Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[C:33]([S:35][C:36]2[N:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([O:49]CC)=[O:48])[CH:42]=3)[N:39]=[N:38][N:37]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:52])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[K+].Cl>CO.O>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[C:33]([S:35][C:36]2[N:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([OH:49])=[O:48])[CH:42]=3)[N:39]=[N:38][N:37]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:52])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)OCC)c2)c2ccccc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)O)c2)c2ccccc2c1O
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
2-(2-Tetradecyloxyphenyl)carbamoyl-4-[1-(3-ethoxycarbonylphenyl)-5-tetrazolylthio]-1-naphthol (19.5 g) was added to a solution of 5.3 g of potassium hydroxide in 50 ml of methanol and stirred for 30 minutes at 40°-50° C. Then 10 ml of concentrated hydrochloric acid was diluted with 500 ml of water and poured into the reaction solution. Crystals precipitated were collected by filtration and recrystallized from methanol to obtain 16.1 g of 2-(2-tetradecyloxyphenyl)carbamoyl-4-[1-(3-carboxyphenyl)-5-tetrazolylthio]-1-naphthol, m.p., 136°-138° C. Yield was 86%.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:36][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)(=[O:17])=[O:16])=[O:8]>FC(F)(F)C(O)=O>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][CH2:37][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[C:28]([C:29]([OH:31])=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:36][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)(=[O:17])=[O:16])=[O:8]
Reactant: COc1ccc(CN(CCCN(C)C)C(=O)c2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC(C)(C)C)OCC2CC32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 30 °C
Yield: 62.2 %

Procedure:
A solution of tert-butyl (1aRS,7bSR)-5-{2-[N-(2,4-dimethoxybenzyl)-N-(3-dimethylamino-propyl)carbamoyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylate (Intermediate 119, 0.03 g) in trifluoroacetic acid (5 mL) was stirred and heated at 30° C. overnight. The mixture was evaporated to dryness and the residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-[2-(3-dimethylaminopropylcarbamoyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.013 g) as a white solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:7]=1[N+:21]([O-])=O.[C:24](O)(=O)[CH3:25]>[Fe]>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]2[N:5]([CH2:4][CH2:3][S:2][CH3:1])[C:24]([CH3:25])=[N:21][C:7]=2[CH:8]=1
Reactant: CC(=O)O
Reactant: CSCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Fe]
Product: CSCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Yield: 84 %

Procedure:
To N-(2-(methylthio)ethyl)-4-(benzoxazol-2-yl)-2-nitroaniline (370 mg, 1.12 mmol) was added iron powder (188 mg, 3.37 mmol) and acetic acid (5 mL), and this was heated to reflux for 10 hours. After the reaction solution was cooled, it was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (305 mg, 84% yield) as pink crystals.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C(#N)C>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12]2)=[CH:16][CH:15]=1
Reactant: ClCc1ccc(Br)cc1
Reactant: c1ccc(C2CNCCN2)cc1
Solvent: CC#N
Product: Brc1ccc(CN2CCNC(c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2 g of 2-phenylpiperazine were dissolved in acetonitrile and cooled to 0° C. A solution of 0.5 quiv. 4-bromobenzylchloride in acetonitrile was added dropwise over 1 h. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (silica, eluent dichloromethane, 0-5% methanol) to afford 1 g of 1-(4-bromo-benzyl)-3-phenyl-piperazine. ES MS (+) m/z 301.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=[N:16][OH:17]
Reactant: O=C1CCOc2c(Br)cc(F)c(F)c21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: ON=C1CCOc2c(Br)cc(F)c(F)c21
Yield: 94.9 %

Procedure:
To a solution of 8-bromo-5,6-difluoro-2,3-dihydrochromen-4-one (7.2 mmol) in 40 mL of ethanol was added hydroxylamine hydrochloride (0.55 g, 7.9 mmol) and sodium acetate (0.65 g, 7.9 mmol). This mixture heated at reflux for 20 hrs. The mixture was cooled, diluted with EtOAc, washed with water and brine, and then dried over Na2SO4. Concentration of the solvent provided the title compound as a white solid (1.9 g). 1H NMR (300 MHz, 10% CD3OD in CDCl3): δ 7.3 (t, 1H), 4.2 (t, 2H), 2.9 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:4][CH:3]=1.[O:18]1[CH2:20][CH:19]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:32])[CH3:31].C(O)(=O)C>C(O)(C)(C)C>[ClH:1].[ClH:1].[C:30]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH2:21][CH:19]([OH:18])[CH2:20][N:10]1[CH2:11][C@@H:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8][C@H:9]1[C:12]([O:14][CH3:15])=[O:13])(=[O:32])[CH3:31]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc(Cl)cc2)CN1
Reactant: CC(=O)Nc1ccccc1OCC1CO1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Cl)cc2)CN1CC(O)COc1ccccc1NC(C)=O
Product: Cl
Temperature: 100 °C
Yield: 216.3 %

Procedure:
Methyl (2S,4S)-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylate (370 mg, 1.0 mmol) and N-[2-(2-oxiranylmethoxy)phenyl]acetamide (207 mg, 1.0 mmol) dissolved in tert-butanol (7 ml) was stirred in a sealed vial at 100° C. over night. Workup of the crude material by flash chromatography on silica (DCM/MeOH 100/2), acidification of the appropriate fractions with 1M HCl and lyophilization from acetic acid afforded the subtitled compound as a white amorphous solid (360 mg, 72%). The substance is a diastereomeric mixture.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:29][CH2:30][CH3:31])[C:21]([O:23]CC(Cl)(Cl)Cl)=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(=O)C>C(Cl)Cl.[Zn]>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([C:21]([OH:23])=[O:22])[O:29][CH2:30][CH3:31])=[CH:15][CH:14]=2)=[CH:33][CH:34]=1)(=[O:4])=[O:3]
Reactant: CCOC(Cc1ccc(C(=O)OCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(Cc1ccc(C(=O)OCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Reaction time: 17 h

Procedure:
To a solution of 4-[2-ethoxy-2-(2,2,2-trichloro-ethoxycarbonyl)-ethyl]-benzoic acid 4-methane sulfonyloxy-benzyl ester (0.02 g, 0.036 mmol) in dry DCM (2 mL) was first added zinc dust (0.047 g, 0.722 mmol), then acetic acid (1.08 mL, 18.06 mmol) at 0° C. The resulting inhomogeneous mixture was stirred for 17 h without removing the ice bath. The zinc was filtered off and washed with DCM and MeOH and the remaining filtrates were combined and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM/MeOH (92:8) as the eluent. The title compound was obtained as an oil (0.005 g, 36%). 1H NMR (400 MHz, CDCl3): δ 7.91-7.93 (d, 2H), 7.42-7.44 (d, 2H, 7.19-7.24 (m, 4H), 5.27 (s, 2H), 4.03 (m, 1H), 3.52 (m, 1H), 3.37 (m, 1H), 2.99-3.14 (m, 2H), 3.08 (s, 3H), 2.63 (t, 3H). Mass Spectrum: M−H+ 421.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1O.[Cl:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:14]([C:12](=[O:13])[CH2:11][Cl:10])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=1
Reactant: CCc1ccc(NC(=O)CCl)cc1
Reactant: Oc1c(F)cccc1Cl
Product: CCc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1

Procedure:
Same procedure as example 6a starting from 2-chloro-6-fluorophenol and 2-chloro-N-(4-ethylphenyl)acetamide.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([C:38]2([CH:41]=O)[CH2:40][CH2:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1>O1CCCC1>[F:37][C:35]1[CH:34]=[C:33]([C:38]2([CH2:41][CH:2]=[O:3])[CH2:39][CH2:40]2)[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: O=CC1(c2cc(F)cc(F)c2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CCC1(c2cc(F)cc(F)c2)CC1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a stirred, cooled (0° C.) solution of (methoxymethyl)triphenylphosphonium chloride (24.9 g) in tetrahydrofuran (190 ml) under an argon atmosphere was added slowly a solution of potassium tert.butoxide in tetrahydrofuran (30 ml) followed (after 30 min stirring) by a solution of 1-(3,5-difluoro-phenyl)-cyclopropanecarbaldehyde (6.3 g) in tetrahydrofuran (40 ml). Stirring was continued overnight, then the reaction mixture was quenched by adding an aqueous sodium chloride solution. The mixture was extracted with ethyl acetate twice and the combined organic layers were dried over MgSO4 and concentrated. The crude enol ether was dissolved in acetone (20 ml) and stirred with 6 M aqueous hydrochloric acid (40 ml) for 6 hours at room temperature. Ethyl acetate was added, the organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (SiO2; heptane/EtOAc=4:1) to give [1-(3,5-difluoro-phenyl)-cyclopropyl]-acetaldehyde as yellow liquid (2.55 g). 1H-NMR (300 MHz, CDCl3, δ): 0.92-0.98 (m, 2H), 1.00-1.06 (m, 2H), 2.65 (d, J=2 Hz, 2H), 6.60-6.67 (m, 1H), 6.75-6.81 (m, 2H), 9.74 (t, J=2 Hz, 1H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]([C:32]#[N:33])=[N:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:23]4[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[C:25]([C:32]#[N:33])=[N:24]4)[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Reactant: N#Cc1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(N2CCC(n3nc(C#N)c4cccnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.080 g, 0.22 mmol), 1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (0.045 g, 0.31 mmol) and K2CO3 (0.070 g, 0.50 mmol) in DMF (2.5 mL) was stirred at 60° C. for 1 hr. It was then cooled to room temperature, quenched with water (30 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜100% EtOAc/hexanes gradient elution) to give 1-[1-[1-(4-fluorophenyl)-5-isopropyl-pyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]pyrazolo[3,4-b]pyridine-3-carbonitrile (0.085 g, 88%).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15](=[O:30])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(=O)=O.[CH3:31][NH:32][CH:33]1[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>ClCCl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:15](=[O:30])/[CH:14]=[CH:13]/[C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:32]([CH3:31])[CH:33]4[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]4)=[CH:8][CH:9]=3)=[CH:22][CH:21]=2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)OCc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Reactant: CNC1CCC(C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCC(N(C)Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A reaction mixture of 100 mg (0.226 mmol) of 4-[(E)-2-(4′-chlorobiphenyl-4-ylcarbamoyl)vinyl]benzyl methanesulfonate, 37.34 mg (0.29 mmol) of methyl-(4-methylcyclohexyl)amine, and 0.1 mL of triethylamine in 10 mL of dichloromethane is stirred for 18 hours at ambient temperature. Then the reaction mixture is extracted between water and dichloromethane, the organic phase is separated off, dried, and evaporated down. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/methanol/ammonia (90:10:1)). Yield: 52 mg (49% of theory); C30H33ClN2O (M=473.05); melting point: 227° C.-258° C.; calc.: molecular ion peak (M+H)+: 473/475 (Cl); found: molecular ion peak (M+H)+: 473/475 (Cl); Rf value: 0.48 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([C:18]1[S:22][C:21]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:25])=[N:20][CH:19]=1)[CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10].Cl[C:38]1[C:39]2[S:46][CH:45]=[CH:44][C:40]=2[N:41]=[CH:42][N:43]=1>C1COCC1>[N:41]1[C:40]2[CH:44]=[CH:45][S:46][C:39]=2[C:38]([O:3][CH2:4][CH:5]([C:18]2[S:22][C:21]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)=[O:25])=[N:20][CH:19]=2)[CH2:6][O:7][Si:8]([CH:15]([CH3:16])[CH3:17])([CH:12]([CH3:13])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[N:43][CH:42]=1
Reactant: CC(C)[Si](OCC(CO)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1)(C(C)C)C(C)C
Reactant: Clc1ncnc2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCC(COc1ncnc2ccsc12)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (0.12 mmol as a 60% oil dispersion) in THF (0.20 mL) was added a solution of compound 73.3 (0.04 mmol) in THF (1.0 mL) at room temperature. After stirring for 1 hour, 4-chlorothieno[3,2-d]pyrimidine (0.04 mmol) was added and the reaction mixture was heated at 60° C. for 1 hour. The reaction was cooled and quenched with the addition of saturated NH4Cl. The reaction mixture was extracted with EtOAc, dried and concentrated to give a residue that was purified by preparative TLC (20% hexanes in EtOAc) to afford 1-{5-[2-(thieno[3,2-d]pyrimidin-4-yloxy)-1-triisopropylsilanyloxymethyl-ethyl]-thiazol-2-yl}-3-(3-trifluoromethyl-phenyl)-urea (compound 73.4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([F:38])[CH:37]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[N+:31]([O-:33])=[O:32])=O.[BH4-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[F:38][C:36]1[CH:35]=[C:4]([CH:3]=[C:2]([F:1])[CH:37]=1)[CH2:5][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)=[CH:20][C:19]=1[N+:31]([O-:33])=[O:32]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(C(=O)c5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Yield: 91.7 %

Procedure:
N-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide (3.61 g, 6.93 mmol) was dissolved in DCM (150 mL) in argon atmosphere and trifluoroacetic acid (150 mL) is added under stirring. Sodium borohydride pellets (2.62 gr, 69.3 mmol) is gradually added over a period of 72 hours. The reaction mixture was evaporated, taken up with a mixture MeOH/acetone and stirred for 1 hour. The resulting mixture was evaporated to dryness, redissolved in MeOH and NaOH 8N was added till basic pH was reached. Crude was evaporated and ice/water was added, the solid thus formed was filtered, washed with water and dried under vacuum at 80° C. affording 3.22 g of title compound (92% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:15])[F:14])[CH:7]=1>S(=O)(=O)(O)O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([O:12][C:13]([F:14])([F:15])[F:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(OC(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)cc1OC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
Fuming nitric acid (20 mL) was added dropwise to concentrated sulfuric acid (40 ml) under cooling (−10° C.), and subsequently, 1-fluoro-3-(trifluoromethoxy)benzene (15 g, 83 mmol) was added to the mixture at −10° C., and the mixture was stirred for 0.5 hours. After the mixture was added into ice-water to stop the reaction, it was extracted with dichloromethane. After the obtained organic layer was washed with a 1N aqueous sodium hydroxide solution and water, it was dried with anhydrous sodium sulfate. After filtration, the solution was concentrated and the residue was purified by silica gel column chromatography (100:0-97:3, hexane:ethyl acetate) to give the title compound (3.1 g, 16%) as an oil.
Reaction SMILES: FC(F)(F)[S:3]([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:26]1(S)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O:33]1[C@H:42]([CH3:43])[C@H:34]1[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=O.O>C(Cl)Cl>[OH:33][C@@H:34]([C@H:42]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:43])[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[S:3]
Reactant: Sc1ccccc1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCCCOC(=O)[C@H]1O[C@@H]1C
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=S)[C@@H](O)[C@@H](C)c1ccccc1
Reaction time: 24 h
Yield: 81.3 %

Procedure:
Ytterbium trifluoromethanesulfonate [Yb(OTf)3] (196 mg) and thiophenol (0.032 mL) were sequentially added at room temperature to a solution of n-butyl (2S,3R)-2,3-epoxybutyrate (50 mg) in methylene chloride (3.0 mL), and the mixture was stirred at the same temperature for 24 hours. The reaction mixture was added to water (20 mL), and extracted with chloroform (20 mL×3). The organic layers were combined, and the combined organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through preparative thin-layer chromatography (n-hexane/ethyl acetate=5/1), to thereby yield colorless oil (69 mg, 81.3%).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:27]([N:28]=[C:29]=[O:30])=[CH:26][C:17]2[N:18]([CH2:23][C:24]#[CH:25])[C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1>>[CH2:7]([O:6][C:4]([CH:3]=[C:2]([NH:1][C:29](=[O:30])[NH:28][C:27]1[C:14]([F:13])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH2:23][C:24]#[CH:25])[C:17]=2[CH:26]=1)[C:9]([F:10])([F:11])[F:12])=[O:5])[CH3:8]
Reactant: C#CCN1C(=O)COc2cc(F)c(N=C=O)cc21
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Product: C#CCN1C(=O)COc2cc(F)c(NC(=O)NC(=CC(=O)OCC)C(F)(F)F)cc21

Procedure:
Analogously to the procedure described in Example 1, starting from ethyl 3-amino-4,4,4-trifluorocrotonate and 3,4-dihydro-7-fluoro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine there is obtained 6-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}-3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine (not isolated) and, after cyclization of this benzoxazine, there is obtained 3-[3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 1H-NMR (CDCl3, 60 MHz): 7.29 ppm (d, 1H), 6.99 ppm (d, 1H), 6.31 ppm (s, 1H), 4.85-4.61 ppm (m, 4H), 2.35 ppm (t, 1H): mass spectrum: m/e 383(20), M+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=O)=[CH:21][C:16]=2[CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:21][C:16]=2[CH2:15][CH2:14]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)CCO2)NCC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
This product was prepared using a two-step procedure. A solution of tryptamine (32.4 g, 0.2 mol) and 2,3-dihydrobenzofuran-5-carboxaldehyde (30.0 g, 1 equiv.) in toluene (1 L) was heated under reflux for 4 hours. After removal of 4 mL of water and evaporation of toluene the residue was dissolved in DCM (1 L) in the presence of TFA (31 mL, 2 equiv.). The resulting mixture was stirred at rt for 16 hours. Then 1 L of a saturated aqueous solution of NaHCO3 was added. After extraction with DCM and drying over MgSO4, the organic solution was evaporated in vacuo. Recrystallization from DCM:iPr2O (2:30) gave the title compound as white crystals in a 80% yield. 1H NMR (CDCl3) δ 7.6 (s, 1H), 7.5-7.6 (m, 1H), 7-7.3 (m, 5H), 6.7-6.75 (d, 1H), 5.1 (s, 1H), 4.5-4.6 (t, 2H), 3.3-3.45 (m, 1H), 3.05-3.2 (t, 3H), 2.7-3 (m, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH3:17].O>ClCCl>[NH2:17][S:2]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(OC)cc1S(=O)(=O)Cl
Reactant: N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)cc1S(N)(=O)=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
A solution of 554 g of the compound of Example 4 in 5 L of dichloromethane was cooled to -40° C. and 79 g of anhydrous ammonia was added at this temperature. The reaction mixture was allowed to warm to -10° C., stirred 1 hour, then poured into 6 L of water. The organic phase was separated and filtered. The filter cake was washed with dichloromethane and dried giving 356 g of crude product. A 180 g portion was recrystallized from methanol to give 130 g of the title compound, m.p. 139°-142° C.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(OC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.