Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.Cl[CH2:23][CH2:24][OH:25].[H-].[Na+]>O1CCCC1.O>[OH:25][CH2:24][CH2:23][S:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1
Reactant: OCCCl
Reactant: C[C@]12CC[C@H](S)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@H](SCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 3 h

Procedure:
To a solution of 2.0 g of 3β-mercapto-androst-5-en-17-one (Swann D. A. and Turnbull J. H., Tetrahedron, 1966, 22, 231) and 0.33 ml of 2-chloroethanol in 5.0 ml of tetrahydrofuran under nitrogen atmosphere at room temperature, 0.030 g of sodium hydride (60% dispersion in mineral oil) were added. The reaction mixture was stirred for 3 hrs, diluted with water and extracted with ethyl acetate; the organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol/30% ammonia solution 95/5/1 as eluant to give 1.2 g of 3β-(2-hydroxyethylthio)-androst-5-en-17-one.
Reaction SMILES: [CH2:1](N(CC)CC)C.IC.[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1>C(#N)C>[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]4[CH2:39][CH2:38][N:37]([CH3:1])[CH2:36][CH2:35]4)[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CCN(CC)CC
Reactant: O=c1[nH]c(-c2ccccc2N2CCNCC2)cc2ccc(N3CCCC(O)C3)cc12
Solvent: CI
Solvent: CC#N
Product: CN1CCN(c2ccccc2-c2cc3ccc(N4CCCC(O)C4)cc3c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
0.0185 ml (0.133 mmol) of triethylamine and 0.00665 ml (0.107 mmol) of iodomethane were added to an acetonitrile solution (0.4 ml) containing 3.6 mg (0.0089 mmol) of the 7-(3-hydroxypiperidin-1-yl)-3-(2-piperazin-1-ylphenyl)-2H-isoquinolin-1-one obtained in Example 102. The obtained mixture was stirred at a room temperature for 4 hours. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was developed and purified by thin-layer chromatography (NH2 F254s, Merck, developing solvent; dichloromethane:methanol=10:1, Rf value: 0.8), so as to obtain 1.8 mg (48%) of 7-(3-hydroxypiperidin-1-yl)-3-[2-(4-methylpiperazin-1-yl)phenyl]-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[CH:13]1[CH:8]([CH2:9][CH2:10][CH:11]([O:19][C:20](=[O:22])[CH3:21])[CH2:12]1)[N:7]=[C:6]2[C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32](=[NH:35])SC)=[O:30])=[CH:25][CH:24]=1.[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37].C(N(CC)CC)C>O1CCOCC1>[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:32](=[N:31][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:6]3[C:5]4[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:13]4[CH:8]([CH2:9][CH2:10][CH:11]([O:19][C:20](=[O:22])[CH3:21])[CH2:12]4)[N:7]=3)=[CH:24][CH:25]=2)=[O:30])[NH2:35])[CH2:41][CH2:40]1)(=[O:38])[CH3:37]
Reactant: COc1cc2c(cc1OC)C1CC(OC(C)=O)CCC1N=C2c1ccc(C(=O)NC(=N)SC)cc1
Reactant: CC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C1CC(OC(C)=O)CCC1N=C2c1ccc(C(=O)N=C(N)N2CCN(C(C)=O)CC2)cc1
Yield: 61.4 %

Procedure:
743.4 mg of acetic acid (2RS,4aRS,10bRS)-8,9-dimethoxy-6-{4-[1-(2-methyl-isothioureido)-methanoyl]-phenyl}-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (compound A1), 384.5 mg of 1-acetylpiperzine and 0.416 ml of triethylamine are stirred in 10 ml of 1,4-dioxane at 90° C. for 5 days. After 2 days another 384.5 mg of 1-acetylpiperazine are added to the reaction mixture. The solvent is removed and the residue three times coevaporated with dichloromethane, than one time with toluene. After redissolving in 25 ml of dichloromethane the solution is extracted with water and aqueous saturated KHCO3 solution successively and the aqueous KHCO3 phase reextracted with dichloromethane. After drying the combined organic layers with sodium sulfate the solvent is removed and the residue purified by chromatography on silica to yield 530 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=2)[O:5][CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=1.[Cl:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]Cl.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.O>[OH:1][C:2]1([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:38][CH2:37][O:36][CH2:35][CH2:34][Cl:33])=[CH:30][CH:31]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=2)[O:5][CH2:4][CH:3]1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Reactant: ClCCOCCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCOCCCl)cc2)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
4-Hydroxy-4-(4-hydroxyphenyl)-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]chroman (770 mg, 1.4 mmol), bis-(2-chloroethyl)ether (810 mg, 5.7 mmol), potassium carbonate (782 mg, 5.7 mmol) and 18-crown-6(132 mg, 0.49 mmol) were dissolved in dry N,N-dimethylformamide (10 mL) under argon atmosphere, which was then stirred at 100° C. for 2.5 hours. The reaction solution was cooled down to normal temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (n-hexane:ethyl acetate=2:1) to give the title compound (0.71 g, yield 35%) as a red oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25](=[O:30])[CH:26]=[CH:27][CH2:28]Br)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25](=[O:30])[CH:26]=[CH:27][CH2:28][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCNCC
Reactant: O=C(C=CCBr)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A solution of 5.17 mL (3.65 g; 50 mmoles) of diethylamine in 20 mL of tetrahydrofuran was stirred and cooled in an ice bath, and a solution of 1.16 g (2.5 mmoles) of 4-Bromo-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide in 10 mL of tetrahydrofuran and 5 mL of N,N-dimethylformamide was added dropwise. After stirring for 2 hours, 45 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate were added, and the layers were separated. The organic layer was extracted with 25 mL of brine, dried over sodium sulfate, and taken to an oil in vacuo. This was chromatographed on silica gel with 1:9 methanol methylene chloride to give 677 mg (59%) of the desired product, which melted at 196-199° C. Mass spectrum (m/e) M+2H 228.5.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:8][C:2]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: C1CCNC1
Product: CCOC(=O)C(C)(C)N1CCCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
Ethyl 2-bromo-2-methylpropanoate (0.6800 g, 3.4861 mmol) was taken up in pyrrolidine (4 mL) and heated to 70° C. The reaction was stirred for 18 h and then concentrated. The residue was taken up in EtOAc (100 mL) and washed with water (1×100 mL), dried over MgSO4, filtered and concentrated to afford 0.4754 g (2.5697 mmol, 74%) of the product. 1H NMR (CDCl3) δ 4.16 (q, 2H, J=7.1 Hz), 2.76 (bs, 4H), 1.76 (bs, 4H), 1.36 (s, 6H), 1.27 (t, 2H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[N:10]3[C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=2)=[CH:4][CH:3]=1.[N+](=[CH2:31])=[N-]>C(OCC)C.C(OCC)(=O)C.C(OCC)C>[CH3:31][O:17][C:16]([C@@H:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:19](=[O:20])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:9]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=3)[N:10]12)=[O:18]
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2C(C(=O)O)CCC3)n1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCn2c(=O)c(-c3ccc(F)cc3)c(-c3ccnc(SC)n3)n21
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 30, in diethyl ether/ethyl acetate (2.5:1, 7o mL) is added freshly generated diazomethane in diethyl ether (5 mL). The reaction is stirred for 5 minutes then quenched by the addition of HOAc (0.5 mL). The resulting solution is washed with NaHCO3, brine, dried, and concentrated in vacuo to afford 1 g (98% yield) of the desired product as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[C:43](O)(=[O:45])[CH3:44].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.CO.C(Cl)Cl.O>[C:43]([N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH2:28][CH3:29])[C:18]2[C:19]([CH3:20])=[C:14]([C:12]([NH:11][CH2:10][C:3]3[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:13])[CH:15]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[CH:32][CH:31]=3)[CH:17]=2)[CH2:27][CH2:26]1)(=[O:45])[CH3:44]
Reactant: CC(=O)O
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(piperidin-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (0.25 g, 0.44 mmol) and acetic acid (0.052 g, 0.86 mmol) in DMF (3 mL), EDCI (0.123 g, 0.64 mmol) and HOBt (0.087 g, 0.64 mmol) was added followed by the addition of triethylamine (0.108 g, 1.06 mmol) and reaction was stirred at room temperature for overnight. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the title compound (0.1 g, 37.31%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[Cl:9].[CH3:10][O-:11].[Na+]>CC(N(C)C)=O.CO.O>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][CH3:10]
Reactant: Clc1cccc(Cl)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cccc(Cl)c1Cl

Procedure:
363 g (1 mole) of 1,2,3-trichlorobenzene is dissolved in 600 ml dimethyl acetamide and heated to 125° with stirring. 500 ml of 25% commercial sodium methoxide in methanol is then added at such a rate that the temperature is maintained at 125°-130°. After addition is complete the temperature is maintained at 130° for 30 minutes. The mixture is diluted with water and extracted with toluene. The toluene extracts are washed with brine, dried and the toluene removed by distillation. The residue is fractionated to yield 200 g of the desired isomer 2,3-dichloroanisole bp 140°/29 mm. By appropriate fractionation the minor isomer 2,3-dichloroanisole may also be obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>>[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:39]=2[S:40][C:41]=1[C:42]([N:20]([CH2:19][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:23][CH2:22]1)=[O:43]
Reactant: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 103 (1.84 g, 3.66 mmol) is treated with acid chloride 8 (1.17 g, 4.38 mmol) using Method D to give the title compound.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9]CC)=O.[CH:16]1([C:19]2[NH:23][N:22]=[C:21]([NH2:24])[CH:20]=2)[CH2:18][CH2:17]1>Cl>[CH:16]1([C:19]2[CH:20]=[C:21]3[NH:24][C:7](=[O:9])[CH:6]=[C:5]([OH:13])[N:22]3[N:23]=2)[CH2:18][CH2:17]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: O=c1cc(O)n2nc(C3CC3)cc2[nH]1
Temperature: 25 °C

Procedure:
A sodium ethoxide solution (EtOH/EtONa, 0.5 N, 400 ml) containing diethyl malonate (50 mmol, 1 eq., 5.8 ml, 6.6 g) and 5-cyclopropyl-1H-pyrazol-3-amine (50 mmol, 1 eq., 6.16 g) is refluxed for 7 hours. After cooling to room temperature, an aqueous hydrochloric acid solution (5 N, 240 ml) is added until pH 5 is obtained. Volatiles are then removed under reduce pressure and the residue dried under vacuum to afford 2-cyclopropyl-7-hydroxypyrazolo[1,5-a]pyrimidin-5(4H)-one x271. To this residue is successively added POCl3 (125 ml, 1.34 mol) and N,N-dimethylaniline (12.5 ml, 0.1 mol, 2 eq.) and the resulting mixture is refluxed during 3 hours. After cooling to room temperature, the reaction mixture is poured on ice and stirred during one hour at this temperature. The reaction mixture is extracted with dichloromethane, and the resulting organic phase is washed twice with water. The organic phase is dried over Na2SO4, filtered and evaporated under reduce pressure. The crude product is purified chromatography on silicagel (CH2Cl2/hexane: 40/60) to afford 5.85 g of 5,7-dichloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x272 as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A round-bottomed flask was charged with 2,4-dichloro-5-fluoropyrimidine (2.5 g, 15 mmol), ethyl 2-aminobenzoate (4.9 g, 30 mmol), N,N-diisopropylethylamine (5.2 mL, 3.9 g, 30 mmol) and isopropanol (50 mL). The flask was fitted with a reflux condenser and the mixture was heated to reflux and stirred for 18 h. After cooling the reaction mixture to room temperature a precipitate appeared. The solid was collected and washed sparingly with isopropanol then copiously with ethyl ether to afford the title compound as a white solid; yield, 1.8 g (41%). MS: M(C13H13ClFN3O2)=295.70 (M+H)+=296.0 and 298.0.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C1([OH:15])C=CC=CC=1>O>[C:1]1([OH:2])[CH:8]=[CH:7][CH:6]=[CH:4][CH:3]=1.[CH:8]1[C:1]([OH:2])=[CH:3][C:4]([OH:5])=[CH:6][C:7]=1[OH:15]
Reactant: Oc1cccc(O)c1
Solvent: O
Solvent: Oc1ccccc1
Product: Oc1cc(O)cc(O)c1

Procedure:
60 cc of distilled water was added to 0.70 g of natural montmorillonite (as the clay; Kunipia P, made by Kunimine Industries), and this was put into a sealed plastic vessel along with a Teflon® agitator and shaken vigorously, which gave a uniform dispersion. To this dispersion was added 0.30 g of resorcinol powder (as a polyhydric phenol; made by Wako Pure Chemical Industries), and this dispersion was poured into a flat-bottomed brass tray that had a circular bottom measuring about 15 cm in diameter, and the dispersion was allowed to stand horizontally so that the clay particles would gradually settle. With the tray held horizontal, the dispersion was dried for 5 hours at a temperature of 50° C. in a forced air oven, which gave a uniform polyhydric phenol composite clay thin film (phloroglucin Kunipia P thin film) with a thickness of approximately 30 μm. The clay thin film thus produced was dried in an oven held at 110° C. This gave a clay thin film that could be easily peeled from the tray.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][C:24]([OH:26])=[O:25])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:34][C:35]([NH2:37])=[NH:36])=[N:11][CH:10]=1.[H-].[Na+].[C:40](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=CC=CC=1)([CH3:43])([CH3:42])[CH3:41].O>COCCOC>[C:40]([O:25][C:24](=[O:26])[CH2:23][N:22]([S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:34][C:35]([NH2:37])=[NH:36])=[CH:17][CH:16]=1)(=[O:20])=[O:21])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 72.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-benzylglycine trifluoroacetate ##STR19## Guanidine hydrochloride (180 mg, 1.88 mmol) was added in one portion to a suspension of NaH (45 mg, 80% dispersion by wt in mineral oil, 1.5 mmol) in DME (11 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-benzylglycine t-butyl ester (225 mg, 0.467 mmol) was added and the mixture heated at 90° C. for 18 h. The cooled mixture was poured into water, extracted with EtOAc (×3) and the combined organic phase was then washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-benzylglycine t-butyl ester (172 mg, 0.34 mmol) as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:20](Cl)(Cl)=[O:21]>ClC1C=CC=CC=1>[N:1]([C:2]1[CH:3]=[C:4]([C:8]2[O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[C:20]=[O:21]
Reactant: Nc1cccc(-c2nc3ccccc3c(=O)o2)c1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C=Nc1cccc(-c2nc3ccccc3c(=O)o2)c1

Procedure:
40 Parts by weight of 2-(m-aminophenyl)-3,1-benzoxazin-4-one are suspended in 300 parts by volume of chlorobenzene and the suspension is treated with hydrogen chloride gas until saturated therewith, and then with phosgene gas for 4 hours at 110° C. The clear solution is concentrated under reduced pressure and the residue is then washed with ether and petroleum ether, giving 39 parts by weight of 2-(m-isocyanatophenyl)-3,1-benzoxazin-4-one of melting point 115°-121° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[S:43][CH:42]=[N:41][CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[S:43][CH:42]=[N:41][CH:40]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2cncs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cncs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](/[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)\[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCC(=O)c1ccccn1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccn1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (500 mg), ethyl 4-oxo-4-(2-pyridyl)butyrate (367 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 20 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(2-pyridyl)butyrate (600 mg, yield 75%) as a colorless oil from an ethyl acetate-hexane (2:7, v/v)-eluted fraction.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][N:13]=1>C(O)=O>[CH:1]([NH:8][C:9]1[S:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][N:13]=1)=[O:3]
Reactant: Nc1ncc(CC(=O)O)s1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1ncc(CC(=O)O)s1
Yield: 86 %

Procedure:
Formic acid (8.4 g) was added to acetic anhydride (18.7 g) under ice-cooling with stirring, and the stirring was continued at 45° to 50° C. for an hour. To the resultant solution was added 2-(2-aminothiazol-5-yl)acetic acid (5.8 g) at ambient temperature, and the mixture was stirred for 35 minutes. After the reaction mixture was evaporated to dryness, the residual product was treated with diisopropyl ether and then collected by filtration to give 2-(2-formamidothiazol-5-yl)acetic acid (5.87 g), mp 229° C. (dec.).