Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[O:13][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
12.4 grams of 2-benzyl-2-ethoxycarbonyl-cyclopentanol obtained from Example 14 were diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, and then using 10% aqueous solution of sodium carbonate for three times. The organic layer was dried, and removing solvent gave 19.71 g of yellow liquid. MS: m/e 353(M++1), 352(M+), 351(M+−1), 279(M+—CO2CH2CH3), 261(M+—CH2C6H5), 247(M+—C6H5CO), 231(M+—C6H5CO2), 201, 184, 156, 139, 105 (base), 91, 77.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Reaction time: 15 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 8-bromo-4H-thieno[3,2-c]chromene-2-carboxylate 2 (2.64 g, 8.12 mmol, 1 equiv) in 4:1 tetrahydrofuran/water (80 mL) was added aqueous potassium hydroxide (24 mL, 24 mmol, 3.0 equiv, 1.0 M solution in water) at 24° C. After 15 hr, the tetrahydrofuran was removed in vacuo (<20 mm Hg). The resulting aqueous suspension was diluted with water until all the solids were dissolved. To the resulting solution was added concentrated hydrochloric acid until the solution reached pH=1. The resulting solids were collected by filtration and dried in vacuo (<1 mm Hg) to afford 3bp as a yellow solid (2.36 g, 93%). 1H NMR (500 MHz, CDCl3), δ: 13.28 (br s, 1 H), 7.64 (d, J=2.4 Hz, 1 H), 7.60 (s, 1 H), 7.40 (dd, J=8.7, 2.4 Hz, 1 H), 6.94 (d, J=8.7 Hz, 1 H), 5.30 (s, 3 H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([OH:8])[CH:4]=1.[C:9](Cl)([Cl:11])=[O:10]>C1C=CC=CC=1>[Cl:11][C:9]([N:6]1[C:5](=[O:8])[CH:4]=[C:3]([CH2:2][Cl:1])[O:7]1)=[O:10]
Reactant: Oc1cc(CCl)on1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)n1oc(CCl)cc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of 673 mg of 5-chloromethyl-3-hydroxyisoxazole, 19 ml of benzene and about 1 ml of liquified phosgene was stirred at room temperature for 5 hours. At the end of this time, the excess phosgene and the solvent were distilled off, giving 900 mg (yield 100% of theory) of the title compound, in the form of a colourless oil having a refractive index, nD24 =1.5391.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.Cl[CH2:10][C:11]1[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:18][O:17][C:12]1[C:11]([CH2:10][N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ncccc1CCl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1CN1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
4.0 g of 4-piperidone hydrochloride, 4.1 g of 3-(chloromethyl)-2-methoxypyridine and 12.6 g of potassium carbonate were suspended in 26 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 5.5 g of the title compound as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1([CH:42]2[CH2:47][C:46](=[O:48])[NH:45][C:44](=[O:49])[CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[O:48]=[C:46]1[CH2:47][CH:42]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:43][C:44](=[O:49])[N:45]1[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CC(c2ccccc2)CC(=O)N1
Reactant: O=C(C=Cc1cccnc1)NCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)CC(c2ccccc2)CC1=O
Temperature: 15 °C
Reaction time: 8 h

Procedure:
9.3 g (42.3 mmol) N-(4-hydroxy-butyl)-3-pyridin-3-yl-acrylamide, 11.1 g (42.3 mmol) triphenylphosphine and 8.0 g (42.3 mmol) 4-phenyl-piperidin-2,6-dione are suspended in 120 ml THF, thereafter 6.7 ml (42.3 mmol) azodicarboxylic acid diethyl ester dissolved in 60 ml THF are added dropwise within three hours under protective atmosphere and light cooling (to ca. 15° C.). The mixture is left standing overnight without further cooling at RT. Subsequently, the solvent is removed under vacuum and the residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and, after withdraw of the solvent, crystallized from acetic acid ethyl ester: Colorless crystals with MP. 160–161° C.; Yield 3.8 g (23%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:16]([N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[CH3:17]
Reactant: CCN(CC)CCSc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CCN(CC)CCSc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-(2-diethylamino-ethylthio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (resin) and piperazine.
Reaction SMILES: ClC1C=C([C@@H](O)CN(CCC2C=CC([C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[C:28](C)[C:27]=3C)=CC=2)C(=O)OC(C)(C)C)C=CC=1.OO.Cl([O-])=[O:40].[Na+]>C(#N)C.C(OCC)(=O)C>[C:32]([OH:33])(=[O:40])[C:29]1[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1c(C=O)ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c1C
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4′-formyl-2′,3′-dimethyl-1,1′-biphenyl-4-yl)ethyl]carbamate in acetonitrile (2.5 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1.3 ml) was added 30% hydrogen peroxide solution (60 μl) and 80% sodium chlorite (128 mg) below 10° C. The reaction mixture was stirred at 40° C. for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (1.0 ml) was added 4N hydrochloride in dioxane (1.18 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2,3-dimethyl-1,1′-biphenyl-4-carboxylic acid hydrochloride (140 mg).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][NH2:35]>C1COCC1>[F:29][C:28]([F:30])([F:31])[C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][C@@H:7]2[CH2:6][NH:35][CH3:34])=[CH:22][CH:23]=1)([OH:33])[CH3:32]
Reactant: CN
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Solvent: C1CCOC1
Product: CNC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1

Procedure:
This compound was synthesized following the procedure outlined for Example 84 The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and methanamine (10 equivalents of a 1.0M solution in THF, Sigma-Aldrich, St. Louis, Mo.) followed by purification via column chromatography on silica gel (0 to 10% MeOH in CH2Cl2) delivered 1,1,1-trifluoro-2-(4-((2S)-2-((methylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers after column chromatography on silica gel (0-10% MeOH in CH2Cl2)
Reaction SMILES: I[Si](C)(C)C.C([O:8][P:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[O:25][C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[C:28](=[O:30])[CH:29]=2)=[O:23])=[CH:17][CH:16]=1)([O:11]CC)=[O:10])C>C(Cl)(Cl)(Cl)Cl>[P:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[O:25][C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[C:28](=[O:30])[CH:29]=2)=[O:23])=[CH:19][CH:20]=1)([OH:10])([OH:11])=[O:8]
Reactant: CCOP(=O)(Cc1ccc(NC(=O)c2cc(=O)c3ccccc3o2)cc1)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(CP(=O)(O)O)cc1)c1cc(=O)c2ccccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
Iodotrimethylsilane [(CH3)3SiI](3.17 g) was added at 0° C. to a mixture of N-(4-diethoxyphosphorylmethylphenyl)-4-oxo-4H-1-benzopyran-2-carboxamide (2.99 g) and carbon tetrachloride (60 ml). This mixture was stirred at 0° C. for 1 hour and then at room temperature for 15 hours, after which it was concentrated under reduced pressure. The residue was dissolved in methanol (45 ml), poured over 4N HCl and stirred at room temperature for 30 minutes. The separated crystals were collected by filtration and recrystallized from methanol to yield N-(4-phosphonomethylphenyl)-4-oxo-4H-1-benzopyran-2-carboxamide (0.22 g, 8.5%) as light yellow prisms having a melting point of 265° to 266° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>ClCCl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19]([N:22]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:38]([Br:37])=[CH:39][CH:40]=1)[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NCCN(C)C)c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
A solution of 5-benzyl-3-bromo-6-(1-{[2-(dimethylamino)ethyl]amino}propyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1-4, 144 mg, 0.33 mmol, 1 equiv) and N,N-diisopropylethylamine (43 mg, 0.33 mol, 1 equiv) in dichloromethane (5 mL) was treated with 4-bromobenzoyl chloride (73 mg, 0.33 mmol, 1 equiv), and the resulting mixture was stirred under ambient conditions for 2 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, then brine, and dried (MgSO4) and concentrated. The residue was purified by flash chromatography. Elution with CH2Cl2 to 10% NH3-EtOH/CH2Cl2 gave N-[1-(5-benzyl-3-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-5) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 10.9 (bs, 1H), 7.56 (m, 2H), 7.33 (m, 5H), 7.15 (m, 2H), 6.04 (d, J=15 Hz, 1H), 5.94 (m, 1H), 5.03 (d, J=15 Hz, 1H), 3.42 (m, 2H), 2.18 (m, 2H), 2.01 (m, 2H), 1.86 (s, 6H), 0.62 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cncc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cncc(F)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (224 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 127 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CC(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)OCCOc1ccc(C=O)cc1Cl
Yield: 41.5 %

Procedure:
A mixture of 3-chloro-4-hydroxybenzaldehyde (10 g, 63.9 mmol), K2CO3 (26.5 g, 191.6 mmol) and 2-bromoethyl acetate (26.7 g, 159.7 mmol) in acetone (250 mL) is refluxed for 18 h before it is diluted with diethyl ether (200 mL) and washed with water (3×200 mL). The washings are extracted with diethyl ether (200 mL). The combined organic extracts are dried over MgSO4 and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to afford the title compound (6.44 g) as colourless solid. 1H NMR (CDCl3): δ 9.85 (s, 1H9, 7.91 (d, J=1.8 Hz, 1H), 7.75 (dd, J=1.8, 8.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.53-4.49 (m, 2H), 4.35-4.31 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[O:3][N:1]=[C:4]3[CH:5]=[CH:6][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:8][C:9]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: N#CCc1cccc(F)c1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4cccc(F)c4)c3c2)cc1

Procedure:
The title compound, light green solid (95 mg, 72%), MS (ISP) m/z=370.2 [(M+H)+], mp 207° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.O1CCCC1.[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37](Cl)=[O:38]>>[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:38]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cc2c(s1)-c1ccccc1OCC2)N1CCCc2ccccc21

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (0.755 mmol) and triethylamine (0.105 mL, 0.755 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonylchloride (0.100 g, 0.378 mmol) portionwise as a solid. Reaction was stirred at room temperature with monitor for formation of desired product. The reaction was stirred overnight. After aqueous workup, the crude was taken into DMF at a concentrated of 100 mg/ml and purified by preparative RP-HPLC to give 218 (yield 80% of theoretical). MS: (ESI+) 362.2
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:46])[CH2:30][CH2:31][N:32]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:46][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:38]=1)[S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41]
Reactant: CC(C)S(=O)(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(=O)(=O)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H34N4O5S
Reaction SMILES: CS[C:3]1[N:18]2[C:19]3[C:10]([S:11][C:12]4[CH:13]=[CH:14][C:15]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:17]=42)=[CH:9][CH:8]=[CH:7][C:6]=3[C:5](=[O:24])[N:4]=1.Cl.C([OH:28])C>>[F:21][C:20]([F:23])([F:22])[C:15]1[CH:14]=[CH:13][C:12]2[S:11][C:10]3[C:19]4=[C:6]([C:5](=[O:24])[NH:4][C:3](=[O:28])[N:18]4[C:17]=2[CH:16]=1)[CH:7]=[CH:8][CH:9]=3
Reactant: CSc1nc(=O)c2cccc3c2n1-c1cc(C(F)(F)F)ccc1S3
Reactant: CCO
Agent: Cl
Product: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2

Procedure:
A stirred suspension of 53.6 g. (0.146 mol.) of 1-methylmercapto-10-trifluoromethyl-3H-pyrimido[5,4,3-kl]phenothiazine-3-one in 240 ml. of concentrated hydrochloric acid and 800 ml. of ethanol was heated under reflux for four hours. The reaction mixture was concentrated to approximately one-half its original volume by boiling off the excess solvents and chilled. The product was collected by filtration and washed thoroughly with water to give the title compound, m.p. 278°-280° (ethanol).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:12]1[C:24]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][NH2:36])[C:31]([OH:33])=[O:32])=[O:28])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH:21]1[C:22]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][NH:36][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[C:31]([OH:33])=[O:32])=[O:28])[C:24]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)C1CCCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexanecarbonyl chloride (86 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude materials were purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (201 mg, 70%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]([C:10]1[C:11]2[CH2:12][C:13]3[N:18]4[CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=[C:17]4[C:16](=[O:27])[NH:15][C:14]=3[C:28]=2[CH:29]=[CH:30][CH:31]=1)[CH3:9])=[O:7])C>O1CCOCC1>[C:6]([CH:8]([C:10]1[C:11]2[CH2:12][C:13]3[N:18]4[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=[C:17]4[C:16](=[O:27])[NH:15][C:14]=3[C:28]=2[CH:29]=[CH:30][CH:31]=1)[CH3:9])([OH:7])=[O:5]
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(C(C)C(=O)OCC)c1C3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C(=O)O)c1cccc2c1Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
19 ml of 1N sodium hydroxide solution are added dropwise, under a stream of nitrogen and at a temperature in the region of 20° C., to a suspension of 1.9 g of ethyl 9-(1-ethoxycarbonylethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate in a mixture of dioxane (245 ml) and distilled water (65 ml). The reaction is continued for 4 hours and 30 minutes at the same temperature. The insoluble material, formed after partial evaporation of the solvents, is filtered, washed with water and then with a mixture of dimethylformamide (10 ml) and methanol (80 ml), and dried. The solid is dissolved in 20 ml of 1N sodium hydroxide solution and stirred for 4 hours at a temperature in the region of 20° C. The reaction mixture is then treated with 1N hydrochloric acid to pH 1 and the precipitate formed is filtered, washed with water and then with acetone and dried to result in 0.62 g of the hydrate of 9-(1-carboxyethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid in the form of a pink powder, the melting point of which is greater than 260° C. (Analysis C17H13N3O5.1.4H2O; % Calculated C: 60.18, H: 3.86, N: 12.38; % Found C: 60.1, H: 3.2, N: 12.5; 1H NMR spectrum in d6-DMSO, T=300 K, δ in ppm (300 MHz): 1.5 (3H, CH3), 3.9 (1H, CH), 4.1 (2H, CH2), 7.3, 7.5, 7.9 (each 1H, 3 arom. CH), 8.6 (1H, imidazole CH), between 12 and 13.5 (3H, 2 COOH and NHCO)).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:34]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:41]4[CH2:42][CH2:43][N:38]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:39][CH2:40]4)=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Reactant: CC(C)(C)N1CCNCC1
Product: CC(C)(C)N1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CCC(F)(F)C4)C3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 186 step 7) and N-tert-butylpiperazine. Light yellow solid (63%). MS (EI): 624.2 (M−H)−.