Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23](=[O:25])[CH3:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(CC)CC>ClCCl>[C:23]([N:22]([S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:14][CH:15]=1)(=[O:20])=[O:21])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(C(C)=O)S(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Reaction time: 168 h
Yield: 31.9 %

Procedure:
To a stirred solution of N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide (Example 39) (0.612 g, 1.72 mmol) in dichloromethane was treated with ethyl bromoacetate (0.20 mL, 0.29 g, 1.72 mmol) and Et3N (0.26 mL, 0.19 g, 1.89 mmol). After 7 days the reaction was still incomplete by TLC. Additional ethyl bromoacetate (0.20 mL, 0.29 g, 1.72 mmol) and Et3N (0.26 mL, 0.19 g, 1.89 mmol) were added and the reaction was stirred for an additional 6 days. The reaction was diluted with dichloromethane and washed with KHSO4 solution, NaHCO3 solution, and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a clear oil. This oil was purified by flash chromatography yielding N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester (0.243 g, 32%) as a clear colorless oil of suitable purity for use in the next step: 1H NMR (CDCl3 /300 MHz) 8.03 (d, 2H, J=8.7 Hz), 7.47-7.27 (m, 9H), 4.61 (s, 2H), 4.21 (q, 2H, J=7.1 Hz), 2.51 (s, 3H), 2.33 (s, 3H), 1.28 (t, 3H, J=7.1 Hz). FABLRMS m/z 443 (M+H). FABHRMS m/z 442.1201 (M+, C22H22N2O6S Calc'd 442.1199).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:27][CH2:28][N:29]([CH2:37][CH2:38][OH:39])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[C:11](=[O:26])[C:10]=1[C:9]=23.[NH2:40][CH2:41][CH2:42][NH:43][CH2:44][CH2:45][OH:46]>CC(O)C>[OH:46][CH2:45][CH2:44][NH:43][CH2:42][CH2:41][NH:40][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:27][CH2:28][N:29]([CH2:37][CH2:38][OH:39])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[C:11](=[O:26])[C:10]=1[C:9]=23
Reactant: NCCNCCO
Reactant: O=C1c2c(OCc3ccccc3)cccc2-c2nn(CCN(CCO)Cc3ccccc3)c3ccc(Cl)c1c23
Solvent: CC(C)O
Product: O=C1c2c(OCc3ccccc3)cccc2-c2nn(CCN(CCO)Cc3ccccc3)c3ccc(NCCNCCO)c1c23
Temperature: 160 °C
Yield: 60.4 %

Procedure:
A mixture of 6.0 g (11.2 mmol) of 5-chloro-2-[2-[(2-hydroxyethyl)(phenylmethyl)amino]ethyl]-7-(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one (8) and 12.2 ml (121 mmol) of 2-(2-aminoethylamino)-ethanol was heated at 160° C. for 24 hr. The cooled mixture was diluted with 60 ml of 2-propanol then maintained at 0°-5° C. for several days. The precipitate was collected, washed with cold 2-propanol then diethyl ether, and dried at 60° C. under vacuum for 18 hours to give 4.1 g (60%) of 10, mp 134°-137° C., 97% pure by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2C3C(=CC=CC=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](O)C[N:51]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:50]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@H:18]2[C@@H:19]([O:27][CH2:28][CH3:29])[CH2:20][N:51]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:50]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.40–7.25, 5.20–5.13, 4.73, 4.10, 3.98, 3.77–3.59, 3.53–3.30, 2.70, 2.46, 1.27, 1.15; HRMS (FAB) calcd for C28H32Cl2N4O3+H 543.1929, found 543.1913. Anal. Calcd for C28H32Cl2N4O3: C, 61.88; H, 5.93; N, 10.31. Found: C, 62.07; H, 6.14; N, 10.16.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[S:15][C:16]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[S:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(C)cc2)sc(Br)c1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)OCc2ccccc2)csc1-c1ccc(C)cc1
Reaction time: 4 h

Procedure:
10% Pd/C is added to methyl 4-(benzyloxycarbonylamino)-5-bromo-2-p-tolylthiophene-3-carboxylate (176) in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 4 h. The mixture is filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provides 177.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][SH:9])=[CH:4][CH:3]=1.Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][C:11]2[CH:21]=[C:15]3[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]3[C:13](=[O:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: Fc1ccc(CS)cc1
Product: CN1CCCn2c1cc(SCc1ccc(F)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E62 starting from (4-fluorophenyl)methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:14]([C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]=[CH:6]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23])[CH3:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(CC)(NCCCn1cnc(CCN)c1)c1ccccc1
Product: CCC(CC)(NCCCn1cnc(CCNC(=O)c2ccccc2)c1)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propylamine (1.0 g) was reacted with benzoyl chloride (0.38 ml) in a similar manner to Example 55 to give N-(2-{1-[3-(1-ethyl-1-phenylpropylamino)propyl]imidazol-4-yl}ethyl)benzamide, as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OC(CC)CC)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCC(CC)Oc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 82 %

Procedure:
To a solution (10 ml) of ethyl 1-(3-cyano-4-(1-ethylpropoxy)phenyl)pyrazole-4-carboxylate (0.8 g) in ethanol was added 2 N aqueous sodium hydroxide solution (1.5 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of ethyl alcohol and water to give 0.6 g of 1-(3-cyano-4-(1-ethylpropoxy)phenyl)pyrazole-4-carboxylic acid, melting point 142-144° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[O:11]=[C:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]2)=[N:13]1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:11])[CH2:20]3)=[O:9])[CH:3]=1
Reactant: O=C1C=c2ccccc2=N1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2cc(C(=O)c3cc(Cl)ncn3)ccc2N1
Temperature: 0 °C

Procedure:
3.93 g (22.2 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 2.96 g (22.2 mmol) 2-oxoindole and 14.8 g (111 mmol) aluminium trichloride were combined and heated for 3 h to 130° C. Then the mixture was mixed with ice water and extracted twice with EtOAc. The organic phases were combined, dried and evaporated down. The residue was triturated in DIPE, suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17])[CH3:2].[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:21]1[CH2:22][CH2:23][CH3:24])[CH3:2]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(CNc1c(N)cnc2ccccc12)OCC
Product: CCCc1nc2cnc3ccccc3c2n1CC(OCC)OCC
Yield: 80.6 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize N4-(2,2-diethoxyethyl)quinoline-3,4-diamine (26.5 g, 96.2 mmol) by reaction with trimethyl orthobutyrate (15.9 g, 107 mmol) to provide 1-(2,2-diethoxyethyl)-2-propyl-1H-imidazo[4,5-c]quinoline (25.4 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:42](Cl)=[O:43])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:42]([N:39]2[CH2:38][CH2:37][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:41][CH2:40]2)=[O:43])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 67.1 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (130 mg, 0.376 mmol) in CH2Cl2 (5 ml) was added ethyl-diisopropyl-amine (0.10 ml, 0.56 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (94 mg, 0.41 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 3:1) afforded 135 mg (66%) of the title compound as a white solid. ES-MS m/e: 535.1 (M+H+).
Reaction SMILES: [C:1](/[C:3](=[C:9]1/[CH2:10][CH2:11][C:12]2[C:17]/1=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)/C(OCC)=O)#[N:2].[C-:19]#[N:20].[K+]>C(O)C.O>[C:1]([CH2:3][C:9]1([C:19]#[N:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)/C(C#N)=C1\CCc2ccc(F)cc21
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCc2ccc(F)cc21
Temperature: 65 °C
Reaction time: 7 h

Procedure:
To a solution of (E)-ethyl 2-cyano-2-(6-fluoro-2,3-dihydro-1H-inden-1-ylidene)acetate (Prep44, 7.5 g, 0.03 mol) in ethanol (100 ml), a solution of KCN (4.65 g, 0.08 mol) in water (30 ml) was added. The mixture was warmed to 65° C., and stirred for 7 h.
Reaction SMILES: CN1S(=O)(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[O:14][C:15](N(C3N=CC=CC=3)C(=O)C1=2)=[O:16].[OH-:26].[Na+]>[Na+].[Cl-]>[C:4]([O:14][CH2:15][O:16][C:4](=[O:14])[C:5]([CH3:10])=[CH2:6])(=[O:26])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN1c2c(oc(=O)n(-c3ccccn3)c2=O)-c2ccccc2S1(=O)=O
Reactant: [OH-]
Agent: [Cl-]
Agent: [Na+]
Product: C=C(C)C(=O)OCOC(=O)c1ccccc1
Reaction time: 45 h

Procedure:
50 mg samples of the polymer (Example 23), as finely divided powder, and 20 ml 0.9% aqueous NaCl were added to each of three reaction vials. To one of the vials was also added 0.1 ml esterase from porcine liver in 3.2M (NH4)2SO4, (Sigma E-3128, 250U). To another of the vials was added 0.1 ml 3.2M (NH4)2SO4. Using a pH-stat (Radiometer), the pH within each of the vials was kept constant at 8.0 by adding 0.1M NaOH. By recording the consumption of NaOH, the rates of hydrolysis were calculated. Over 45 hours at 37° C., the hydrolysis of the polymer with esterase was found to be 11 times faster than the control with (NH4)2SO4 without esterase. In the control containing polymer in 0.9% NaCl no hydrolysis was found (see FIG. 1 of the accompanying drawing).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[NH2:8][C:9]1[C:10]([Cl:30])=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=[CH:14][CH:13]=2>C(#N)C>[Cl:30][C:10]1[C:9]([NH:8][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:18]([NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)c(Cl)nc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: CC#N
Product: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 93.1 %

Procedure:
A solution of ethoxyacetyl chloride (857 mg, 6.99 mmol) in acetonitrile (5 mL) was added to solution of tert-butyl 2-[(3-amino-2-chloroquinolin-4-yl)amino]ethylcarbamate (2.14 g, 6.35 mmol) in acetonitrile (20 mL). After five minutes, the solution was cooled in an ice bath and a white precipitate began to form. After one hour, the precipitate was isolated by filtration and dried under vacuum to afford the hydrochloride salt of tert-butyl 2-({2-chloro-3-[(ethoxyacetyl)amino]quinolin-4-yl}amino)ethylcarbamate (2.50 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([CH:14]=[O:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[F:23])[CH:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[CH:10][CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[F:23])[C:13]=1[CH:14]=[O:15]
Reactant: CC(C)(C)OC(=O)Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a stirred solution of tert-butyl(4-(4-chloro-2-fluorophenyl)-3-formylpyridin-2-yl)carbamate (0.9 g, 2.57 mmol) in CH2Cl2 (15 mL) was added TFA (3.95 mL, 51.3 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (15 mL) and extracted with CH2Cl2 (2×15 mL). The combined organic extracts were washed with brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude 2-amino-4-(4-chloro-2-fluorophenyl)nicotinaldehyde (0.6 g, 2.40 mmol, 41% yield) was carried into the next step without further purification. LCMS (ESI) m/e 251.0 [(M+H)+, calcd for C12H9ClFN2O 251.0]; LC/MS retention time (Method C): tR=1.67 min.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4].CO.O1CCCC1.O.[OH-].[Li+]>O>[CH2:1]([NH:5][C:6]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A solution of methyl 4-[5-(butylcarbamoyl)methyl-1-methylindol-3-ylmethyl]-3-methoxybenzoate (0.23 g) in a combination of methanol (2.5 ml), tetrahydrofuran (2.5 ml), and water (1.5 ml) was treated with lithium hydroxide monohydrate (0.14 g). The mixture was stirred for 18 hr and the organic solvents evaporated. The resultant aqueous solution was acidified with 10% (v/v) hydrochloric acid. The ivory precipitate which formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (0.21 g, 94%) as a pale pink powder: mp 92°-95°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.Cl.[CH3:33][NH:34][CH3:35]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:34]([CH3:35])[CH3:33])=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: CNC
Agent: Cl
Product: CN(C)Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and dimethylamine hydrochloride (39.5 mg; 0.48 mmol) to give Example 131 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.62 (2H, dd, J=4.5, 1.7 Hz), 7.84 (2H, d, J=8.1 Hz), 7.78 (1H, td, J=7.6, 1.7 Hz), 7.63-7.56 (1H, m), 7.48 (2H, dd, J=4.5, 1.7 Hz), 7.42-7.35 (4H, m), 3.38 (2H, s), 2.08 (6H, s). LC/MS (Method C): 442 (M+H)+. HPLC (Method E) Rt 2.14 min (Purity: 94.2%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH2:37][O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH2:37][O:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(OCCOc1ccccc1)c2CN1CCNCC1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0380 g, 0.0637 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, and added with water (4 mL) and saturated aqueous sodium hydrogencarbonate (4 mL), and the mixture was stirred for 1 hour. The reaction mixture was filtered, and then the resulting solid was washed with water to obtain the objective (Z)-2-((1H-indazol-3-yl)methylene)-6-(2-phenoxyethoxy)-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0280 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:21]1([NH:27][C:15]([C:14]2[CH:13]=[C:12]([CH:20]=[CH:19][CH:18]=2)[O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoic acid (0.73 g, 2.98 mmol), cyclohexylamine (0.34 ml, 2.98 mmol), EDCI (0.7 g, 3.58 mmol) and HOBT (0.49 g, 3.58 mmol) in DMF was added DIPEA (1.0 ml, 5.57 mmol). The resulting mixture was stirred at room temperature for 18 h, concentrated, and partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (30 to 65% EtOAc-hexanes gradient) gave tert-butyl 2-(3-(cyclohexylcarbamoyl)phenoxy)ethylcarbamate as an orange oil. Yield (0.20 g, 20%): 1H NMR (400 MHz, CD3OD) δ 7.31-7.38 (m, 3H), 7.06-7.09 (m, 1H), 4.04 (t, J=5.6 Hz, 2H), 3.78-3.87 (m, 1H), 3.41-3.45 (m, 2H), 1.90-1.98 (m, 2H), 1.78-1.84 (m, 2H), 1.63-1.71 (m, 1H), 1.43 (s, 9H), 1.18-1.38 (m, 5H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[CH2:18]([N:6]1[CH2:7][CH2:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH:5]1[CH2:4][NH2:1])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [N-]=[N+]=NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 2azidomethyl-1,4-dibenzyl-piperazine (9.0 g, 0.028 mol) in TBFE (90 mL) and water (5 mL) was added triphenylphosphine (22.3 g, 0.085 mol) and the mixture stirred for 18 h. The reaction was concentrated to an oil, dissolved in 1N hydrochloric acid (100 mL) and washed with ethyl acetate (2×100 mL). The acidic aqueous layer was cooled to 0° C. and the pH adjusted to 8.5 with 3N sodium hydroxide. The mixture was extracted with ethyl acetate (2×100 mL) and extracts dried over sodium sulfate and concentrated to an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:15]([CH2:14][CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:7]=2)[CH:9]=[N:10]1)[CH:17]1[CH2:19][CH2:18]1)#[N:16]
Reactant: N#CCC(C1CC1)n1cc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: N#CCC(C1CC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopropylpropanenitrile (2.74 g, 0.0100 mol), p-aminobenzoic acid (2.06 g, 0.0150 mol), and p-toluenesulfonic acid (1.5 g, 0.0085 mol) in dry 1,4-dioxane (80 mL) was refluxed overnight. The mixture was cooled to room temperature, filtered. The solid was washed with dioxane, air dried to yield the desired product as a racemic mixture (3.02 g, 80.58%). LCMS (M+H) 375.3.