Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6].[N:25]1(C(OC(C)(C)C)=O)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CS(C)=O.O>[N+:22]([C:3]1[C:2]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:12][CH:11]([CH2:17][CH:15]([CH2:14]3)[CH2:16]1)[CH2:10]2)=[O:6])([O-:24])=[O:23]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(N2CCNCC2)c1[N+](=O)[O-]
Temperature: 120 °C
Yield: 118.8 %

Procedure:
A mixture of 3-chloro-2-nitro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (2.80 g, Example 1a) and piperazine-1-carboxylic acid, tert-butyl ester (7.47 g) in dry dimethyl sulfoxide (10 ml) was heated at 120° C. under a nitrogen atmosphere for 24 h. The cooled reaction mixture was diluted with water and extracted thrice with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a solid. Purification by chromatography over silica gel, eluting with iso-hexane/ethyl acetate (2:1) gave the subtitle compound as a solid (3.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH2:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH2:16])(=[O:19])[CH3:18]
Reactant: Nc1ccc2c(N)c3ccccc3nc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(N)c3ccccc3nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25 mL rbf equipped with a nitrogen bubbler were charged 3,9-diaminoacridine (50 mg, 0.24 mmol) and anhydrous DCM (2 mL). To the resulting red suspension was added acetic anhydride (25 μL, 0.26 mmol) followed by triethylamine (37 μL, 0.26 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. LCMS showed incomplete reaction but only formation of expected product. Starting material was not really soluble in DCM. Pyridine (0.5 mL) was thus added and the mixture stirred overnight. LCMS still showed incomplete reaction. A further portion of acetic anhydride (25 μL, 0.26 nmol) was added and the reaction mixture was stirred at room temperature over three days. LCMS showed reaction completion.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[S:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:28]1[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[S:11][C:10]([C:16]3[CH:17]=[C:18]4[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:28]3[CH2:29][CH2:30][N:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])[CH2:32][CH2:33]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(CNCC2CC2)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCC5CC5)s4)cc23)CC1
Yield: 20 %

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (cyclopropylmethyl)amine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 19.1 mg of the title compound (20%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+].CC[N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl.CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:36])=[O:25])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(N)=O)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.12 mmol), ammonium chloride (25 mg, 1.44 mmol), EDCI (36 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol) in dichloromethane (3 mL), DMF (0.5 mL) and Et3N (27 mg, 0.24 mmol) was stirred at room temperature for 16 h. The solution was concentrated in vacuo, washed with water (10 mL×3), purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (24 mg, 48%) as a yellow oil. 1H NMR (300 MHz, DMSO): δ 9.67 (s, 1H), 8.85 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.13-7.99 (m, 3H), 7.68-7.59 (m, 2H), 7.49-7.42 (m, 2H), 6.73 (d, 1H, J=7.8 Hz), 6.08 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.60-3.57 (m, 1H), 3.44-3.38 (m, 1H), 2.06-1.95 (m, 3H), 1.67 (s, 1H), 1.08 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 414, tR=1.633 min, HPLC: 98.33% at 214 nm, 97.74% at 254 nm, tR=5.64 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]=3[O:22][CH3:23])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:30]1[CH2:32][C@H:31]1[CH2:33][O:34][C:35]1[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=1>>[OH:30][C@@H:31]([CH2:32][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]=3[O:22][CH3:23])=[O:16])[CH2:13][CH2:14]2)=[CH:28][CH:29]=1)[CH2:33][O:34][C:35]1[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)Nc1cccc(OC[C@@H]2CO2)c1
Reactant: COc1c(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)sc2ccccc12
Product: COc1c(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4cccc(NC(C)=O)c4)cc3)CC2)sc2ccccc12
Yield: 23.4 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(3-methoxy-1-benzothiophen-2-yl)methanone (0.170 g, 0.415 mmol) was reacted with N-{3-[(2S)oxiranylmethoxy]phenyl}acetamide (0.086 g, 0.415 mmol) according to Procedure G to give the title compound (0.06 g, 0.097 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].F[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:11][C:12]=1[S:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1cccnc1
Reactant: Sc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccc(Cl)c(Sc2ccccn2)c1
Temperature: 100 °C

Procedure:
89.5 g (0.500 mol) of 2,5-dichlorobenzenethiol, 53.4 g (0.55 mol) of 3-fluoropyridine, 82.9 g (0.60 mol) of potassium carbonate, and 550 mL of anhydrous N,N′-dimethyl acetamide were weighed in a 2 L three-necked flask equipped with a stirrer, thermometer, cooling pipe, and nitrogen inlet tube. The reaction solution was heated to 100° C. for 3 hours under a nitrogen atmosphere using an oil bath. After confirming the disappearance of raw materials by way of thin-layer chromatography, the reaction liquid was allowed to cool to room temperature. Thereafter, the reaction liquid was gradually added to 3 L of water, and the product was solidified and filtered. The product obtained by filtering was dissolved in 2.5 L of toluene, and then washed with a sodium chloride solution using a separating funnel till the aqueous layer became neutral. The organic layer was dried using magnesium sulfate, and then the solvent was removed by an evaporator to obtain 2,5-dichlorophenyl pyridyl sulfide of an intermediate in an approximate yield amount of 129 g.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC)=[O:44])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(CC(=O)O)cc3)oc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl)oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.28 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (0.15 g, yield 56%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=O)[O:22]C1C=CC=CC=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([CH:3]1[C:2](=[O:1])[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]1=2)=[O:22]
Reactant: O=C1Cc2ccccc2S1
Reactant: O=C(Nc1ccccc1F)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1ccccc1F)C1C(=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 50 g of 2,3-dihydro-2-oxo-benzo[b]thiophene in 200 ml of hexamethylphosphoric acid triamide is added dropwise to a suspension of 16 g of a 50% strength sodium hydride/mineral oil dispersion in 500 ml of hexamethylphosphoric acid triamide, whilst cooling, the temperature being kept below 15°. After stirring for one hour at room temperature, 77 g of phenyl N-(2-fluorophenyl)-carbamate are added in portions, with external cooling. The reaction mixture is stirred for a futher 16 hours at room temperature and poured into a mixture of 300 ml of 2 N hydrochloric acid and 3,000 ml of ice water. An oil separates out and this crystallises after about 2 hours. The crystalline product, in which solvent is incorporated, is dissolved in 1,000 ml of diethyl ether and the solution is washed with water. The organic phase is separated off, dried over sodium sulphate and evaporated to dryness. The crude product is recrystallised from diethyl ether and gives N-(2-fluorophenyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophenecarboxamide, melting point 155°-156°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CC(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([CH3:16])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1cccc([C@H](C)c2nccn2C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of the compound of Example 58 (100 mg, 0.5 mmol) and caesium carbonate (407 mg, 1.25 mmol) in acetone (4 ml) was added iodomethane (78 μl, 1.25 mmol). The reaction mixture was stirred at room temperature, under nitrogen, for 4 h and then concentrated in vacuo. to the residue was added water (10 ml) and the solution was extracted with ethyl acetate (2×10 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: C[S-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([Cl:13])[C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:16][CH2:15]1.O.Cl>CN(C=O)C>[Cl:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([Cl:13])[C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)[CH2:16][CH2:15]1
Reactant: COc1cc(Cl)c(N2CCN(c3cccc(C(F)(F)F)c3)CC2)c(Cl)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(Cl)c(N2CCN(c3cccc(C(F)(F)F)c3)CC2)c(Cl)c1
Temperature: 100 °C
Yield: 63.9 %

Procedure:
A suspension of 0.8 gram (0.011 mole) of sodium methanethiolate in 25 mL of DMF was stirred, and a solution of 1.8 grams (0.0044 mole) of 1,3-dichloro-5-methoxy-2-{4-[3-(trifluoromethyl)phenyl]piperazinyl}benzene in 40 mL of DMF was added. Upon completion of addition, the reaction mixture was heated to 100° C. where it stirred for two hours. After this time, the reaction mixture was cooled in an ice-water bath and 50 mL of water, followed by 25 mL of an aqueous solution of 10% hydrochloric acid, were added dropwise. The reaction mixture was then saturated with sodium chloride and extracted with two 50 mL portions of diethyl ether. The combined extracts were dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane, then 100% methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH:19][C:25]2[N:26]=[CH:27][C:22]([Br:21])=[CH:23][N:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Reactant: Clc1ncc(Br)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCNc2ncc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
2-{[4-(3-Aminopropyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.3 g) synthesized in Example 33 and 5-bromo-2-chloropyrimidine (3.24 g) were dissolved in N-methylpyrrolidone (60 mL), diisopropylethylamine (5.8 mL) was added, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (5.65 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:16]=[O:17]>>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:16]=[O:17])[C:12]([OH:15])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(O)cc1
Reactant: C=O
Product: CCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 98 °C
Yield: 85 %

Procedure:
The procedure described in Example 4 was followed, replacing the phenol (48 g) by 4-octylphenol (105 g 0.5 mole). During addition of the paraformaldehyde, the internal temperature was maintained at 95°-98° C. and the reaction mixture was stirred at 98° C. for a further hour. In other respects, the conditions were as described in Example 4. The product, 5-octylsalicylaldehyde, was obtained in 85% yield.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH3:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[C:5]([CH3:11])[CH:6]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cc(Br)ccc1CO
Reaction time: 3 h

Procedure:
A solution of methyl4-bromo-2-methyl-benzoate (1.05 g, 4.58 mmols) in 10 mL of Et2O was cooled to 0° C. and treated with LiAlH4 (177.0 mg, 4.58 mmols), stirred for 3 hours, and then carefully quenched with H2O. The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure. The title compound, 830.0 mg (90%), was isolated by column chromatography (10-30% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 95 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (543.7 mg, 1.90 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (500 mg, 2.09 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (884.7 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 95.2%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.C(N(CC)CC)C.C1C=CC=CC=1.[Cl:27][C:28]([Cl:33])([Cl:32])[C:29](Cl)=[O:30]>O>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:29](=[O:30])[C:28]([Cl:33])([Cl:32])[Cl:27])=[C:7]([CH3:12])[CH:6]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(NC(=O)C(Cl)(Cl)Cl)c(C)c1

Procedure:
To a slurry of 3-methyl-4-aminophenyl N-methylcarbamate (1.8g., 0.01 mole), triethylamine (1.11g., 0.011 mole), and 25 ml. of benzene was added trichloroacetyl chloride (2.0g., 0.011 mole) dropwise. After refluxing for one hour, the reaction mixture was poured into water and the resulting solid product was filtered (3.05g., m.p. 185°-87° C.).
Reaction SMILES: [N:1]#[C:2]N.Cl[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].Cl.[CH2:12]([S:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1)[CH2:13][CH3:14]>O.CO>[CH2:12]([S:15][C:16]1[CH:21]=[CH:20][C:19]2[N:22]=[C:2]([NH:1][C:5]([O:7][CH3:8])=[O:6])[NH:23][C:18]=2[CH:17]=1)[CH2:13][CH3:14]
Reactant: COC(=O)Cl
Reactant: CCCSc1ccc(N)c(N)c1
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCSc1ccc2nc(NC(=O)OC)[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Preparation of methyl 5-propylthio-2-benzimidazole carbamate--A 1.82 g portion of cyanamide was dissolved in 10 ml of water. Methyl chloroformate, 4.64 g, and 6.34 g of 50% aqueous sodium hydroxide in 6 ml of water were added simultaneously so as to maintain the pH at approximately 7 as determined by a pH meter. The reaction mixture was stirred at 50° C. for one hour. A portion of 7.4 g of concentrated hydrochloric acid in 7 ml of water was added until the pH was 4. The methanol solution of 4-propylthio-o-phenylenediamine from Example IV was added at once. More of the hydrochloric acid solution was added to adjust the pH to 4. The reaction mixture was heated to distill the methanol. As methanol was nearly removed more hydrochloric acid solution was added to keep the pH at 4. Water was added from time to time to keep the slurry from becoming too thick. The reaction slurry was heated at 100° C. for one hour after the methanol had been removed. The reaction slurry was cooled, filtered and washed liberally with water. The solids were air dried to produce 8.77 g of crude methyl 5-propylthio-2-benzimidazole carbamate. The crude solids were washed 3 times with cold acetone and dried to produce 7.52 g of product assaying 97% methyl-5-propylthio-2-benzimidazole carbamate by HPLC, 73% yield from the 4-propylthio-2-nitroaniline employed in Example IV.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH2:25].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH3:23][O:24][NH:25][C:14](=[O:16])[CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][C:10]=1[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1
Reactant: CON
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl acetic acid (100 mg), methoxyamine hydrochloride (37.6 mg), 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg), 1-hydroxybenzotriazole (67 mg) and triethylamine (0.14 ml) in N,N-dimethylformamide (3 ml) was stirred at room temperature overnight. Water was added to the reaction mixture, the mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=20:1), and triturated with diethyl ether-hexane to obtain N-methoxy-[2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl]acetamide (75 mg) as colorless powder.