Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]1)([CH3:10])[CH3:9].[OH:33][C:34]1([C:41]2[S:42][C:43]([CH3:46])=[CH:44][N:45]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH:16][CH:37]2[CH2:38][CH2:39][C:34]([C:41]3[S:42][C:43]([CH3:46])=[CH:44][N:45]=3)([OH:33])[CH2:35][CH2:36]2)[CH2:12]1)([CH3:10])[CH3:9]
Reactant: Cc1cnc(C2(O)CCC(=O)CC2)s1
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(C2(O)CCC(N[C@@H]3CC[C@@](C(=O)N4CCc5ccc(C(F)(F)F)cc5C4)(C(C)C)C3)CC2)s1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine TFA salt (40 mg, 0.1 mmol) of Step C-2 from Example 1 and 4-hydroxy-4-(5-methyl-1,3-thiazol-2-yl)cyclohexanone (32.6 mg, 0.15 mmol) in dichloromethane (10 mL) was added triethylamine (31 μL, 0.22 mmol) followed by sodium triacetoxyborohydride (56 mg, 0.26 mmol) at room temperature. After being stirred overnight, the mixture was diluted with methylene chloride and neutralized with NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica eluting with 5% MeOH/CH2Cl2 to give two isomers (13 mg and 10 mg). LC-MS calculated for C29H38F3N3O2S: (M+H)+550; found 550.2.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[OH:20][C:21]([CH3:27])([C:25]#[CH:26])[CH2:22][C:23]#[N:24]>>[C:23]([CH2:22][C:21]([OH:20])([CH3:27])[C:25]#[C:26][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1)#[N:24]
Reactant: C#CC(C)(O)CC#N
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)CC#N
Yield: 30 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-hydroxy-3-methylpent-4-ynenitrile to give the titled compound as a brown solid (70 mg, 30%).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:8]2[CH:9](C)[NH:10][CH2:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl.CC([OH:18])C>>[OH:18][C:7]1[CH:6]=[CH:5][C:4]([C:8]2[CH2:9][NH:10][CH2:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: CC1NCC=C1c1cccc(O)c1
Agent: Cl
Product: Oc1ccc(C2=CCNC2)cc1

Procedure:
(±)-3-(3-hydroxyphenyl)-2-methyl-3-pyrroline·HCl (3n), mp 202° C. (from propanol-2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=2)=[CH:10][O:9][N:8]=1.CC1O[N:27]=[C:26](C2C=CC=CC=2)[C:25]=1[CH2:35][O:36][C:37]1N=CC(C(O)=O)=N[CH:42]=1.NC1CCOCC1>>[O:36]1[CH2:35][CH2:25][CH:26]([NH:27][C:20]([C:17]2[CH:16]=[N:15][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[CH:19][N:18]=2)=[O:22])[CH2:42][CH2:37]1
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccccn2)cn1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Agent: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1cnc(OCc2conc2-c2ccccn2)cn1
Yield: 87 %

Procedure:
As described for example 2b, 5-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (75.4 mg, 2.5 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid, was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (SiO2, heptane:ethyl acetate 1:1 to 0:1, 83.8 mg, 87%) which was obtained as a white solid. MS: m/e=382.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.ON1C2C=CC=CC=2N=N1.N=C=N.[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1.C(=O)([O-])[O-]>ClCCl>[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH:43][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:40][CH:39]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: NCc1ccc(Cl)cc1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)NCc3ccc(Cl)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg), 1-hydroxybenzotriazole (28.0 mg), PS-carbodiimide (240 mg) and dichloromethane (4 mL) were mixed together and the mixture was stirred at room temperature for 15 minutes. 4-chlorobenzylamine (19.0 μL) was then added and the mixture was stirred at room temperature for further 24 hours. Subsequently, MP-carbonate (270 mg) was added and the mixture was stirred at room temperature for 5 hours and was left overnight. The insoluble material in the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by a silica gel column (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-[4-[N-(4-chlorophenylmethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (29.1 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][CH:26]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[NH2:20])[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-aminophenylboronic acid pinacol ester with reaction time of 15 h. Column chromatography (hexane/ethyl acetate 1:1) gave the title compound as an colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(C=O)c1
Temperature: 25 °C

Procedure:
3-Hydroxybenzaldehyde (2.00 g, 16.4 mmol) was dissolved in 25 mL of dry tetrahydrofuran under nitrogen with 3.5 g of potassium carbonate and 3.01 g (18.0 mmol) of ethyl bromoacetate. The reaction was heated at reflux for 6 hr, then cooled to room temperature and filtered from inorganic salts. The filtrate was evaporated, redissolved in 30 mL of methylene chloride, washed with 2×15 mL of water, and dried over sodium sulfate. Evaporation of solvent gave 2.92 of ethyl 3-formylphenoxyacetate as a yellow oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][CH2:33][CH3:34])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(C1CCCN1)CC>>[CH:28]1([N:27]([CH2:26][C:24]2[S:23][CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)[CH:25]=2)[CH3:31])[CH2:29][CH2:30][CH2:34][CH2:33][CH2:32]1
Reactant: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Agent: CCCC1CCCN1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C5CCCCC5)c4)cc23)CC1
Yield: 27.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting cyclohexyl(methyl)amine (113 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 15.0 mg of the title compound (27.6%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][CH:12]=1.Cl.O1CCOCC1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCOCCCCBr)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CCCCOCCCCBr)cc1
Reaction time: 8 h
Yield: 101.6 %

Procedure:
1,1-Dimethylethyl 4-{4-[(4-bromobutyl)oxy]butyl}benzoate (1.05 g, 2.72 mmol, e.g. which can be as prepared in Intermediate 24) was treated with a 4M solution of HCl in 1,4-dioxane (10 ml, 40 mmol, 15 equivalents) and the mixture was allowed to stand at room temperature overnight (about 16 hours). The solvent was evaporated in vacuo followed by several co-evaporations with dichloromethane and a trituration with diethyl ether (the material failed to solidify). The diethyl ether was evaporated off to give the title compound as greenish gum (0.91 g; product contained diethyl ether by NMR). LCMS showed MH+=329/331 (Bromine isotope pattern); TRET=3.60 min.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:9][C:10](=[O:14])[CH:11](Br)[CH3:12])[CH3:8].[O:15]=[S:16]1(=[O:41])[C:22]2[CH:23]=[C:24]([OH:28])[C:25]([Br:27])=[CH:26][C:21]=2[N:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][C:18]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:35][CH3:36])[CH2:17]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:41]=[S:16]1(=[O:15])[C:22]2[CH:23]=[C:24]([O:28][CH:11]([C:10]([O:9][CH2:7][CH3:8])=[O:14])[CH3:12])[C:25]([Br:27])=[CH:26][C:21]=2[N:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][C:18]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:35][CH3:36])[CH2:17]1
Reactant: CCOC(=O)C(C)Br
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(O)cc2S(=O)(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C)C(=O)OCC)cc2S(=O)(=O)C1
Yield: 94.5 %

Procedure:
Sodium carbonate (0.30 g, 2.83 mmol), 2-bromopropanoic acid ethyl ester (0.145 g, 0.796 mmol) and tetrabutylammonium bromide (0.022 g, 0.07 mmol) was added to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 96/16051; 0.300 g, 0.663 mmol) in MeCN (10 ml). The suspension was heated under reflux over night. The solvent was evaporated and the crude mixture was extracted (DCM/H2O), dried (MgSO4), evaporated and purified by flash chromatography (Hex:EtOAc-5:1) to give the title compound 0.346 g (95%) as a white solid. NM (400 MHz) 0.70-0.85 (m, 6H), 1.00-1.75 (m, 8H), 1.35 (t, 3H), 1.70 (d, 3H), 3.05-3.25 (m, 2H), 3.55-3.90 (m, 2H), 4.20-4.35 (m, 2H), 4.80 (q, 1H), 7.00-7.10 (m, 3H), 7.15 (s, 1H), 7.25-7.35 (m, 2H), 7.45 (s, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1.[C:18]([O:24][CH2:25][N:26]1[C:30]2[N:31]=[C:32](Cl)[N:33]=[C:34]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=3)[C:29]=2[CH:28]=[CH:27]1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)(C)C>[C:18]([O:24][CH2:25][N:26]1[C:30]2[N:31]=[C:32]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][CH:6]4[CH2:7][N:4]([CH2:3][CH2:2][F:1])[CH2:5]4)=[CH:10][C:11]=3[O:16][CH3:17])[N:33]=[C:34]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=3)[C:29]=2[CH:28]=[CH:27]1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Reactant: COc1cc(NC2CN(CCF)C2)ccc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: COc1cc(NC2CN(CCF)C2)ccc1Nc1nc(Oc2cccc([N+](=O)[O-])c2)c2ccn(COC(=O)C(C)(C)C)c2n1
Temperature: 45 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of N1-(1-(2-fluoroethyl)azetidin-3-yl)-3-methoxybenzene-1,4-diamine (870 mg, 3.64 mmol) and (2-chloro-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1.55 g, 3.83 mmol), potassium carbonate (1.35 g, 9.77 mmol), tris(dibenzylideneacetone)dipalladium (173 mg, 0.19 mmol) and dicyclohexyl (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (222 mg, 0.47 mmol), a magnetite, and t-BuOH (35 mL) was heated to reflux and stirred under nitrogen for 2 h. The mixture was cooled to 40-50° C. and was filtered through diatomaceous earth, washing with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (DCM/MeOH=50/1 as elution) to give the title compound (1.7 g, yield 74%, M+H+=608.3) as a light yellow solid.
Reaction SMILES: C(N(CC)CCC1C=CC([C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=2[C:19]=34)=CC=1)C.Br[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[NH:36][C:37](=[O:39])[CH3:38]>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([NH:36][C:37](=[O:39])[CH3:38])=[C:29]([C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=2[C:19]=34)[CH:34]=1
Reactant: CC(=O)Nc1ccc(F)cc1Br
Reactant: CCN(CC)CCc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Product: CC(=O)Nc1ccc(F)cc1-c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
In a manner similar to that described for 2-[4-(2-diethylamino-ethyl)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (Example YY), the tricyclic bromide (300 mg, 1.13 mmol) and N-(2-bromo-4-fluoro-phenyl)-acetamide (276 mg, 1.19 mmol) were coupled to yield N-[4-fluoro-2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-acetamide, 83 mg (22%) as a beige solid: m.p. 260-261° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 1.97 (s, 3H), 2.66 (m, 2H), 3.33 (m, 2H), 7.25 (m, 3H), 7.56 (dd, J=7.5, 0.6 Hz, 1H), 7.70 (dd, J=7.2, 0.6 Hz, 1H), 7.76 (m, 1H), 8.04 (br t, 1H), 11.50 (br s, 1H). MS (FAB, MH+): 338. Anal. (C16H19FN3O2.0.16 H2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[H-].[Na+].CC1C=CC(S(O[CH:33]2[CH2:42][CH2:41][C:36]3([O:40][CH2:39][CH2:38][O:37]3)[CH2:35][CH2:34]2)(=O)=O)=CC=1>CN(C=O)C>[O:37]1[C:36]2([CH2:41][CH2:42][CH:33]([N:11]3[C:7]4[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=4[C:9]([C:12]4[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=4)=[N:10]3)[CH2:34][CH2:35]2)[O:40][CH2:39][CH2:38]1
Reactant: COc1nccc2[nH]nc(-c3csc(C(N)=O)c3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a solution of 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (65.0 mg) in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 19.0 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (148 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (53.9 mg).
Reaction SMILES: C(C(O)=O)(C)(C)C.NC1C=NC2C(C=1NN)=CC=CC=2.[CH:21]([NH:24][N:25]1[C:37]2[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:30]=[C:29]([NH2:38])[C:28]=2[N:27]=[C:26]1[CH2:39][CH2:40]C)([CH3:23])[CH3:22].C(OCC)(OCC)(OCC)CC.C(OC)(OC)(OC)CCC>>[CH2:39]([C:26]1[N:25]([NH:24][CH:21]([CH3:22])[CH3:23])[C:37]2[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:30]=[C:29]([NH2:38])[C:28]=2[N:27]=1)[CH3:40]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1NC(C)C
Agent: CC(C)(C)C(=O)O
Agent: CCCC(OC)(OC)OC
Agent: CCOC(CC)(OCC)OCC
Product: CCc1nc2c(N)nc3ccccc3c2n1NC(C)C

Procedure:
2-Ethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine was prepared in 5 steps from N′-(3-aminoquinolin-4-yl)hydrazine tert-butyl carboxylate in analogous fashion to the preparation of N1-Isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (Example 16). Triethyl orthopropionate was used in lieu of trimethyl orthobutyrate. The material was purified by chromatography (SiO2, 20% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield an off white solid. The solid was crystallized from MeCN to yield 2-ethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.358 g) as light pink crystals. mp 245–247° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 6.95 (s, 1H), 6.44 (s, 2H), 3.54–3.46 (m, 1H), 3.04–2.88 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), 1.01 (d, J=5.8 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 155.6, 152.0, 145.0, 132.8, 126.8, 126.1, 124.1, 121.3, 120.9, 115.0, 51.2, 20.6, 19.7, 12.4; MS (APCI) m/z 270 (M+H)+; Anal. Calcd for C15H19N5: C, 66.89; H, 7.11; N, 26.00; Found: C, 66.81; H, 7.22; N, 25.95.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])(=O)CCCCCCCCCCCCCCCCC.[K+:45].[CH3:46][S:47]([O:50]CCCC)(=[O:49])=[O:48]>>[CH3:46][S:47]([O-:50])(=[O:49])=[O:48].[K+:45].[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCOS(C)(=O)=O
Agent: CCCCCCCCCCCCCCCCCC(=O)OCCCC
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [K+]
Product: CS(=O)(=O)[O-]

Procedure:
An esterification reaction mixture (94 g), consisting of butanol (ca., 4.9% w/w), butyl stearate (95.1% w/w), residual stearic acid (trace), residual methanesulfonic acid catalyst (1383 ppm) and undesired butyl methanesulfonate (613 ppm) was treated with 45% aqueous KOH (229 mg, 1.84 mmol as compared to 1.74 mmol MSA originally charged to the reaction). The resulting mixture was heating at 50° C. for 40 minutes. Without wishing to be bound by any particular theory or explanation, it is believed that reaction of butyl stearate with KOH produced potassium stearate, which retains significant solubility in the butyl stearate medium. The formed potassium stearate then reacted with butyl methanesulfonate to produce potassium methanesulfonate and butyl stearate. After filtration of the by-product solid salts (0.6325 g), analysis of the mixture by gas chromatography revealed only 300 ppm unreacted butyl methanesulfonate, a 51% reduction.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]([O:11]CC)=[O:10])=[O:5])C.Cl.[Na+].[Cl-]>[OH-].[Na+]>[C@@H:7]1([C:9]([OH:11])=[O:10])[CH2:8][C@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)[C@@H]1C[C@H]1C(=O)O
Temperature: 22 °C
Reaction time: 18 h

Procedure:
Diethyl carboxylate 3 (16.9 g, 19.3 mmol) was dissolved in 170 ml of 2N NaOH and heated under reflux for 1 h. The solution was stirred for additional 18 h at 22° C. The solution was cooled, adjusted to pH 3 with 2N HCl, saturated with NaCl, and finally extracted with ethyl acetate (2×100 ml). The pooled extracts were dried (Na2SO4), evaporated to dryness, and the white residue was used for the next step without further purification (8.5 g, 79%); mp 175-176° C. 1H-NMR (D2O): δ1.42 (m, 2H), 2.18 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:19]1[NH:23][N:22]=[C:21]([NH:24][C:25]2[CH:30]=[C:29]([F:31])[C:28]([N:32]3[CH:36]=[N:35][C:34]([CH3:37])=[N:33]3)=[CH:27][CH:26]=2)[N:20]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:31][C:29]1[CH:30]=[C:25]([NH:24][C:21]2[N:20]=[C:19]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:23]3[N:22]=2)[CH:26]=[CH:27][C:28]=1[N:32]1[CH:36]=[N:35][C:34]([CH3:37])=[N:33]1
Reactant: Cc1ncn(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(OCC(F)(F)F)cc4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ncn(-c2ccc(Nc3nc4n(n3)CCCCC4c3ccc(OCC(F)(F)F)cc3)cc2F)n1
Yield: 50.1 %

Procedure:
A solution of 5-(5-chloro-1-(4-(2,2,2-trifluoroethoxy)phenyl)pentyl)-N-(5-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (1.03 g, 1.91 mmol), sodium iodide (1.43 g, 9.54 mmol), and diisoproplylethylamine (0.1.67 mL, 9.54 mmol) in acetone (10 mL) was heated in a sealed vessel at 100° C. for 4 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 480 mg (48% yield) of the titled compound as an off-white solid. This material was recrystallized from EtOH to afford 225 mg (23% yield) of the titled compound as a crystalline white solid, LC-MS (M+H)+ 502.4. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=2.1 Hz, 1 H), 7.69 (dd, J=13.7, 2.1 Hz, 1 H), 7.60 (t, J=8.7 Hz, 1 H), 7.13 (d, J=8.2 Hz, 2 H), 7.01 (d, J=8.9 Hz, 1H), 6.95 (d, J=8.5 Hz, 2H), 6.80 (s, 1 H), 4.36 (q, J=8.2 Hz, 2 H), 4.28 (d, J=7.3 Hz, 1 H), 4.21-4.26 (m, 2 H), 2.50 (s, 3 H), 2.17-2.28 (m, 1 H), 2.04-2.14 (m, 1 H), 1.84-2.03 (m, 4 H).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.Cl[C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1([NH:2][C:24]2[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:17]=[CH:18][CH:19]=[N:20]1
Reactant: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2cnc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-amino-2-methylcyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 26; 287 mg, 1.01 mmol) in dry DMSO (3.4 ml) was added 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 202 mg, 1.11 mmol) and DIPEA (527 μl, 3.02 mmol). The reaction was stirred at 140° C. for 1 hour and was then partitioned between ethyl acetate and water. The organics were washed with water, brine, filtered through a hydrophobic frit and concentrated in vacuo. This was purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-20% methanol/ethyl acetate) and was then recrystallised from ethyl acetate to afford the title compound.
Reaction SMILES: ClC1C=C(NC(=O)C(C2C=CC(C(O)=O)=CC=2)C(NC2C=CC=C(Cl)C=2)=O)C=CC=1.NC1C=CC=CC=1[NH:38][C:39]([C:41]1[CH:46]=[CH:45][C:44](C(C(NC2C=CC=C(Cl)C=2)=O)C(NC2C=CC=C(Cl)C=2)=O)=[CH:43][CH:42]=1)=[O:40]>>[C:39]([NH2:38])(=[O:40])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2cccc(Cl)c2)C(=O)Nc2cccc(Cl)c2)cc1
Agent: O=C(O)c1ccc(C(C(=O)Nc2cccc(Cl)c2)C(=O)Nc2cccc(Cl)c2)cc1
Product: NC(=O)c1ccccc1

Procedure:
Additional benzamide analogs were prepared using procedures similar to those described for the preparation of the above 4-(2-[(3-Chlorophenyl)amino]-1-{[(3-chlorophenyl)amino]carbonyl}-2-oxoethyl)benzoic acid and 2-(4-{[(2-Aminophenyl)amino]carbonyl}phenyl)-N,N′-bis(3-chlorophenyl)malonamide.