Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]>C(Cl)Cl>[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:14][CH:13]=2)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
N-(tert-Butoxycarbonyl)-p-phenylenediamine (0.209 g, 1.002 mmol), triethylamine (0.101 g, 1.002 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.279 g, 1.002 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ethanol to obtain the titled compound (0.180 g, 0.319 mmol, 48%).
Reaction SMILES: CI.[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][NH:6][C:5]1=[S:15].[OH-].[Na+].[CH2:18](Cl)Cl>CCO>[CH3:3][N:4]1[C:5]([S:15][CH3:18])=[N:6][N:7]=[C:8]1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClCCl
Reactant: Cn1c(-c2cccnc2)n[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Product: CSc1nnc(-c2cccnc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
MeI (2 mL, 32 mmol) in EtOH (10 mL) was added to a mixture of 4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione in 1 M NaOH (70 mL, 70 mmol). After 1 h stirring at r.t., DCM was added and the layers were separated. The water phase was washed with DCM and the combined organic phases were dried and concentrated to give 6.5 g (98%) of the title compound. 1H NMR: 2.76 (s, 3H) 3.59 (s, 3H) 7.43 (m, 1H) 7.99 (m, 1H) 8.71 (m, 1H) 8.86 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([N:9]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:10])=[O:8].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)=[N:32]1>O>[Cl:1][C:2]1[C:3]([O:47][C:44]2[CH:45]=[C:46]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][N:38]=[C:37]3[NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=2)=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([N:9]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:10])=[O:8]
Reactant: CN(C)CCN(C)C(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)CCN(C)C(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
5,6-Dichloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide (126 mg, 0.46 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred overnight under a nitrogen atmosphere at 130° C. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform. The organic layer was washed with water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate to chloroform:methanol=1:4 to 100:2) to obtain the entitled compound (25 mg, yield: 25%) as a pale yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:30][C@H:31]2[CH2:35][CH2:34][NH:33][CH2:32]2)=[C:14]([CH:29]=1)[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[O:16])#[N:9]>N1C=CC=CC=1>[C:1]([N:33]1[CH2:34][CH2:35][C@H:31]([NH:30][C:13]2[CH:12]=[CH:11][C:10]([C:8]#[N:9])=[CH:29][C:14]=2[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:16])[CH2:32]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@H]2CCNC2)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@H]2CCN(C(C)=O)C2)cc1OC
Temperature: 25 °C
Yield: 69.8 %

Procedure:
Acetic anhydride (64 mg) was added to a solution of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (80 mg) in pyridine (1 mL). The mixture was stirred for an hour at ambient temperature. The mixture was partitioned between ethyl acetate and 1% hydrochloric acid. The organic layer was washed with an aqueous saturated sodiunn bicarbonate solution and brine. The resultant was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a thin layer chromatography developed with 5% methanol in chloroform to give (S)-2-(1-acetylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (62mg) as amorphous powders.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[O:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[O:21]1[CH2:25][CH2:24][CH:23]([C:26]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:27])[CH2:22]1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Reactant: O=C(O)C1CCOC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)C1CCOC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 92 mg 3-tetrahydrofuranecarboxylic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. 1.09 g of the residue are purified by silica gel flash chromatography. 110 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=3)[N:19]([CH2:30][C:31]#[CH:32])[C:18]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[CH2:41][OH:42])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl>[CH:11]1([C:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=3)[N:19]([CH2:30][C:31]#[CH:32])[C:18]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[CH:41]=[O:42])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C#CCn1c(-c2ccc(OC)cc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C#CCn1c(-c2ccc(OC)cc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.5 eq., 2M solution in DCM) was added at −70° C. under nitrogen atmosphere over a solution of DMSO (5 eq.) in anhydrous DCM and the mixture was stirred for 30 min; a solution of methyl 3-cyclohexyl-2-[2-(hydroxymethyl)-4-methoxyphenyl]-1-prop-2-yn-1-yl-1H-indole-6-carboxylate in DCM was then added and stirring was continued at the same temperature for 30 min. before NEt3 (8 eq.) was added. After stirring at 0° C. for 20 min. the mixture was diluted with DCM, washed with water, 1N HCl, saturated aq. NaHCO3 solution and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The obtained yellow solid was used in the next step without purification. MS (ES+): 430.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1.[CH3:32]N(C=O)C.[H-].[Na+].IC>O>[NH2:1][C:2]1[C:7]([N:8]([CH3:32])[C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)N(C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
54 mg (0.13 mmol) of ethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate from Example 2 are added to 5 ml of DMF, the mixture is cooled to 0° C., and 7.67 mg (0.19 mmol) of sodium hydride are added. Then 18.14 mg (0.13 mmol) of iodomethane are added dropwise, and the mixture is stirred for one hour. The mixture is mixed with water and extracted with dichloromethane. The combined organic phases are dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is purified first by column chromatography (mobile phase: dichloromethane/methanol=10:1) and then by preparative RP-HPLC.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:27][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([C:11]3[N:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:5][CH:6]=2)=[O:10])([CH3:25])[CH3:26])=[CH:22][CH:23]=1
Reactant: CC(C)(N)c1ccc(Br)cc1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NC(=O)c1cnc(-c2cccnn2)nc1O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (110 mg, 0.5 mmol), 2-(4-bromophenyl)propan-2-amine, 36-b, (70 mg, 0.32 mmol), HATU (290 mg, 0.76 mmol) and DIEA (82 mg, 0.64 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was washed with aqueous NH4Cl (15 mL) and extracted with EtOAc (30 mL). The organic layers were dried and concentrated in vacuo. The residue was washed with hexane to afford compound 36-c (80 mg, 57%). 1H NMR (300 MHz, CDCl3) δ11.62 (s, 1H), 9.55 (s, 1H), 9.41 (dd, J=1.5, 4.8 Hz, 1H), 9.00 (d, J=4.2 Hz, 1H), 8.63 (dd, J=1.5, 8.1 Hz, 1H), 7.78 (dd, J=5.1, 8.4 Hz, 1H)), 7.43 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 1.78 (s, 6H). LC-MS: (M+H)+ 414.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2S[C:12]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:21]=1)(=[O:3])C.[OH-:22].[Na+].[S:24](S([O-])=O)([O-:27])(=O)=[O:25].[Na+].[Na+]>Cl[O-].[Na+]>[CH:17]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:21]=[C:4]([C:1]([OH:3])=[O:22])[CH:5]=[CH:6][C:7]=3[S:24](=[O:27])(=[O:25])[C:12]=2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=1
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: [OH-]
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2(=O)=O
Temperature: 75 °C

Procedure:
Add 2 g. of 8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid to a stirred solution of 50% sodium hypochlorite (400 ml.) and 15 ml. of 20% aqueous sodium hydroxide at 60° C. Heat for 48 hours at 75° C. Cool to room temperature and add sodium metabisulfite. Acidify and separate the solids by filtration. Purify by chromotography over silica gel eluting with a mixture of 80 parts toluene, 20 parts dioxane and 4 parts acetic acid. (m.p.~375° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OCc3ccccc3)cc(C)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 0.8 mmol) in anhydrous DMF (3 mL) was added sodium hydride (0.08 g, 1.6 mmol). After stirring for 15 minutes bromomethyl-benzene (0.274 g, 1.6 mmol) was added and the resulting mixture stirred at room temperature for 4 hours then quenched with crushed ice. The pH was adjusted to 4 with 6M HCl and the mixture extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Biotage (5-60% EtOAc in hexane) to give 6-benzyloxy-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 73%). 1H NMR 400 MHz (DMSO-d6) δ 9.15 (s, 1H), 7.45-7.31 (m, 5H), 7.11 (d, J=2.0 Hz, 1H), 6.94 (d, =2.0 Hz, 1H), 5.44 (dd, J=9.2, 2.4 Hz, 1H), 5.10 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.08 (dd, J=15.2, 2.4 Hz, 1H), 2.26 (s, 3H), 2.21 (m, 1H), 1.08 (t, 3H).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:5]=1[NH3+:6].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)CCl>[Cl:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[C:5]=1[NH:6][C:17](=[O:18])[CH2:16][Cl:15]
Reactant: [NH3+]c1c(CCl)cccc1C(F)(F)F
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)Nc1c(CCl)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A slurry of 19.85 g (0.0947 mol) of 2-(chloromethyl)-6-(trifluoromethyl) anilinium chloride (prepared as in Example 1 from 20.0 g of sulfoxide) was refluxed in ethylene dichloride with 11.2 g (0.0991 mol) of chloroacetyl chloride for 30 minutes followed by addition of 1.0 g (0.0089 mol) of additional CAC and further reflux for 30 minutes. The virtually clear solution was then cooled to room temperature, washed with 10% aqueous sodium carbonate (80 ml) and dried using sodium sulfate. Evaporation and drying gave 22.14 g of white 2'-(chloromethyl)-6'-(trifluoromethyl)-2-chloroacetanilide assaying 93.5% for an overall yield from sulfoxide of 85.7%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: BrCc1ccccc1
Solvent: CS(C)=O
Product: COC(=O)c1cccc2c1nc(N)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
To a solution of 0.1 g (0.52 mmol) of 2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester (intermediate A) in DMSO (1 mL) was added 0.089 g (0.52 mmol) of benzyl bromide, the reaction mixture was stirred at room temperature for 3 h. The conversion was monitored by LCMS. After usual work up, the residue was purified by column chromatography eluting with DCM/methanol (v/v=10:1) to afford 0.08 g (55%) of 2-amino-1-benzyl-1H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 281 (M+1)+; 1H NMR (DMSO-d6, 400 MHz): δ 7.49 (dd, 1H), 7.29 (t, 2H), 7.25 (m, 2H), 7.16(m, 2H), 7.05 (bs, 2H), 6.85 (t, 1H), 5.28 (s, 2H), 3.79 (s, 3H) ppm.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=1>>[ClH:20].[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:15][CH2:16][N:17]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=4)[CH2:18][CH2:19]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C1CCNCC1)N1CCCN(C2CCC2)CC1
Reactant: N#Cc1cc(Cl)ccn1
Product: Cl
Product: N#Cc1cc(N2CCC(C(=O)N3CCCN(C4CCC4)CC3)CC2)ccn1

Procedure:
The title compound (E137) was prepared in a similar manner to that described in Example 98, using 1-cyclobutyl-4-(piperidine-4-carbonyl)-[1,4]-diazepane (D10) and 4-chloro-2-cyanopyridine (T. Sakamoto, S-I. Kaneda, S. Nishimura and H. Yamanaka, Chem. Pharm. Bull., 1985, 33(2), 565-571). 1H NMR δ [DMSO-d6]: 1.51-1.83 (6H, m), 2.01-2.23 (3H, m), 2.37-2.49 (3H, m), 2.72-3.15 (5H, m), 3.30-3.85 (6H, m), 4.01-4.10 (3H, m), 7.14 (1H, dd, J=7, 3 Hz), 7.64 (1H, d, J=3 Hz), 8.26 (1H, d, J=7 Hz), 11.19 and 11.34 (2×br. m, in ˜2:1 ratio, total of 1H); LCMS electrospray (+ve) 368 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[CH3:11][CH2:12][CH2:13][CH2:14][CH:15]([CH:17]([CH3:19])C)C.[CH3:20][CH2:21]CC(CC(C)C)C.CC(CC(C(C)C)C)C>>[CH2:1]([C:4]1[CH:9]=[C:8]([CH2:20][CH2:21][CH2:19][CH2:17][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3]
Reactant: CCCCC(C)C(C)C
Reactant: CCCC(C)CC(C)C
Reactant: CCCc1ccccc1O
Agent: CC(C)CC(C)C(C)C
Product: CCCCCCCCCc1ccc(O)c(CCC)c1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
2-n-Propylphenol (5 mol, 681 g), dry Amberlyst 15 (50 g) and tripropylene (5.5 mol, 694 g, 951 ml) were placed in a 3000 ml 3N RBF. The mixture was heated and maintained at 120° C. under vigorous stirring for 7 hrs. After cooling to ambient temperature, the reaction mixture was filtered and distilled to obtain 2-n-propyl-4-nonylphenol in vacuo (135-150° C. at 0.5-2 T). Total 960 g of 2-n-propyl-4-nonylphenol was obtained as amber oils (71% yield with 95% plus purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>O1CCOCC1.C(OCC)(=O)C.CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C=CC(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3.9 g (0.023 mole) of 2-(4-chlorophenyl)propionaldehyde in 25 mL of 1,4-dioxane is added in one portion 9.0 g (0.026 mole) of (carbethoxymethylene)triphenylphosphorane. The reaction mixture is stirred for approximately 16 hours at ambient temperature after which the solvent is evaporated under reduced pressure, leaving a residue which is then dissolved in ethyl acetate. Approximately 10 g of silica gel is mixed with the resulting solution. The solvent is evaporated from this mixture, and the residue is placed in a sintered glass filter. The silica gel is then eluted with 100 mL of heptane/ethyl acetate (3:1). These solvents are evaporated under reduced pressure, leaving a residue. This residue is dissolved in 30 mL of heptane/ethyl acetate (9:1), treated with 5 g of silica gel, and filtered. The filtrate is evaporated under reduced pressure, leaving ethyl 4-(4-chlorophenyl)-2-pentenoate as a residue.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1)(=[O:32])=[O:31]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(=O)Nc1nc(CCl)cs1
Product: CC(=O)Nc1nc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cs1

Procedure:
Following General Procedure A, B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, N-(4-Chloromethyl-thiazol-2-yl)-acetamide and 1-benzofuran-2-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[Cl:8][C:9]1[C:10]([NH:15][NH2:16])=[N:11][CH:12]=[CH:13][CH:14]=1>>[F:1][C:2]([F:7])([F:6])[C:3](=[N:16][N:15]=[C:10]1[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][NH:11]1)[CH3:5]
Reactant: NNc1ncccc1Cl
Reactant: CC(=O)C(F)(F)F
Product: CC(=NN=c1[nH]cccc1Cl)C(F)(F)F
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to (3-chloro-pyridin-2-yl)-hydrazine (alternatively named (3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20-25° C. After the addition was complete, the mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure, and the mixture was partitioned between ethyl acetate (100 mL) and saturated sodium carbonate solution (100 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), m.p. 64-64.5° C. (after crystallization from ethyl acetate/hexanes).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:12]([CH:15]=[C:16](SC)[NH:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[NH:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])([O-:14])=[O:13]
Reactant: NCCCCc1ccccn1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCCCc1ccccn1

Procedure:
When 2-(4-aminobutyl)pyridine is reacted with 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-ethylene in the procedure of Example 1 (a) (ii), the title compound is produced.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.C(N(CC)CC)C.[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][S:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: Fc1ccc(S)cc1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CSc1ccc(F)cc1

Procedure:
To a solution of bromo acetic acid methyl ester (1.53 g, 0.95 ml, 10.0 mmol) and triethylamine (3.0 ml) in dry THF (25 mL) was added 4-fluoro-benzenethiol (1.62 g, 12.6 mmol) in one portion at room temperature. The resulting mixture was heated to reflux and stirred until the TLC showed the completion of the reaction. The reaction mixture was diluted with EtOAc and washed sequentially with aqueous HCl, water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography with 0˜5% EtOAc in hexanes. MS: 201.3 (M+H)+.