Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH:3]([C:8]1[C:9](=[O:17])[C:10]([OH:16])=[C:11]([CH3:15])[N:12]([CH3:14])[CH:13]=1)[C:4]([F:7])([F:6])[F:5].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[OH:16][C:10]1[C:9](=[O:17])[C:8]([CH:3]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:4]([F:7])([F:6])[F:5])=[CH:13][N:12]([CH3:14])[C:11]=1[CH3:15]
Reactant: C1CCNCC1
Reactant: Cc1c(O)c(=O)c(C(Cl)C(F)(F)F)cn1C
Agent: Cl
Product: Cc1c(O)c(=O)c(C(N2CCCCC2)C(F)(F)F)cn1C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(piperidin-1-yl)ethyl]pyridin-4(1H)-one (Apo7054) was prepared from the reaction of 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (304 mg, 1.0 mmol) and piperidine (2.0 mL, 20.3 mmol). The reaction was completed within 20 min, and Apo7054 was obtained as a solid product (232 mg). Yield=73%; HPLC Method 1, purity (AUC)=99.4% at 280 nm; 1H NMR (DMSO-D6) δ (ppm): 7.66 (s, 1H), 4.83-4.94 (m, 1H), 3.71 (s, 3H), 2.56 (m, 2H), 2.41 (m, 2H), 2.27 (s, 3H), 1.46 (br, 4H), 1.28 (br, 2H); MS-ESI m/z 305 [M+1]+ (100%), 220. (ii) 3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(1H-imidazol-1-yl)ethyl]pyridin-4(1H)-one (Apo7055) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (505 mg, 1.7 mmol) and imidazole (3.5 g, 51.4 mmol). The reaction was stopped when analysis of the HPLC chromatogram (Method 1) of the reaction mixture indicated higher than 98% conversion. The reaction mixture was concentrated to give a solid. The solid was dissolved in de-ionized water (4 mL), and the pH of the solution was adjusted to 6.5 with a 6.00 N hydrochloric acid solution. The resulting solution was repeatedly extracted with dichloromethane (15 mL×4, 30 mL×2). The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated. The desired compound Apo7055 was obtained as a solid from dichloromethane (320 mg). Yield=64%; HPLC purity (AUC): 99.7% at 280 nm); 1H NMR (DMSO-D6) δ (ppm): 8.15 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H), 6.96 (s, 1H), 6.66 (q, J=9.1 Hz, 1H), 3.76 (s, 3H), 2.29 (s, 3H). MS-ESI m/z 288 [M+1]+, 220 (100%). (iii) 3-Hydroxy-1,2-dimethyl-5-[2,2,2-trifluoro-1-(methylamino)ethyl]pyridin-4(1H)-one (Apo7056) was prepared from 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (400 mg, 1.4 mmol) and methylamine (3.0 mL, 34.4 mmol). The reaction was essentially completed within 15 min. The reaction mixture was concentrated to give a solid. A sample of salt free Apo7056 product was obtained by purification using the Biotage instrument (C18 reversed phase; eluant: water and acetonitrile; gradient, 100:0 to 100:4). (48 mg).
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:44]=[CH:43][C:42]=1[NH2:55].COCC(O)C>>[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:44]=[CH:43][C:42]=1[NH:55][C:18]1[N:17]=[CH:16][C:15]2=[CH:14][CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]2[N:19]=1
Reactant: COc1cc(CN2CCN(C)CC2)ccc1N
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 120 °C
Yield: 30 %

Procedure:
Into a 8-dram vial, Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (89 mg, 0.20 mmol), N,N-Diisopropylethylamine (0.0757 mL, 0.435 mmol), 2-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine and 1-Methoxy-2-propanol (0.71 mL) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in CAN. The collected fraction afforded N-(2-{2-[2-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide as a yellow solid (32 mg, 30%). LCMS (E/I+) 536.16 (M+H). NMR 1H (DMSO-d6)-8.99 (s, 1H), 8.04 (d, 1H, J=8.09 Hz), 7.95-8.01 (m, 1H), 7.79 (s, 1H), 7.62-7.70 (m, 1H), 7.51-7.59 (m, 2H), 7.06 (s, 1H), 7.02 (d, 1H, J=4.66 Hz), 7.00 (d, 1H, J=4.66 Hz), 6.86 (d, 1H, J=8.22 Hz), 3.88 (s, 3H), 3.20-3.80 (m, 10H), 3.08 (s, 3H), 2.88 (s, 3H), 2.78 (s, 3H).
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)=[O:9])[CH2:3][CH2:4]1)=[O:26]
Reactant: O=C(c1ccc2[nH]c(=O)ccc2c1)N1CCNCC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(Cl)c1)N1CCN(C(=O)c2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 Gram of 6-(1-piperazinylcarbonyl)carbostyril monohydrochloride, 0.72 g of m-chlorobenzoylchloride and 1.4 ml of triethylamine were suspended in 15 ml of dichloromethane and the suspension was stirred at a room temperature for 2 hours. Crystals formed in the reaction mixture were collected by filtration and recrystallized from dimethylformamide to obtain 1.07 g of 6-[4-(3-chlorobenzoyl)-1-piperazinylcarbonyl]-carbostyril. Colorless powdery crystals. Melting point: over 300° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][NH2:25])=[CH:21][CH:20]=1>O1CCCC1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][NH:25][S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])=[CH:21][CH:20]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccc(F)cc1)c1ccc(Br)s1
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromothiophene-2-sulfonyl chloride (600 mg) in tetrahydrofuran (5 mL) was added dropwise triethylamine (0.64 mL) and 4-fluorophenethylamine (0.36 mL) on an ice bath. After stirring for 15 minutes on an ice bath, the solution was further stirred at room temperature for 2 hours. After dilution with ethyl acetate and washing with 5N hydrochloric acid, water, an aqueous solution of saturated sodium bicarbonate and saturated sodium chloride water, the solution was dried with anhydrous sodium sulfate. Silica gel filtration was carried out, and the solvent was removed by evaporation to provide the title compound (860 mg) as a colorless oily matter.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:59])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]4[NH:40][C:41]([CH:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49](=[O:58])[CH:50]([NH2:57])[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)=[N:42][CH:43]=4)[CH:35]=2)[CH:30]=1)=[CH:23][CH:22]=3)=[O:10])[CH:6]([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[O:69]1[CH2:72][CH:71]([O:73][C:74](=O)[O:75]C2C=CC([N+]([O-])=O)=CC=2)[CH2:70]1>C(#N)C>[CH3:1][O:2][C:3](=[O:59])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]4[NH:40][C:41]([CH:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49](=[O:58])[CH:50]([NH:57][C:74]([O:73][CH:71]5[CH2:72][O:69][CH2:70]5)=[O:75])[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)=[N:42][CH:43]=4)[CH:35]=2)[CH:30]=1)=[CH:23][CH:22]=3)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(N)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC7COC7)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Reaction time: 3 h
Yield: 311.9 %

Procedure:
(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.200 g, 0.22 mmol) was dissolved in acetonitrile (2.2 mL). DIPEA (0.155 mL, 0.8905 mmol) and Carbonic acid 4-nitro-phenyl ester oxetan-3-yl ester (0.059 g, 0.244 mmol) was added, and the solution was allowed to stir for about three hours. Upon completion, the crude product was purified by reverse phase HPLC (10-50% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving [2-Methyl-1-(2-{7-[6-(2-{1-[2-(oxetan-3-yloxycarbonylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.61 g, 31% yield). LCMS-ESI+: calc'd for C51H52N8O7: 888.40 (M+); Found: 889.86 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)[N:14]([C@H:29]([C:31]2[CH:41]=[CH:40][C:34]([C:35]([O:37]CC)=[O:36])=[CH:33][CH:32]=2)[CH3:30])[N:13]=1.[OH-].[Na+]>CO.O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)[N:14]([C@H:29]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:40][CH:41]=2)[CH3:30])[N:13]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(C(F)(F)F)ccc3F)cc2-c2ccc3cc(OC)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COc1ccc2cc(-c3cc(-c4cc(C(F)(F)F)ccc4F)nn3[C@@H](C)c3ccc(C(=O)O)cc3)ccc2c1
Reaction time: 8 h

Procedure:
Ethyl 4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate (2.87 g, 5.11 mmol) was dissolved in MeOH-dioxane (1:2, 60 ml) and treated with NaOH (2.5 g, excess) in water (20 ml). The mixture slowly cleared with stirring, and was left overnight. The reaction mixture was first concentrated to 30 ml, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine 2× and dried over Na2SO4. Evaporation of solvent and vacuum drying afforded 4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoic acid as colorless dry foam. NMR (500 MHz, CDCl3) δ: 2.00 (d, J=7.0 Hz, 3H); 3.95 (s, 3H); 5.65 (q, J=7.0 Hz, 1H); 6.88 (d, JF-H=4.2 Hz, 1H); 7.17 (d, J=2.5 Hz, 1H); 7.20 (dd, J=2.5 Hz, 8.9 Hz, 1H); 7.26 (t, J=8.6 Hz, 1H); 7.31 (dd, J=1.8 Hz, 8.5 Hz, 1H); 7.32 (d, J=8.4 Hz, 2H); 7.56 (m, 1H); 7.66 (d, J=1.8 Hz, 1H); 7.68 (d, J=8.9 Hz, 1H); 7.77 (d, J=8.5 Hz, 1H); 8.06 (d, J=8.4 Hz, 2H); 8.48 (dd, J=2.9 Hz, 6.9 Hz, 1H). MS C30H22F4N2O3 Cald: 534.16; Obsd (M+1): 535.17.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>ClCCl>[C:22]([O:21][C:19](=[O:18])[N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Oc1ccc(CNCCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(O)cc1
Yield: 52.8 %

Procedure:
Suspend 4-(phenethylaminomethyl)phenol (0.750 g, 3.30 mmol) in dichloromethane (10 mL). Add a solution of (BOC)2O (1.08 g, 4.95 mmol) in dichloromethane (6.5 mL). Quench with 1.0 N NaOH (75 mL) after 19 hours. Extract with dichloromethane (2×200 mL). Wash the organic layer with brine (1×75 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 20-30% ethyl acetate in hexanes to give the title compound (0.570 g, 52.8%): MS ES+ 328.3 (M+H)+, base peak ES+ 272.1 (M+2H—C(CH3)3)+, ES− 326.3 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=14.7 min, 100% purity.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH:24]([F:26])[F:25])=[CH:20][CH:21]=3)[C:16]([C:27]3[N:28]=[C:29]4[C:35]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][N:33](COCC[Si](C)(C)C)[C:30]4=[N:31][CH:32]=3)=[N:15]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[C:38]([NH:37][C:36]([C:35]1[C:29]2[C:30](=[N:31][CH:32]=[C:27]([C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[C:19]([O:23][CH:24]([F:25])[F:26])[CH:18]=4)[N:14]([CH2:13][CH:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[N:15]=3)[N:28]=2)[NH:33][CH:34]=1)=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CCN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CCNC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
In a round-bottomed flask, 3-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-ylmethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (134 mg, 0.188 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.58 ml, 7.53 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1 ml) and ethylenediamine (0.76 ml, 11.3 mmol) was added. The light yellow solution was stirred at room temperature for 45 min then water and ethyl acetate were added. The resulting suspension was filtered and washed with hot water and ethyl acetate then dried under high vacuum to provide 33 mg (35%) of 2-(5-difluoromethoxy-1-pyrrolidin-3-ylmethyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow powder. MS: (M+H)+=484; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.06 (s, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.88 (s, 1H), 7.40 (d, J=9.1 Hz, 1H), 7.20 (t, J=74.8 Hz, 1H), 4.50 (d, J=6.8 Hz, 2H), 2.58-2.97 (m, 6H), 1.69-1.84 (m, 1H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2-chloro-3-fluoro-pyridin-4-yl)-methanol (0.9 g, 5.76 mmol) and activated MnO2 (5.76 g, 66.2 mmol) in CH2Cl2 was stirred at RT overnight. The solid was filtered off and washed with CH2Cl2, and the filtrate was concentrated under mildly reduced pressure to afford the title compound as a colorless liquid. MS (LC/MS): 191.0 [M+MeOH]+; tR (HPLC conditions b): 2.02 min.
Reaction SMILES: C([N:11]1[CH2:15][C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][C@H:12]1[CH2:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)(OCC1C=CC=CC=1)=O.[F-].C([N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1>[OH:16][C@H:14]1[CH2:15][NH:11][C@H:12]([CH2:24][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:13]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COc2cccnc2)N(C(=O)OCc2ccccc2)C1
Agent: CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@H]1CN[C@H](COc2cccnc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1.35 g sample of the compound from step 72d above was dissolved in 9 mL of THF and 9.3 mL of tetra-(t-butyl)ammonium fluoride was added. The reaction mixture was stirred at room temperature for 16 hours, and the volatiles were removed under vacuum. The residue was purified on silica gel, eluting with 3:1 ethyl acetate:hexane, to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>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.[Cu]I>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:9]#[C:10][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1cncc(N)c1
Reaction time: 0.08 h
Yield: 27 %

Procedure:
5-Bromopyridin-3-amine (0.94 g, 5.43 mmol), PdCl2(PPh3)2 (0.076 g, 0.109 mmol) and ethynyltrimethylsilane (0.64 g, 6.52 mmol) were combined in TEA (12.0 mL). After stirring for 5 min, CuI (0.010 g, 0.054 mmol) was added. The reaction mixture was flushed with N2 and stirred at RT overnight, followed by at 55° C. overnight. The reaction was filtered and the solid was washed with EtOAc (30 mL). The combined organics were concentrated in vacuo and purified by chromatography to afford 5-(2-(trimethylsilyl)ethynyl)pyridin-3-amine (0.279 g, 27% yield) as a white solid. MS (ESI) m/z: 191.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[C:4]([CH3:10])([CH3:9])[CH:5]([CH3:8])[CH2:6][CH:7]=1.CC1(C)CC1CCC(C)=C=CCC(=O)C>>[CH3:10][C:4]1([CH3:9])[CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH:11]=[CH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)C=CC1C(C)=CCC(C)C1(C)C
Agent: CC(=O)CC=C=C(C)CCC1CC1(C)C
Product: CC(=O)C=CC=C(C)CCC1CC1(C)C

Procedure:
A process for the manufacture of 4-(2,5,6,6-tetramethyl-2-cyclohexen-1-yl)-3-buten-2-one and 4-(2,5,6,6-tetramethyl-1-cyclohexen-1-yl-3-buten-2-one which process comprises isomerizing 8-(2',2'-dimethylcyclopropyl)-6-methyl-4,5-octadien-2-one in the presence of a base or an acid to form 8-(2',2'-dimethylcyclopropyl)-6-methyl-3,5-octadien-2-one and cyclizing said 8-(2',2'-dimethylcyclopropyl)-6-methyl-3,5-ocatadien-2-one.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[C:16]([F:17])=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1.B(OC)(OC)[O:19]C.OO.Cl>C1COCC1.O.C(O)(=O)C>[F:6][C:7]1[C:16]([F:17])=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][C:8]=1[OH:19]
Reactant: COB(OC)OC
Reactant: Fc1ccc2c(c1F)OCCC2
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Oc1cc2c(c(F)c1F)OCCC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
81.2 ml (0.13 mol) of n-BuLi (15% soln. in hexane) are added to a soln. of 20.0 g (0.12 mol) of 7,8-difluorochroman in 400 ml of THF at −70° C. After 3 h at this temperature, 14.4 ml (0.13 mol) of trimethyl borate are added dropwise, and the batch is warmed to RT. 30 ml of dilute acetic acid (about 30%) are added, and 30 ml of aqueous hydrogen peroxide solution (35%) are carefully added to the batch. When the addition is complete, the mixture is stirred at RT for 17 h. Water is added, and the batch is acidified using 2 N hydrochloric acid. The solution is extracted a number of times with MTBE, and the combined organic phases are washed successively with water, sat. sodium chloride soln. and ammonium iron(II) sulfate soln. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane: MTBE=2:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:7][CH:6]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (80 mg, 0.27 mmol) in pyridine (5 mL) was added 4-methylbenzene-1-sulfonyl chloride (57 mg, 0.30 mmol) with ice cooling. Upon completion of the addition, the resultant mixture was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 70 mg of 3,3-dimethyl-2-(4-(4-methylphenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow powder. Yield: 69%; MS (ESI+APCI) M+1=451.20.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>C(#N)C>[CH3:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC1CCCNC1
Solvent: CC#N
Product: CC1CCCN(C[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)C1
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.20 g, 0.5 mmol), 3-methylpiperidine (0.35 ml, 3 mmol) and ACN (2 ml) was heated under microwave radiation at 120° C. for 30 min. Purification on flash column chromatography (Isooctane/EtOAc/MeOH). Yield: 0.097 g, 85%. The amine was converted to the fumaric acid salt and crystallized from MeOH/(i-Pr)2O. M.p. 159° C. MS m/z (rel. intensity, 70 eV) 325 (M+, 1), 113 (83), 112 (bp), 69 (43), 55 (46). [α]=+50° (MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](O)[C:11]([C:14]3[C:15](=[O:31])[NH:16][CH:17]=[CH:18][C:19]=3[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[OH:23])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>CO.[Cl-].[Ti+3].[Cl-].[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:14]3[C:15](=[O:31])[NH:16][CH:17]=[CH:18][C:19]=3[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[OH:23])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]ccc(NCC(O)c2cccc(Cl)c2)c1-c1ncc(-c2ccc(Br)cc2)n1O
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: O=c1[nH]ccc(NCC(O)c2cccc(Cl)c2)c1-c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 65 °C
Yield: 41.2 %

Procedure:
To a stirred solution of 3-[5-(4-bromo-phenyl)-1-hydroxy-1H-imidazol-2-yl]-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-1H-pyridin-2-one (0.015 g, 0.030 mmol) in methanol (4 mL) was treated with titanium(III) chloride ((9.25 wt % in 27.4 wt % hydrochloric acid, ˜200 μL). The reaction was heated at 65° C. for 1 hour, then quenched with water and the solvents were evaporated. The residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title material (0.006 g, 41%) as a beige solid. HPLC 100% (220 nm), LCMS (+ESI, M+H+) m/z 485,487, (−ESI, M−H−) m/z 483, 485; 1H NMR (400 MHz, methanol-d4) δ (ppm): 3.64 (1H, dd, J=13.3 and 7.1 Hz), 3.74 (1H, dd, J=13.3 and 4.5 Hz), 5.03 (1H, m), 6.26 (1H, d, J=7.5 Hz), 7.23-7.56 (9H, m), 7.77 (1H, d, J=8.6 Hz).