Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(F)ccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Fc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
16.7 g of 6-fluoro-3,4-dihydro-2(1H)-naphthalenone in 200 ml of benzene are boiled at reflux for 2.5 hours with 8.4 ml of pyrrolidine and 0.35 g of anhydrous p-toluenesulfonic acid. The 1-(6-fluoro-3,4-dihydro-2-naphthyl)pyrrolidine obtained is treated, without purification, with 10.8 g of acrylamide and 0.5 g of p-toluenesulfonic acid. The mixture is heated under nitrogen at 100° for 2 hours and at 150° for 2 hours. The mixture is dissolved in 180 ml of chloroform, washed with water and chromatographed over 150 g of silica gel with chloroform. Recrystallization from ethyl acetate gives 8-fluoro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one with melting point 223°-224°.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:32]12[CH2:37][CH:35]([CH2:36]1)[CH2:34][NH:33]2>>[CH:32]12[CH2:37][CH:35]([CH2:36]1)[CH2:34][N:33]2[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1NC2CC1C2
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Agent: Cl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CC5CC4C5)c3)nc12

Procedure:
1-[2-[3-(2-Azabicyclo[2.1.1]hex-2-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared from 1-[2-(3-Iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2-azabicyclo[2.1.1]hexane hydrochloride as described above (34%; MS=361 M+H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].CN1C(=O)CCC1.O.[OH-].[Li+]>O>[C:16]([C:17]1[S:18][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]=1[NH2:7])([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1N
Temperature: 2 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
A 22-L, 3-necked, round-bottom flask equipped with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, was charged with 1.20 kg (5.55 mole) of 2-nitro-4-trifluoromethylbenzonitrile, 589.3 g (496 mL, 5.55 mole) of methyl thioglycolate, and 4.3 L of NMP. After the resulting yellow solution was cooled to 2° C., a solution prepared from 466.0 g (11.11 mole, 2.0 eq) of lithium hydroxide monohydrate in 3.36 L of water was slowly added over a period of 78 min while maintaining a temperature of 2-20° C. The brown slurry was allowed to warm to 21° C. over a 2 h period, then was diluted with 8.0 L of water (Texo->27° C.). After stirring for 40 min and cooling to 18° C., product was collected by filtration, rinsing with 10 L of water, then air-drying at ambient temperature to give 1.295 kg (84.7% yield) of 2-carbomethoxy-3-amino-6-trifluoromethylbenzo[b]thiophene, as a light-yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18][CH2:19][CH3:20])[N:9]([CH3:21])[C:6]2=[N:7][CH:8]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH2:19][CH3:20])=[O:30])[N:9]([CH3:21])[C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccccc1-c1nc2cc(C#N)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1ccccc1-c1nc2cc(C#N)cnc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a mixture of 6-cyano-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (0.40 g) and chloroform (5 ml), 70% of 3-chloroperbenzoic acid (0.35 g) was added under ice-cooling, and stirred at room temperature for 2 hours. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 0.40 g of 6-cyano-2-(2-ethylsulfinylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 49).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH2:20][CH3:21])[CH:3]=1.[NH3:22].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[NH2:22][CH2:17][C:13]1[C:12]([CH2:19][CH2:20][CH3:21])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[NH2:22][CH2:17][C:13]1[C:12]([CH2:19][CH2:20][CH3:21])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CCCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Reactant: N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCCc1c(CN)cccc1Oc1cc(Cl)ccc1C#N
Yield: 111.5 %

Procedure:
4-Chloro-2-(3-chloromethyl-2-propylphenoxy)-benzonitrile (0.16 g, 0.50 mmol) in ammonia (7N in methanol, 25 mL, 175 mmol) was stirred for 65 h at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (58 mg, 0.50 mmol) in methanol (3 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 2-(3-aminomethyl-2-propyl-phenoxy)-4-chloro-benzonitrile hemifumarate (200 mg, 96%) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[CH:17][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][N:6]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)#[N:20]>C(#N)C>[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[S:3][C:4]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]4[N:14]([CH:16]=[CH:17][N:18]=4)[CH:15]=3)=[O:8])=[CH:5][N:6]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: O=C(Nc1ccc2nccn2c1)c1cnc(Br)s1
Reactant: N#Cc1ccc(CN)cc1
Solvent: CC#N
Product: N#Cc1ccc(CNc2ncc(C(=O)Nc3ccc4nccn4c3)s2)cc1
Temperature: 180 °C

Procedure:
To a solution of 2-bromo-N-(imidazo[1,2-a]pyridin-6-yl)thiazole-5-carboxamide (165 mg, 0.511 mmol) in acetonitrile (2553 μl) was added 4-cyanobenzylamine (67.5 mg, 0.511 mmol). The mixture was heated in a microwave (Biotage Initiator) at 180° C. for 30 minutes. The heating was repeated again after another equivalent of 4-cyanobenzylamine was added. The reaction mixture was purified by normal phase chromatography to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]([C:14]([O:16]CC)=[O:15])=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO>[C:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(C(=O)OC(C)(C)C)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)c1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a mixture of ethyl 5(tert-butoxycarbonyl)pyrazine-2-carboxylate (0.742 g, 2.78 mmol) and methanol (20 mL) was added potassium hydroxide (0.23 g, 4.1 mmol) in wafer (2 mL) and the reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in wafer (5 mL) and acidified to pH 2 with 1M hydrochloric acid. The solid precipitate was collected by filtration to afford the title compound (0.61 g). MS (ESI) m/z 240.2 [M+H]+
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])[N:28]=4)[N:25]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[C:37]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])[N:28]=4)[N:25]=3)[CH2:15][CH2:16]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(CCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 63 %

Procedure:
905 mg of ethyl 2-[6-[3-[4-(diphenylmethoxy) piperidino]propyl]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate dihydrochloride was dissolved in 6 ml of ethanol; 5.9 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 2 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and ajusted to pH 4.5 by the addition of 1 N hydrochloric acid. The mixture was crystallized by the addition of acetone, washed with acetone and dried to yield 476 mg of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:16])[CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[OH:16][CH:10]1[CH:11]([CH2:14][OH:15])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCC1CCN(Cc2ccccc2)CC1O
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: OCC1CCNCC1O
Yield: 107.2 %

Procedure:
To a solution of 1-benzyl-3-hydroxy-4-hydroxymethylpiperidine (7.1 g) and hydrazine monohydrate (1.56 ml) in ethanol was added 10% palladium carbon (3 g), and the resulting mixture was stirred at refluxing temperature for 5 hr. 10% Palladium carbon was filtered off and the solvent was evaporated under reduced pressure to give 4.51 g of 3-hydroxy-4-hydroxymethylpiperidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-fluoro-phenyl)-carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (417 mg).
Reaction SMILES: [O:1]=[C:2]1[N:10]2[CH:11]([C:14]3[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]3)[NH:3]1.[Br:22]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:22][C:7]1[C:8]2[O:13][CH2:12][CH:11]([C:14]3[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][CH:19]=3)[N:10]3[C:2](=[O:1])[NH:3][C:4]([C:9]=23)=[CH:5][CH:6]=1
Reactant: N#Cc1ncccc1C1COc2cccc3[nH]c(=O)n1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ncccc1C1COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A solution of 3-(2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile (709 mg, 2.548 mmol) in N,N-dimethylformamide (25.0 mL) was treated with N-bromosuccinimide (630 mg, 3.54 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (0.44 g, 48%) as a racemic mixture. LCMS calculated for C15H10BrN4O2 (M+H)+: m/z=357.0, 359.0. found: 356.8, 358.8.
Reaction SMILES: O.NN.[C:4]([O:8][CH:9]([O:27][C:28]1[CH:29]=[C:30]([N+:72]([O-])=O)[CH:31]=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[C:33]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:10][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][CH3:26])(=[O:7])[CH:5]=[CH2:6]>C(O)C>[C:4]([O:8][CH:9]([O:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[C:33]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[NH2:72])[CH2:10][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][CH3:26])(=[O:7])[CH:5]=[CH2:6]
Reactant: C=CC(=O)OC(CCCCCCCCCCCCCCCCC)Oc1cc([N+](=O)[O-])cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: NN
Solvent: O
Solvent: CCO
Product: C=CC(=O)OC(CCCCCCCCCCCCCCCCC)Oc1cc(N)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Yield: 71.4 %

Procedure:
Thereafter, loaded were 3 ml of hydrazine monohydrate and 10 ml of ethanol in the presence of graphite, 3.9 g of 3-(1′-acryloyloxyoctadecyloxy)-4,5-dioctadecyloxy nitrobenzene was reduced via heat-refluxing for 24 hours. Via recrystallized from mix solution of chloroform-methanol to obtain 2.7 g of 3-(1′-acryloyloxyoctadecyloxy)-4,5-dioctadecyloxy aniline (yield: 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[B:18]([OH:23])[OH:19]
Reactant: COc1cccc2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(B(O)O)ccc2ccccc12
Temperature: -50 °C
Yield: 41.6 %

Procedure:
To a stirred mixture of 1-methoxynaphthalene (20.0 g, 126.6 mmol) in THF (100 mL) was added n-butyllithium (53.16 mL, 132.9 mmol, 2.5M solution in hexanes) at room temperature over 5 min. The reaction mixture was cooled to −50° C., and triisopropyl borate (43.8 mL, 35.7 g, 190 mmol) was added dropwise over 0.25 h. The resulting precipitate was broken up by the addition of THF (100 mL), and the mixture was allowed to warm to 0° C. with stirring. At this point the mixture was poured into 1N HCl (100 mL), the product extracted with ethyl acetate, the combined extracts dried over anhydrous sodium sulfate, and filtered. After concentrating the filtrate in vacuo at ambient temperature, the residue was partially dissolved in diethyl ether, triturated with hexane, and the resulting precipitate filtered and washed with hexane to afford 10.64 g (41%) of the title compound 1-methoxynaphthalene-2-boronic acid as an off-white crystalline solid (MW 202.02, C11H11BO3).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=O)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]1[C@@H:35]([OH:36])[CH2:34][NH:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH2:25][N:33]3[CH2:32][CH2:31][C@@H:35]([OH:36])[CH2:34]3)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:29])([F:30])[F:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O[C@@H]1CCN(Cc2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 20 mg, 0.049 mmol), 3R-Pyrrolidinol (21.23 mg, 0.244 mmol), sodium triacetoxyborohydride (31.0 mg, 0.146 mmol) and dichloromethane (1 mL) was stirred at room temperature overnight. The mixture was concentrated and dissolved in methanol. HPLC purification (Column: Waters XBridge C18, 19×250 mm, 5-nm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) and concentration gave the titled compound (18.8 mg, 0.039 mmol, 80% yield) as a solid. The compound had an HPLC retention time=2.15 min. (Column: Supelco Ascentis Express C-18, 4.6×50 mm, 2.7 um; Solvent A=0.05% TFA in H2O:MeCN (95:5); Solvent B=0.05% TFA in H2O:MeCN (5:95)); LC/MS M+1=482.1; 1H NMR (400 MHz, MeOD) δ ppm 7.95 (1H, d, J=7.7 Hz), 7.73 (2H, d, J=7.3 Hz), 7.53-7.66 (3H, m), 7.36-7.43 (2H, m), 4.39-4.47 (1H, m), 3.87-4.01 (2H, m), 2.97-3.14 (6H, m), 2.83 (2H, d, J=19.6 Hz), 2.14-2.27 (1H, m), 1.81-1.93 (1H, m, J=13.6 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](O)=[O:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:25](=[O:26])[CH:24]([CH2:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(CCCc1ccccc1)CCCc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)C(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
1-Benzyl-4-aminopiperidine (0.5 g; 2.63 mmol) is dissolved in DMF (25 mL) at ambient temperature. 5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid (22) (0.78 g; 2.62 mmol), triethylamine (0.46 mL; 3.28 mmol), 1-hydroxybenzotriazole (0.444 g; 3.28 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.554 g; 2.89 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then poured onto ethyl acetate (250 mL) and extracted successively with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (10%→67% ethyl acetate in hexanes) affording the desired product (1.07 g) as a white solid. ESMS: MH+ 469.4 (base).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([F:34])([F:33])[F:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (84 mg, 77%), MS (ISP) m/z=437.3 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3,3,3-trifluoro-propionic acid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]3[NH:6][C:4](=[O:5])[C:3]4[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=4[N:1]=3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(O)CC4)cc3)nc2n1
Temperature: 135 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-4,6-dimethoxy-nicotinamide (0.60 g, 3.0 mmol), 4-(4-hydroxy-piperidin-1-yl)-benzaldehyde (0.81 g, 3.9 mmol), p-toluenesulfonic acid monohydrate (1.25 g, 6.6 mmol) and sodium bisulfite (1.06 g, 6.0 mmol) in N,N-dimethylacetamide (8.0 mL) was stirred at 135° C. under N2 for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (40 mL) was added to the residue and stirred for 0.5 hours. The precipitate was filtered and the solid was rinsed with water and air-dried. The crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 4% methanol in dichloromethane) to afford the title compound, as a yellow solid. Yield: 0.29 g (25.2%). MP 284-286° C. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 8.12 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.32 (s, 1H), 4.73 (d, J=4.4 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.72 (m, 3H), 3.05 (m, 2H), 1.80 (m, 2H), 1.43 (m, 2H). MS (ES+) m/z: 383.06 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[CH:20]([N:24]3[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]3)[CH2:19][CH2:18]4)[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>CO>[OH:39][C:37]([C:36]([F:41])([F:40])[F:35])=[O:38].[CH3:1][CH:2]([CH3:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[CH:20]([N:24]3[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]3)[CH2:19][CH2:18]4)[N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CN(C2CCc3cc(-c4noc(-c5ccc(CC(C)C)cc5)n4)ccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)Cc1ccc(-c2nc(-c3ccc4c(c3)CCC4N3CC(C(=O)O)C3)no2)cc1
Reaction time: 2 h

Procedure:
A solution of methyl 1-(5-(5-(4-(2-methylpropyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate, Enantiomer 1 (from Step A, 0.10 g, 0.23 mmol) and sodium hydroxide (1N aqueous solution, 0.6 mL) were heated in methanol (1 mL) at 60° C. After 2 h, the reaction was cooled and acidified with trifluoroacetic acid. HPLC purification (HPLC B) gave the title compound as a white solid: 1H NMR (500 MHz, CD3OD) δ 8.19 (s, 1H), 8.13–8.15 (m, 3H), 7.74 (d, J=7.8 Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 5.06 (dd, J=2.5, 7.8 Hz, 1H), 4.52–4.60 (m, 2H), 4.41–4.48 (m, 2H), 3.71 (m, 1H), 3.27 (dt, J=8.15, 16.7 Hz, 1H), 3.13 (ddd, J=3.7, 9.2, 16.7 Hz, 1H), 2.56–2.66 (m, 3H), 2.22–2.30 (m, 1H), 1.92–2.00 (m, 1H), 0.96 (d, J=6.6 Hz, 6H); ESI-MS 418.1 (M+H).