Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)=[O:17])C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][CH:18]2[C:16]([OH:17])=[O:15])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: CCCSc1ncccc1CCl
Product: CCCSc1ncccc1COc1ccc(C2CC2C(=O)O)cc1Cl
Yield: 69 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (47 mg, 0.23 mmol) obtained in Step C of Preparation Example 14 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (61 mg, 0.25 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (60 mg, 73%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[C@@H:9]([CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[N:17]([CH3:26])[C:15]1=[O:16])(=O)=O.O>CS(C)=O>[C:1]([C@H:9]([CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[N:17]([CH3:26])[C:15]1=[O:16])#[N:2]
Reactant: [C-]#N
Reactant: C[C@@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OS(C)(=O)=O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](C#N)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 50 °C
Yield: 45 %

Procedure:
Potassium cyanide (280 mg, 4.30 mmol) was added to a solution of (5)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (prepared as described for CT11558) (770 mg, 2.15 mmol) in dimethylsulfoxide (10 ml). After heating at 50° C. for 24 hours, the mixture was poured into water (50 ml) and extracted with ethyl acetate (3x 50 ml). The combined extracts were washed with water (40 ml), saturated aqueous sodium chloride solution (40 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-cyanohexyl)-3,7-dimethylxanthine (CT16575) (280 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([NH:28][S:29]([C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)(=[O:31])=[O:30])=[O:27])[CH2:22][CH2:21]1.Cl>CS(C)=O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:20]1[CH2:25][CH2:24][CH:23]([C:26]([NH:28][S:29]([C:32]2[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=2)(=[O:30])=[O:31])=[O:27])[CH2:22][CH2:21]1)([O-:19])=[O:18]
Reactant: O=C(NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCN(c2ccccc2[N+](=O)[O-])CC1
Reaction time: 18 h

Procedure:
0.13 g of DIEA and 0.07 g of 1-fluoro-2-nitrobenzene are added to a solution of 0.22 g N-(piperidine-4-carbonyl)-3,5-bis-trifluoromethyl-benzenesulfonamide in the form of a hydrochloride in 4 ml of DMSO. The mixture obtained is stirred for ca. 18 h at 80°, solvent is evaporated and the evaporation residue is subjected to flash chromatography on silica gel (eluent: EtAc). N-[1-(2-Nitro-phenyl)-piperidine-4-carbonyl]-3,5-bis-trifluoromethyl-benzenesulfonamide is obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([C:17]([OH:19])=[O:18])[CH2:12][CH:11]1[CH2:13][CH:14]([CH3:16])[CH3:15])=O)(C)(C)C.[ClH:20].CCOCC>O1CCOCC1>[ClH:20].[NH2:8][CH2:9][C:10]1([C:17]([OH:19])=[O:18])[CH2:12][CH:11]1[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)CC1CC1(CN)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid (2.8 g, 10.3 mmol) in dry 1,4-dioxane (60 mL) was added 4N HCl (40 mL, in 1,4-dioxane). The reaction mixture was stirred at room temperature overnight and ether was added (100 mL). The white solid was collected and dried to give 1.6 g (76%) of 1-aminomethyl-2-isobutyl-cyclopropanecarboxylic acid hydrochloride: mp: 254–255° C.; 1H NMR (300 MHz, D2O) δ 0.95 (t, J=6.2 Hz, 6H), 0.96 (m, 1H), 1.21–1.28 (m, 1H), 1.51–1.80 (m, 4H), 3.06 (d, J=13.8 Hz, 1H), 3.58 (d, J=13.8 Hz, 1H); 13C NMR (75 MHz, D2O) δ 21.7, 21.9, 22.2, 25.3, 28.1, 28.6, 37.1, 40.2, 178.1; MS (APCI) m/z 172 [M+H]+. Anal. Calcd. For C9H17NO2—HCl: C, 52.05; H, 8.74; N, 6.74. Found: C, 52.10; H, 8.73; N, 6.67.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=O)C.[C:16](Cl)(=[O:28])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>Cl>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:16]([N:4]2[CH2:9][CH2:8][CH:7]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2)=[O:28])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CCC(C(=O)O)C1CCN(C(C)=O)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCC(C(=O)O)C1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of (1-acetyl-4-piperidinyl)butyric acid (11.6 g, 54.4 mmol) and concentrated hydrochloric acid (30 ml) was refluxed for 16 hours, at the end of which time the hydrochloric acid was distilled off under reduced pressure. The residue was washed with ether and dissolved in 5N-NaOH/H2O (30 ml), followed by addition of ether (30 ml). To this mixture with ice-bath cooling was added p-nitrobenzyl chlorocarbonate (11.7 g, 54.3 mmol) in small portions, and the mixture was stirred at room temperature for 1 hour. This reaction mixture was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated NaCl/H2O and dried over MgSO4, and the solvent was distilled off under reduced pressure. The residual oil was treated with ether to provide the title compound (13.5 g) as colorless powders.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1C
Product: Cc1ccc(-c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1C

Procedure:
The product of Example 163A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 8.38-8.40 (m, 1H), 7.88-8.02 (m, 2H), 7.74 (d, J=6.5 Hz, 1H), 7.38-7.44 (m, 4H), 7.33-7.36 (m, 1H), 7.27-7.33 (m, 2H), 3.70 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H); MS (APCI+) M/Z 418 (M+H)+.
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1)=[O:5])=[N-].FC(F)(F)C(O)=[O:15].O>C(OCC)C>[OH:15][CH2:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1)=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C(=O)C=[N+]=[N-])no1
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C(=O)CO)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
2-Diazo-1-(5-methylisoxazol-3-yl)ethanone (7.0 g, 46 mmol) was dissolved in diethyl ether (100 ml) and trifluoroacetic acid (25 ml) and water (100 ml) were added. The solution was stirred at room temperature for 2 hours, then the diethyl ether was removed in vacuo and the aqueous solution was stirred at room temperature for 18 hours. Further water (100 ml) was added and the aqueous solution was extracted twice with ethyl acetate. The organic extracts were washed successively with water, 10% aqueous potassium carbonate solution and brine, and dried (Na2SO4). Evaporation of the solvent yielded the title-compound as a pale solid (4.0 g, 61%), 1H NMR (360 MHz, CDCl3) 2.52 (3H, s), 4.90 (2H, s), 6.44 (1H, s).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21][NH2:22]>O1CCCC1>[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21][NH:22][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: NCc1cc(Cl)ccc1Cl
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cc(Cl)ccc2Cl)c(=O)c1=O
Yield: 88.5 %

Procedure:
Tetrahydrofuran (13 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5 mmol) and 2,5-dichlorobenzylamine (0.88 g, 5 mmol) were stirred together for approximately 64.5 hours. Removal of solvent and thorough trituration of the residue with diethyl ether gave 1.51 g of a light yellow solid. As purification of this material by three recrystallizations from acetonitrile was unrewarding, the recovered crude product was subjected to HPLC. The solid isolated from the appropriate fractions was recrystallized from acetonitrile to afford 0.598 g of the title compound as a white solid: mp 195°-196° C. MS (m/z) 340/342/344 (M+). HPLC indicates a major component (>99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH:21]([CH3:24])[CH2:22][CH3:23]>CC(C)=O>[CH3:20][CH:21]([CH2:22][CH3:23])[CH2:24][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CCC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Cn1cc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
Methyl 3-nitropyrrole-2-carboxylate (22) (2.7 g, 15.9 mmol), potassium carbonate (6.5 g), and iodo-2-methylbutane (5.2 ml) were dissolved in 100 ml of acetone and refluxed for 10 hours. The reaction mixture was then cooled to room temperature, concentrated in vacua, partitioned between 200 ml of dichloromethane and 200 ml of water and extracted with dichloromethane (2×200 ml). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography to provide the substituted nitro pyrrole 23 (2.5 g, 70% yield). 1H NMR (DMSO-d6) δ8.30 (d, 1 H, J=2.0 Hz), 7.33 (d, 1 H, J=1.9 Hz), 4.15 (d, 2 H, J=7.4 Hz), 3.77 (s. 3H), 2.03 (m, 1 H, J=3.1 Hz), 0.80 (d. 6 H, J=6.7 Hz); 13C NMR (DMSO-d6) δ160.30, 134.79, 129.80, 122.40, 112.76, 105.00, 56.63, 52.41, 29.72, 19.73; FABMS, 226.096 calcd, 226.095 found.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[OH:11].C(Cl)(=O)C([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Product: O=C(Cl)c1ccc(Cl)c(O)c1
Temperature: 60 °C

Procedure:
An amount of 1 g (5.57 mmol) of 4-chloro-3-hydroxy benzoic acid is added 10 ml (115.8 mmol) of oxalyl chloride and refluxed at 60° C. till the solid had gone into solution. After cooling, the mixture is evaporated to dryness to give 4-chloro-3-hydroxy-benzoyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:20]2[N:19]=[CH:18][C:17]=1[C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]([S:44]([NH2:47])(=[O:46])=[O:45])[CH3:43]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]([NH:47][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])=[O:26])=[C:20]2[N:19]=[CH:18][C:17]=1[C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(Nc3ccccc3OCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3OCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 61.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-benzyloxyphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (200 mg, 0.37 mmol) obtained in step 2 and ethanesulfonamide (192 mg, 1.85 mmol), the title compound (146 mg, 63%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: CN1CCN(CCCCl)CC1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: CN1CCN(CCCN2C(=O)S/C(=C\c3ccc4c(ccn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-[(1-{[4-Chloro-2-(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 243) and 4-(3-chloropropyl)-1-methylpiperazine dihydrochloride following General Procedure H.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCc2cc(Oc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
In an oven-dried round-bottomed flask was combined 5-hydroxy-1-indanone (112 mg, 0.76 mmol), phenylboronic acid (170 mg, 1.51 mmol) and anhydrous copper (II) acetate (195 mg, 1.13 mmol) in 2.5 mL of dichloromethane. Anhydrous pyridine (0.11 mL, 1.5 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was concentrated to dryness and was purified with ISCO column chromatography (Teledyne Isco Inc., Lincoln Nebr.) (0-40% ethyl acetate/heptanes gradient) to give the desired product (SM-1i, 170 mg, 97%) as a clear oil which solidified on standing. MS (ES+) 225.3 (M+H)+. 1H NMR (CDCl3) δ 2.48-2.70 (m, 2H), 2.87-3.08 (m, 2H), 6.78-7.01 (m, 2H), 7.03-7.11 (m, 2H), 7.15-7.30 (m, 1H), 7.32-7.53 (m, 2H), 7.70 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].Cl>C(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Yield: 66.7 %

Procedure:
A mixture of 0.30 g (0.91 mmole) 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138) and 0.18 g (1.09 mmole) 4-amino-3-methoxy-benzoic acid in a 1:4 mixture of 5 mL of ethanol and 1 M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.28 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-156).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)(=[O:11])=[O:10].Cl[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([S:30][CH3:31])[N:21]=1.[F-].[K+]>C(#N)C>[CH3:31][S:30][C:22]1[N:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([N:14]2[CH2:15][CH2:16][C@H:12]([S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:17])([F:1])[F:18])(=[O:11])=[O:10])[CH2:13]2)[N:21]=1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Reactant: O=S(=O)(c1ccccc1C(F)(F)F)[C@H]1CCNC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CSc1nc(N2CC[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C2)cc(C(F)(F)F)n1

Procedure:
(S)-3-(2-Trifluoromethyl-benzenesulfonyl)-pyrrolidine (500 mg) was dissolved in acetonitrile (3.5 mL) in a microwave tube. 4-Chloro-2-(methylsulfanyl)-6-(trifluoromethyl)pyrimidine (450 mg), TEA (0.75 mL) and KF (10 mg) were added. The reaction mixture was irradiated in the microwave oven at 150° C. for 1.5 h. The reaction mixture was evaporated to dryness and purified by flash chromatography (50 g silica gel, ethyl acetate/n-heptane:0:1→1:0) to yield a light yellow oil (790 mg; 94%) MS: m/z=472.2 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.[N+:24]([C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30])([O-:26])=[O:25]>ClCCl>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[N+:24]([O-:26])=[O:25])[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21
Reaction time: 12 h
Yield: 107.9 %

Procedure:
To a stirring solution of 1-Boc-6-aminoindazole (1.5 g, 6.4 mmol) in dichloromethane (25 mL) was added pyridine (1.55 mL, 19.2 mmol) followed by 2-nitrobenzoyl chloride (1 mL, 7.1 mmol). After stirring for 12 h, the solvent was removed by rotary evaporation and the residue was partitioned between ethyl acetate (250 mL) and water (250 mL). The aqueous phase was separated and the organic phase was washed with 1 M citric acid, brine, satd aq NaHCO3, and brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to give 2.64 g of off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](O)=[O:7]>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: OCCOc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.6 %

Procedure:
To a solution of 2,4-dichlorophenoxy acetic acid (15.0 g) in tetrahydrofuran (300 mL) was added dropwise 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (96 mL) under ice-cooling over 1.5 hours. The reaction solution was stirred at room temperature for 22 hours. After the reaction solution was concentrated, the residue was diluted with saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saturated ammonium chloride, saturated aqueous sodium hydrogencarbonate solution (×2) and saturated ammonium chloride, dried over anhydrous sodium sulfate and then concentrated, to give the title compound as a colorless oil (14 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[H-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1>C1COCC1>[Cl:9][C:10]1[N:11]=[CH:12][N:13]=[C:14]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:15]=1
Reactant: Nc1nccs1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(Nc2nccs2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,3-Thiazol-2-amine 52-1 (2.0 g, 20.0 mmol) was dissolved in THF and 1 equivalent of sodium hydride (0.8 g, 60% dispersion in oil) was added. This was stirred for 30 min at room temperature. Then 4,6-dichloropyrimidine 7-1 (2.97 g, 20.0 mmol) and the other equivalent of sodium hydride were added simultaneously. This was refluxed for 30 minutes. The reaction was quenched with methanol and water and then evaporated. The residue was partitioned with DCM:MeOH:water (50:5:50). The organic layer was drawn off, dried and evaporated to afford crude material which was purified on a silica column eluted with 99:1:0.1 (DCM:MeOH:NH4OH). Rf=0.4 (DCM:MeOH:NH4OH 98:2:0.2). 1H-NMR(DMSO-d6): 11.96 (s, 1H); 8.71(s, 1H); 7.49(d, 1H); 7.25(d, 1H); 7.13(br s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)[C:3]([OH:5])=[O:4].[CH3:17][C:18]1C=CC(S(O)(=O)=O)=C[CH:23]=1>COC(OC)(C)C>[CH3:17][C:18]1([CH3:23])[O:1][CH:2]([CH:6]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7]2)[C:3](=[O:5])[O:4]1
Reactant: O=C(O)C(O)C1Sc2ccccc2NC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Product: CC1(C)OC(=O)C(C2Sc3ccccc3NC2=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
A mixture of hydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid (0.13 mmol) and p-TSA (1 mg) in 1.5 mL of 2,2-dimethoxypropane is stirred at room temperature for 16 hours. Solvent is removed under vacuum and the residue is treated with a saturated aqueous solution of NaHCO3 (2 mL). The resulted mixture is extracted with EtOAc (3×5 mL). The organic layers are combined and concentrated to provide the crude 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-4H-benzo[1,4]thiazin-3-one which was used directly for next step without further purification. Yield: 31%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:25][CH2:26][CH:27]([NH2:29])[CH3:28]>>[OH:25][CH2:26][CH:27]([NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])[CH3:28]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)CO)n(C)n1
Yield: 17 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1-methylethylamine instead of isopropylamine, to the title compound (6.7 mg, 17%) which was obtained as an off white solid. MS: m/e=385.2 [M+H]+.