Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[NH:7][CH:6]=1.C(O[CH:18](O)[C:19]([F:22])([F:21])[F:20])C.C(O)(=O)C>C(O)C>[ClH:1].[F:20][C:19]([F:22])([F:21])[CH:18]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: CCOC(O)C(F)(F)F
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3C(F)(F)F

Procedure:
A mixture of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (0.5 g), trifluoroacetaldehyde ethyl hemiacetal (0.35 mL), acetic acid (0.32 mL) and ethanol (22.5 mL) was heated at reflux for 16 h. The solvent and excess reagents were evaporated to dryness under vacuum. The residue was washed with diethyl ether to afford 1-trifluoromethyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-ol hydrochloride (0.5 g).
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1>[CH3:21][O:22][C:23]1[C:28]([CH2:29][N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:16][CH2:15]2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COc1ncccc1C=O
Reactant: c1ccc(-c2ccccc2CCC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ncccc1CN1CCC(CCc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.8 %

Procedure:
181 mg of 4-(2-phenylphenethyl)piperidine synthesized from the corresponding raw material in the same manner as in the above-mentioned process, 150 mg of 2-methoxy-3-pyridinecarboxaldehyde and 226 mg of sodium triacetoxy borohydride were suspended in 5 ml of tetrahydrofuran, and the mixture was stirred for 20 hours at room temperature. The reaction mixture was basified by adding a 1N aqueous sodium hydroxide thereto, and then extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (ethyl acetate:hexane=1:19), to give 213 mg of the title compound as a colorless oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][CH:29]([CH3:32])[CH2:30][NH2:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH2:30][CH:29]([CH3:32])[CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)CN
Solvent: CC#N
Product: CC(C)CNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), 2-methylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 333 (M+, 2), 292 (8), 290 (20), 86 (bp), 70 (8), 57 (9).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:34][C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:24][CH2:25][CH:20]([C@@:18]3([CH3:26])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:33][CH:32]=1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ncc(Cl)cn3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2,5-dichloro-pyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 6): tR=1.78 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][CH2:22][O:23][C@@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][CH2:22][O:23][C@@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(N2C[C@H]3OCCO[C@@H]3C2)nc1Cc1ccccc1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CO
Product: O[C@]1(C#Cc2ccc(N3C[C@H]4OCCO[C@@H]4C3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of 5.12 g of 2-benzyl-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]-3-iodopyridine, 1.83 g of (3R)-3-ethynyl-3-quinuclidinol, 140 mg of tetrakis(triphenylphosphine)palladium(0), 115 mg of cuprous iodide, 3.4 ml of triethylamine and 12 ml of methanol was stirred at room temperature overnight in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and the mixture was extracted with ethyl acetate/tetrahydrofuran (1:1). Then, the organic phase was washed with brine and the solvent was removed. The residue was crystallized from tetrahydrofuran/methanol/ethyl acetate, to give 3.59 g of the target compound.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:19])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2Cl)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]1([C@H:7]([O:9][C:10](=[O:19])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:24]2[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: C[C@@H](OC(=O)Nc1cnccc1Cl)c1ccccc1
Product: C[C@@H](OC(=O)Nc1cnccc1-c1ccc(O)cc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: (4-Chloro-pyridin-3-yl)-carbamic acid (R)-1-phenyl-ethyl ester and 4-hydroxyphenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]3[O:18][C:17](=[O:19])[N:16]([C:20]4[CH:25]=[CH:24][C:23]([O:26]CC5C=CC=CC=5)=[CH:22][CH:21]=4)[CH2:15]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>CO.[Ni]>[F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]3[O:18][C:17](=[O:19])[N:16]([C:20]4[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=4)[CH2:15]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@@H](CN2CCC(Cc3ccc(F)cc3)CC2)CN1c1ccc(OCc2ccccc2)cc1
Agent: [Ni]
Solvent: CO
Product: O=C1O[C@@H](CN2CCC(Cc3ccc(F)cc3)CC2)CN1c1ccc(O)cc1

Procedure:
At atmospheric pressure and 20° C., a solution of 1 g of (5S)-(−)-5-[4-(4-fluorobenzyl)-1-piperidinyl-methyl]-3-(4-benzyloxyphenyl)oxazolidin-2-one [obtainable by reaction of (5R)-(−)-5-(methanesulfonyloxy-methyl) -3-p-benzyloxyphenyloxazolidin-2-one with 4- (4-fluorobenzyl)piperidine hydrochloride] in 25 ml of methanol is hydrogenated over 1 g of Raney nickel. The mixture is filtered and the solvent is removed, giving (5S)-(−)-5-[4-(4-fluorobenzyl)-1-piperidinylmethyl]-3-(4-hydroxyphenyl) oxazolidin-2-one,
Reaction SMILES: [K+].[Br-].[CH3:3][O:4][C:5]([C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)=[CH:9][CH:8]=1)=[O:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:17]=[C:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][O:11][C:10]2[CH:22]=[CH:23][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8][C:9]1=2
Reactant: COC(=O)c1ccc(OCc2ccccc2C(=O)O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
IR (KBr disk): 3400, 1700, 1610, 1260, 1235 cm-1The thus obtained 2-(4-methoxycarbonylphenoxy) methyl benzoic acid (392.7 g) is suspended in 5.0 l of methylene chloride and 266.0 g of trifluoroacetic anhydride is added thereto. After stirring the mixture at room temperature for one hour, 19.4 g of boron trifluoride-ethylether complex is added thereto and the mixture is stirred at room temperature for two hours. The reaction solution is poured into ice water. After an organic solvent layer is separated from the mixture, the organic layer is washed with diluted aqueous sodium hidroxide solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 335.3 g of methyl 11-oxodibenz[b,e]oxepin-2-carboxylate as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br-:12].[Li+].C[Si](Cl)(C)C>C(#N)C>[Br:12][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1cccc(Cl)c1
Reactant: [Br-]
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(Br)c1cccc(Cl)c1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 5, using 8.5 grams (0.05 mole) of 2-(3-chlorophenyl)propan-2-ol, 8.7 grams (0.1 mole) of lithium bromide, and 13.5 grams (0.125 mole) of trimethylsilyl chloride in 100 mL of acetonitrile, yielding 2-bromo-2-(3-chlorophenyl)propane.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:13])[C:9]([F:12])([F:11])[CH3:10])(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[F:11][C:9]([F:12])([CH3:10])[C@H:8]([NH2:7])[CH3:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(C)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(C)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, ((R)-2,2-difluoro-1-methyl-propyl)-carbamic acid tert-butyl ester (148 mg, 0.71 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1.6 ml, 20.8 mmol) was slowly added. The reaction mixture was stirred at room temperature for 1.5 h then concentrated to give (R)-2,2-difluoro-1-methyl-propylamine trifluoroacetate as a light brown oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[Cl:32][CH2:33][C:34](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Cl:32][CH2:33][C:34]1[O:31][C:3]2[CH:4]=[CH:5][C:6]3[NH:7][C:8]([C:14]4[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]5[C:22]([C:23]=4[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:9][S:10](=[O:12])(=[O:13])[C:11]=3[C:2]=2[N:1]=1
Reactant: COC(CCl)(OC)OC
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc4oc(CCl)nc34)N2)c(O)c2ccccc21
Yield: 51 %

Procedure:
A solution of Example 354 (0.030 g, 0.067 mmol) in dimethylformamide (3 mL) was treated with 2-chloro-1,1,1-trimeth oxyethane (0.50 mL) and a catalytic amount of para-toluenesulfonic acid at 60° C. for 4 hours. The solvent was removed under a stream of warm nitrogen and the resulting residue was triturated with water and filtered, then triturated with methanol and filtered to yield the title compound (22 mg, 51%). The sodium salt was made by the procedure of Example 1D. MS (ESI−) m/z 500 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, J=6.62 Hz, 6 H) 1.87 (m, J=20.04, 13.42, 6.99 Hz, 1 H) 2.63 (m, 2 H) 5.13 (s, 2 H) 5.95 (t, J=6.99 Hz, 1 H) 7.08 (t, J=7.54 Hz, 1 H) 7.36 (d, J=9.19 Hz, 1 H) 7.57 (m, 2 H) 7.99 (d, J=8.82 Hz, 1 H) 8.09 (dd, J=7.91, 1.29 Hz, 1 H) 16.59 (s, 1 H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH2:32][CH2:33][CH2:34][N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:8]3[C:16]([F:23])=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:7]=3[F:6])[CH2:11][CH2:12]2)=[CH:29][CH:30]=1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(C(CCCN2CCC(Oc3c(F)c(F)c(F)c(F)c3F)CC2)c2ccc(F)cc2)cc1
Temperature: 78 °C
Reaction time: 20 h

Procedure:
A stirring mixture of 10 g of sodium bicarbonate in 50 ml dimethylformamide was treated with 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine followed by a solution of 4.06 ml of 4,4-bis-(4-fluorophenyl)butyl chloride in 10 ml of dimethylformamide, and then stirred at 78° C. for 20 hours. After filtering, the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration followed by evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 20% ethyl acetate/dichloromethane) to afford 5.44 g of 1-[4,4-bis-(4-fluorophenyl)butyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. The oil was dissolved in hot isopropanol and acidified with an etheral solution of oxalic acid to precipitate the corresponding oxalate salt. Recrystallization from isopropanol afforded 2.75 g (30.0%) of 1-[4,4-bis-(4-fluorophenyl)butyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine oxalate, m.p. 183°-185° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[NH3:22].CO>>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)NCc2cccnc2)ccc1Cl
Reactant: N
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NCc2cccnc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a saturated ammonia-methanol solution (60 ml) was added 4-chloro-3-nitro-N-(pyridin-3-ylmethyl)benzenesulfonamide (2.77 g), followed by about 2 days of heating at 100° C. in a sealed tube. After the reaction, the solvent was evaporated under reduced pressure and the formed yellow crystals were collected by filtration and dried to obtain 4-amino-3-nitro-N-(pyridin-3-ylmethyl)benzenesulfonamide (2.51 g). Hereinafter, the compound of Reference Examples 26 was obtained similarly.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=1[C:8]=23>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]=[C:9]3[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=1[C:8]=23
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ncco4)c(c23)C1
Yield: 37.1 %

Procedure:
A solution of 0.65 g (2.0 mmol) of (-)(2aR,4S)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 30 ml of CH2Cl2 was sonicated (50-55 KHz) in the presence of 2.5 g of MnO2 for 5 hours. The oxidant was removed by filtration through celite. The crude product obtained after filtering and removing the solvent was chromatographed over 15 g of silica gel using 1:9 EtOAc/toluene, then crystallized from isooctane to provide 0.24 g of title compound.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]1[N:24]=[CH:25][N:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.CC(O)C.Cl>CO>[ClH:21].[NH2:8][CH:9]([CH2:22][C:23]1[N:24]=[CH:25][N:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CN(C)C(=O)n1cnc(CC(COc2noc3ccc(Cl)cc23)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CN(C)C(=O)n1cnc(CC(N)COc2noc3ccc(Cl)cc23)c1

Procedure:
To a solution of 0.2 g of 3-[2-tert-butoxycarbonylamino-3-(1-dimethylcarbamoyl-4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole in 2 ml of methanol is added 1.2 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature and they are subjected to reaction at the same temperature for ten hours, after which the solvent is removed by distillation under reduced pressure. Diisopropyl ether is added to the residue obtained and the crystals precipitated are collected by filtration, to obtain 0.1 g of pale brown, crystalline 3-[2-amino-3-(1-dimethylcarbamoyl-4-imidazolyl)propoxy]-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 167.0°-169.5° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.CO>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])=[CH:18][CH:17]=1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc(F)cc1

Procedure:
5-Nitro-isochromen-1-one (1 g, 0.005 mol) and 4-fluoro-benzene methanamine, (2 g, 0.02 mol) were refluxed in methanol (20 mL, 0.5 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (40 g of silica gel, 0-50% EtOAc/Hexane) gave a bright yellow solid. MS m/z (M+H) 299.1
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:28]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Yield: 79.7 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 3-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2→1:1)). 1.52 g (80%) of 1-benzyl-piperidin-4-yl 3-methoxy-benzoate were obtained as a yellowish oil. MS: me/e (% basic peak)=325 (C20H23NO3+, 7.6), 248 (4), 173 (30.3), 135 (13), 91 (78), 82 (100).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Reactant: OB(O)c1cccs1
Product: CN1CCC(c2c[nH]c3ccc(-c4cccs4)nc23)CC1
Yield: 66.5 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (158 mg, 0.435 mmol) and 2-thiopheneboronic acid (83 mg, 0.653 mmol) were converted to 86 mg of the title compound by the procedure of Example 1 except that a wash with 3:1 chloroform:isopropanol was performed between the base and brine and the solvent system for chromatography was 0-5% methanol/dichloromethane. (67%). MS(FD) m/e 297.2 (M+). EA calculated for C17H19SN3: C, 68.69; H, 6.40; N, 14.14. Found: C, 69.02; H, 6.49; N, 14.23.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[Br:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:11][CH2:10][CH2:9][Br:8])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)Cl
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(=O)OCCBr
Temperature: 0 °C
Reaction time: 19.5 h

Procedure:
4-Pentenoyl chloride (2.8 mL, 25.4 mmol) was dissolved in anhydrous methylene chloride (50 mL) and cooled to 0° C. under nitrogen. 2-Bromoethanol (2.0 mL, 28.2 mmol) and triethylamine (3.8 mL, 27.3 mmol) was added to the reaction solution resulting in a thick yellow slurry. The reaction solution was stirred for 19.5 h while slowly warming to 22° C. The reaction mixture was diluted to 100 mL with methylene chloride and extracted with 75 mL of each of the following: water, sat. ammonium chloride, and sat. sodium bicarbonate. The organic phase was dried (MgSO4), filtered and condensed in vacuo to yield a yellow oil (5.2 g cu. 100%) which was used as is for the next step. 1H NMR δ 5.90-5.65 (m, I H), 5.15-4.90 (m, 2H), 4.39 (t, 2H, J=6.0), 3.48 (t, 2H, J=6.0), 2.50-2.30 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].OC1C2C(=CC=C([C:28]([F:31])([F:30])[F:29])C=2)N=CC=1C(OCC)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:28]([F:31])([F:30])[F:29])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1O
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Cl

Procedure:
The title compound was prepared following the procedure described in Step 2 for the synthesis of 3a using 2h instead of 2a. 1H NMR (CDCl3) δ (ppm): 1.46 (3H, t, J=7.14 Hz), 4.51 (2H, q, J=7.14 Hz), 8.00 (1H, dd, J=8.79, 1.92 Hz), 8.26 (1H, d, J=8.79 Hz), 8.78 (1H, dd, J=1.92, 0.83 Hz), 9.34 (1H, s). m/z 304.6 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CC(O)=O.[Br:11][C:12]1[CH:31]=[CH:30][C:15]2[O:16][CH2:17][C:18](=O)[CH2:19][N:20]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:22]=[C:21]3[C:14]=2[CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:11][C:12]1[CH:31]=[CH:30][C:15]2[O:16][CH2:17][CH:18]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH2:19][N:20]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:22]=[C:21]3[C:14]=2[CH:13]=1
Reactant: O=C1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)CCNC1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N′,N′-dimethylethane-1,2-diamine (39 mg, 0.440 mmol) and CH3COOH (26 mg, 0.440 mmol) were added to the mixture of 2-bromo-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7(8H)-one (100 mg, 0.293 mmol) in 1,2-dichloroethane (2 mL). The mixture was stirred at room temperature for 20 minutes. Then NaBH(OAc)3 (93 mg, 0.440 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated NaHCO3 (30 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using p-TLC (dichloromethane:MeOH=1:1) to provide N1-(2-bromo-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-yl)-N2,N2-dimethylethane-1,2-diamine. 1H-NMR (CDCl3, 400 MHz) δ 7.51˜7.56 (m, 2H), 7.42 (s, 1H), 7.29˜7.32 (m, 1H), 7.16˜7.18 (m, 1H), 7.06 (t, J=7.2 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 6.56 (s, 1H), 3.86˜4.32 (m, 4H), 2.81˜3.03 (m, 5H), 2.59 (s, 6H). MS (M+H)+: 414/416.