Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([CH:5]1[CH2:11][CH2:10][N:9](C(OC(C)C)=O)[C:8]2[CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[C:20]([CH2:22][CH3:23])=[CH:21][C:7]=2[C:6]1=[O:28])=O.[Cl-].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[CH2:22]([C:20]1[C:19]([C:24]([F:27])([F:25])[F:26])=[CH:18][C:8]2[NH:9][CH2:10][CH2:11][CH2:5][C:6](=[O:28])[C:7]=2[CH:21]=1)[CH3:23]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCC(C(=O)OC)C2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc2c(cc1C(F)(F)F)NCCCC2=O
Temperature: 25 °C
Yield: 60.8 %

Procedure:
Heat a mixture of 7-ethyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1,4-dicarboxylic acid 1-isopropyl ester 4-methyl ester (23.55 g, 58.61 mmol), sodium chloride (52.50 g), and water (10.0 mL) in dimethylsulfoxide (500 mL) at reflux for 46 h. Allow the mixture to cool to room temperature and dilute it with water (200 mL) and ethyl acetate (200 mL). Wash the organic layer with water (350 mL). Dry the organic layer over anhydrous sodium sulfate and filter. Remove the solvents under reduced pressure and purify the resulting residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as a yellow solid (9.17 g, 61%) TLC Rf 0.32 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.10-1.23 (m, 3H), 2.13-2.21 (m, 2H), 2.63-2.71 (m, 2H), 2.83-2.92 (m, 2H), 3.22-3.31 (m, 2H), 4.74 (bs, 1H), 7.03 (s, 1H), 7.68 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:7]1[N:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C)c[n+]([O-])c1C(=O)OCC
Product: CCOC(=O)c1cc(C)c(Cl)nc1C(=O)OCC
Temperature: 25 °C

Procedure:
199.9 g (0.79 mol) of diethyl 5-methylpyridine-2,3-dicarboxylate N-oxide were introduced a little at a time, in the course of 1 hour at from 60° to 70° C., into 1 l of phosphoryl chloride, and the mixture was refluxed for 5 hours. After cooling to 25° C., the reaction mixture was evaporated down under reduced pressure and the residue was taken up on methylene chloride. After filtering through a suction funnel containing silica gel and evaporating down, 148.2 g (69% of theory) of the title compound were obtained as a pale syrup, which subsequently solidified. Mp 84°-86° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[CH:11]=[C:10]([CH3:20])[N:9]=2)[CH2:3]1.[C:21](=O)([O:32][C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[O:22]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C@@H:33]([O:32][C:21](=[O:22])[NH:1][C@@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]2[N:9]=[C:10]([CH3:20])[CH:11]=[C:12]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:13]=2)[CH2:3]1)[CH3:38]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H](C)[C@H](N)C2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H](C)[C@@H](NC(=O)O[C@@H](C)C(F)(F)F)C2)n1
Temperature: 60 °C

Procedure:
To a mixture of 2-[(3S,4R)-3-amino-4-methylpyrrolidin-1-yl]-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (20 mg) in CHCl3 (10 ml) was added 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (41 mg) prepared in Step 1 of Example 1 and DIEA (19 mg) at room temperature. After 4-hour stirring at 60° C., the resulting mixture was cooled to room temperature and concentrated. The residue was diluted with MeOH (5 mL). To the resulting mixture was added potassium carbonate (100 mg) at 0° C. and stirred at 0° C. for 30 min. The mixture was poured into saturated aqueous solution of NH4Cl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜80/20) to give (2S)-1,1,1-trifluoropropan-2-yl{(3R,4R)-4-methyl-1-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]pyrrolidin-3-yl}carbamate as a pale yellow foam.
Reaction SMILES: C(O)(=O)C.[N:5]1([C:11]2[C:12](=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:18]=[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[C:11]1[N:5]1[CH2:6][CH2:7][N:8]([CH2:20][C:21]#[N:22])[CH2:9][CH2:10]1
Reactant: O=c1cccccc1N1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: N#CCN1CCN(c2cccccc2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.7 %

Procedure:
A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one acetate (10.0 g, described in Example 2), chloroacetonitrile (13.2 g) and potassium carbonate (14.5 g) in acetonitrile (110 ml) was stirred at room temperature for 16 hr, and filtered. The filtrate was evaporated. The residue was chromatographed on silica gel (300 g) using ethyl acetate-acetone (4:1) give 1.9 g of the title compound, which was then crystallized from acetone-diethyl ether: mp 133°-135° C.; ir(CHCl3) 2230 and 1565 cm-1 ; uv max(MeOH) 350 (ε=9810), 254 (ε=14575) and 222 nm(ε=11960); nmr(CDCl3) δ2.75 (t, 4H), 3.4 (t, 4H), 3.55 (s, 2H) and 7.0 (m, 5H); and Anal. Calcd for C13H15N3O: C, 68.4% H, 6.56% N, 18.38% and Found: C, 68.15% H, 6.68% N, 18.25%.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]([SH:10])[CH2:13][C@H:8]1[C:9]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: CN1CCNCC1
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 33 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (30.6 mg) in tetrahydrofuran (1 ml) was added 4-methylpiperazine (15.8 mg). The mixture was stirred for 33 hours at room temperature. After the reaction was over, the mixture was diluted with ethyl acetate (2 ml). Distillation of the solvent gave oily 1-[(2S,4S)-1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarbonyl]-4-methylpiperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]1[N:31]([CH2:32][CH2:33][NH2:34])[CH2:30][CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:34][CH2:33][CH2:32][N:31]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(4-morpholino)ethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.79 (1H, s), 10.76 (1H, br s), 10.12 (1H, br), 8.18 (1H, m), 7.35-7.24 (3H, m), 7.12 (2H, br m), 3.98 (2H, br s), 3.56 (4H, m), 3.40 (2H, m), 2.39 (6H, m); ES+ MS: 427 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].B>C1COCC1>[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(Br)cc1N
Agent: B
Solvent: C1CCOC1
Product: NCc1ccc(Br)cc1N
Temperature: 0 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
To a solution of compound (11) (2 g, 10.0 mmol) in dry THF at 0° C. under an argon atmosphere was slowly added borane (15 mL, 1.0 M in THF). The reaction mixture was stirred for 10 min at 0° C. and further 72 h at room temperature. The reaction mixture was cooled to 0° C. and quenched by addition of ethanol (96%). The resulting suspension was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate. Ethyl acetate was completely removed under reduced pressure and the residues were chromatographed over silica column, eluting with ethyl acetate:hexanes (1:1) and changing to (100%) afforded 1.73 g (85%) of compound (12) as a dark brown thick gum. IR (KBr) νmax. cm−1: 3438, 3318 (NH2), 3052 (Ar—H), 2911 (Alph-H), 1604, 1512, 1416 (C═C). 1H NMR (500 MHz, CDCl3) δ=4.19 (s, 2H, NH2); 4.42 (s, 2H, CH2); 6.52 (d, 1H, J=8.2 Hz, H-3); 7.16 (dd, 1H, J=2.2, 8.2 Hz, H-4); 7.18 (d, 1H, J=2.2 Hz, H-6); 13C NMR (125.7 MHz, CDCl3) δ=63.78 (CH2), 109.56 (C-2), 117.51 (C-6), 126.57 (C-5), 131.58 (C-3/C-4), 131.86 (C-3/C-4), 145.06 (C-1). Calculated (%) for C7H9BrN2 (199.99); C: 41.82, H: 4.51, N: 13.93. found (%); C: 41.74, H: 4.58, N: 13.84.
Reaction SMILES: [Cl:1][C:2]1[CH:50]=[CH:49][CH:48]=[CH:47][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]([CH:30]=[N:31][NH:32]C(=O)CN1C(=O)C2C(=CC=CC=2)C1=O)[C:16](=O)[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28])=[O:5].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:50]=[CH:49][CH:48]=[CH:47][C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]1[CH:30]=[N:31][N:32]=[C:16]1[CH2:17][N:18]1[C:26](=[O:27])[C:25]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:20]2[C:19]1=[O:28]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 7, 1,3-dioxo-2-isoindolineacetic acid, [[N-[2 -(o-chlorobenzoyl)-4-nitrophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide is heated to 100°-110°C with trifluoracetic acid to give 2'-chloro-5-nitro-2-[3-(phthalimidomethyl)-4 H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]3[C:13]4[N:20]([CH2:21][CH3:22])[C:19]([C:23]5[C:24]([NH2:28])=[N:25][O:26][N:27]=5)=[N:18][C:14]=4[CH:15]=[N:16][CH:17]=3)[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[Na+]>O1CCOCC1.Cl>[NH2:28][C:24]1[C:23]([C:19]2[N:20]([CH2:21][CH3:22])[C:13]3[C:12]([CH2:11][N:8]4[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]4)=[CH:17][N:16]=[CH:15][C:14]=3[N:18]=2)=[N:27][O:26][N:25]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(CN3CCC4(CC3)OCCO4)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1c(-c2nonc2N)nc2cncc(CN3CCC(=O)CC3)c21
Temperature: 25 °C

Procedure:
The product from Step 1 (0.245 g, 0.64 mmole) in 1,4-dioxane (20 ml) and aqueous hydrochloric acid (5M, 10 ml) was heated under reflux for 18 hours. The mixture was allowed to cool to ambient temperature, neutralised by addition of aqueous sodium hydroxide solution (5M) and extracted into dichloromethane.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5](=[O:12])[CH2:6][C:7](OCC)=O)[CH3:2].[CH3:16][C:17]([CH3:21])=[CH:18]CCl.[O-]CC.[Na+].[OH-].[Na+]>>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:12])[CH2:6][CH2:7][CH:16]=[C:17]([CH3:21])[CH3:18])[CH3:15]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: CC(C)=CCCl
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCOC(OCC)C(=O)CCC=C(C)C
Yield: 57.2 %

Procedure:
Following the procedure stated in Referential example 1, reaction of 7.3 g of ethyl 4,4-diethoxyacetoacetate with 4.0 g of 3-methyl-2-butenyl chloride was carried out in the presence of sodium ethoxide and the resultant was decarboxylated with the alcoholic sodium hydroxide to yield 4.1 g of the desired product, b.p. 102°-103° C./ 1 mmHg.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[N:23]=[CH:24][NH:25][C:21]=2[CH:20]=1>>[NH:23]1[C:22]2[CH:26]=[CH:27][C:19]([NH:18][C:12]([C:8]3[CH:7]=[C:6]([N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:15][CH2:16][CH3:17])[N:11]=[CH:10][N:9]=3)=[O:14])=[CH:20][C:21]=2[N:25]=[CH:24]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]cnc3c2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclopropylmethyl-propyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 21) and 5-aminobenzimidazole (ABCR), the title compound was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:12][C:9]2=[CH:10][N:11]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:32][CH2:33][O:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=4)[O:46][C:47]=3[CH3:48])[CH2:36]2)(=O)=O)=CC=1>CN(C=O)C.[Na+].[Cl-].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([CH2:32][CH2:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH:37]([O:41][CH2:42][C:43]4[N:44]=[C:45]([C:49]5[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=5)[O:46][C:47]=4[CH3:48])[CH2:36]3)[C:9]2=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCCOC)ncc2n1CCOC1CCCC(OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
66 mg of ethyl 5-(2-methoxyethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate are dissolved in 2 ml of dry DMF, and 12 mg of 60 percent strength sodium hydride suspension are added. After 30 min at room temperature, 100 mg of ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate in 2 ml of DMF are added. The mixture is stirred at 40° C. until the reaction has gone to completion (monitored by LC-MS). After cooling, the mixture is diluted with sat. NaCl solution and ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=1:2). This gives ethyl 5-(2-methoxyethoxy)-1-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxylate as a yellowish solid. C33H41N3O7 (591.71), MS (ESI): 592 (M+H+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:20])(=[O:19])[NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:8][C:7]=1[F:21])=O.[OH-].[Na+].Cl>O>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:20])=[O:19])=[CH:8][C:7]=1[F:21]
Reactant: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.5 %

Procedure:
Synthesized according to general procedure 71. A solution of 2,2,2-trifluoro-N-(2-fluoro-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (2.0 g, 5.42 mmol), NaOH (2.17 g, 54.2 mmol), and H2O (9.7 mL) was stirred at RT for 1 h, then cooled to 0° C. 1 N hydrochloric acid (54.2 mL, 54.2 mmol) was added, and the reaction was stirred at 0° C. for 20 min. The formed precipitate was filtered off and dried under vacuum to give 4-amino-3-fluoro-N-(thiazol-2-yl)benzenesulfonamide (1.03 g, 70%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=274.1; tR=0.51 min
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:25])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]([CH3:24])[CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:25])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:34](=[O:35])[CH2:33][Cl:32])[CH:19]([CH3:24])[CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: CC1Cc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1Cc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc2N1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
4-Phenyl-1-(2-methylindoline-5-sulfonyl)-2-imidazolone (300 mg, 0.85 mmol) prepared in Preparation 3 was dissolved in 10 m of dichloromethane. Pyridine (75 μ, 0.93 mmol) and chloroacetylchloride (74 μ, 0.93 mmol) were added thereto one after another, and then the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After stirring, the reaction mixture was diluted with 50 m of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1, v/v) to afford 342 mg of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28]>>[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[N:28]1[CH2:20][CH2:19][N:4]([C:5]2[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cn1ccnc1N
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3nccn3C)CC2)c(C)c2c1OC(C)(C)C2
Yield: 51.9 %

Procedure:
By using N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (330 mg, 1.0 mmol) synthesized in Reference Example 146 and 1-methyl-1H-imidazole-2-amine (146 mg, 1.5 mmol), the reaction was carried out in the same manner as Example 117 to obtain 184 mg of the title compound as an oily product (yield 52%).
Reaction SMILES: C(C1C=[C:5](C=CC=1OC)[C:6](OC)=[O:7])#N.[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26]>>[C:6]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:26])([F:27])[F:28])(=[O:7])[CH3:5]
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Product: CC(=O)Oc1ccc(C(=O)O)cc1C(F)(F)F

Procedure:
A reaction and treatment was carried out in the same manner as in Reference Example 62 except that the methyl 3-cyano-4-methoxybenzoate used in Reference Example 62 was replaced with methyl 4-methoxy-3-trifluoromethyl benzoate, thereby giving 4-hydroxy-3-trifluoromethylbenzoic acid. Using this compound, a reaction and treatment was carried out in the same manner as in Reference Example 80, thereby giving the desired compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:28])[NH:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[C:19]([Cl:26])[C:18]=1[F:27])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:26][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([CH2:16][NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([F:13])[CH2:12][NH:8]2)=[O:28])[C:18]=1[F:27])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (2S,4R)-2-(5-carboxy-3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (146 mg, 0.3 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL). The reaction mixture was stirred for 1 h at ambient temperature and the solvent was removed in vacuo to give the title compound which was used without further purification. tR (HPLC conditions c): 3.11 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCC(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
Under an inert atmosphere, 4-methoxy-2-nitrophenol (1.5 g; 8.86 mmol) is dissolved in 30 ml of acetone, and then 2-bromoacetophenone (1.5 eq.; 13.29 mmol; 2.79 g) and also potassium carbonate (1.2 eq.; 10.64 mmol; 1.47 g) are added. The mixture is stirred vigorously, at reflux, for 3 hours. After returning to ambient temperature, the potassium carbonate is filtered off, the filtrate is evaporated and the residue is taken up in a water/ethyl acetate mixture. The organic phase is dried over MgSO4 and then concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (8/2)). The title product is obtained in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[Br:42]Br>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([Br:42])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: BrBr
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(Br)sc3c12)c1ccccc1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with bromine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[O:12][C:13]3[C:18]([C:19](=O)[C:20]=2[CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1.Cl.[NH2:24][OH:25].Cl>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[O:12][C:13]3[C:18]([C:19](=[N:24][OH:25])[C:20]=2[CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1
Reactant: Cc1c(-c2cc3ccccc3cn2)oc2ccccc2c1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(-c2cc3ccccc3cn2)oc2ccccc2c1=NO
Temperature: 130 °C

Procedure:
To a suspension of 2-Isoquinolin-3-yl-3-methyl-chromen-4-one (example 71A) (200 mg, 0.69 mmol) in anhydrous pyridine (5 ml) was added hydroxylamine hydrochloride (96 mg, 1.39 mmol). The mixture was heated to 130° C. under microwave irradiation for 30 min. The reaction mixture was poured into a 1N aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with a 1N aqueous solution of hydrochloric acid, brine and dried over sodium sulfate and concentrated. The title compound was isolated as a white solid after Preparative HPLC purification (gradient 45-30% Water/Methanol+0.05% trifluoroacetic acid) (9 mg, 4%).