg) was added and the whole was hydrogenated for 24 hours at room temperature under normal pressure. The catalyst was removed from the mixture by filtration and 10% palladium-carbon (45 mg) was added again. The whole was hydrogenated for additional 24 hours at room temperature under normal pressure. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to give a residue, which was subjected to silica gel chromatography. Elution with hexane-acetone (1:1) provided the titled compound (72 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:16][NH2:17].C(N(CC)CC)C>C(O)C>[NH:16]([C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1)[NH2:17]
Reactant: O=C(c1ccc(Cl)nc1)N1CCOCC1
Reactant: NN
Solvent: CCO
Solvent: CCN(CC)CC
Product: NNc1ccc(C(=O)N2CCOCC2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To (6-chloro-pyridin-3-yl)-morpholin-4-yl-methanone (0.649 g, 2.86 mmoles) in ethanol (6 mL) was added 0.270 uL (3.0 equivalents) of hydrazine, followed by triethylamine 438.9 uL (1.1 equivalents). The reaction was stirred overnight at 100° C. to give (6-hydrazino-pyridin-3-yl)-morpholin-4-yl-methanone. The reaction was filtered and then concentrated to dryness. The crude residue, (6-hydrazino-pyridin-3-yl)-morpholin-4-yl-methanone, weighed 0.372 g (76% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=1[O:17][CH3:18].C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]2=[O:13])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: CCCC(CC(=O)O)Cc1ccc(F)c(OC)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC1CC(=O)c2cc(F)c(OC)cc2C1
Yield: 95.3 %

Procedure:
3-{[4-Fluoro-3-(methyloxy)phenyl]methyl}hexanoic acid (132) (1.92 g, 7.55 mmol) was treated with oxalyl chloride followed by AlCl3 in CH2Cl2 to give 1.70 g (95%) of the title compound (133) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.90-0.95 (m, 3H), 1.35-1.45 (m, 4H), 2.10-2.30 (m, 2H), 2.60-2.75 (m, 2H), 2.90-3.00 (m, 1H), 3.93 (s, 3H), 6.74 (d, J=7.7 Hz, 1H), 7.70 (d, J=11.5 Hz, 1H). LCMS (ESI): m/z 236 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C-:21]#[N:22].[Na+]>CS(C)=O>[F:20][C:16]1([F:19])[CH2:15][CH2:14][CH:13]([CH2:12][C:21]#[N:22])[CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC1CCC(F)(F)CC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of Example 184B (4.5 g, 15 mmol) in dimethylsulfoxide (100 mL) was added sodium cyanide (Aldrich, 2.2 g, 45 mmol). The reaction mixture was stirred at 80° C. for 14 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% pentane in ether) to afford the title compound. MS (ESI+) m/z 177 (M+NH4)+.
Reaction SMILES: C(OC([NH:8][CH:9]([O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:10][CH2:11][O:12][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([O:32][CH:9]([NH2:8])[CH2:10][CH2:11][O:12][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCC(NC(=O)OC(C)(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCC(N)OC(=O)CCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
720 mg (1 mmol) 8, dissolved in 3 ml abs. CH2Cl2 was placed in a round-bottom flask and 1 ml (13.06 mmol) TFA was added. After stirring for 30 min. at room temperature the reaction mixture was diluted with 50 ml CH2Cl2, washed with saturated NaHCO3 solution and dried over Na2SO4. After removing the solvent 589 mg (95%) of a colourless oil was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][C:20]([OH:22])=O)[C:7]2[NH:8][C:9]3[C:10]4[CH2:18][CH2:17][CH2:16][CH2:15][C:11]=4[CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4][O:3]1.[CH2:23]([N:25](CC)[CH2:26]C)C.ClC(OCC)=O.CNC>O1CCCC1>[CH3:23][N:25]([CH3:26])[C:20](=[O:22])[CH2:19][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:10]4[CH2:18][CH2:17][CH2:16][CH2:15][C:11]=4[CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4][O:3]1
Reactant: CCN(CC)CC
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1c3c(ccc21)CCCC3
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1(C)OCCc2c1[nH]c1c3c(ccc21)CCCC3
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
1,2,3,4,7,8,10,11-Octahydro-10-methylbenzo[g]pyrano[3,4-b]indole-10-acetic acid (4.5 g), described in Example 69, is suspended in anhydrous tetrahydrofuran (120 ml); triethylamine (4.2 ml) is added, followed by dropwise addition of ethyl chloroformate (2.14 ml) at -5° C. After stirring for 105 minutes at 0° C., the solution is added dropwise at 0° C., to a stirred solution of 40% aqueous dimethyl amine (62 ml). After 2 hr. at room temperature, the tetrahydrofuran is evaporated and water added. The mixture is extracted with chloroform, the organic solution washed with water (2 x), dried and taken to dryness to give the title compound, m.p. 176°-178° C., νmaxCHCl3 3360, 1630 cm-1. This compound exhibits antibacterial activity.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:23])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15](OS(C)(=O)=O)[CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]([C:34]1[CH:39]=[C:38]([SH:40])[CH:37]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]=1[OH:45])([CH3:33])([CH3:32])[CH3:31]>CCC(C)=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:23])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([S:40][C:38]3[CH:37]=[C:36]([C:41]([CH3:42])([CH3:43])[CH3:44])[C:35]([OH:45])=[C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:39]=3)[CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](OS(C)(=O)=O)C2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@@H](Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2)n1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of (S)-5-(3-methanesulfonyloxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 13b, 7.75 g, 21.2 mmol) and cesium carbonate (11.6 g, 31.8 mmol) in degassed MEK (85 mL) at 60° C. was added 2,6-di-tert-butyl-4-mercaptophenol (7.6 g, 31.8 mmol). The resulting solution was stirred at 60° C. for 3 h. Upon completion, as determined by HPLC, the reaction was diluted with H2O (200 mL) and Ethyl acetate (100 mL). The layers were cut and the aqueous layer was extracted with Ethyl acetate (3×100 mL). The combined organic cuts were washed with a saturated ammonium chloride solution (1×100 mL), a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure. Silica gel chromatography (Ethyl acetate:hexanes, 1:2) afforded 9.34 g (87%) of (R)-5-[3-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-pyrrolidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a white solid, mp 83-85° C. 1H-NMR (400 MHz, CDCl3): δ 7.23 (d, 1H, J=2.0 Hz), 7.21 (s, 2H), 7.17 (d, 1H, J=2.0 Hz), 5.30 (s, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 3.59 (dd, 1H, J=10.4, 7.2 Hz), 3.47 (pentet, 1H, J=6.8 Hz), 3.28-3.39 (m, 2H), 3.10 (dd, 1H, J=10.4, 6.4 Hz), 2.12-2.20 (m, 1H), 1.75-1.84 (m, 1H), 1.42 (s, 18H). Anal. Calcd. for C25H36N2O5S2: C, 59.03; H, 7.13; N, 5.51; S, 12.61. Found: C, 59.63; H, 7.34; N, 5.39; S, 12.23.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][C@@H:5]([CH2:8][OH:9])[O:4][CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([NH:18][CH3:19])[N:12]=1.C([O-])([O-])=O.[K+].[K+].Cl>CCO.CCOCC.O>[Cl:10][C:11]1[N:12]=[C:13]([NH:18][CH3:19])[N:14]=[C:15]([N:7]2[C@H:2]([CH3:1])[CH2:3][O:4][C@H:5]([CH2:8][OH:9])[CH2:6]2)[CH:16]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CO[C@H](CO)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CNc1nc(Cl)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Yield: 55.9 %

Procedure:
A mixture of [(2S,5R)-5-methyl-2-morpholinyl]methanol (11.50 g, 65.2 mmol), 4,6-dichloro-N-methyl-2-pyrimidinamine (11.38 g, 63.9 mmol), and K2CO3 (19.87 g, 144 mmol) in EtOH (250 mL) was stirred at reflux under nitrogen for 23 hours. The mixture was cooled, poured into water (500 mL), and extracted with CH2Cl2 (3×400 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give a cream solid. The residue was purified by flash chromatography (400 g SiO2, 10-60% EtOAc in hexanes gradient). The product was collected and concentrated in vacuo to give a very sticky foam. The residue was taken up in Et2O (250 mL) and HCl (4.0 M in 1,4-dioxane, 10 mL) was added dropwise while the mixture was swirled. The solid that formed was collected by vacuum filtration and dried in the vacuum oven overnight to give a hydrochloride salt of the title compound (9.75 g) as a white solid. LC-MS (ES) m/z=273, 275 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:9]3[C:14]([CH:15]=2)=[C:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38]>C(Cl)Cl.CCOCC>[ClH:38].[C:1]1([C:7]2[N:8]([S:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:30])=[O:31])[C:9]3[C:14]([CH:15]=2)=[C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(-c2ccccc2)n3S(=O)(=O)c2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2c(N3CCNCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-[2-phenyl-1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate (30 mg, 0.058 mmol) was dissolved in CH2Cl2 (1 mL) followed by addition of HCl in ether (1 mL). The reaction was shaken for 2 h at room temperature. The resulting precipitate was filtered off and washed with ether giving 20 mg of the desired compound (80%). 1H NMR (270 MHz, DMSO-d6) δ 9.02 (br, 1H), 7.90-7.80 (m, 3H), 7.75-7.55 (m, 3H), 7.32 (s, 1H), 7.22 (t, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 3.35-310 (m, 8H). MS (ESI+) for m/z 418 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[NH3:16].C(O)C.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH2:16])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1ccc2c(c1)CCCC2N
Temperature: 0 °C
Yield: 24 %

Procedure:
3,4-Dihydro-6,7-dimethoxynaphthalen-1(2H)-one (25.0 mmol), titanium(IV) isopropoxide (50.0 mmol) and 2 M solution of ammonia in ethanol (120 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0° C. and sodium borohydride was added portionwise during 10 min. (40.0 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 130 mL), the precipitate that formed was filtered off and washed with ethyl acetate (25 mL×3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL×2). The combined organic extracts were washed with 1 M HCl (50 mL). The acidic aqueous extracts were washed with ethyl acetate (100 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (75 mL×3). The combined organic extracts were washed with brine (75 mL), dried (Na2SO4), and concentrated in vacuo to afford the desired product (24% yield). 1H NMR (400 MHz, CDCl3): δ 7.31 (d, 1H), 6.74 (dd, 1H), 6.60 (d, 1H), 3.94 (m, 1H), 3.78 (s, 3H), 2.75 (m, 2H), 2.01 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][N:8]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:5]2=[N:6][CH:7]=1.Cl.O1CCOCC1>CO>[ClH:1].[NH:20]1[CH2:19][CH:18]([NH:17][C:15]2[C:14]([F:29])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:8]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:9]=3)[N:16]=2)[CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Temperature: 80 °C

Procedure:
A suspension of tert-butyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate, 6b, (0.23 g, 0.40 mmol) in methanol (10 mL) was treated with 4N HCl/dioxane (5 mL, 20 mmol) then heated at 80° C. for 30 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 62.9 %

Procedure:
The general procedure from Example 9 was followed using 4-methylchlorobenzene (152 mg, 1.2 mmol) and PhB(OH)2 (1.2 mmol) with Pd2 (dba)3 (20 mg, 0.0218 mmol) and (Me3C)2PH(O) from Experiment 2 (14.5 mg, 0.0878 mmol) and CsCO3 (651 mg, 2.0 mmol) in 4.0 mL of 1,4-dioxane. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 127 mg (63% yield) of 4-phenyltoluene. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.74 (d, J=7.50 Hz, 2H), 7.65 (d, J=8.05 Hz, 2H), 7.57 (m, 2H), 7.47 (m, 1H), 7.40 (m, 2H), 2.54 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 141.1, 138.3, 136.9, 129.4, 128.6, 126.9, 126.8, 21.0 ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)C(N)=O.C[O-].[Na+].BrBr.[OH-].[K+].C[NH:22]C(=O)[O-]>O.CO>[Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[NH2:22]
Reactant: CNC(=O)[O-]
Reactant: COc1cc(C)c(Br)cc1C(N)=O
Agent: BrBr
Agent: C[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(Br)cc1N
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 250 ml 3-neck RBF fitted with a magnetic stirring bar, a thermometer, a dropping funnel and a condenser was charged with 5-bromo-2-methoxy-4-methylbenzamide 12b (6 g, 24.6 mmol), anhydrous MeOH (40 mL) and 25% NaOMe solution in MeOH (21 mL, 98.4 mmol). This slurry was cooled to 5° C. and bromine (1.4 mL, 27.1 mmol) was added drop wise causing an exothermic reaction and the formation of a cloudy solution. The reaction mixture was stirred for 30 min at RT, and then heated to reflux for 1 hour. The solvent was removed under vacuum, the residue was re-dissolved in EtOH (50 mL) and KOH (5.5 g, 98.4 mmol) was added. The mixture was allowed to react under reflux for 16 hours in order to hydrolyze the intermediate methylcarbamate. Then the reaction mixture was diluted with H2O (300 mL) and the product was extracted into Et2O (3×100 mL). The combined organic layers were filtered through a pad of silica gel and evaporated to dryness to give 5-bromo-2-methoxy-4-methylaniline 12c (4.8 g, 90% yield) pure by 1H NMR as a light brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([OH:16])[CH2:14][CH3:15]>S(=O)(=O)(O)O>[CH2:13]([O:16][C:7](=[O:8])[CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=1)[CH2:14][CH3:15]
Reactant: CCCO
Reactant: COc1cc(CCO)ccc1O
Agent: O=S(=O)(O)O
Product: CCCOC(=O)Cc1ccc(O)c(OC)c1
Temperature: 100 °C

Procedure:
4-Hydroxy-3-methoxyphenethyl alcohol (Sigma-Aldrich) was dissolved in anhydrous 1-propanol. To this solution ˜5 drops of concentrated sulphuric acid were added and the solution was heated at 100° C. for 3–5 hours in a pressure tube. When the reaction was complete, the 1-propanol was removed under reduced pressure, the resulting oil was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, distilled water, and then brine. The solution was dried over magnesium sulfate and filtered and the solvent was removed under reduced pressure, giving 15-A as a red oil in almost quantitative yield.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([N:16]1[CH2:33][CH2:32][CH2:31][N:19]2[C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][C:21]=3[N:30]=[C:18]2[CH2:17]1)(=[O:15])=[O:14].[OH-].[NH4+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH3:12][S:13]([N:16]1[CH2:33][CH2:32][CH2:31][N:19]2[C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N+:23]([O-:9])=[CH:22][C:21]=3[N:30]=[C:18]2[CH2:17]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCCn2c(nc3c[n+]([O-])c4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
mCPBA (2.55 g of 77%, 11.38 mmol) was added to a suspension of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline (3.0 g, 9.5 mmol) in chloroform, and the reaction was stirred for 30 minutes at ambient temperature. The reaction was incomplete as determined by LC/MS analysis. Additional mCPBA (approximately 0.5 equivalent) was added twice, and the reaction was stirred overnight. The solvent was removed under reduced pressure, and a solution of potassium hydroxide in methanol was added to adjust to pH 7.5. The methanol was removed under reduced pressure, and residue was dissolved in chloroform. Additional mCPBA (1.2 equivalents) was added, and the reaction was stirred for two hours. Additional mCPBA was added, and the reaction was stirred overnight at ambient temperature. Ammonium hydroxide (15 mL) and p-toluenesulfonyl chloride (1.99 g, 10.4 mmol) were added, and the reaction was stirred at ambient temperature for two hours. The organic layer was separated, concentrated under reduced pressure, and purified by normal phase preparative HPLC on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 42-minute gradient from 0:100 to 25:75). The resulting solid was recrystallized from 5:2:1 acetonitrile/ethanol/methanol to provide 9-(methylsulfonyl)-5-oxido-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline, which was dissolved in chloroform, treated with ammonium hydroxide and p-toluenesulfonyl chloride, and purified by chromatography and recrystallization again as described above to provide 161 mg of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, mp 280° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([OH:36])[CH:30]=2)([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1>CN(C=O)C>[CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([O:36][CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH:30]=2)([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(NC1CCCC1)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(O)c1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of (R)-1-cyclopentyl-3-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, prepared as described in Procedure 59, (20 mg, 0.039 mmol) in DMF (0.1 mL) was added K2CO3 (12 mg, 0.086 mmol), followed by 2,2-dimethyloxirane (28 mg, 0.39 mmol). The resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was washed with H2O, sat. NaCl and dried over Na2SO4 and filtered. The organic solvent was evaporated under reduced pressure and the residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea (Example 304) as white lyophillate (11 mg, 56% yield). LCMS: RT=4.066 min [M+H] 577.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm (retention time, column type, size, solvent, flow rate, gradient). NMR: 400 MHz 1H (CD3OD) ppm 1.27 (d, J=2.20 Hz, 6H), 1.32-1.49 (m, 2H), 1.54-1.76 (m, 4H), 1.81-1.98 (m, 2H), 3.53 (d, J=9.23 Hz, 1H), 3.69 (d, J=9.23 Hz, 1H), 3.78 (d, J=12.74 Hz, 1H), 3.91 (t, J=6.15 Hz, 1H), 4.02 (d, J=12.74 Hz, 1H), 6.63-6.70 (m, 1H), 6.72-6.79 (m, 3H), 7.01 (dd, J=10.99, 8.79 Hz, 1H), 7.09-7.20 (m, 3H), 7.27-7.42 (m, 3H).