Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([NH:4][C:5]1[S:6][C:7]([Br:37])=[C:8]([C:10](=[N:34][O:35][CH3:36])[C:11]([NH:13][CH:14]2[C:32](=[O:33])[N:16]3[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]4[S:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[ClH:1].[NH2:4][C:5]1[S:6][C:7]([Br:37])=[C:8]([C:10](=[N:34][O:35][CH3:36])[C:11]([NH:13][CH:14]2[C:32](=[O:33])[N:16]3[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]4[S:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1nc(N)sc1Br
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Conc. hydrochloric acid (1.5 ml.) was added to a solution of 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.) in methanol (30 ml.) and stirred at room temperature for 7 hrs. The reaction mixture was evaporated in vacuo. To the residue was added ethyl acetate and water was removed by evaporation. The residue was pulverized with ethyl acetate and the precipitates were collected by filtration, washed with ethyl acetate and diethyl ether successively and then dried to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 1.0 g.).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:71])[C:67]([F:70])([F:69])[F:68])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18])=O)(C)(C)C>ClCCl>[NH2:15][C@H:16]([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:71])[C:67]([F:68])([F:70])[F:69])[C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:59])([OH:60])=[O:58])([OH:40])=[O:39])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)C(F)(F)F)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)[C@H](N)CCCCNC(=O)C(F)(F)F)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 88.4 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.21 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroacetamido)hexanoate (Compound tk54) (5.3 mg, 5.52 μmol) in dichloromethane (0.1 mL), and the mixture was stirred at room temperature for 55 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-(2,2,2-trifluoroacetamido)hexanoate (Lys(Tfa)-pdCpA) (Compound tk55) (4.2 mg, 88%).
Reaction SMILES: C=O.[C:3](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:21][C:22]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][NH:51]2)=[CH:46][C:23]=1[C:24]([NH:26][C:27]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25]>C(Cl)Cl>[OH:21][C:22]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][N:51]2[CH3:3])=[CH:46][C:23]=1[C:24]([NH:26][C:27]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCCCN2)ccc1O
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCCCC1c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 37% aqueous solution of formaldehyde (8.2 μL), acetic acid (9.7 μL), and sodium triacetoxyborohydride (0.045 g) were sequentially added to a methylene chloride (1.5 mL) solution of the obtained tert-butyl 2-(2-hydroxy-5-(piperidin-2-yl)benzamido)-4-phenylbenzoate (0.040 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and chloroform was added thereto. The insoluble substance was removed by filtration, and then a saturated aqueous solution of sodium bicarbonate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.040 g of tert-butyl 2-(2-hydroxy-5-(1-methylpiperidin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1.Cl[C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16]>CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2ccn(C)c2c1
Reactant: COC(=O)C(=O)Cl
Solvent: CCOCC
Product: COC(=O)C(=O)c1cn(C)c2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
6-Methoxy-1-methyl-1H-indole (1.0 g, 6.19 mmol) was dissolved in ether (10 mL) and cooled to 0° C. Methyl chlorooxoacetate (1.17 mL, 12.4 mmol) was added dropwise. Stirring was continued at 0° C. for 6 h. The mixture was filtered and washed well with ether to give methyl (6-methoxy-1-methyl-1H-indol-3-yl)glyoxylate (621 mg, 41%).
Reaction SMILES: Cl[CH:2]([C:7]1[S:11][C:10]([C:12]2[S:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)=[N:14][CH:13]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C)C=O>[N:28]([CH:2]([C:7]1[S:11][C:10]([C:12]2[S:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)=[N:14][CH:13]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(Cl)C(F)(F)F)s3)s2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(N=[N+]=[N-])C(F)(F)F)s3)s2)cc1
Yield: 71.6 %

Procedure:
A mixture of Example 5C (0.6 g, 0.0013 mol) and sodium azide (1.0 g, 0.013 mol) in N,N-dimethylformamide was heated at 80° C. under nitrogen for 4 hours. Water was added and the solution was extracted with ether. The organic layer was then washed with brine, dried and filtered. The filtrate was concentrated to give 0.5 g of crude as a yellow oil, which was purified on silica gel (10˜30% ethyl acetate in hexane) to give 0.41 g of pure product as a light yellow oil (72% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6H) 4.44-4.61 (m, 1H) 5.10 (q, J=6.62 Hz, 1H) 6.87-6.96 (m, 2H) 6.97 (d, J=3.68 Hz, 1H) 7.08-7.14 (m, 1H) 7.16-7.24 (m, 2H) 7.32 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH2:25]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCCCCCCCNCCCCCCCC
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Solvent: CC(=O)CC(C)C
Product: CCCCCCCCN(CCCCCCCC)CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 1.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 8.3 ml of dioctylamine, and 50 ml of methyl isobutylketone, a reaction similar to that conducted in Example 142 was carried out. As a result, 0.9 g of N-(trans-4-methylcyclohexyl)-4-(2-dioctylaminoethoxy )-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10](I)[CH:9]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)CCC.[F-].[Cs+].CO>C(#N)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:25]3[CH:30]=[CH:29][N:28]=[N:27][CH:26]=3)[CH:9]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: CO
Product: Oc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1-c1ccnnc1
Temperature: 45 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
4′-Chloro-3-iodo-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 55, 167 mg, 0.42 mmol) was dissolved in acetonitrile (1 mL) and 4-(tributylstannyl)pyridazine (200 mg, 0.55 mmol), caesium fluoride (127 mg, 0.84 mmol), copper iodide (16 mg, 0.084 mmol) and tetrakis(triphenylphosphine)palladium (0) (46 mg, 0.04 mmol) were added. The reaction was stirred at 45° C. for 40 minutes and then partitioned between ethyl acetate (50 mL) and water (10 mL) containing 0.880 ammonia (1 mL). The mixture was stirred for 20 minutes. The ethyl acetate was separated, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica eluting with a gradient of dichloromethane:methanol: 0.880NH3 100:0:0 to 92:8:0.8 to give the title compound (95 mg, 0.27 mmol, 64%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH3:17])[CH:11]=[CH:12]2)=[N:7]1.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>C(O)(C)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([N:16]([CH3:17])[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:28][C:29]4[CH:30]=[C:31]([S:35]([NH2:38])(=[O:36])=[O:37])[CH:32]=[CH:33][CH:34]=4)[N:19]=3)[CH:11]=[CH:12]2)=[N:7]1
Reactant: Cc1c2ccc(N(C)c3ccnc(Cl)n3)cc2nn1Cc1cccc(Cl)c1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c2ccc(N(C)c3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)cc2nn1Cc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-chlorobenzyl)-N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amine (40 mg, 0.1 mmol) and 3-aminobenzenesulfonamide (17.3 mg, 0.1 mmol) in isopropanol (2 ml) was added 2 drops of conc. HCl. The mixture was heated to reflux overnight. The mixture was cooled to rt. Precipitate was collected via filtration and washed with EtOH. HCl salt of 3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]-pyrimidin-2-yl}amino)benzenesulfonamide was isolated as off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) δ 9.52 (br s, 1H), 8.54 (br s, 1H), 7.85 (d, J=5.9 Hz, 1H), 7.77-7.79 (m, 2H), 7.49 (s, 1H), 7.30-7.36 (m, 5H), 7.22 (br s, 2H), 7.14 (br s, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.80 (d, J=5.8 Hz, 1H), 5.64 (s, 2H), 3.48 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 534 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[C:5]#[C:6][C:7](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:8]([F:11])(F)F)[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]2[C:8]([F:11])=[C:7]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:6]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:21][CH2:22][CH3:23])[N:30]=2)=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(C#CC(=Nc1ccc(OC)cc1)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 80 °C

Procedure:
In a typical reaction, N-(5,5-diethoxy-1,1,1-trifluoro-pent-3-yn-2-ylidene)-4-methoxyaniline is mixed with about a 2.5 to 3 fold excess of p-chlorobenzylamine and about a 2.5 to 3 fold excess of cesium carbonate in anhydrous tetrahydrofuran. The mixture is heated at about 80° C. until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude 2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxyphenyl)pyridin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]2([OH:13])[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: OC1(c2cccc(Cl)c2F)CCNC1
Solvent: O=CO
Product: CN1CCC(O)(c2cccc(Cl)c2F)C1

Procedure:
Preparation according to Example 26: 3-(3-chloro-2-fluorophenyl)-pyrrolidin-3-ol (0.6 g, 2.78 mmol), formic acid (8.1 mL), aqueous formaldehyde (40%, 7.2 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 2:8 to 3:8) and by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 100:0). Yield: 0.3 g. The amine was converted to the fumaric acid salt and evaporated to a solid residue: MS m/z (relative intensity, 70 eV) 229 (M+, 10), 157 (8), 129 (5), 58 (28), 57 (bp).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)=[S:4].C(OCC)(=O)C.[CH3:20][N:21]=[C:22]=[O:23].C(N(CC)CC)C>CCCCCC>[CH3:1][N:2]([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:22](=[O:23])[NH:21][CH3:20])[CH:7]=1)=[S:4]
Reactant: CN(C)C(=S)Nc1cccc(O)c1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CNC(=O)Oc1cccc(NC(=S)N(C)C)c1
Temperature: 20 °C

Procedure:
1,1-dimethyl-3-(meta-methylcarbamoyloxyphenyl)-2 -thiourea is prepared by charging to a suitable equipped reaction vessel about 32.7 parts by weight of 1,1-dimethyl-3-(meta-hydroxyphenyl)-2-thiourea, about 100 parts by weight of ethyl acetate, about 12 parts by weight of methyl isocyanate and about 1 part by weight triethylamine, refluxing for about 1 hour with stirring, diluting the resulting slurry with about 100 parts by weight of hexane, cooling to about 20° C., recovering the precipitate from the remainder by filtration, washing the recovered solid with ethyl acetate and hexane and air drying.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24]([O:26]C)=O)[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[CH3:30][NH2:31].Cl>CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24]([NH:31][CH3:30])=[O:26])[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1ccnc(NCCCN2CCN(c3cccc(Cl)c3)CC2)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CNC(=O)c1ccnc(NCCCN2CCN(c3cccc(Cl)c3)CC2)n1
Temperature: 25 °C

Procedure:
4.5 g (11.5 mmols) of methyl 2-[[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]amino]pyrimidine-4-carboxylate and 200 ml of methanol are introduced into a 0.5 l, round bottomed flask and then the solution is saturated with gaseous methylamine. The reaction mixture is stirred at room temperature while saturating several times with gaseous methylamine. The solvent is evaporated under reduced pressure. 4.05 g (10.4 mmols) of base are obtained to which 104 ml of 0.1N hydrochloric acid in 2-propanol are added. The solvent is evaporated and the product is recrystallised from 2-butanone. 3.8 g of compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH2:56][NH:57][CH2:58][CH:59]=2)=[CH:51][CH:50]=1>CN(C=O)C>[F:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2[CH2:56][N:57]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:58][CH:59]=2)=[CH:53][CH:54]=1
Reactant: Fc1ccc(C2=CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CC=C(c3ccc(F)cc3)C2)cc1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 3-(4-fluorophenyl)-2,5-dihydro-1H-pyrrole hydrochloride (20 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z calcd for C21H17F N2O2: 348.1274, found 348.1266.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:13])[CH3:3].[S:14](N)(N)(=[O:16])=[O:15]>N1C=CC=CC=1>[F:12][C:11]1[C:6]2[CH2:5][N:4]([CH:2]([CH3:1])[CH3:3])[S:14](=[O:16])(=[O:15])[NH:13][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)NCc1c(N)cccc1F
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CC(C)N1Cc2c(F)cccc2NS1(=O)=O
Temperature: 115 °C
Reaction time: 24 h

Procedure:
N-(1-methylethyl)-(2-amino-6-fluorophenyl)methylamine (0.3 g, 1.6 mmol) and sulphamide (5.08 g, 2.5 mmol) were suspended in 7 ml of dry pyridine and the mixture stirred at 115° C. for 24 hours in argon atmosphere. After cooling at room temperature the solvent was removed in vacuo and the residue dissolved in EtOAc (50 ml) and washed with 5N HCl (2×50 ml). Solvents removal afforded 5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:5]([CH2:12][NH2:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH2:12][N:13]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:4]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cc1cc([N+](=O)[O-])cc(CN)c1N1CCOCC1
Reactant: BrCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cc(CN2CCCC2)c1N1CCOCC1
Temperature: 60 °C
Yield: 58.5 %

Procedure:
A mixture of [3-Methyl-2-(morpholin-4-yl)-5-nitrophenyl]methanamine hydrochloride (160 mg, 0.56 mmol), 1,4-dibromobutane (80 μL, 0.67 mmol) and K2CO3 (542 mg, 3.92 mmol) in 10 mL of acetonitrile was heated at 60° C. for 48 h. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a pale yellow oil (100 mg, 58% yield); m/z (ESI) 306.3 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][NH2:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[SH:41][C:42]1[N:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](O)=[O:45]>C1COCC1.CC(=O)OCC>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][NH:9][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[N:50][C:42]=1[SH:41]
Reactant: NCC1CC2CCC1C2
Reactant: O=C(O)c1cccnc1S
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCC1CC2CCC1C2)c1cccnc1S
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.5 %

Procedure:
5.0 g (40.0 mmol) of bicyclo[2.2.1]heptan-2-ylmethanamine, 16.0 g (42.0 mmol) of HATU and 5.8 ml (42.0 mmol) of NEt3 were added in succession to a solution of 6.2 g (40.0 mmol) of 2-mercapto-nicotinic acid in THF (320 ml), and the mixture was stirred for 4 d at RT. Dilution with EA was then carried out. The organic phase was separated off, washed with a 1M aq. Na2CO3 sol. and a 4M aq. NH4Cl sol., dried over MgSO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3→1:1→3:7) was carried out with the residue. The resulting prepurified product was dissolved in 1N aq. NaOH (100 ml) and the solution was washed with ether. The aqueous phase was adjusted to pH ˜2 with 2M hydrochloric acid. The resulting precipitate was filtered off and then washed with pentane and dried in vacuo. 5.3 g (20.2 mmol, 50%) of N-(bicyclo[2.2.1]heptan-2-ylmethyl)-2-mercapto-nicotinamide were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: NCc1ccccc1Cl
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccccc4Cl)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, 2-chlorobenzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 13. Purity by LC/MS=95%, [M+H]+=411.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:10][C:9]2[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:20][C:21]#[N:22]>CN(C)C=O.O>[C:21]([CH2:20][N:8]1[C:9]2[CH2:10][C:2]([F:1])([F:16])[CH2:3][CH2:4][C:5]=2[CH:6]=[C:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:22]
Reactant: CCOC(=O)c1cc2c([nH]1)CC(F)(F)CC2
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC#N)CC(F)(F)CC2
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 113l (5.0 g, 21.81 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), followed by the addition of sodium hydride (1.3 g, 54.17 mmol, 1.40 equiv, 60%) in several batches at 0° C. over 10 min. (FIG. 14). To this was added 2-bromoacetonitrile (3.7 g, 30.85 mmol, 1.40 equiv) dropwise with stirring at 20° C. over 10 min. The resulting solution was stirred at room temperature for 7 h, diluted with 100 mL of water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 1×100 mL of water and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to afford 3.3 g (56%) of 113m as a light yellow oil.