Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[N:10]([N:11]=[C:12]([C:18]4[N:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:20]=[CH:21][N:22]=4)[CH:13]=3)[C:9]=2[CH:28]=1)=O.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1.CO>[F:26][C:24]([F:25])([F:27])[CH2:23][N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([N:11]=2)[C:9]2[CH:28]=[C:5]([CH2:3][OH:2])[CH:6]=[CH:7][C:8]=2[O:17][CH2:16][CH2:15]3)=[N:22][CH:21]=[N:20]1
Reactant: COC(=O)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a solution of 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid methyl ester (393 mg, 1 mmol) in THF (10 mL) at −70° C. was added DIBAL (3 mL, 1 M solution in toluene, 3 mmol) and the reaction mixture stirred at 0° C. for 1 h. The reaction mixture was diluted with methanol (5 mL), then with saturated aqueous sodium potassium tartrate solution. The resultant mixture was extracted with ethyl acetate (3×20 mL), then the combined organic fractions dried (MgSO4) and concentrated in vacuo to give the title compound (370 mg, 100%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N+:6]([O-:8])=[O:7])C.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(O)C>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N+:6]([O-:8])=[O:7])=[N:16][CH:17]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC=C(C(=O)OCC)[N+](=O)[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(Br)cn1)[N+](=O)[O-]
Yield: 63.2 %

Procedure:
A mixture of 2-ethoxy-1-ethoxycarbonyl-1-nitroethene (5.7 g) and 2-amino-5-bromopyridine (5.2 g) in toluene was heated at reflux with slow removal of the ethanol formed during 2 hours. The reaction mixture was cooled and concentrated in vacuo to give a yellow powder which was triturated with hot ethanol, to give 2-(5-bromopyrid-2-ylamino)-1-ethoxycarbonyl-1-nitroethene (6.0 g) in the form of a pale yellow powder, m.p. 141°-142° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:9]=1.[S:18]1[CH2:24][C:22](=[O:23])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:19]1=[S:20].[Cl-].[NH4+].N>C(O)C>[CH2:14]([O:13][C:11]([C:10](=[C:24]1[S:18][C:19](=[S:20])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:22]1=[O:23])[C:8]1[N:9]=[C:5]([NH:4][C:3]([NH:2][CH3:1])=[O:17])[S:6][CH:7]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)NC)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)NC)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 3.17 g of ethyl 2-(3-methylureido)thiazol-4-ylglyoxylate, 2.2 g of rhodanine-3-acetic acid, 1.2 g of ammonium chloride, 1.2 ml of 28% v/v aqueous ammonia and 50 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C@H:8]([O:10][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: BrCCOC1CCCCO1
Product: COC(=O)C1C[C@H](N=[N+]=[N-])[C@@H](OCCOC2CCCCO2)C1

Procedure:
In analogy to example 11A (1R,3S,4S)-3-azido-4-hydroxy-cyclopentanecarboxylic acid methyl ester (CAS 213742-85-9) was reacted with 2-(2-bromoethoxy)tetrahydro-2H-pyran to give (3S,4S)-3-azido-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-cyclopentanecarboxylic acid methyl ester. Light yellow oil. MS 336.3 ([M+H]+).
Reaction SMILES: [B:1](Cl)([C:13]1[C:22]([F:23])=[C:20]([F:21])[C:18]([F:19])=[C:16]([F:17])[C:14]=1[F:15])[C:2]1[C:11]([F:12])=[C:9]([F:10])[C:7]([F:8])=[C:5]([F:6])[C:3]=1[F:4]>C1(C)C=CC=CC=1>[F:4][C:3]1[C:2]([B:1]([C:13]2[C:14]([F:15])=[C:16]([F:17])[C:18]([F:19])=[C:20]([F:21])[C:22]=2[F:23])[C:2]2[C:3]([F:4])=[C:5]([F:6])[C:7]([F:8])=[C:9]([F:10])[C:11]=2[F:12])=[C:11]([F:12])[C:9]([F:10])=[C:7]([B:1]([C:13]2[C:14]([F:15])=[C:16]([F:17])[C:18]([F:19])=[C:20]([F:21])[C:22]=2[F:23])[C:2]2[C:3]([F:4])=[C:5]([F:6])[C:7]([F:8])=[C:9]([F:10])[C:11]=2[F:12])[C:5]=1[F:6]
Reactant: Fc1c(F)c(F)c(B(Cl)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Product: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(B(c3c(F)c(F)c(F)c(F)c3F)c3c(F)c(F)c(F)c(F)c3F)c(F)c2F)c(F)c1F
Temperature: 140 °C
Reaction time: 12 h
Yield: 35.5 %

Procedure:
Into a thick-walled flask containing a J. Young valve, 1,4-C6F4(SnMe3)2 (0.60 g, 1.26 mmol) and (C6F5)2BCl (2.87 g, 7.56 mmol) were added. Toluene (40 mL) was added, the flask was evacuated to 0.1 torr, and the J. Young valve was closed. The flask was heated at 140° C. for 72 h. The solvent was removed in vacuo, and the residue washed with pentane (4×20 mL). The resulting light yellow solid was exposed to dynamic vacuum (10−5 torr) for 12 h, giving the desired product as a microcrystalline pale yellow solid (0.75 g, 71 percent).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7](=[S:27])[NH:8][C:9]1[S:19][C:12]2[CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH2:16][C:11]=2[C:10]=1[C:20]([O:22]C(C)(C)C)=[O:21])=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7](=[S:27])[NH:8][C:9]1[S:19][C:12]2[CH2:13][O:14][C:15]([CH3:17])([CH3:18])[CH2:16][C:11]=2[C:10]=1[C:20]([OH:22])=[O:21])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2F)sc2c1CC(C)(C)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2c(sc(NC(=S)NC(=O)c3ccccc3F)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To tert-butyl 2-(3-(2-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (36 mg, 0.077 mmol) was added a solution of 2,2,2-trifluoroacetic acid (0.75 mL, 9.76 mmol) in CH2Cl2 (1.1 mL) [40% v/v] and the mixture stirred at RT for 1 h. The solvent was evaporated in vacuo and the residue chromatographed using reversed-phase MPLC (0-100% ACN—H2O; 40 g C18 column) to yield 2-(3-(2-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (10.5 mg, 0.026 mmol, 33% yield) as a pale yellow solid. 1H NMR (500 MHz, DMSO) δ 14.70 (s, 1H), 11.94 (s, 1H), 7.72 (apparent d, J=7.3, 1H), 7.65 (s, 1H), 7.38-7.32 (m, 2H), 4.65 (s, 2H), 2.73 (s, 2H), 1.22 (s, 6H). 13C NMR (126 MHz, DMSO) δ 173.69, 165.48, 163.91, 160.34, 158.35, 146.81, 134.19, 134.12, 130.50, 129.19, 124.64, 124.61, 124.24, 122.28, 122.17, 116.60, 116.32, 116.14, 70.20, 58.87, 37.32, 26.23. LCMS retention time: 3.275 min; LCMS purity at 214 nm=99.6%. HRMS m/z calculated for C18H18FN2O4S2 [M++1]: 409.0687. found 409.0687. Melting point 202.8° C., decomposition.
Reaction SMILES: C=O.[CH:3](C1C=C(C=CC=1)C(OC)=O)=O.Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C@H:26]3[CH2:27][NH:28][CH2:29][C@@H:25]3[CH2:24][N:23]([CH3:30])[C:22](=[O:31])[C:21]=2[CH:32]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C@H:26]3[CH2:27][N:28]([CH3:3])[CH2:29][C@@H:25]3[CH2:24][N:23]([CH3:30])[C:22](=[O:31])[C:21]=2[CH:32]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CN1C[C@H]2CNC[C@@H]2c2ccc(F)cc2C1=O
Agent: C=O
Agent: Cl
Product: CN1C[C@@H]2CN(C)C(=O)c3cc(F)ccc3[C@H]2C1

Procedure:
The title compound was prepared according to the procedure outlined in Example 68 substituting formaldehyde for methyl 3-formylbenzoate and substituting (3aR,10bS)-8-fluoro-5-methyl-1,2,3,3a,4,5-hexahydrobenzo[c]pyrrolo[3,4-e]azepin-6(10bH)-one hydrochloride (Example 225B) for Example 2. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (dt, J=16.6, 8.3, 1H), 7.27 (td, J=8.5, 2.8, 1H), 7.18 (dd, J=8.5, 5.6, 1H), 3.36 (ddd, J=19.2, 14.5, 5.7, 3H), 3.15-2.92 (m, 5H), 2.71 (dt, J=25.9, 9.0, 2H), 2.41 (d, J=6.1, 3H), 2.24-2.07 (m, 1H); MS (ESI+) m/z 249.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[S:21]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])(=[O:24])(=[O:23])[NH2:22]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:21](=[O:24])(=[O:23])[NH2:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 17.2 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and o-sulfamoylaniline (180 mg, 1.05 mmol) to give 85 mg of the title compound (17%) after silica gel column chromatography of the crude product with 1% acetic acid/ethyl acetate as an eluent: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 9.36 (s, 1H), 8.01 (d, 1H, J=8.1 Hz), 7.85 (d, 2H, J=8.1 Hz), 7.60 (t, 1H, J=8.1 Hz), 7.58 (s, 2H), 7.32 (t, 1H, J=8.1 Hz), 7.23 (d, 1H, J=2 Hz), 7.16 (d, 1H, J=2 Hz), 5.17~5.27 (m, 1H), 3.07 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=17.1 Hz), 2.71~2.76 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.78~1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[F:12][C:13]1[CH:23]=[C:17]([C:18](OCC)=[O:19])[C:16]([NH2:24])=[CH:15][CH:14]=1.C[O-].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:16](=[CH:15][CH:14]=[C:13]([F:12])[CH:23]=2)[NH:24][C:10]1=[O:11]
Reactant: CCOC(=O)c1cc(F)ccc1N
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A solution of 2,4-dichlorophenyl isocyanate (18.8 g, 0.10 mol) in N-methylpyrrolidone (50 ml) is metered at room temperature into a solution of ethyl 5-fluoroanthranilate (18.3 g, 0.10 mol) in N-methylpyrrolidone (70 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. 1.80 ml of a 30% strength solution of methanolic sodium methoxide (0.010 mol) are metered in and the mixture is stirred under reflux for a further 2 hours, ethanol and methanol being distilled off. After cooling, the product is precipitated by addition of dilute hydrochloric acid (100 ml). The product is then filtered off with suction, washed with water and dried. 29.8 g of 3-(2,4-dichlorophenyl)-6-fluoro-2,4(1H,3H)-quinazolinedione (yield: 91.7% of theory) of melting point 311° to 313° C. are obtained.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1O.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:5][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Oc1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCOc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluorophenol (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(2,4-difluorophenoxy)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=397.1). 1H NMR (DM50-d6, 400 MHz) δ 4.41 (m, 2H), 4.53 (m, 2H), 6.63 (m, 1H), 6.72 (m, 1H), 6.99 (m, 1H), 7.23 (m, 4H), 7.55 (br s, 2H, NH2), 7.92 (s, 1H). Anal. calculated for (C19H14F2N6O2+0.5 H2O): C, 56.30; H, 3.73; F, 9.37; N, 20.73; O, 9.87. Found C, 56.36; H, 3.59; N, 18.51.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:13]=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:27])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>CO>[C:15]([O:19][C:20](=[O:27])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:13][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=Cc1ncccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNCc1ncccc1-c1ccccc1
Yield: 81 %

Procedure:
An anhydrous MeOH solution (2.0 mL) of 3-phenyl-pyridine-2-carbaldehyde (38 mg, 0.21 mmol) (Iqbal, N. et al. J. Med. Chem. 1998, 41, 1827-1837) and (4-Amino-butyl)-carbamic acid tert-butyl ester (40 mg, 0.21 mmol) was stirred overnight at room temperature, after which NaBH4 (16 mg, 0.41 mmol) was added and the reaction mixture stirred for an additional hour. The solvent was removed in vacuo and the residue dissolved in CH2Cl2 (15 mL) and treated with saturated aqueous NaHCO3 (25 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford {4-[(3-Phenyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (59 mg, 0.17 mmol) as a yellow oil. The yellow oil was used without further purification.
Reaction SMILES: [CH2:1]([C:3]([CH3:10])([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH:19][OH:20].N1C=CC=CC=1>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][N:19]1[C:4](=[O:5])[C:3]([CH2:1][CH3:2])([CH3:10])[C:7](=[O:8])[O:20]1
Reactant: CCC(C)(C(=O)Cl)C(=O)Cl
Reactant: ONCc1ccccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(C)C(=O)ON(Cc2ccccc2Cl)C1=O
Yield: 68.1 %

Procedure:
This compound was prepared in the manner of Example IV, using 8.2 grams (0.045 mole) of 2-ethyl-2-methylmalonyl dichloride, 7.1 grams (0.045 mole) of N-(2-chlorophenylmethyl)hydroxylamine and 16 ml of pyridine in 184 ml of methylene chloride. After purification on a silica gel column, 8.2 grams of 2-[(2-chlorophenyl)methyl]-4-ethyl-4-methylisoxazolidine-3,5-dione were obtained as an oil. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][S:2][CH:3]([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[Cl:14][C:15]1[C:19]([NH:20][CH2:21][C:22]#[CH:23])=[CH:18][N:17]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:16]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[Cl:14][C:15]1[C:19]([N:20]([CH2:21][C:22]#[CH:23])[C:4](=[O:5])[CH:3]([S:2][CH3:1])[CH3:7])=[CH:18][N:17]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:16]=1
Reactant: CSC(C)C(=O)O
Reactant: C#CCNc1cn(-c2cccnc2)nc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCN(C(=O)C(C)SC)c1cn(-c2cccnc2)nc1Cl
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 2-(methylthio)propanoic acid (0.36 g, 3.00 mmol) in DCM (3 mL) was added oxalyl dichloride (0.29 ml, 3.31 mmol) followed by one drop of DMF. The reaction mixture was stirred for 30 min before all of the solvent was evaporated. The resulting residue was dissolved in DCM (2 mL) and the solution was added to a pre-stirred solution of 3-chloro-N-(prop-2-yn-1-yl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.35 g, 1.50 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.57 ml, 3.31 mmol) in DCM (5.5 mL). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and the residue was purified using silica gel chromatography (0-100% EtOAc/hexanes) to afford the title compound as a yellow oil (432 mg, 1.23 mmol, 85%): 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.5 Hz, 1H), 8.66-8.60 (m, 1H), 8.25 (s, 1H), 8.08-8.01 (m, 1H), 7.49-7.42 (m, 1H), 4.86 (s, 1H), 4.29-3.97 (m, 1H), 3.31 (d, J=6.5 Hz, 1H), 2.30-2.24 (m, 1H), 2.09 (s, 3H), 1.46 (d, J=6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.30, 148.66, 140.71, 140.18, 135.71, 127.87, 126.35, 124.11, 122.12, 78.53, 72.92, 53.39, 37.97, 16.42, 11.07; ESIMS m/z 335 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:5]([N+:14]([O-])=O)=[C:4]([N+:17]([O-])=O)[C:3]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.[OH-].[Na+]>[Fe].C(O)(=O)C>[F:8][C:7]1[C:2]([F:1])=[C:3]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:4]([NH2:17])=[C:5]([NH2:14])[C:6]=1[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1c(-c2cccs2)c(F)c(F)c(-c2cccs2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1c(N)c(-c2cccs2)c(F)c(F)c1-c1cccs1
Yield: 83.6 %

Procedure:
2,3-difluoro-1,4-di(2-thienyl)-5,6-dinitro-benzene (3.0 g, 8.15 mmol), iron powder (5.5 g, 98 mmol) and acetic acid (100 ml) were stirred at 45° C. for 4 h. Then the mixture was poured into cold 5% NaOH solution (250 ml) and extracted with diethyl ether three times. The ether phase was washed with NaHCO3 solution, dried over MgSO4 and concentrated. Purification with column chromatograph afforded 2,3-difluoro-1,4-di(2-thienyl)-5,6-diamino-benzene as yellow powder (2.1 g, 84%). 1H and 19F NMR spectra were as expected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([NH:17][NH:18][CH:19]=O)[N:14]([CH3:21])[C:13](=[N:22][C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]3[CH:19]=[N:18][N:17]=[C:15]3[N:14]([CH3:21])[C:13](=[N:22][C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(NNC=O)n2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c3nncn23)cc1OC
Temperature: 110 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
The mixture of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-(2-formylhydrazino)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.81 g) and polyphosphoric acid (8.2 g, 116% as phosphoric acid) was stirred at 110° C. for 2 hours and cooled to ambient temperature. The reaction mixture was poured into water and neutralized with aqueous sodium hydroxide solution. The precipitates were collected by filtration and washed with water to give 7,8-dihydro-5-(3,4-dimethoxyphenyl)-8-methyl-7-(2,4,6-trimethylphenylimino)-1,2,4-triazolo[4,3-a]pyrimidine (0.65 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)cn1
Yield: 102.9 %

Procedure:
A solution of the compound (373 mg, 0.73 mmol) obtained in Example 32-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (297 mg, quant.) as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13]1([S:19]([O-:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>CN(C)C=O.O>[C:13]1([S:19]([CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Cc1cccc2ccccc12)c1ccccc1

Procedure:
A solution of 1-(chloromethyl)-naphthalene (17.6 g) in dimethyl formamide (20 ml) was added to a stirred suspension of sodium benzenesulphinate (16.4 g) in dimethyl formamide (80 ml). After 20 hours at room temperature the mixture was diluted with water and the white precipitate filtered. Recrystallisation from ethyl acetate-petroleum ether 60°-80° C. gave the title product, m.p. 89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1ccccc1
Yield: 112.3 %

Procedure:
Following General Procedure A, the title compound (819 mg, 100%) was prepared from 2-amino-4-chlorobenzenethiol (700 mg, 4.39 mmol), (bromomethyl)benzene (560 mg, 2.92 mmol), K2CO3 (2.0 g, 14.62 mmol) in DMF (20 ml).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH2:11]([C@@:14]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:19][CH2:18][N:17]([C@H:20]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH3:21])[C:16](=[O:29])[NH:15]1)[CH:12]=[CH2:13]>>[CH2:11]([C@@:14]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:19][CH2:18][N:17]([C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:24][CH:23]=2)[CH3:21])[C:16](=[O:29])[NH:15]1)[CH:12]=[CH2:13]
Reactant: C=CC[C@@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reactant: OB(O)c1ccc(F)cc1
Product: C=CC[C@@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)N1

Procedure:
(S)-4-allyl-1-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one was prepared following a procedure analogous to that described in Example 4 using 4-fluorophenylboronic acid and (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:19]([OH:22])(=[O:21])[CH3:20].Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:20]([C:19]([OH:22])=[O:21])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a round bottom flask containing 3-(4-fluorophenyl)-1H-indazole-5-carbonitrile (8.05 g, 0.034 mol) was added acetic acid (250 mL) and concentrated HCl (250 mL). The reaction was heated to reflux temperature for 7.5 hours and then 105° C. for two and one half-hours. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and a solid crashed out of solution. The solid was collected by filtration and dried in a low temperature oven to yield the title compound (7.5 g, 86% yield). 1H NMR (DMSO-d6) δ 13.6 (br s, 1H), 13.0 (br s, 1H), 8.64 (s, 1H), 8.0-7.9 (m, 3H), 7.68 (d, 1H), 7.42 (t, 2H); ES-MS (m/z) 301 [M+1]+.