Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][CH:28]=2)=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1nc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: OC[CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(SC1C=CC(C(F)(F)F)=CC=1C(O)=O)C=CC>>[CH3:3][S:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1SCCO
Agent: CC=CCSc1ccc(C(F)(F)F)cc1C(=O)O
Product: CSc1ccc(C(F)(F)F)cc1C(=O)O

Procedure:
In a similar manner are prepared: 2-(2-hydroxyethylthio)-5-trifluoromethylbenzoic acid, m.p. 153°-154° C.; 2-crotylthio-5-trifluoromethylbenzoic acid, m.p. 139°-141° C.; 2-methallythio-5-trifluoromethylbenzoic acid, m.p. 150°-152° C. and 2-allythio-5-trifluoromethylbenzoic acid, m.p. 178°-190° C.
Reaction SMILES: [CH3:1]I.[C:3]([C@@H:6]1[CH2:10][C@H:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)[CH2:8][NH:7]1)(=[O:5])[NH2:4].[C:21](=[O:24])(O)[O-].[Na+]>CN(C)C=O>[C:3]([C@@H:6]1[CH2:10][C@H:9]([S:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([O:24][CH3:21])[CH:18]=2)[CH2:8][N:7]1[CH3:1])(=[O:5])[NH2:4]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Reactant: CI
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.07 ml of methyl iodide was added, whilst ice-cooling, to a solution of 0.6 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (5) above] dissolved in 4.5 ml of dry dimethylformamide. The mixture was then stirred at 0° to 5° C. for 5 minutes and at room temperature for 20 minutes. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was subjected to column chromatography using a Lobar column (Merck, LiChroprep Si 60, size B), and 252 mg of the title compound, melting at 113°-114° C., were obtained as crystals from the fractions eluted with a 9:1 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[N:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[CH3:16])[CH:6]=[C:5]([CH3:17])[C:4](=[O:18])[C:3]=1[Cl:19].[NH2:20][C:21]1[C:26](=[N:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([CH3:35])[CH:29]=2)[CH:25]=[C:24]([CH3:36])[C:23](=[O:37])[C:22]=1[Cl:38].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.[OH-].[Na+]>[NH2:1][C:2]1[C:3]([Cl:19])=[C:4]([OH:18])[C:5]([CH3:17])=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[CH3:16].[NH2:20][C:21]1[C:22]([Cl:38])=[C:23]([OH:37])[C:24]([CH3:36])=[CH:25][C:26]=1[NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([CH3:35])[CH:29]=1
Reactant: CC1=CC(=Nc2ccc(N)c(C)c2)C(N)=C(Cl)C1=O
Reactant: CC1=CC(=Nc2ccc(N)cc2C)C(N)=C(Cl)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N)ccc1Nc1cc(C)c(O)c(Cl)c1N
Product: Cc1cc(Nc2cc(C)c(O)c(Cl)c2N)ccc1N

Procedure:
10 mg (0.04 mol) of 3-amino-4-[(4-amino-2-methylphenyl)imino]-2-chloro-6-methylcyclohexa-2,5-dien-1-one and 3-amino-4-[(4-amino-3-methylphenyl)imino]-2-chloro-6-methylcyclohexa-2,5-dien-1-one are added to a solution comprising 16 mg of sodium hydrosulphite in 500 μl of methanol and 5 μl of an aqueous sodium hydroxide solution. The reaction medium is stirred and then the solution is treated according to the usual procedure and characterized. 3-Amino-4-[(4-amino-2-methylphenyl)amino]-2-chloro-6-methylphenol/3-amino-4-[(4-amino-3-methylphenyl)amino]-2-chloro-6-methylphenol (2c) are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:21]([O:25][C:26]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[NH2:35])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([NH:35][C@H:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]2[NH:28][C:26](=[O:27])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.2 %

Procedure:
To a solution of 4.80 g of 2,4-dichloro-6-methylquinazoline in 100 ml of methylene chloride, 9.12 g of triethylamine and 5.31 g of (1S,2R)-2-(t-butoxycarbonylamino)cyclohexylamine were added, and then the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated, mixed with water, extracted with methylene chloride and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 8.30 g of the desirable compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[F:12])#[N:2].[CH3:13][C:14]1[C:19]2[NH:20][C:21](=[O:23])[O:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[F:12][C:4]1[CH:5]=[C:6]([C:7]([C:16]2[CH:15]=[C:14]([CH3:13])[C:19]3[NH:20][C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)=[O:8])[CH:10]=[CH:11][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1F
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2ccc(C#N)c(F)c2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
0.73 g (4.0 mmol) 4-cyano-3-fluoro-benzoic acid chloride, 0.60 g (4.0 mmol) 4-methyl-3H-benzoxazol-2-one and 2.1 g (16 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. After cooling to RT the mixture was combined with ice water. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([NH:28][C:18]([CH:16]1[CH2:15][C:14](=[O:13])[CH2:17]1)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CC(C(=O)NCc2ccccc2)C1
Yield: 89.9 %

Procedure:
CDI (10.2 g, 0.063 mol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (6 g, 0.052 mol) in THF (60 ml) at 0° C. under stirring, the mixture was stirred at RT for 1 h. Benzylamine (6.9 ml, 0.063 mol) was added to the mixture and the mixture was stirred at RT for 3 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 300 g, CHCl3/MeOH 100:0→95:5) to give the title compound (9.5 g, 89%) as white crystals. LC/MS data: 204.0, 205.1 (M+H) (calculated for C12H13NO2 203.24). 1H NMR data (DMSO-d6): 8.62 (br.s, 1H, NH); 7.21-7.36 (m, 5H, Ph); 4.32 (d, 2H, CH2, J=6.1 Hz); 3.10-3.28 (m, 5H).
Reaction SMILES: ClC1C=CC([C:8](NC2C=CC3CCCC(CCl)=C(C)C=3C=2)=[O:9])=NC=1.NC(N)=S.Cl.[C:30]([S:33][CH2:34][C:35]1[CH2:36][CH2:37][CH2:38][C:39]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:56])[C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=3)=[CH:43][C:40]=2[C:41]=1[CH3:42])(=[NH:32])[NH2:31].[F:57][C:58]([F:64])([F:63])S(O)(=O)=O>C(O)C.C(O)(C(F)(F)F)=O>[F:57][C:58]([F:64])([F:63])[C:8]([OH:9])=[O:56].[NH2:32][C:30]1[S:33][CH2:34][C@H:35]2[CH2:36][CH2:37][CH2:38][C:39]3[CH:46]=[CH:45][C:44]([NH:47][C:48]([C:49]4[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=4)=[O:56])=[CH:43][C:40]=3[C@@:41]2([CH3:42])[N:31]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC1=C(CSC(=N)N)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Reactant: CC1=C(CCl)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Agent: Cl
Agent: NC(N)=S
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: C[C@]12N=C(N)SC[C@H]1CCCc1ccc(NC(=O)c3ccc(Cl)cn3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a solution of (E)-5-chloro-N-(8-(chloromethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide from step 3C (30 mg, 0.083 mmol) in ethanol (0.5 mL) was added thiourea (6.32 mg, 0.083 mmol). The mixture was heated to reflux for 3 h. The solvent was removed to give crude (2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (36.3 mg, 0.083 mmol, 100% yield), which was used directly for the next step without purification. To a solution of the crude (2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (36 mg, 0.082 mmol) in TFA (2 mL) was added trifluoromethanesulfonic acid (0.5 mL). The reaction mixture was stirred at rt for 16 h. The mixture was then concentrated and dried by azetropic distillation with toluene. The residue was then dissolved in 1.5 mL of MeOH, and a precipitate was removed by filtration. The mother liquor was purified via HPLC under standard conditions to give 5-chloro-pyridine-2-carboxylic acid (rel-(4aS,11bS)-2-amino-11b-methyl-4,4a,5,6,7,11b-hexahydro-3-thia-1-aza-dibenzo[a,c]cyclohepten-10-yl)-amide, 2,2,2-trifluoroacetate salt (16 mg, 0.030 mmol, 36% yield). LCMS (M+H)+=401.2. 1H NMR (500 MHz, methanol-d4) δ 8.72 (br. s., 1H), 8.21 (br. s., 1H), 8.08 (dd, J=8.4, 2.0 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.58 (dd, J=8.1, 2.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 3.22-3.10 (m, 1H), 2.99-2.80 (m, 3H), 2.57-2.40 (m, 2H), 2.10 (dd, J=14.7, 3.7 Hz, 1H), 1.90 (dd, J=14.5, 3.5 Hz, 1H), 1.87 (s, 3H), 1.64-1.52 (m, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][SH:30]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:30][CH2:29][C:28]([F:32])([F:31])[F:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Reactant: FC(F)(F)CS
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSCC(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 2,2,2-trifluoroethanethiol.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:29])[C:13]([C:26]([OH:28])=[O:27])=[CH:14][N:15]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:10][C:9]=1[F:30].C[C:32](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:33].C(O)=O>CN(C=O)C>[CH:32]([N:5]1[CH2:6][CH:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:29])[C:13]([C:26]([OH:28])=[O:27])=[CH:14][N:15]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:10][C:9]=1[F:30])=[O:33]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3CC4CC3CN4)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=CN1CC2CC1CN2c1cc2c(cc1F)c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
0.5 g (1.2 m Mol) 7-(2,5-diazabicyclo(2.2.1)hept-2-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was suspended in 20 ml DMF and treated with 3 ml of the mixed anhydride of acetic and formic acid. After 90 mins. stirring at room temperature the volatiles were removed under reduced pressure. The oily residue was triturated with ether, the residue filtered and recrystallized from a mixture of 20 ml DMF and 5 ml ligroin to give 0.24 g (45.3%) of product, mp 252° C.-258° C. dec.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1)=[O:5])C.[OH-].[Na+]>C1COCC1>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]2)(=[O:20])=[O:21])=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cn(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cc(C(=O)O)nn2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 4 mL scintillation vial was charged with 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (synthesized according to general procedure G, 10 mg, 0.02 mmol) and 3 M NaOH (aq)/THF (1:3) (1 mL). The reaction was heated to 60° C. and stirred overnight. The following day, the volatiles were removed in vacuo and the residue was purified by preparative TLC to afford 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid: MS (ES) M+H expected 435.1, found 435.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].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.[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([CH2:72][CH2:73][NH2:74])=[CH:68][CH:67]=1>CN(C=O)C.O>[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([CH2:72][CH2:73][NH:74][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:22]=[CH:23][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:31])=[CH:9][C:10]=3[CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[O:18])=[CH:68][CH:67]=1
Reactant: CN(Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)O)cc1)S(C)(=O)=O
Reactant: NCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1)S(C)(=O)=O
Yield: 17.6 %

Procedure:
To a stirred solution of 4-(4(2-tert-butoxy-2-oxoethyl)-2-((N-methylmethylsulfonamido)methyl)phenoxy)benzoic acid (50 mg, 0.111 mmol) and HATU (46.5 mg, 0.122 mmol) in DMF (1 ml) was added DIEA (23.2 μL, 0.133 mmol) followed by 2-(4-chlorophenyl)ethanamine (11.2 μL, 0.111 mmol). The reaction was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-((N-methylmethylsulfonamido)methyl)phenyl)acetate (0.0115 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1C=CC(S([CH2:31][N+:32]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.COCCOC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[C:31]#[N:32])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: N#CC(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone (2.43 g, 8.5 mmol), prepared as described in Procedure 2, in DME (60 mL), was added TosMIC (2.23 g, 11.4 mmol). The reaction mixture was cooled in an ice bath. A solution of potassium tert butoxide (1.0 M potassium tert butoxide in tert butanol, 22.8 mmol) in tert butanol/DME (22 mL t-BuOH, 20 mL DME) was added via a funnel at a slow stream. Upon completion of addition, the ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water (approx 50 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL) and the combined organic portions were washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (120 g) with elution at 40 mL/min gradient 0 to 15% EtOAc in hexane over 30 min (RT=23-29 min). 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrile (1.8 g, 72% yield) was isolated as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([Cl:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CC#N>[C:33]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([Cl:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(N)cc21
Solvent: CC#N
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(C)=O)cc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea (0.100 g, 0.221 mmol) was suspended in acetic anhydride (5 mL, 53.0 mmol) and stirred with gradual heating to 110° C. After 5 h, the mixture was cooled to RT and diluted with MeCN (15 mL). The solids were collected by filtration, rinsed with MeCN and dried to afford 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea (107 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.13 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.57 (d, J=4.0 Hz, 1H) 7.42-7.40 (m, 2H), 7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.14 (s, 3H), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 494.1 [M+H]+.
Reaction SMILES: C([C:3](CC)(Cl)[C:4]([N:6]([CH:18]([C:22]([O-:24])=[O:23])[C:19]([O-:21])=[O:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17])=[O:5])C.[CH2:28](N(CC)CC)[CH3:29].[CH:35]1C=CC=C[CH:36]=1>>[CH2:28]([O:21][C:19]([C:18]1([C:22]([O:24][CH2:35][CH3:36])=[O:23])[CH2:3][C:4](=[O:5])[N:6]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17])=[O:20])[CH3:29]
Reactant: c1ccccc1
Reactant: CCN(CC)CC
Reactant: CCC(Cl)(CC)C(=O)N(Cc1ccc(OC)cc1OC)C(C(=O)[O-])C(=O)[O-]
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 35 g (0.087 mole) of diethyl-[N-(2,4-dimethoxy-benzyl)-N-(chloro-acetyl)-amino-malonate], 15.9 ml (11.4 g, 0.113 mole) of triethylamine and 200 ml of anhydrous benzene is heated to boiling for 8 hours. The mixture is extracted successively with 100 ml of water, 100 ml of diluted hydrochloric acid and 100 ml of water, the benzene phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. Thus 28,4 g of diethyl-[1-(2,4-dimethoxy-benzyl)-4-oxo-2,2-azetidine-dicarboxylate] are obtained, yield: 89%. B.p.: 175°-180° C./0.1 Hgmm.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[O:10]=[C:11]([CH2:15][CH2:16][C:17]([O-:19])=[O:18])[C:12]([O-:14])=[O:13]>>[C:4]([O-:6])(=[O:5])[CH2:3][C:2]([C:7]([O-:9])=[O:8])=[O:10].[NH2:1][C@H:11]([C:12]([O-:14])=[O:13])[CH2:15][CH2:16][C:17]([O-:19])=[O:18]
Reactant: O=C([O-])CCC(=O)C(=O)[O-]
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Product: O=C([O-])CC(=O)C(=O)[O-]

Procedure:
reaction of aspartate and α-ketoglutarate in the presence of a suitable transaminase 1 to give oxalacetate and glutamate and
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[I-].[Na+].[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1>CN(C)C=O>[F:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)=[O:34])=[CH:41][CH:42]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Reaction time: 7 h
Yield: 24.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (4.2 g), triethylamine (2.1 cc), sodium iodide (2.2 g) and 4-(4-fluorobenzoyl)piperidine (3.1 g) in dimethylformamide (50 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 7 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (15 cc), 2-{3-[4-(4-fluorobenzoyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.65 g) is obtained, m.p. 132° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:1].[CH2:15]([N:9]1[CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:12]=2[CH2:11][CH2:10]1)[CH:14]=[CH2:13]
Reactant: Clc1cccc2c1CCNCC2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCN1CCc2cccc(Cl)c2CC1
Product: Cl

Procedure:
A mixture of 0.52 g. of 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.34 g. of allyl bromide, 0.6 g. of potassium carbonate and 20 ml. of 90% ethanol was stirred at room temperature for 17 hours. The mixture was filtered and the filtrate concentrated in vacuo. The residue was extracted with 35 ml. of ether and the ethereal extract treated with isopropanolic hydrogen chloride to precipitate 3-allyl-6-chloro-2,3,4,5-tetra-hydro-1H-3-benzazepine hydrochloride. Recrystallization of this salt from absolute ethanol gave 3-allyl-6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride having a melting point of 248°-249°.