Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Br)=[CH:47][C:46]=1[F:53]>CN(C)C=O.O>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:49][C:48]3[CH:51]=[CH:52][C:45]([Cl:44])=[C:46]([F:53])[CH:47]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Fc1cc(CBr)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(Cl)c(F)c3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
An ice cold solution of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (21 mg, 0.055 mmol) in N,N-Dimethylformamide (DMF) (500 μl) was treated with K2CO3 (37.9 mg, 0.275 mmol), DIEA (47.9 μl, 0.275 mmol), and 4-chloro-3-fluorobenzyl bromide (61.4 mg, 0.275 mmol), stirred at rt for 1 hr, and then heated to 70° C. for 18 hours. The reaction was diluted with water, extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/hexane) gave methyl 2-(tert-butoxy)-2-(1-(4-chloro-3-fluorobenzyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (26.2 mg, 0.050 mmol, 91% yield) as clear oil. The ester intermediate was dissolved in Methanol (500 μl) and Tetrahydrofuran (THF) (500 μl), treated with 2M LiOH (150 μl, 0.3 mmol), and stirred at 60° C. for 2.5 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA, 12 min) to give title compound (11.6 mg, 0.022 mmol, 40.9% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9H), 2.43 (s, 3H), 3.65 (s, 3H), 5.46 (s, 1H), 5.79 (d, J=2.3 Hz, 2H), 6.06 (d, J=2.8 Hz, 1H), 6.94-7.07 (m, 3H), 7.24-7.31 (m, 2H), 7.30-7.38 (m, 2H), 7.49-7.56 (m, 1H); LCMS (m/z) ES+=511 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:29])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)=[O:29])=[CH:35][CH:34]=3)=[CH:14][C:6]1=2
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3Cl)CCN4)cc2)CC1
Yield: 49 %

Procedure:
1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (49% yield). M.p. (foam), LCMS: m/z=498.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (s, 3H), 2.32-2.50 (m, 4H), 3.44-3.51 (m, 2H), 3.45-3.84 (m, 4H), 3.63-3.68 (m, 2H), 4.49 (s, 2H), 5.21 (s, 1H), 6.62 (d, J=1.5 Hz, 1H), 7.18-7.21 (m, 1H), 7.24-7.29 (m, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.39-7.42 (m, 4H), 7.72 (d, J=1.8 Hz, 1H).
Reaction SMILES: [C:1]1(C)[CH:6]=[C:5](C)[CH:4]=[C:3](C)[C:2]=1[Mg]Br.[C:12]1(=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C1([Mg]Cl)C=CC=CC=1.Cl>C1COCC1.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.CCCCC>[C:1]1([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: O=C1CCCc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: C1=C(c2ccccc2)c2ccccc2CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
20.0 mL (20.4 mmol) 1.02 M mesitylmagnesium bromide in THF was added over 10-15 minutes to a solution of 2.66 mL (20.0 mmol) 1-tetralone and 4.56 mL (22.0 mmol) diphenyl chlorophosphate in 4 mL THF at 0° C. The solution was stirred at 0° for 30 min, allowed to warm to room temperature, and then stirred for an additional 30 min. The reaction mixture was then treated with 0.140 g (1 mol%) dichlorobis(triphenylphosphine)palladium and warmed to 65°. 11.5 mL (24.0 mmol) 2.08 M phenylmagnesium chloride in THF was added over 5-10 minutes, resulting in a gentle reflux of the solvent. After stirring at 65° for 30 min, the mixture was cooled to room temperature and poured into a mixture of 3 N HCl (30 mL) and pentane (30 mL). The phases were separated, and the aqueous portion was extracted with pentane (25 mL). The combined organic phase was washed sequentially with 3 N HCl (15 mL), 3 N NaOH (twice, with 15 mL each time), and brine (20 mL). The resulting organic phase was dried (MgSO4), concentrated, and then distilled using a Kugelrohr apparatus (oven temp=120-150° C.); 0.1 torr) to provide 3.51 g 1-phenyl-3,4-dihydronaphthalene (85% yield on 1-tetralone).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br>C(O)C>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COC(CBr)OC
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(OC)OC)C(=O)OCC
Yield: 44.1 %

Procedure:
Diethyl malonate (168.18 g, 1.05 mol) was added to a solution of sodium ethoxide (from 23.0 g, 1.00 mol of sodium) in 500 ml of dry ethanol at 50° C. during 45 min. Bromoacetaldehyde dimethylacetal (74.2 g, 1.06 mol) was added at the same temperature during 45 min. and the mixture was refluxed over-night. Ethanol was evaporated in vacuum, and the residue was dissolved in 200 ml of water and extracted with 3×300 ml of ether. The extracts were dried (MgSO4), evaporated, and distilled in vacuum to give 115.0 g (46%) of the title compound. B.p. 97°-101° C. (0.6 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])C(OC)=O.[Li+].[Cl-].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCC(CC)(CC)C(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(CC)(CC)CC(=O)OC
Temperature: 170 °C
Yield: 100.3 %

Procedure:
Step C To a solution of 2-(1,1-diethyl-propyl)-malonic acid dimethyl ester (2.5 g, 11 mmol) in DMSO (30 mL) was added LiCl (0.91 g, 21.6 mmol) and H2O (0.19 mL, 11 mmol). The reaction mixture was heated at 170° C. for 4 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3,3-diethyl-pentanoic acid methyl ester as a yellow oil (1.9 g, 100%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:25][N:26]([CH:35]=[O:36])[O:27]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[CH3:24])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:25][N:26]([CH:35]=[O:36])[OH:27])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[CH3:24])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CC[C@@H](C(=O)Nc2ccncn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CC[C@@H](C(=O)Nc2ccncn2)N1C(=O)[C@H](CC1CCCC1)CN(O)C=O
Reaction time: 2 h
Yield: 71.2 %

Procedure:
(3S)-2-[(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-methyl-N-4-pyrimidinyl-3-pyrazolidinecarboxamide (120 mg, 0.243 mmol) was dissolved in methanol (14 mL). To this mixture was added palladium hydroxide on carbon (34.1 mg, 0.049 mmol). The reaction mixture was degassed and placed under 1 atm of H2. After 2 h, the reaction mixture was filtered and concentrated. The residue was purified by RP-HPLC to afford (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-1-methyl-N-4-pyrimidinyl-3-pyrazolidinecarboxamide (70 mg, 0.173 mmol, 71.3% yield) as white foam solid. LC-MS (ES) m/e 405.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1COCC1.[Cl-].[NH4+]>[C:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[C:9]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])[S:8][C:7]=12)#[N:2]
Reactant: N#Cc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C#N)c2s1
Reaction time: 1 h

Procedure:
A solution of 903 mg of 7-cyanoimidazo[5,1-b]thiazole in 35 ml of THF was cooled to −78° C. under the atmosphere of argon, and 6.36 ml of a 1.0 N solution of lithium bistrimethylsilylamide in THF was added dropwise at an internal temperature of −70-−65° C. After the reaction mixture was stirred at the same temperature for 1 hour, 1.81 ml of tri-n-butylstannyl chloride was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with 100 ml of a semi-saturated aqueous ammonium chloride solution and extracted with 100 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give the title compound in a yield of 795 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl[O-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][N:3]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F

Procedure:
2.11 g (0.01 mol) of 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.17 g (0.0005 mol) of tetrabutylammonium bromide are dissolved in 25 ml of methylene chloride at room temperature. 12 ml (0.02 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 5 minutes, with vigorous stirring and the mixture is stirred for a further 4 hours during which the reaction temperature rises to 30° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.5 mbar, 100°-120° C. bath temperature), 1.47 g (70.5% of theory) of 2-chloro-5-trifluoroacetylpyridine are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:47]=[CH:46][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:41][C:42]([O:44]C)=[O:43])[CH2:36][C:37]([O:39]C)=[O:38])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:36][C:37]([OH:39])=[O:38])[CH2:41][C:42]([OH:44])=[O:43])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:46][CH:47]=1)=[O:11]
Reactant: COC(=O)CN(CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1)CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN(CC(=O)O)CC(=O)O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of dimethyl 2,2′-[(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)imino]diacetate (100 mg, 0.15 mmol) in a mixture of THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 4 hours and poured into 50 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give 2,2′-[(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)imino]diacetic acid as white solid. Yield: 82 mg, 78%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]=[O:17]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:16](=[O:17])[NH:15][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCN=C=O
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Product: CCOC(=O)CCNC(=O)Nc1cc(I)c(OC)c(C(C)(C)C)c1
Yield: 83 %

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl 3-isocyanatopropionate were reacted in the same manner as Example 15 Part A and purified on an Isco 40 g silica cartridge eluting with ethyl acetate/hexane (0% to 25%) to give the title compound (373 mg, 83%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1.CCN(C(C)C)C(C)C>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([CH2:16][N:13]3[C:11]4=[N:12][C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:8][N:9]=[C:10]4[N:15]=[N:14]3)[CH2:18]2)=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCNC4)c3n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(Br)cn5)C4)c3n2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-1-(piperidin-3-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (0.26 g, 0.89 mmol) was dissolved in EtOH (15 ml), and then 5-bromo-2-chloropyrimidine (0.33 g, 1.33 mmol) and DIPEA (0.77 ml, 4.43 mmol) were added, followed by stirring at 50° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (1-((1-(5-bromopyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (0.28 g, 70%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(#N)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]2[C:3]([CH2:2][N:30]3[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]3)=[N:4][N:5]=[N:6]2)=[CH:9][C:10]=1[C:16]([F:19])([F:18])[F:17])#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
To a solution of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 24, 575 mg, 2.00 mmol) in acetonitrile (10 mL) was added triethylamine (0.558 mL, 4.00 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (410 mg, 2.20 mmol). The mixture was then heated to 120° C. for 20 min in a microwave reactor. The crude product was purified by silica chromatography (Biotage SP4, 40+S), eluting with 30% ethyl acetate in hexane (2 column volumes) then a gradient from 30-60% ethyl acetate in hexane (10 CV) then 60% ethyl acetate in hexane (2 column volumes). The relevant fractions were evaporated under vacuum to leave a white solid, 1,1-dimethylethyl 4-({1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (532 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].[C:19]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[C:32]1([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][NH:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=3[N+:16]([O-:18])=[O:17])[CH2:30][CH2:31]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 10 parts of N-(3-chloropropyl)-2-nitro-4-(trifluoromethyl)benzenamine, 8.11 parts of 1-(diphenylmethyl)piperazine, 8.37 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled and water is added. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 4-(diphenylmethyl)-N-[2-nitro-4-(trifluoromethyl)phenyl]-1-piperazinepropanamine; mp. 113.7° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C=O.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.C(OCC)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: O=CCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(CCCCCCCCCl)OCC
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
12.0 gms of 9-chloro-nonaldehyde was heated at reflux with 20 gms of triethyl orthoformate, 9 gms anhydrous ethanol and one drop of concentrated sulphuric acid for one hour. The reaction was cooled, 10 gms of sodium carbonate was added and the mixture stirred 10 minutes. The mixture was diluted with 100 mls of diethyl ether and extracted twice with 50 mls of saline solution. The organic layer was dried over sodium sulphate, concentrated on rotary evaporator and distilled. The major fraction distilled at 84° at 0.1 torr yielding 13.3 gms of 1,1-diethoxy-9-chloro nonane. N.M.R. (CdCl3): triplet 4.47 ppm (1H), multiplet 3.58 ppm (6H), triplet 1.21 ppm.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]4[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:22]3[CH2:27][CH2:26][N:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH3:33][C:34](=O)[CH3:35].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:31]([S:28]([N:25]1[CH2:26][CH2:27][CH:22]([C:13]2[C:12]3[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[CH2:1][N:2]([CH:34]([CH3:35])[CH3:33])[CH2:3]5)[CH:11]=3)[NH:15][CH:14]=2)[CH2:23][CH2:24]1)(=[O:29])=[O:30])[CH3:32]
Reactant: CC(C)=O
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(C)C)C5)cc23)CC1
Yield: 2.5 %

Procedure:
To a solution of 5-(2,3-dihydro-1H-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.066 mmol) in MeOH (0.5 mL), was added 2-propanone (12 mg, 0.198 mmol), sodium cyanoborohydride (8 mg, 0.133 mmol) and zinc chloride (9 mg, 0.066 mmol). The resultant mixture was heated in a microwave for 30 min at 100° C. Mixture was then concentrated, filtered and purified by Gilson Preparatory HPLC to give 0.8 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 100.9 %

Procedure:
N-t-butyloxycarbonyl-L-valine (8.69 g, 40 mmole), L-proline benzylester hydrochloride (9.67 g, 40 mmole) and HOBt (5.40 g, 40 mmole) were dissolved in methylene chloride (150 ml), and N-methylmorcholine (4.05 g, 40 mmole) and WSC hydrochloride (7.67 g, 40 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than ° C., and then overnight at room temperature, washed with aqueous sodium bicarbonate (150 ml, twice), 5% aqueous citric acid (150 ml, twice) and water (150 ml) in the order given and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-t-butyloxycarbonyl-L-valyl-L-proline benzylester(yield: 16.32 g, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:9][C:8]1[C:3]([CH:2]=[O:1])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(CO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(O)c(C=O)n1
Reaction time: 48 h
Yield: 7.1 %

Procedure:
To a solution of 2-hydroxymethyl-6-methyl-pyridin-3-ol (1.0 g, 7.19 mmol) in methylene chloride (30 mL) at ambient temperature was added manganese dioxide (12.5 g, 143 mmol). The reactions was stirred for 48 hours, then filtered through celite and concentrated to give the title compound (0.070 g).
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@@H:12]2[C@@H:17]([CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:16]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[C@@H:15]([O:35][C@@H:36]([C:38]3[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=3)[CH3:37])[O:14][CH2:13]2)=O)=CC=1)([O-])=O.[OH-].[Na+]>CO>[CH2:20]([O:19][CH2:18][C@H:17]1[C@H:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[CH3:34])[C@@H:15]([O:35][C@@H:36]([C:38]2[CH:43]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=2)[CH3:37])[O:14][CH2:13][C@@H:12]1[CH2:11][OH:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@H](COC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@H](CO)[C@H]1COCc1ccccc1
Temperature: 45 °C

Procedure:
The intermediate from step G (3.98 g, 5.31 mmol) was dissolved in 100 mL of MeOH and was added 0.1 mL of 2N NaOH. The mixture was heated to 45° C. for 1 hr. Volatiles were removed in vacuo. The crude residue was purified on silica gel and eluted a combination of EtOAc/hexanes (10-30% EtOAc/hexanes linear gradient). This provided the title compound. MS: (MH)+601