Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17](Br)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[N:13]2[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH2:1]([O:8][C:9]1[C:17]([C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[N:13]2[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)Cc2c1ccc(Br)c2OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2OCc1ccccc1
Temperature: 130 °C

Procedure:
To 4-benzyloxy-5-bromo-1-methyl-1,3-dihydro-indol-2-one (100 mg, 0.301 mmol) was added 3-pyridineboronic acid (CAS#1692.25-7, 44.4 mg, 0.361 mmol), 1,2-dimethoxyethane (2 mL) and 2 M aqueous sodium carbonate (0.376 ml, 0.753 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (82 mg, 0.0093 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 130° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 100%) to afford 4-benzyloxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 331.1447 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.16 (s, 3H), 3.77 (s 2H), 4.93 (s, 2H), 6.88 (d J=8.08 Hz, 1H), 7.16-7.21 (m, 2H), 7.27-7.31 (m, 3H), 7.35 (d, J=8.08 Hz, 1H), 7.41 (qd, 1H), 7.86 (dt, J=7.83, 2.02 Hz, 1H), 5.52 (dd, J=4.80, 1.77 Hz, 1H), 8.67 (dd, J=2.27, 0.76 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH3:12][O:13][C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1>O1CCOCC1>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16]2[N:15]=[C:14]([O:13][CH3:12])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1OC
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2ccc(OC(F)F)cc2)nc1OC
Temperature: 150 °C
Yield: 70.9 %

Procedure:
A mixture of 4-(difluoromethoxy)aniline (0.285 mL, 2.305 mmol) and ethyl 4-methoxy-2-(methylsulfonyl)pyrimidine-5-carboxylate (0.4 g, 1.537 mmol) in dioxane was heated in the microwave at 150° C. for 50 min. The mixture was then cooled to room temperature and concentrated. The residue was purified by flash chromatography on silica gel using 5-50% ethyl acetate in hexanes. The desired fractions were concentrated to give ethyl 2-((4-(difluoromethoxy)phenyl)amino)-4-methoxypyrimidine-5-carboxylate as an orange solid (0.37 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 (s, 1H), 7.67-7.58 (m, 2H), 7.37 (br. s., 1H), 7.20-7.09 (m, 2H), 6.74-6.12 (m, 1H), 4.35 (q, J=7.0 Hz, 2H), 4.08 (s, 3H), 1.38 (t, J=7.0 Hz, 3H). LCMS: R.T.=0.96; [M+H]+=340.1.
Reaction SMILES: [NH:1]([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[Br:31][CH2:32][C:33](Br)=[O:34].O>C(Cl)(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([CH2:13][N:1]([CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[C:33](=[O:34])[CH2:32][Br:31])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CNCC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CN(CC(=O)OCc1ccccc1)C(=O)CBr)OCc1ccccc1
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of dibenzyl iminodiacetate (9.7 g, 0.031 mol) and triethylamine (4.05 g, 0.04 mol) in 30 ml of carbon tetrachloride was added dropwise to a solution of bromoacetyl bromide (8.88 g, 0.044 mol in 20 ml of carbon tetrachloride at 0° C., and stirring was continued for 2 h at 25° C. After addition of water, the organic layer was washed with a saturated NaHCO3 solution and saturated brine, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel, hexane:EtAOc (3:1)] and yielded 12.66 g (94%) of compound 2. NMR (CDCl3): 3.86 (s,2H), 4.25 (s,2H), 4.27 (s,2H), 5.15 (s,2H), 5.19 (s,2H), 7.3-7.5 (m,10H). Anal. calcd. for C20H20BrNO5 : C, 55.31; H, 4.64; Br, 18.40; N, 3.23. Found: C, 55.38; H, 4.69; Br, 18.46; N, 3.19.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][CH:21]=[C:22]([C:24]([NH2:26])=[O:25])[N:23]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[S:20][CH:21]=[C:22]([C:24]([NH2:26])=[O:25])[N:23]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Reactant: NC(=O)c1csc(Br)n1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(C(N)=O)cs3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-thiazole-4-carboxamide (J. Am. Chem. Soc. 1952, 74, 5799).
Reaction SMILES: [C:1]([NH:5][C:6](=[S:19])[NH:7][C:8]1[CH:14]=[C:13]([S:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:9]=1[NH2:10])([O:3][CH3:4])=[O:2].[CH3:20][C:21]1[CH:28]=[CH:27][C:24](C=O)=[CH:23][CH:22]=1.[CH3:29]O>>[NH:10]=[C:9]1[CH:11]=[CH:12][C:13]([CH3:29])([S:15][CH2:16][CH2:17][CH3:18])[C:14]([CH2:20][C:21]2[CH:28]=[CH:27][CH:24]=[CH:23][CH:22]=2)=[C:8]1[NH:7][C:6]([NH:5][C:1]([O:3][CH3:4])=[O:2])=[S:19]
Reactant: CCCSc1ccc(N)c(NC(=S)NC(=O)OC)c1
Reactant: CO
Reactant: Cc1ccc(C=O)cc1
Product: CCCSC1(C)C=CC(=N)C(NC(=S)NC(=O)OC)=C1Cc1ccccc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of 2-(3-carbomethoxythioureido)-4-propylthioaniline (9.0 g; 0.03 mole) in methanol (100 ml), cooled to 10° C., there is added p-methylbenzaldehyde (3.6 g; 0.03 mole). The mixture is stirred at 10° C. for 1 hr. and at room temperature for 18 hrs. The suspension that forms is vacuum filtered and the filter cake is air dried to afford 1-imino(4-methyl)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (10.75 g; 89%), m.p. 135°-141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([CH:14]([N+:16]#[C-:17])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:18][C:19]1[S:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1.Cl(O)(=O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:19]1[S:23][C:22]([C:24]2[N:1]=[C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]3[C:17]=2[NH:16][CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: Nc1cnccn1
Reactant: [C-]#[N+]C(C)c1ccccc1
Reactant: O=Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)Cl
Product: CC(Nc1c(-c2ccc(Br)s2)nc2cnccn12)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 21 %

Procedure:
951 mg (10.0 mmol) of 2-aminopyrazine were dissolved together with 1.31 g (10.0 mmol) of 1-phenylethylisonitrile and 1.08 ml (10.0 mmol) of 5-bromothiophene-2-carbaldehyde in chloroform (24 ml). After addition of perchloric acid (1.00 ml), the mixture was stirred at RT for 5 d. The mixture was then combined with a sat. aq. sodium carbonate solution and the phases were separated. The aqueous phase was extracted with DCM. The combined organic phases were washed with a sat. aq. sodium carbonate solution and dried over magnesium sulfate, filtered and evaporated under a vacuum. After carrying out column chromatography (EA/DCM 1:1) with the group, 831 mg (2.1 mmol, 21% of theoretical) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-(1-phenyl-ethyl)-amine were obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH:6][CH:7]1[CH2:13][CH:12]2[N:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=3)[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[ClH:1].[ClH:1].[C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([N:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:8][CH:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:32]2[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]2)[CH2:13]3)=[CH:16][CH:17]=1)#[N:26]
Reactant: N#Cc1ccc(N2C3CCC2CC(NC(=O)CCCl)C3)c2ccccc12
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN1CCN(CCC(=O)NC2CC3CCC(C2)N3c2ccc(C#N)c3ccccc23)CC1
Product: Cl
Yield: 79.3 %

Procedure:
165RL50 (65 mg, 0.18 mmol), 1-ethylpiperazine (45 μL, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol) were stirred in acetonitrile (6 mL) at 50° C. for 2 days. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (2×10 mL). The organic solution was dried over sodium sulfate, filtered and evaporated. The product was purified by column chromatography using ethyl acetate/MeOH (9:1) to give the title compound (37 mg, 46%) pure product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl>C1COCC1>[C:10]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCCC2)cc1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a 0.5M solution of 4-fluorophenylmagnesium bromide (298 mL, 149 mmol) in THF at 0° C. was carefully added cyclopentanone (13.23 mL, 149 mmol). Upon the end of the addition, the reaction mixture was heated at reflux for 2 h. Ice (10 g) and 6N aqueous hydrochloric acid were added. The reaction mixture was extracted with ether. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen sulfite, a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 1-cyclopentenyl-4-fluorobenzene (24.155 g, 149 mmol, 100% yield) as colorless oil. LC-MS (M+H)+=163.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.35-7.42 (2H, m), 6.95-7.02 (2H, m), 6.06-6.13 (1H, m), 2.63-2.71 (2H, m), 2.47-2.56 (2H, m), 1.96-2.06 (2H, m).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][C:34](=[O:49])[C@H:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:36][CH3:37])=[CH:27][CH:26]=1>CO.C(Cl)Cl>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][C:34](=[O:49])[C@H:35]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[N:36]([C:21](=[O:22])[C@H:9]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])[CH3:37])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1
Solvent: ClCCl
Solvent: CO
Product: CN(C(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1

Procedure:
Using Procedure B, coupling of Boc-β-(2-naphthyl)alanine and Nδ-Boc-Nα-methylornithine 2-(4-hydroxyphenyl)ethylamide, followed by silica gel chromatography (2.5% MeOH/CH2Cl2): 1H NMR (400 MHz, CDCl3) 6 1.41 (m, 21H), 1.85 (m, 1H), 2.20 (m, 2H), 2.45 (m, 1H), 2.67 (m, 4H), 3.03 (m, 4H), 4.91 (m, 2H), 6.77 (m, 2H), 6.87 (d, J=8.7 Hz, 1H), 6.98 (d, J=10.0 Hz, 1H), 7.34 (m, 1H), 7.46 (m, 2H), 7.66 (m, 1H), and 7.78 (m, 3H); mass spectrum (ES+) m/e 663 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.BrC[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1)[CH2:22][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: BrCC1CCCCC1
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Product: CCCCCCOc1ccc2c(c1)C(=O)OC(C)(C)O2

Procedure:
The title compound was prepared from 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (example 38-a) and (bromomethyl)cyclohexane under conditions analogous to experimental example 38-b, to give the desired product as a white solid. MS: (+) m/z 279.16 (M+1)
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:24])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:25]([C:28]([CH3:30])=[CH2:29])[CH2:26]C[C@]1(C(O)=O)C[CH2:3]2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:41])C=CC=CC=1.C([N:54]([CH2:58]C)[CH:55]([CH3:57])[CH3:56])(C)C>O1CCOCC1>[N:54]([C@:55]12[CH2:56][CH2:26][C@@H:25]([C:28]([CH3:30])=[CH2:29])[C@@H:6]1[C@@H:7]1[C@@:2]([CH3:1])([CH2:3][CH2:57]2)[C@@:19]2([CH3:20])[C@@H:10]([C@:11]3([CH3:24])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:21])([CH3:22])[C:14](=[O:23])[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)=[C:58]=[O:41]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.5 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (2.1 g, 4.62 mmol) in dioxane (20 mL) was added diphenylphosphoryl azide (DPPA 1.294 mL, 6.00 mmol) and N,N-diisopropylethylamine (2.092 mL, 12.01 mmol) forming a clear solution. The mixture was stirred at RT for 40 minutes before it was immersed into an oil bath at 102° C. under a nitrogen atmosphere for 16 hrs. The crude mixture was evaporated to dryness, re-dissolved into 100 mL DCM, washed 3 times with water. The product was purified by silica gel chromatography eluted with mixture of 20% ethyl acetate in hexanes to give 1.91 gm (92% yield) of the title product. MS: m/e 452.35 (M+H)+, 5.58 min (method 10). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.76 (d, J=2.0 Hz, 1H), 4.66-4.64 (m, 1H), 2.60-2.47 (m, 2H), 2.43 (dd, J=7.5, 4.5 Hz, 1H), 2.11 (br. s., 1H), 1.96-1.77 (m, 5H), 1.76-1.70 (m, 1H), 1.69 (d, J=0.5 Hz, 3H), 1.64-1.42 (m, 10H), 1.42-1.29 (m, 4H), 1.23-1.15 (m, 1H), 1.10 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H), 0.96 (s, 6H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([CH2:16][C:17]([NH:19][C:20]2[S:24][C:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C:22]=3[C:21]=2[C:29]([NH2:31])=[O:30])=[O:18])[N:10]=1)([CH3:8])([CH3:7])[CH3:6].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[C:5]([C:9]1[C:13]([CH2:14][NH:4][CH2:3][CH2:1][OH:2])=[CH:12][N:11]([CH2:16][C:17]([NH:19][C:20]2[S:24][C:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C:22]=3[C:21]=2[C:29]([NH2:31])=[O:30])=[O:18])[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1CNCCO
Reaction time: 1 h
Yield: 40.8 %

Procedure:
Ethanolamine (189 mg, 0.186 mL, 3.09 mmol) was added to a solution of 2-(2-(3-tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (120 mg, 0.309 mmol) and acetic acid (0.5 mL, 8.7 mmol) in DMF (3 mL) and stirred for 1 h. Sodium triacetoxyborohydride (655 mg, 3.09 mmol) was added and the mixture stirred for 17 h at ambient temperature. Water (500 μL) was added and the mixture stirred for 30 min. The mixture was filtered and purified by preparative reverse phase HPLC. The clean fractions were passed down an SCX cartridge and the free base eluted with 2M NH3 in MeOH. Volatiles were blown down under a nitrogen atmosphere to yield the title compound (54.8 mg, 0.126 mmol, 41%).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[C:9]([O:13][C:14](=[O:17])[NH:15][NH2:16])([CH3:12])([CH3:11])[CH3:10].[CH2:18](N(CC)CC)[CH3:19]>C(O)C>[C:9]([O:13][C:14]([N:15]1[C:6]([NH2:7])=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2][CH2:19][CH2:18]2)=[N:16]1)=[O:17])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NN
Reactant: N#CCC(=O)C1CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)n1nc(C2CCCC2)cc1N
Reaction time: 72 h

Procedure:
(Method B) 1.09 g (10 mmol) of 3-cyclopropyl-3-oxopropanenitrile and 1.32 g (10 mmol) of tert-butylcarbazate in 25 ml of anhydrous ethanol were stirred at room temperature for 4 hours, then 0.5 ml of triethylamine were added at room temperature. After 3 days under stirring the solution was evaporated to dryness under reduced pressure. The resulting residue was taken up with 100 ml of n-hexane-ethylacetate 70/30 and stirred for 3 hours at 5° C. The solid was filtered through a Buchner funnel and then dried at 40° C. under vacuum yielding 2 g (90 %yield) of the title compound. Following the same method, but employing 3-cyclobutyl- or 3-cyclopentyl-oxopropanenitrile, tertbutyl-5-amino-3-cyclobutyl- or tertbutyl-5-amino-3-cyclopentyl-1H-pyrazole-1-carboxylate can be prepared.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH2:20][OH:21])([CH2:18][OH:19])[C:9]1=[O:22])=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:18][OH:19])([CH2:20][OH:21])[C:9](=[O:22])[NH:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(CO)(CO)c2ccc(Cl)cc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(Cl)ccc2C1(CO)CO
Temperature: 20 °C
Reaction time: 5 h
Yield: 189.3 %

Procedure:
A mixture of 6-chloro-3,3-bis-hydroxymethyl-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.9 g, 5.8 mmol), DCM (50 mL) and TFA (10 mL) was stirred at 20° C. for 5 h then evaporated in vacuo to give a semi-solid. Azeotrope with THF was performed to give the title compound (2.5 g). MS: [M+H]+=228.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[NH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][NH2:16])[CH2:11][CH2:12][NH2:13].[OH-:17].[K+]>C1C=CC=CC=1.O>[C:4]([NH:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][NH:16][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][NH:13][C:4]([O:3][CH2:1][CH3:2])=[O:17])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: [OH-]
Reactant: NCCN(CCN)CCN
Reactant: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)NCCN(CCNC(=O)OCC)CCNC(=O)OCC
Temperature: 5 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
In accord with the procedure of H. Schmidt et al., Z. anoro. allq. Chem., 578, 75 (1989), ethylchloroformate (33.4 g, 0.310 mol) was added dropwise to a solution of tris(2-aminoethyl)amine (TREN) (29.2 g, 0.20 mol) dissolved in a mixture of benzene (225 mL) and water (100 mL) cooled to 5° C. After the addition was completed, KOH (36.4 g, 0.650 mol) dissolved in water (35 mL) was added dropwise simultaneously with more ethylchloroformate (33.4 g, 0.310 mol). The reaction mixture was stirred for 2 hr. at 5° C. and then for 8 hr. at room temperature. The benzene layer was separated and the water layer extracted with chloroform (2×100 mL). The combined organic fractions were dried over MgSO4, decanted and the decantate evaporated to dryness to give the intermediate tris(2-carbethoxyaminoethyl)amine (5) in 85% yield as a thick oil which was used in subsequent reactions without further purification (1H NMR (CDCl3)δ1.27 (9H, t, 3JHH =7.1 Hz), δ2.60 (6H, t, 3JHH =5.7 Hz), δ3.23 (6H, br), δ4.10 (6H, q, 3J=7.1 5.50 (3H, br); IR 3300, 1720, 1530, 1250 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[F:14].[F:15][C:16]([F:21])([F:20])[C@@H:17]1[CH2:19][O:18]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([CH2:19][C@H:17]([OH:18])[C:16]([F:21])([F:20])[F:15])[CH2:11][CH2:12][O:13]2)=[CH:4][C:3]=1[F:14]
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: Fc1cc([C@@H]2CNCCO2)ccc1Cl
Solvent: ClCCl
Product: O[C@@H](CN1CCO[C@H](c2ccc(Cl)c(F)c2)C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(R)-2-(4-chloro-3-fluorophenyl)morpholine (230 mg, 1.07 mmol) was mixed with (S)-2-(trifluoromethyl)oxirane (180 mg, 1.6 mmol) in 1 mL of dichloromethane in a tube. The tube was sealed and stirred at 60° C. overnight. The solution was evaporated to dryness to afford (S)-3-((R)-2-(4-chloro-3-fluorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol as an oil (340 mg), which was used as is in the next step. (M+H)+=328 m/e.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)=[O:12].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)[OH:12]
Reactant: COc1cccc(C(=O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Reaction time: 1 h

Procedure:
To a stirred solution of (2,3-dimethoxyphenyl) [1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methanone (6.0 g, 16.2 mmol) in MeOH (100 mL) at 0° C. was added NaBH4 (1240 mg, 32.8 mmol) in two portions, over a one hour period. After stirring overnight, the solution was concentrated to a solid. The solid was partitioned between water and ether. The layers were separated and the aqueous layer was extracted with ether. The combine organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a solid. The solid was chromatographed on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to afford a white solid. The solid was recrystallized from cyclohexane to afford (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol as white needles, m.p. 126-127° C. Anal. Calcd for C22H28FNO3: C, 70.75; H, 7.56; N, 3.75. Found: C, 70.86; H, 7.72; N, 3.93.