Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN1C(=O)CCC1.O>[CH2:19]([NH:26][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Cl)nc(NCc2ccccc2)c1
Temperature: 150 °C

Procedure:
2,6-Dichloro-4-methylpyridine (2.00 g, 12.3 mmol) was suspended in NMP (10 mL). N,N-Diisopropylethylamine (4.31 mL, 24.7 mmol) and benzylamine (1.42 mL, 13.0 mmol) were added, and the reaction mixture was heated to 150° C. in a microwave for 90 minutes. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether (2×). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-10% ethyl acetate/hexanes, linear gradient) to give N-benzyl-6-chloro-4-methylpyridin-2-amine. MS ESI calc'd. for C13H14ClN2 [M+H]+ 233. found 233.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:10](Cl)=[O:11].O>O1CCCC1>[CH3:16][N:15]([CH3:17])[C:13]([N:9]([CH3:8])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])=[O:14]
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 146.9 %

Procedure:
Into 50 ml of anhydrous tetrahydrofuran, 7.4 g (0.08 mol) of aniline was added thereinto and dissolved and the mixture was cooled below 0° C. under stirring. Into this cooled mixture, a solution obtained by dissolving 6.4 g (0.04 mol) of 2,4,4-trimethylallophanoyl chloride in 10 ml of anhydrous tetrahydrofuran was added drop-wise under stirring. After the reaction was continued for 1 hour at room temperature, the solvent was remvoed by distillation under reduced pressure. To the residue thus obtained, water was added and insoluble material was separated by filtration and was recrystallized from ethanol to obtain 13.0 g (yield: 73%) of 1,1,3-trimethyl-5-phenylbiuret having a melting point of 89.5°-90.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1)=[O:4].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:45][CH2:44][CH2:43][C@@:30]3([C:34](=[O:35])[N:33]([C@H:36]4[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[CH2:29]2)=[C:24]([F:46])[CH:23]=1>>[F:46][C:24]1[CH:23]=[C:22]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:1])[CH3:20])=[O:4])=[N:6][CH:7]=2)[CH:27]=[CH:26][C:25]=1[N:28]1[CH2:45][CH2:44][CH2:43][C@@:30]2([C:34](=[O:35])[N:33]([C@H:36]3[CH2:37][CH2:38][C@@H:39]([OH:42])[CH2:40][CH2:41]3)[CH2:32][CH2:31]2)[CH2:29]1
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCN(c1ccc(Br)cc1F)C2
Product: CN(C)C(=O)c1ccc(-c2ccc(N3CCC[C@]4(CCN([C@H]5CC[C@@H](O)CC5)C4=O)C3)c(F)c2)cn1

Procedure:
This compound was prepared by using procedures that were analogous to those described for the synthesis of Example 1, Step 8 starting from N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide and (5S)-7-(4-bromo-2-fluorophenyl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC/MS m/e 495.3 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8.86 (1H, d, J=1.7 Hz), 8.15 (1H, dd, J=8.1, 2.3 Hz), 7.51-7.65 (3H, m), 7.12 (1H, t, J=8.9 Hz), 4.37 (1 H, d, J=3.1 Hz), 3.78 (1H, m), 3.71 (1H, m), 3.22-3.38 (3H, m), 3.06 (1H, d, J=11.7 Hz), 3.00 (3H, s), 2.97 (3H, s), 2.64-2.74 (2H, m), 2.18-2.27 (1H, m), 1.60-1.91 (8H, m), 1.39-1.51 (3H, m), 1.22-1.30 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:34]3[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=3)[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:13])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4([C:34]5[CH:35]=[CH:36][C:37]([N:40]6[C:11](=[O:13])[C:4]7=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=[C:5]7[C:6]6=[O:8])=[CH:38][CH:39]=5)[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=5[C:28]5[C:33]4=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:19][CH:20]=3)[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=1
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2C(=O)N1c1ccc(C2(c3ccc(N4C(=O)c5ccc(O)cc5C4=O)cc3)c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of 4-hydroxyphthalic acid (4.0 g, 22 mmol), 9,9-bis(4-aminophenyl)fluorene (3.5 g, 10 mmol), and 40 ml of acetic acid was stirred and heated under reflux for 48 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with acetic acid (2×25 ml) to provide the title compound as a colorless powder having a melting point greater than 300° C. (3.4 g, 53.1% yield). The nuclear magnetic resonance and infrared spectrum were consistent with the structure.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, product of step B above) by following the indications of general procedure H using DIEA (0.19 mL, 1.09 mmol) and aniline (0.16 mL, 1.76 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (90 mg, 48% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:4]1)[CH3:2].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCn1cc(S(=O)(=O)n2cc(CNC)c(F)c2-c2cccnc2F)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
tert-Butyl {[1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (290 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 196 mg, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][N:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2nccn2Cc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1

Procedure:
A mixture of 5 mmol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours in a Parr hydrogenator at 35 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][C:31]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:32])[CH:34]=[CH:35][CH:36]=1
Reactant: Cc1cccc(C=CC(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cccc(C)c1
Yield: 98.4 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.2 g, 98%) as an oily product.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([Sn:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11]>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:17])=[O:5].[CH2:8]([Sn+2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Sn](=O)CCCC
Reactant: O=C1C=CC(=O)O1
Product: CCCC[Sn+2]CCCC
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
Maleic anhydride and dibutyltin oxide are mixed with one another, and the mixture is reacted in a twin-screw laboratory extruder in accordance with Example 1. Dibutyltin maleate (compound 3) is obtained as the end product in the form of a white free-flowing powder.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](O)=[O:5].CC[N:11]([CH:15]([CH3:17])C)[CH:12]([CH3:14])C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(O[C:41]([N:43]1C(C(OC(C)(C)C)=O)CCC(C(O)=O)C1)=O)(C)(C)C>C1COCC1>[NH2:43][CH:41]1[CH2:14][CH2:12][N:11]([C:4](=[O:5])[CH2:3][C:2]([OH:1])([CH3:8])[CH3:7])[CH2:15][CH2:17]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(O)CC(=O)O
Reactant: CC(C)(C)OC(=O)C1CCC(C(=O)O)CN1C(=O)OC(C)(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Product: CC(C)(O)CC(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-hydroxy-3-methyl butyric acid (1.20 equiv), DIPEA (2.00 equiv), and T3P (1.50 equiv) were added to a stirring solution of compound 1 (1.00 equiv) in THF (0.2M) at room temperature under nitrogen. TLC analysis after 2 hours showed almost complete conversion, so reaction was concentrated. Residue was dissolved in ethyl acetate then washed with water, dilute HCl, saturated NaHCO3, and brine. The phases were separated and the organics dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography (SiO2, 12 g; 0% to 10% methanol in methylene chloride). The resulting material was dissolved in methylene chloride (0.97M) and TFA (0.97M) was added under nitrogen and the mixture was stirred at room temperature for 1 hour at which time HPLC analysis indicated the reaction was complete. Reaction was concentrated and the resulting residue was dissolved in 1N NaOH and stirred at room temperature for 30 minutes. The aqueous mixture was extracted with methylene chloride. The phases were separated and the organics dried over sodium sulfate, filtered, and concentrated affording the title compound, 1-(4-aminopiperidin-1-yl)-3-hydroxy-3-methylbutan-1-one. 1H NMR (300 MHz, CDCl3) δ 4.40 (d, 1H, JHz=13.9), 3.73 (d, 1H, JHz=12.1), 2.99-2.95 (m, 1H), 2.90 (m, 1H), 2.70-2.63 (m, 1H), 2.33 (s, 2H), 1.76 (m, 2H), 1.12 (s, 8H).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:16]Cl.C(N(CC)CC)C.S(=O)(=O)(O)O>ClC(Cl)C>[CH3:1][N:2]([S:16][N:15]([CH2:14][CH2:13][O:12][CH3:11])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4]
Reactant: CNC(=O)ON=C(C)SC
Reactant: COCCN(CCC(=O)OC)SCl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COCCN(CCC(=O)OC)SN(C)C(=O)ON=C(C)SC
Yield: 87.8 %

Procedure:
A 14.6 g (0.09 mole) quantity of S-methyl N-[(methylcarbamoyl)oxy]thioacetimidate was poured into 100 ml of a dichloroethane solution containing 22.75 g (0.1 mole) of N-methoxyethyl-N-methoxycarbonylethylaminosulfenyl-chloride. The mixture was agitated by a stirred and 18 g (0.18 mole) of triethylamine was added dropwise at less than 5° C. over a period of 30 minutes. Thereafter the mixture was agitated at the same temperature for 1 hour. A 5% aqueous solution of sulfuric acid was added to the mixture until a pH of 6 was achieved. The dichloroethane solution was washed with a 5% aqueous solution of sodium hydrogencarbonate and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated at reduced pressure, giving 31 g of a yellow brown oily product in a yield of 87.8%.
Reaction SMILES: Br[C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[F:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=1>>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[C:3]([N:25]3[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:20])([F:21])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:24]=2)[CH:35]=[N:34][CH:33]=1
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 220.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.58 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=513.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.76 (m, 1H) 1.78-1.89 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.13-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.19 (br. s, 1H) 4.85 (d, J=3.13 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.76-7.90 (m, 3H) 8.03-8.09 (m, 1H) 8.49 (s, 1H) 8.58 (d, J=2.74 Hz, 1H) 8.72-8.82 (m, 1H) 8.99-9.00 (m, OH) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.6 %

Procedure:
To a solution of 2-[(1-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (382 mg) in dry chloroform (4.52 mL) at 0° C. was added NBS (234 mg) in a single portion. The reaction was warmed to room temperature and stirred for 5 h. The reaction mixture was taken up in DCM (20 mL) and was washed with water (30 mL). The organics were separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give a green/brown foam (493 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.55 g (99%) of N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 243-245 _C. Anal. Calc'd. for C18H15F3N4O3S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.64; H, 3.43; N, 12.64; S, 7.37.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH:17](=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH3:22]>C1COCC1>[OH:4][CH:3]([CH2:5][C:17](=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH3:22])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: CC=CC=CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC=CC=CC(=O)CC(O)CC(=O)OC
Temperature: -78 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
To a cold (-30° C.) solution of methyl acetoacetate (41.5 g, 357 mmol) in THF (500 mL) was added lithium diisopropylamide (476 mL, 1.5M solution in cyclohexane, 714 mmol). The resultant solution was stirred for 15 minutes at -30° C. After cooling to -78° C., 2,4-hexadienal (34.3 g, 357 mmol) was added and the solution stirred for 10 minutes at -78° C. and for 16 hours at ambient temperature. The solution was concentrated under reduced pressure and the residual syrup was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated. The residue was purified by chromatography on silica gel (diethyl ether:hexane/2:1) to afford 18.5 g (24.4%) of the title compound as an oil.
Reaction SMILES: CO.[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([C:27](O)=[O:28])[CH2:16]1)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Li+].O>O1CCCC1>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([CH2:27][OH:28])[CH2:16]1)=[O:13])=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Yield: 97.8 %

Procedure:
Methanol (8 mL) was added over a period of 1 hr to a refluxed mixture of trans-4-N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline methyl ester (Compound D103 (B), 1.39 g) and lithium borohydride (328 mg) in tetrahydrofuran (30 mL). After being cooled, water was added to the mixture and the product was extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, then evaporated in vacuo and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5, v/v) to give title compound (1.31 g): 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.47 (s, 9H), 1.89 (m, 1H), 1.98 (m, 1H), 3.34 (dd, J=11.7, 3.9 Hz, 1H), 3.60 (d, J=5.9 Hz, 1H), 3.64 (d, J=5.9 Hz, 1H), 3.69 (m, 1H), 3.75 (d, J=5.9 Hz, 1H), 4.04 (m, 1H), 4.42 (m, 1H), 4.55 (m, 1H), 5.15 (m, 1H), and 6.44 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9](SC)[N:8]=2)=[CH:4][CH:3]=1.O[O:17][S:18]([O-:20])=O.[K+].[CH3:22]C(C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([S:18]([CH3:22])(=[O:20])=[O:17])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CSc1ncc(C)c(-c2ccc(Br)s2)n1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: Cc1cnc(S(C)(=O)=O)nc1-c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(5-Bromothiophen-2-yl)-5-methyl-2-(methylthio)pyrimidine (2.5 g, 3.3 mmol) dissolved in acetone (50 mL) was treated, via slow addition, with a solution of oxone (15.3 g, 24 mmol) in water (50 mL). The reaction was allowed to stir overnight at ambient temperature. The white precipitate that formed during the course of the reaction was collected by filtration and washed several times with water and then dried in a vacuum oven at 60° C. Yield=2.3 g. MS (M+H)+ 334.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:27])=[CH:7][C:8]([CH2:14][C:15]2[C:16]([CH3:26])=[N:17][N:18]([CH2:21][CH2:22][C:23]([NH2:25])=[O:24])[C:19]=2[CH3:20])=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29]>O1CCCC1>[CH3:3][O:4][C:5]1[C:6]([CH3:27])=[CH:7][C:8]([CH2:14][C:15]2[C:16]([CH3:26])=[N:17][N:18]([CH2:21][CH2:22][C:23]([NH:25][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[O:24])[C:19]=2[CH3:20])=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COc1c(C)cc(Cc2c(C)nn(CCC(N)=O)c2C)c2c1CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C)cc(Cc2c(C)nn(CCC(=O)NS(=O)(=O)C(C)C)c2C)c2c1CCC2
Reaction time: 0.33 h
Yield: 12.2 %

Procedure:
To the suspension of 60% Sodium hydride (76 mg, 0.0019 mole) in Tetrahydrofuran (2 ml), the solution of 3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionamide (500 mg, 0.00146 mole) in Tetrahydrofuran (5 ml) was added at room temperature and stirred for 20 minutes. A solution of Isopropyl sulfonyl chloride (0.18 ml, 0.0016 moles) in Tetrahydrofuran (3 ml) was added at 0-5° C. and stirred at 15-25° C. for 3 hours. Tetrahydrofuran was distilled under vacuum, dilute hydrochloric acid (20 ml) was added to the reaction mixture and extracted with Ethyl Acetate (50 ml). The Ethyl acetate layer was dried over Sodium sulphate and distilled under vacuum to give a crude product which was purified by column chromatography using Ethylacetate as a mobile phase. The fractions were distilled to give 80 mg of desired compound as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=1[C:25]#[N:26])=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([O-:31])=[O:30].[C:25]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH2+:8]1)#[N:26]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(OC[C@H]2CCCC[NH2+]2)cccc1[N+](=O)[O-]
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 15e, 2.18 g, 6.03 mmol) in anhydrous DCM (65 mL) was added trifluoroacetic acid (7.91 mL) at room temperature. The reaction mixture was stirred at room temperature for over 1 hour. The solvent was removed under reduced pressure and the residue was dried under the vacuum to give the title product which could be used for the next step reaction without further purification. MS 262 (MH+).