Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH:11]=[CH2:12])[C:8]([CH:13]=[C:14]([CH3:16])[CH3:15])=[N:7][CH:6]=1)[CH3:2].CCO>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[C:8]([CH2:13][CH:14]([CH3:15])[CH3:16])=[N:7][CH:6]=1)[CH3:2]
Reactant: C=Cc1cc(C(=O)OCC)cnc1C=C(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(CC(C)C)c(CC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
To solution of 6-(2-methyl-propenyl)-5-vinyl-nicotinic acid ethyl ester (1.37 g, 6.74 mmol) in THF (20 mL), Pd/C (100 mg, 10% Pd) followed by EtOH (20 mL) is added. The mixture is stirred under 1 atm of H2 at rt for 24 h. The catalyst is removed by filtration and the filtrate is concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 5-ethyl-6-isobutyl-nicotinic acid ethyl ester (970 mg) as a colourless oil, LC-MS: tR=0.79 min, [M+1]+=236.20; 1H NMR (CDCl3): δ0.97 (d, J=6.8 Hz, 6H), 1.27 (t, J=7.5 Hz, 3H), 1.42 (t, J=7.0 Hz, 3H), 2.17-2.28 (m, 1H), 2.69-2.78 (m, 4H), 4.42 (q, J=7.0 Hz, 2H), 8.07 (s, 1H), 9.00 (s, 1H).
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:7][C:6]=1[C:15]1[NH:28][C:18]2=[N:19][CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:22]=[C:17]2[N:16]=1)(C)C.[OH-].[Na+].[C:31](O)(=O)[CH2:32][C:33]([CH2:38][C:39](O)=O)(C(O)=O)O.[CH2:44]([OH:46])[CH3:45]>>[CH2:44]([O:46][C:10]1[CH:5]=[C:6]([C:15]2[NH:28][C:18]3=[N:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[CH:22]=[C:17]3[N:16]=2)[CH:7]=[C:8]([O:11][CH:12]([CH3:14])[CH3:13])[CH:9]=1)[C:45]1[CH:39]=[CH:38][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1cnc2[nH]c(-c3cc(OC(C)C)ccc3OC(C)C)nc2c1
Reactant: CCO
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1cc(OCc2ccccc2)cc(-c2nc3cc(C(=O)O)cnc3[nH]2)c1

Procedure:
A solution of ethyl 2-(2,5-diisopropoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (40 mg) and 1N aqueous sodium hydroxide solution (1 ml) in ethanol (2 ml) was stirred at room temperature for 48 hr. The reaction mixture was adjusted with 1N citric acid to pH 4, and the precipitated crystals were collected by filtration and washed with water and ethanol to give the title compound (27 mg) as colorless crystals. purity 94%. M+H: 404. 1H NMR (DMSO-d6) δ: 1.32 (6H, d, J=6.0 Hz), 4.70-4.78 (1H,m), 5.21 (2H, s), 6.75 (1H, s), 7.32-7.53 (8H, m), 8.44 (1H, s), 8.92 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][O:27]2)=[CH:22][N:21]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][CH:26]([C:23]3[CH:22]=[N:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)[OH:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1ccc(C2CO2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 5.0 mmol) was dissolved in DMF (8 mL). Sodium hydride (600 mg, 15 mmol) was added portionwise under nitrogen at 0° C. 2-Methoxy-5-oxiranyl-pyridine (1.130 g, 7.5 mmol) was diluted in DMF (2 mL) was added dropwise under nitrogen atmosphere and the reaction mixture stirred at RT for 3 h. By monitoring TLC & NMR after consumption of starting material, the reaction mixture was then quenched with ice water and extracted with EtOAc (3×40 mL). The combined organic layer was washed with water (4×30 mL) and dried over anhydrous sodium sulfate and concentrated to obtain 1.0 g of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(6-methoxy-pyridin-3-yl)-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.11 (s, 1H), 7.55 (d, 1H), 7.18 (s, 1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.72 (d, 1H), 4.98 (t, 1H), 4.11 (m, 2H), 3.93 (s, 3H), 3.60 (q, 2H), 2.88 (d, 1H), 2.78 (m, 2H), 2.69 (d, 1H), 2.51 (s, 3H), 2.44 (s, 3H). Separation by chiral HPLC provided enantiomers 51a and 51b.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].C(Cl)(=O)C(Cl)=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[N:19]=[CH:18][C:17]([C:26]#[N:27])=[C:16]2[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.[CH2:42]1C[O:45][CH2:44][CH2:43]1>CN1CCCC1=O>[C:26]([C:17]1[CH:18]=[N:19][C:20]2[C:15]([C:16]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=1)=[CH:14][C:13]([NH:12][C:44](=[O:45])/[CH:43]=[CH:42]/[CH2:4][N:2]([CH3:1])[CH3:3])=[C:22]([O:23][CH2:24][CH3:25])[CH:21]=2)#[N:27]
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2cc1N
Reactant: CN(C)C=O
Reactant: C1CCOC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2cc1NC(=O)/C=C/CN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-N,N-dimethyl-aminocrotonic acid hydrochloride (1.28 g) in THF (18 mL) and a catalytic amount of DMF was cooled to 5° C., the oxalyl chloride (0.67 mL) was added dropwise. The mixture was then warmed to room temperature and stirred for 3 hours. A solution of 6-amino-7-ethoxy-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile in N-methyl-2-pyrrolidinone (20 ml) was added dropwise over 10 minutes. The reaction mixture was stirred overnight and then quenched with water. Aqueous sodium hydroxide was added slowly to bring the pH to 11. It was stirred for another 1 hour and the resulting precipitate was filtered and washed with water. The wet solid was recrystallized in acetonitrile and THF and dried to give desired product (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide (1.56 g). 1H-NMR (400 MHz, CDCl3, ppm): 9.17 (1H, s), 8.52 (1H, s), 8.10 (1H, s), 7.37-6.97, (13H, m), 6.20 (1H, d, J=15.6 Hz), 4.32 (2H, q, J=7.2 Hz), 3.17-3.15 (2H, m), 2.31 (6H, s), 1.57-1.69 (3H, t, J=7.2 Hz). MS m/z 508.3[M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]([C:34]([O:36][CH2:37][CH:38]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[C@H:25]([C:31](O)=[O:32])[CH2:26][O:27]C(C)=O.C1CCC([N:57]=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:34]([NH:24][C@H:25]([C:31]([NH2:57])=[O:32])[CH2:26][OH:27])([O:36][CH2:37][CH:38]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(=O)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 64.2 %

Procedure:
(Z)-1-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene (1.5 g, 4.76 mmols), 2.1 g (5.7 mmols) of Fmoc-L-Ser(Ac), 1.2 g (5.7 mmols) of DCC and 0.87 g (5.7 mmols) of HOBt.H2O were dissolved in 30 ml of N,N-dimethylformamide, and the mixture was reacted at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate, then filtered and concentrated. The product was purified through silica-gel column chromatography (mixture of ethyl acetate and hexane at a ratio by volume of 1:2) to produce 1.96 g of the final product in a yield of 61.8%.
Reaction SMILES: Br[C:2]1(Br)[C:6]([O:7][CH3:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[NH:3]1.[OH2:25].[CH3:26]S(C)=O>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[N:4]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:3]=[C:2]([CH:26]=[O:25])[C:6]=2[O:7][CH3:8])=[CH:10][CH:11]=1
Reactant: COC1=C(c2ccc(Cl)cc2)N(c2ccc(Cl)cc2Cl)NC1(Br)Br
Reactant: O
Reactant: CS(C)=O
Product: COc1c(C=O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
Under nitrogen, 5 g of the 3,3-dibromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methoxy-1H-pyrazole obtained in stage G is placed in 30 ml of DMSO, and it is heated at 120° C. for 6 hours. The reaction mixture is poured into 100 ml of water and it is extracted twice with 100 ml of AcOEt. The organic phase is washed with 100 ml of saturated NaCl and then dried over Na2SO4. After evaporating to dryness, 4 g of the unpurified expected compound is obtained.
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.[C:20]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30]Br)=[C:25]([O:34][CH3:35])[CH:24]=1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O.O.[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46]>CCOCC.C1(C)C=CC=CC=1>[OH2:22].[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46].[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]([CH2:30][CH2:29][CH2:28][O:27][C:26]3[CH:32]=[CH:33][C:23]([C:20](=[O:22])[CH3:21])=[CH:24][C:25]=3[O:34][CH3:35])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCBr
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 7.5 g (0.030 mole) of 4-diphenylmethylenepiperidine, 6.3 g (0.032 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl bromide, 25 g (0.18 mole) of potassium carbonate and 150 ml of toluene was heated at reflux for 16 hr, cooled, filtered and the solvent evaporated at reduced pressure. The residual oil was dissolved in benzene, washed with water, dried over magnesium sulfate and then the solvent was evaporated. The free base was dissolved in 2-propanol and treated with 3.8 g (0.03 mole) of oxalic acid dihydrate in dry ether. The white salt which separated was recrystallized from a 2-propanol-methanol mixture. The produce weighed 8.5 g (54%), m.p. 186°-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:40].[C:41](Cl)(=O)[O:42]C1C=CC([N+]([O-])=O)=CC=1.[NH2:54][CH2:55][C:56]([CH3:59])([OH:58])[CH3:57].C(N(CC)CC)C>ClCCl>[Si:33]([O:32][C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH:54][CH2:55][C:56]([OH:58])([CH3:59])[CH3:57])=[O:42])=[C:3]([Cl:40])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[CH:22][CH:21]=1)([C:24]([F:25])([F:26])[F:27])[C:28]([F:31])([F:29])[F:30])([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35]
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
(4-Amino-3-chlorophenyl)(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)benzyl)piperazin-1-yl)methanone (0.410 mmol, 250 mg) and 4-nitrophenyl carbonochloridate (0.410 mmol, 83 mg) in dichloromethane (1 ml) were combined and heated at reflux for 1 hour. The reaction was allowed to cool to room temperature before the addition of 1-amino-2-methylpropan-2-ol (0.820 mmol, 73.1 mg) and triethylamine (0.410 mmol, 0.057 mL, 41.5 mg). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the resulting residue was purified by column chromatography (2-5% methanol in dichloromethane) to afford the title compound (190 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16](N(C)C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].[CH3:28][O-:29].[Mg+2].C[O-].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CO.CS(C)=O.C(OCC)(=O)C>[C:38]([O:37][C:35](=[O:36])[CH2:34][N:11]1[C:10](=[O:21])[C:9]([OH:22])=[C:8]2[C:13]([CH2:14][CH2:15][N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=3)[C:7]2=[O:23])=[C:12]1[C:16]([O:29][CH3:28])=[O:17])([CH3:41])([CH3:40])[CH3:39]
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[O-]
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c2c(c(O)c(=O)n1CC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (0.50 g, 1.31 mmol; Example 1, Step 9) and magnesium methoxide in methanol (6.6 mL, 6-10% methanol solution available from Aldrich) in DMSO (13 mL) was heated at 60° C. for one hour. Methanol was exhaustively removed under vacuum over 45 minutes. The resultant DMSO solution was treated with tert-butyl bromoacetate (1.80 g, 10.50 mmol) and stirred at 50° C. under an atmosphere of nitrogen for one hour. The reaction mixture was diluted with ethyl acetate and washed with ice cold dilute hydrochloric acid. The organic extract was washed with aqueous sodium thiosulfate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of diethyl ether and ethyl acetate. The solid precipitated was collected by filtration to provide the title compound. ES MS M+1=495
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][C:5]1([CH2:8][C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]1.C[O-].[Na+]>O1CCCC1.CO.C(OC)(C)(C)C>[CH2:6]1[C:5]2([CH2:4][C:3](=[O:12])[CH2:10][C:9](=[O:11])[CH2:8]2)[CH2:7]1
Reactant: COC(=O)CC1(CC(C)=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C1CC(=O)CC2(CC2)C1
Reaction time: 6 h

Procedure:
23.3 g of crude [1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester (60% purity, from step 5) are dissolved in 135 ml of tetrahydrofuran and 17.1 g of a sodium methanolate solution in methanol (30% in methanol) are added at room temperature and the mixture is stirred for six hours. Then the solution is diluted with 135 ml of methyl tert-butyl ether and quenched with 135 ml of water. Stirring is continued for five minutes, then the phases are separated. The aqueous phase is extracted with 67.5 ml of methyl tert-butyl ether, then acidified to pH 2-3 with 37% HCl and washed twice with 67.5 ml of methyl tert-butyl ether each. The combined organic phases are washed with 18 ml of water and concentrated to dryness. The crude product is stirred with 18 ml of cold methyl tert-butyl ether and then the precipitate is isolated by filtration. The filter cake is washed with 18 ml of cold methyl tert-butyl ether to yield the product as an off-white solid.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]3[O:14][C@:15]4([CH2:23][N:24]=3)[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]4)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>C1COCC1>[N:1]1([C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]3[O:14][C@:15]4([CH2:23][N:24]=3)[CH:20]3[CH2:21][CH2:22][N+:17]([O-:30])([CH2:18][CH2:19]3)[CH2:16]4)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cn(-c2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncn2)cn1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cc(-n4ccnc4)ncn3)O1)C2
Yield: 95.3 %

Procedure:
A solution of (R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (52.9 mg, 0.163 mmol) and 3-chlorobenzoperoxoic acid (33.7 mg, 0.195 mmol) in 2 mL THF was stirred at room temperature for 24 h. The reaction was concentrated and the crude product was purified by flash chromatography on a 40 g silica gel cartridge with 20 to 40% [9:1 MeOH/NH4OH] in EtOAc, 40 min. Pure fractions were pooled, concentrated, and dried. The residue was dissolved in CDCl3, filtered through a 0.4μ filter, concentrated, and dried under high vacuum to yield (S)-2-(6-(1H-imidazol-1-yl)pyrimidin-4-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (53 mg, 95% yield).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[C:2]=[O:3].[CH3:17][N:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=2[CH:20]=[N:19]1.N1C2C=CC=C(N)C=2C=N1>>[CH3:17][N:18]1[C:26]2[C:21](=[C:22]([NH:27][C:2]([NH:1][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)=[O:3])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19]1
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(N2CCCCC2)cc1
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCC4)cc3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 9.43 (s, 1H), 8.37 (s, 1H), 7.82 (d, 2H), 7.69 (d, 1H), 7.63 (m, 3H), 7.22 (t, 1H), 7.11 (t, 1H), 4.40 (d, 2H), 3.99 (s, 3H), 3.50 (m, 4H), 1.98 (m, 4H), 1.67 (m, 2H); MS (ESI) (M+H)+364.
Reaction SMILES: [CH2:1]([S:19][CH2:20][CH2:21][CH2:22]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCCCC.[NH:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27].C(O)C1C=CC=CC=1.[OH-].[Na+]>>[CH2:1]([S:19][CH2:20][CH2:21][CH2:22][N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCCNCCO
Reactant: CCCCCCCCCCCCCCCCCCSCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: OCc1ccccc1
Product: CCCCCCCCCCCCSCCCN(CCO)CCO

Procedure:
A mixture of 3-octadecylthiopropyl chloride (3.53 g., 0.01 mole), diethanolamine (2.1 g., 0.02 mole) and benzyl alcohol (5 ml.) is heated under reflux for one-half hour, then treated with an ethanolic solution of sodium hydroxide (0.4 g., 0.01 mole) and refluxed for five more minutes. The mixture is cooled, filtered, and the ethanol removed by evaporation. The benzyl alcohol is then removed by distillation in vacuo and the residue chromatographed on silica using first ether then methanol as eluants. The desired product is contained in the methanol eluate. It is isolated by evaporation of the solvent, m.p. 53°-54° C. Its hydrochloride salt melts at 65°-66° C.
Reaction SMILES: [CH3:1][N:2]1[C:18]2[C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[N:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:23][I:24]>>[I-:24].[CH3:23][N+:10]1[C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:2]([CH3:1])[C:18]=2[C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2
Reactant: CI
Reactant: COC(=O)c1c2ccccc2nc2c3ccccc3n(C)c12
Product: COC(=O)c1c2ccccc2[n+](C)c2c3ccccc3n(C)c12
Product: [I-]

Procedure:
A solution of methyl 10-methylquindoline-11-carboxylate (0.5 g, 1.72 mmol) from Example 13 in methyl iodide (5 mL, 50.3 mmol) was stirred at room temperature for 48 hours. The excess of CH3I was removed in vacuo and the residue was dissolved in MeOH (10 mL). Diethyl ether (30 mL) was added and the precipitate was filtered and washed thoroughly with diethyl ether to afford, after drying, 0.33 g (44.6%) of the title compound as an orange solid, mp 257.0-257.5° C. (decomp.); 1H NMR (DMSO-d6) δ 8.90 (dd, J=2.8, J=9.2, 2H), 8.33 (d, J=8.0, 1H), 8.24 (t, J=6.8, 1H) 8.10 (t, J=5.2, 2H), 8.04 (t, J=8.4, 1H), 7.62 (t, J=8.0, 1H), 5.08 (s, 3H), 4.31 (s, 3H), 3.99 (s, 3H); 13C NMR (DMSO-d6) δ 164.95, 148.00, 140.47, 135.11, 134.96, 132.61, 129.99, 128.74, 126.96, 125.76, 124.86, 122.31, 122.27, 118.72, 113.60, 111.71, 54.67, 41.20, 30.98; MS (LSIMS, m/z) 305 (M+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][C:15](SC)=[N:16][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].CCO>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][C:15]([NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])=[N:16][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2C(C)(C)CC1
Reactant: COC(CN)OC
Solvent: CCO
Product: COC(CNC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2C(C)(C)CC1)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(5,5-Dimethyl-2-methylsulfanyl-4,5-dihydro-3H-1-benzazepin-8-yl)-carbamic acid tert-butyl ester (1.281 g, 3.8 mmol), Aminoacetaldehyde dimethyl acetal (0.542 mL, 5 mmol), and EtOH (100 mL, 2 mol) were heated to reflux for 2 hrs and stirred at rt for 72 h. LCMS 392 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O.CCOC(C)=O>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH2:11][C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:23](=[O:26])(=[O:25])[N:24]=1
Reactant: CCCC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a solution of (R)-2-amino-6-((1-butyrylpiperidin-2-yl)methoxy)benzonitrile (Example 16a, 1.0 g, 3.32 mmol) in DMA (15.0 mL) was added sulfamoyl chloride (2.68 g, 23.21 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen for 2 hrs and the solution was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%). The intermediate was dissolved in EtOH (25.0 mL) and aq.NaOH (2.0 N, 5.0 mL) was added at room temperature. The reaction mixture was then refluxed overnight then cooled to 0° C. and neutralized carefully with 1 N HCl. The precipitate was collected by filtration and was recrystallized with 20% water/EtOH to provide the title compound as a white solid (730 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6, room temperature) δ 0.86 (t, J=7.6 Hz, 3H), 1.35-1.76 (m, 8H), 2.28-2.32 (m, 2H), 3.14 (t, J=13.6 Hz, 1H), 3.74 (d, J=14 Hz, 1H), 4.07-4.11 (m, 1H), 4.25-4.38 (m, isomer), 4.50 (t, J=10 Hz, 1H), 5.16 (t, J=4.4 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.68 (s, isomer), 7.77 (s, 1H), 8.23 (s, 1H), 8.36 (s, isomer), 10.89 (s, 1H). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 0.88 (t, J=7.6 Hz, 3H), 1.35-1.40 (m, 1H), 1.49-1.67 (m, 7H), 1.77 (d, J=11.6 Hz, 1H), 2.27-2.32 (m, 2H), 3.85-3.90 (m, 1H), 4.18-4.20 (m, 1H), 4.07-4.11 (m, 1H), 4.46 (t, J=10 Hz, 1H), 5.00-5.03 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.81 (s, 2H), 10.64 (s, 1H). MS 381 (MH+).