Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[C:8]([CH3:15])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:16][C:17]1([CH3:37])[O:21][C@H:20]([CH2:22][O:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30][OH:31])=[NH:29])=[CH:26][C:25]=2[CH2:35][CH3:36])[CH2:19][O:18]1.Cl>O1CCOCC1>[CH3:16][C:17]1([CH3:37])[O:21][C@H:20]([CH2:22][O:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]3[N:30]=[C:12]([C:10]4[CH:9]=[C:8]([CH3:15])[CH:7]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[N:11]=4)[O:14][N:29]=3)=[CH:26][C:25]=2[CH2:35][CH3:36])[CH2:19][O:18]1.[CH2:35]([C:25]1[CH:26]=[C:27]([C:28]2[N:29]=[C:12]([C:10]3[CH:9]=[C:8]([CH3:15])[CH:7]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:11]=3)[O:31][N:30]=2)[CH:32]=[C:33]([CH3:34])[C:24]=1[O:23][CH2:22][C@@H:20]([OH:21])[CH2:19][OH:18])[CH3:36]
Reactant: CCC(CC)c1cc(C)cc(C(=O)O)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(-c2noc(-c3cc(C)cc(C(CC)CC)n3)n2)cc(C)c1OC[C@@H](O)CO
Product: CCc1cc(-c2noc(-c3cc(C)cc(C(CC)CC)n3)n2)cc(C)c1OC[C@@H]1COC(C)(C)O1

Procedure:
2-{(R)-3-[4-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-6-(1-ethyl-propyl)-4-methyl-pyridine (42 mg) is prepared by coupling and cyclizing 6-(1-ethyl-propyl)-4-methyl-pyridine-2-carboxylic acid (67 mg, 323 μmol) with (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-N-hydroxy-5-methyl-benzamidine (130 mg, 420 μmol) as described in Example 1. This material is dissolved in dioxane (5 mL) and 2 M aq. HCl (1 mL) and the mixture is stirred at rt for 16 h. The mixture is concentrated and the crude product is purified on prep. TLC using DCM containing 10% of 7 N NH3 in methanol to give the title compound (25 mg) as a pale yellow glass; LC-MS**: tR=0.80 min, [M+H]+=440.27; 1H NMR (CDCl3): δ0.85 (t, J=7.3 Hz, 6H), 1.32 (t, J=7.3 Hz, 3H), 1.79 (quint, J=7.3 Hz, 4H), 2.40 (s, 3H), 2.49 (s, 3H), 2.72-2.83 (m, 4H), 3.82-4.00 (m, 5H), 4.13-4.21 (m, 1H), 7.16 (s, 1H), 7.91 (s, 1H), 7.92 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:36][CH:35]=5)=[O:32])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].CC(O)C>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:36][CH:35]=4)=[O:32])=[N:28][CH:29]=3)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=2)[N:10]=1
Reactant: COCCOc1ccc(NC(=O)Nc2ccc(Nc3ncc(Cl)cc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COCCOc1ccc(NC(=O)Nc2ccc(Nc3ncc(Cl)cc3-c3nc(C)nc(N)n3)cn2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A solution of 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)-3-(4-(2-methoxyethoxy)phenyl)urea (0.176 g, 0.231 mmol) and trifluoromethanesulfonic acid (0.020 mL, 0.231 mmol) in TFA (2 mL) was stirred at rt for 30 min then warmed up to 60° C. and stirred overnight. After cooling to rt, solid sodium carbonate was added in portions until effervescence subsided. 25% iPrOH in CHCl3 (+1% NH4OH) was added to the residue, and the organic phase was washed with sodium bicarbonate. The material was not fully soluble in the organic layer so the organic layer containing solid was directly dried under vacuum (no drying agent was added). The crude product was purified by preparative HPLC using Phenomenex, Gemni 5 micron C18 100×30 mm column (1%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 15 min). The fractions containing product were collected and concentrated in vacuo. Sodium bicarbonate was added and the resulting solid was collected to give 1-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)-3-(4-(2-methoxyethoxy)phenyl)urea (0.0834 g, 69% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.82 (br. s., 1H); 10.10 (br. s., 1H); 9.30 (br. s., 1H); 8.62-8.86 (m, 2H); 8.36 (d, J=2.54 Hz, 1H); 8.13 (br. s., 1H); 7.96 (br s., 1H); 7.84 (br. s., 1H); 7.51 (br. s., 1H); 7.33-7.46 (m, 2H); 6.90 (d, J=8.41 Hz, 2H); 4.04 (br. s., 2H); 3.64 (d, J=3.72 Hz, 2H); 3.30 (d, J=5.87 Hz, 3H); 2.44 (d, J=5.48 Hz, 3H). m/z (ESI, +ve ion) 521.9 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:10][C:11]1([CH3:34])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:34])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[CH2:12]1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a suspension of cyclopropanesulfonamide (610 mg, 5.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (200 mg, 5.0 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A31. A solution of 4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 1.0 mmol) and 1,1′-carbonyldiimidazole (320 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B31. Solution B31 was added to Solution A31 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (140 mg, 30%) as a white solid: MS (ESI) M+1=453.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[C:11]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18]2)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18]2)(=[O:13])[CH3:12]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
3,4-Dichlorobenzyl bromide (5.96 g) was added to a stirred solution of ethyl 5-acetoxyindole-2-carboxylate (5.4 g) and potassium carbonate (6.94 g) in acetonitrile (500 ml) under an atmosphere of argon. The reaction was heated at 80° C. for 16 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water. Combined organic extracts were washed with water, saturated aqueous sodium chloride and dried (MgSO4). The solvent was removed in vacuo and the residue was triturated with iso-hexane to give the product as a cream solid (5.55 g, 63%): NMR δ(CD3SOCD3) 1.27 (t, 3H), 2.27 (s, 3H), 4.28 (q, 2H), 5.82 (s, 2H), 6.90 (d, 1H), 7.09 (dd, 1H), 7.33-7.40 (m, 2H), 7.46 (d, 1H), 7.52 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)OC(=O)CN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 71.5 %

Procedure:
A mixture of amine 20 (779 mg, 3.12 mmol), isopropyl bromoacetate (575 mg, 3.18 mmol), K2CO3 (1.34 g, 3 eq), and acetonitrile (28 mL) was stirred at reflux overnight. The reaction mixture was filtered, evaporated to dryness, and then chromatographed over silica gel using 5:1 heptane/EtOAc to give 0.78 g of 15d as an oil that crystallized on standing. The structure was confirmed by 1H NMR. (Acetate esters 15b and 15c were similarly prepared.) Cyclopentyl [4-(diphenylmethylidene)piperidin-1-yl]ethanoate (15e. A solution of 15b (1.02 g, 3.17 mmol) in anhydrous THF (10 mL) was added (under N2) to a mixture of isobutyl alcohol (10 mL) and sodium hyride (258 mg of a 60% oil dispersion). After stirring for 1 h, the reaction mixture was partitioned between water and EtOAc, wherein a small amount of brine was added to prevent emulsion formation. The organic layer was then removed, the aqueous layer was extracted further with EtOAc, and the combined organics were dried with Na2SO4, filtered, and evaporated to dryness. Chromatography over silica gel using 5:1 heptane/EtOAc gave 0.8 g of 15e as an oil. (Acetate ester 15f was similarly prepared.) Isopropyl [4-(diphenylmethylidene)piperidin-1-yl]ethanoate, oxalic acid salt (15d-oxalate). A solution of oxalic acid (234 mg, 2.6 mmol) in ethanol (4 mL) was added dropwise to a stirred solution of 15d (910 mg, 2.6 mmol) in ethanol (12 mL). After cooling the reaction mixture to −15° C. for 15 min, the solid was filtered, washed with cold ethanol, and vacuum dried to give 891 mg of 15d-oxalate as a white crystalline solid. The structure of the product was confirmed by 1H NMR, MS, and elemental analysis. (The oxalate salts of 15c, 15e, and 15f were similarly prepared.)
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH3:16])C.[OH-].[K+]>CO.O>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:16])=[C:6]2[CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(F)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c2ccc(F)cc2c1CC(=O)O
Reaction time: 2 h

Procedure:
This ester (4.5 g, 0.019 mol.) was added to a solution of KOH (2.13 g, 38 mmol.) in methanol (100 ml), and the mixture was heated at reflux for 30 min. For working up, the mixture was diluted with water (100 ml) and methanol was distilled off using a rotary evaporator. The aqueous phase was adjusted to pH 4 with 2M HCl and stored for 2 h at 4° C. The white solid that precipitated was filtered off with suction and washed with methanol. (5-Fluoro-2-methyl-1H-indol-3-yl)acetic acid was obtained in a yield of 3.25 g (m.p. 136–138° C.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]#N)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-:37].[Na+].Cl.[OH2:40]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([OH:40])=[O:37])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:30][CH:31]=1
Reactant: O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC#N)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Yield: 38 %

Procedure:
To a mixture of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile (0.20 g), tetrahydrofuran (0.5 mL) and ethanol (1 mL) was added a 2N aqueous sodium hydroxide solution (1.5 mL) and the mixture was stirred with heating under reflux for 10 hrs. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.08 g, 38%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 144-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:19][CH:18]([F:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCNCC1
Reactant: O=C(O)C(F)c1ccccc1
Product: O=S(=O)(c1ccc(Br)cc1)C1CCN(CC(F)c2ccccc2)CC1

Procedure:
4-(4-Bromophenylsulphonyl)piperidine (0.7 g, 2.3 mmol) was reacted with α-fluorophenylacetic acid (0.53 g, 3.45 mmol) in a similar manner as described for Example 13, Steps a and b, to give the required product as a colourless solid, 0.56 g (58%), m.p. 126-127° C. (EtOAc-pet. ether 60-80°). δH (400 MHz, CDCl3) 1.70-1.77 (2H, m), 2.00-2.03 (2H, m), 2.13-2.20 (2H, m), 2.57-2.69 (1H, m), 2.83-2.93 (2H, s), 3.04-3.18 (2H, m), 5.51-5.65 (1H, m), 7.28-7.39 (5H, m), 7.70-7.75 (4H, m).
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].[CH3:22][NH:23][C:24](=[O:27])[NH:25][NH2:26].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[CH3:22][NH:23][C:24](=[O:27])[NH:25]/[N:26]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:19]([CH3:21])[CH3:20])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2
Reactant: CNC(=O)NN
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC(=O)N/N=C1/C(=O)N(CCN(C(C)C)C(C)C)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To a solution of 1.00 g of 1-(2-diisopropylaminoethyl)-5-methylisatin and 0.34 g of 4-methylsemicarbazide in 15 ml of a mixture of ethanol and water (2:1) was added 3.8 ml of a 1N-hydrochloric acid. The mixture was stirred for 16 hours at room temperature. To the reaction mixture was added an aqueous sodium bicarbonate solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 0.77 g of (E)-1-(2-diisopropylaminoethyl)-5-methylisatin 3-(4-methylsemicarbazone) having a melting point of 157.5°-158.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([NH2:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6]2.C(N(CC)C(C)C)(C)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30]([NH:16][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]1[CH2:9][CH2:8]2)=[O:31]
Reactant: CN1C2CCC1C(N)(c1ccccc1)CC2
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCC2CCC1N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1RS,2RS,5SR)-8-methyl-2-phenyl-8-aza-bicyclo[3.2.1]oct-2-ylamine (intermediate A1) (670 mg, 3.1 mmol) in dichloromethane (10 ml) under nitrogen at room temperature, was added N,N-diisopropylethylamine (1.23 g, 1.61 ml, 9.29 mmol), followed drop-wise by a solution of 2-methoxy-6-(methylthio)-4-(trifluoromethyl)benzoyl chloride (intermediate B1) (970 mg, 3.41 mmol) in dichloromethane (7 ml). The reaction mixture was stirred at room temperature for 2 hours. The solution was washed once with a 2M sodium carbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude yellow oil (2.04 g), which crystallized in the fridge, was suspended in diethyl ether. The white precipitate was filtered and rinsed with diethyl ether to provide 1.16 g (y: 80.6%) of the title compound as a white solid. MS (m/e): 465.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[OH:24].IC.[C:28]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[O:24][CH3:28]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoic acid methyl ester (10 g, 28 mmol) from Step 1 was dissolved in DMF (100 mL) and cooled to 0° C. To the stirred solution was added iodomethane (6.1 g, 43 mmol) and Cs2CO3 (10 g, 31 mmol). The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 12 h. The solids were removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 20-40% EtOAc-hexane. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=[O:17])[CH2:5]1.[Li+].[OH-].Cl>C1COCC1.CO>[C:12]([O:11][C:9]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.11 g, 7.7 mmol) in a mixture of THF (38 mL) and MeOH (15 mL) was added LiOH (2.5 M aqueous, 15 mL, 38.6 mmol). The resulting solution was stirred at room temperature for 2 h, and acidified with aqueous HCl (1N). The desired product was extracted with CH2Cl2 (4×). The combined organic layers were dried over Na2SO4 and concentrated to provide (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (2.0 g, 99%). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotamers, major reported) 4.33 (t, 1H), 3.65 (m, 1H), 3.35 (m, 2H), 3.32 (s, 3H), 3.16 (t, 1H), 2.45 (m, 2H), 2.12 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]=[CH:14][C:15]#[N:16])=[O:5].S([CH:31]([N+:33]#[C-])C)(C1C=CC(C)=CC=1)(=O)=O.CS(C)=O.[H-].[Na+].[CH3:41][CH2:42]OCC>O>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[C:14]([C:31]#[N:33])=[CH:15][NH:16][C:41]=1[CH3:42])=[O:5]
Reactant: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: CCOCC
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1[nH]cc(C#N)c1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Reaction time: 2 h

Procedure:
A mixture of 34.5 g (121 mmole) of 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 25.3 g (121 mole) of 1-tosylethyl isocyanide, 200 ml of dimethyl sulfoxide and 400 ml of ether was added dropwise to a suspension of 8.9 g (184 mmole) of 50% sodium hydride in mineral oil and 450 ml of ether. When the addition was complete stirring was continued for 2 hr. The mixture was diluted with water and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a dark oil. Crystallization from ether gave off-white crystals. A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[CH:12][C:5]=12.C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN(C=O)C>[I:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[N:11]=[CH:12][C:5]=12
Reactant: Ic1ccnc2[nH]ncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ncc2c(I)ccnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of NaH (0.9 g) in anhydrous THF (25 ml) at −5° C. was added 4-iodo-1H-pyrazolo[3,4-b]pyridine (5 g) in anhydrous THF (75 ml) and DMF (25 ml). Triethylamine (3 ml) was added and the reaction was stirred for 30 min at 0° C. Benzenesulfonyl chloride (2.9 ml) in anhydrous THF (25 ml) was added dropwise over 10 min and the reaction was stirred for 1 h at 0° C. then quenched with water. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and then evaporated to yield a solid residue that was triturated with methanol to give title compound, 4.1 g.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH:11]1[CH2:16][NH:15][C:14](=[O:17])[CH2:13][CH2:12]1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][CH2:10][CH:11]1[CH2:16][NH:15][C:14](=[O:17])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CO)CN1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCC(=O)NC1
Temperature: 22 °C
Reaction time: 35 h
Yield: 50.2 %

Procedure:
To a solution of 5.8 g tert-butyl(dimethyl)silyl chloride and 5.0 g of 5-hydroxymethyl-2-piperidone in 150 ml of anhydrous DMF was added 5.3 g of imidazole. After stirring for 35 hours at 22° C., the mixture was evaporated under vacuum to remove most of the DMF. Following the addition of water, the residue was extracted with three portions of ethyl acetate. The combined organic extracts were washed with water, 0.5N HCl, water and brine, dried over magnesium sulfate and evaporated. The resulting oil was chromatographed over silica gel eluting with 5% methanol in chloroform to give 4.7 g of the title compound as an oil: MS m/z 244 (M+), 186 [M+-58 (t-butyl) ]; 300-MHz 1H NMR (CDCl3) δ0.05 (s, 6H), 0.85 (s, 9H), 1.42-1.57 (m, 1H), 1.77-1.88 (m, 1H), 1.89-2.03 (m, 1H), 2.25-2.45 (m, 2H), 3.03 (t, J=9 Hz, 1H), 3.30-3.41 (m, 1H), 3.45-3.59 (m, 2H), 5.95 (s, 1H).