Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C:16]([C:21]1[N:26]=[N:25][C:24]([S:27][CH3:28])=[N:23][C:22]=1Cl)([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:22]3[N:23]=[C:24]([S:27][CH3:28])[N:25]=[N:26][C:21]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(SC)nc1Nc1ccc2[nH]cc(CCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 6-carbethoxy-5-chloro-3-methylthio-1,2,4-triazine [Pesson, M. et al., Eur. J. Med. Chem., 269 (1972)] were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Chromatography afforded the title compound (53%) as an orange solid: mp, 197.0°-199.0° C. with effervescence; 13C NMR (DMSO-d6) δ173.2, 165.5, 150.5, 133.9, 132.5, 127.7, 127.1, 123.9, 116.8, 113.0, 112.2, 111.5, 62.0, 60.0, 45.2, 23.1, 14.0, 13.2; LRMS (m/z, relative intensity) 400 (M30 , 11 ), 386 (5), 195 (11), 163(13), 58 (100). Anal. calcd. for C19H24N6O2S.0.3 H2O: C, 56.22 ; H, 6.11; N, 20.70. Found: C, 55.50; H, 5.89; N, 20.33.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:37][O:38][C:39](=[O:42])[CH2:40][NH2:41]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:41][CH2:40][C:39]([O:38][CH3:37])=[O:42])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)CN
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Yield: 34.7 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (1.18 g, 3.00 mmol) and triethylamine (1.51 g, 15.00 mmol) in ethanol (30 ml) was treated with glycine methyl ester hydrochloride (1.88 g, 15.00 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (90:10) gradually changing to hexane:ethyl acetate (50:50) to afford the title compound (456 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH2:34](Br)[C:35]#[CH:36]>>[CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:5]([CH2:36][C:35]#[CH:34])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: C#CCBr
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Product: C#CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Yield: 103 %

Procedure:
In a manner analogous to that described in Example 45(i), from 5.0 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1,1,2(R)-pentanetricarboxylate and 3.3 g of propargyl bromide there were obtained 5.58 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-yn-1-yl)-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS 493 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][S:15]SC.[OH-].[Na+]>CC(N(C)C)=O.[Cu]>[CH3:14][S:15][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CSSC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CSc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 135 °C
Reaction time: 1.5 h

Procedure:
A stirred mixture of 2-chloro-4-nitrobenzoic acid (24.2 g, 120 mmol), methyldisulfide (5.6 mL), copper powder (7.6 g) in 160 mL of DMA was heated to 135° C. during 1 hours, kept at that temperature for 90 minutes, and then heated at 165° C. for 2 hours. After the reaction was completed, the solvent was removed in vacuum to afford the crude compound, which was poured into 40% w/v aqueous sodium hydroxide solution. The mixture was filtered and the filtrate was washed with EtOAc and the aqueous layer was acidified with concentrated aqueous hydrochloric acid and filtered. The solid residue was washed with water and then dissolved in EtOAc, and the solution was dried over anhydrous Na2SO4 and evaporated to dryness under reduced pressure. The residue was crystallized from aqueous EtOH to give 2-(methylsulfanyl)-4-nitrobenzoic acid. 1H-NMR (400 MHz, MeOD) δ ppm 8.2˜8.33 (rn, 1H), 8.12˜8.17 (m, 1H), 7.95˜7.98 (m, 1H), 2.53 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(O)(=O)C.[CH2:22]([SH:25])[CH2:23][SH:24].B(F)(F)F>C(Cl)Cl>[C:12]1([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH:2]=[CH:3][C:4]=4[CH:9]=3)[S:25][CH2:22][CH2:23][S:24]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: SCCS
Reactant: O=C(c1ccccc1)c1ccc2occc2c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(C2(c3ccc4occc4c3)SCCS2)cc1
Reaction time: 8 h

Procedure:
To a solution of benzofuran-5-yl(phenyl)methanone (2.45 g, 11.0 mmol), glacial acetic acid (1.27 mL, 22.0 mmol) and 1,2-ethanedithiol (1.39 mL, 16.5 mmol) in 30 mL DCM at ambient temperature was added boron trifluoride diethyletherate (1.38 mL, 11.0 mmol). The reaction was allowed to stir overnight, and was quenched by the addition of 1N NaOH. The aq. layer was extracted 1×DCM, and the combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography, ISCO, 0-20% EtOAc/hexanes provided 5-(2-phenyl-1,3-dithiolan-2-yl)benzofuran as a clear/colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.48-7.57 (m, 3H), 7.38-7.45 (m, 1H), 7.29-7.36 (m, 2H), 7.24 (t, J=7.3 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H) 3.43 (s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([C@@H:19]3[CH2:23][CH2:22][CH2:21][O:20]3)[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:24]C(=O)C1C=CC=CC=1)=[N:10]2.Cl.C1([C@@H]2OC[C@]3(C4C=CC(F)=CC=4F)N=C(N)S[C@H](CF)[C@@H]3C2)CC1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([C@@H:19]3[CH2:23][CH2:22][CH2:21][O:20]3)[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH2:24])=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H]([C@@H]3CCCO3)C[C@H]2CS1)c1ccccc1
Agent: Cl
Agent: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@H]2[C@@H](CF)S1
Product: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H]([C@@H]3CCCO3)C[C@H]2CS1

Procedure:
N-{(4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-[(2S)-tetrahydrofuran-2-yl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide (C103) was converted to the product using the method described for the synthesis of (4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine, hydrochloride salt (6) in Example 6. Purification by reversed phase HPLC {Column: Phenomenex Gemini C18, 8 μm; Gradient: 36% to 56% acetonitrile in water [ammonia (pH 10)]} provided the product as a white solid. Yield: 193 mg, 0.545 mmol, 25%. LCMS m/z 355.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.31-7.37 (m, 1H), 6.75-6.87 (m, 2H), 4.06 (dd, J=11, 2.0 Hz, 1H), 3.73-3.90 (m, 4H), 3.51 (ddd, J=10.8, 6.5, 2.3 Hz, 1H), 2.95 (dd, J=12.0, 4.0 Hz, 1H), 2.83-2.89 (m, 1H), 2.60 (dd, J=12.3, 2.3 Hz, 1H), 1.97-2.05 (m, 1H), 1.73-1.94 (m, 4H), 1.64-1.69 (m, 1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][C:34](O)=[O:35])[C:28]2=[O:37])=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:34](=[O:35])[CH2:33][N:29]2[CH2:30][CH2:31][CH2:32][C:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[C:28]2=[O:37])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylpiperazine (0.227 g, 0.90 mmol) in dichloromethane (15 mL) under nitrogen was added the product of Example 90D (0.31 g, 0.90 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.344 g, 1.80 mmol) and N,N-dimethylpyridin-4-amine (0.011 g, 0.09 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.42 (m, 4H), 7.15-7.32 (m, 10H), 6.93-7.00 (m, 4H), 4.23 (s, 1H), 4.16 (s, 2H), 3.62-3.66 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.40-3.45 (m, 2H), 2.55-2.65 (m, 2H), 2.36-2.43 (m, 4H), 1.77-1.86 (m, 2H); MS (DCI+) m/z 580 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:49]=[C:48]([N:50]([CH2:52][CH2:53][N:54]([CH3:56])[CH3:55])[CH3:51])[CH:47]=[CH:46][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:8]=1)=[O:5].[O:57]1[CH2:62][CH2:61][C:60](=O)[CH2:59][CH2:58]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:25][C:23]1[CH:24]=[C:19]([S:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[NH:6][C:4](=[O:5])[C:3]2[CH:46]=[CH:47][C:48]([N:50]([CH2:52][CH2:53][N:54]([CH3:55])[CH3:56])[CH3:51])=[CH:49][C:2]=2[NH:1][CH:60]2[CH2:61][CH2:62][O:57][CH2:58][CH2:59]2)(=[O:18])=[O:17])[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: CN(C)CCN(C)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N)c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-benzamide (400 mg, 0.52 mmol) in dichloromethane (5 mL) were added tetrahydro-pyran-4-one (0.071 mL, 0.78 mmol), trifluoroacetic acid (0.108 mL, 1.4 mmol) and tetramethylammonium triacetoxyborohydride (205 mg, 0.78 mmol). The mixture was stirred at room temperature overnight, then additional trifluoroacetic acid (0.8 mL) and tetramethylammonium triacetoxyborohydride (410 mg) were added. After stirring for additional 3 hours at room temperature the mixture was diluted with dichloromethane, washed with saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH4OH 96:4:0.5 as the eluant, affording 175 mg of the title compound as a pale yellow solid.
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([O:13][C:14]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.C([O:36][C:37](=[O:50])[C:38]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][C:39]=1[O:45][CH2:46][CH2:47][O:48][CH3:49])C>CC#N>[C:9]([O:13][C:14]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([NH:44][C:42]1[CH:41]=[CH:40][C:39]([O:45][CH2:46][CH2:47][O:48][CH3:49])=[C:38]([CH:43]=1)[C:37]([OH:50])=[O:36])=[O:25])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CCOC(=O)c1cc(N)ccc1OCCOC
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: CC#N
Product: COCCOc1ccc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)ccc2Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (166 μL; 1.25 mmol) was added to a mixture of 5-(tert-butoxycarbonylamino)methyl-2-chloro benzoic acid (263 mg; 0.92 mmol) in MeCN (10 mL) and stirred at rt for 15 min. Pyridine (198 μL; 2.51 mmol) and 5-amino-2-(2-methoxyethoxy)-benzoic acid ethyl ester (200 mg; 0.84 mmol) was added and it was stirred at rt overnight. The mixture was filtered through a pad of Alox B, washed with DMF/MeOH 9/1 and concentrated i. vac. The residue was mixed with 15 mL MeOH and 15 mL 2 M aq NaOH and stirred for 3 days at rt. After concentration, the residue was diluted with 10 mL 4M aq. HCl, extracted with EtOAc, dried with Na2SO4 and concentrated i. vac. The crude was mixed with 50 mL Dioxan; 5 mL H2O and di-tert-butyldicarbonate (200 mg), stirred at rt for 2 h and concentrated. Yield: 380 mg (95%); MS: [M+H]+=479 (Cl isotope pattern); HPLC: Rt=2.01 min (Method CC-4)
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13]O)[C@@H:10]([OH:11])[C@H:8]1[OH:9]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Yield: 92.1 %

Procedure:
The 5-Fluorouridine derivative obtained in Example 4 (1.77 g, 6.18 mmol) was dissolved in a 90% by weight aqueous solution of CF3COOH (10 ml) and reacted at a room temperature for 1 hour with stirring. After the reaction, the reaction mixture was evaporated under a reduced pressure. The residue was recrystallized from methanol to obtain white crystalline 5'-deoxy-5-fluorouridine (1.40 g, 5.69 mmol. Yield, 92.1%) of the formula: ##STR14##
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][NH:3]1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:17][CH:14]1[CH2:15][CH2:16][CH:11]([N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)=[N:9]2)[CH2:12][CH2:13]1
Reactant: NC(=O)c1cc(-c2nn(C3CCC(=O)CC3)c3cc[nH]c(=O)c23)cs1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: NC(=O)c1cc(-c2nn(C3CCC(O)CC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 4-(4-oxo-1-(4-oxocyclohexyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (40.0 mg) obtained in Example 170 in methanol (5 mL) was added sodium borohydride (8.49 mg) at 0° C., and the mixture was stirred overnight under nitrogen atmosphere at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (cis/trans mixture, 30.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH:25]([F:27])[F:26])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C1COCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH:25]([F:27])[F:26])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F

Procedure:
The crude (3-Chloro-4-fluoro-phenyl)-[7-(2,2-difluoro-ethoxy)-6-nitro-quinazolin-4-yl]-amine was dissolved in THF and reduced using Raney nickel catalyst to yield N4-(3-Chloro-4-fluoro-phenyl)-7-(2,2-difluoro-ethoxy)-quinazoline-4,6-diamine.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][OH:20])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=[O:20])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCCO)cc1-c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propan-1-ol (200 mg, 0.774 mmol), PCC (334 mg, 1.548 mmol), SiO2 (334 mg) was added with 5 mL of CH2Cl2 under nitrogen atmosphere and stirred for 5 hrs at room temperature. The progress and completion of the reaction were confirmed by means of TLC. Upon completion of the reaction, the reaction mixture was cooled down to room temperature and the solvent was removed from the reaction mixture under reduced pressure. The reaction mixture was diluted with EtOAc, and added with water. The aqueous layer was extracted with EtOAc and the organic layer was dried with anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure and the resulting concentrate was passed through column chromatography (Ether:Hexane=2:3, v/v) to obtain 149 mg (75%) of target compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]([F:23])([F:21])[F:22])=[CH:10][C:9]2[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH:38]=[CH:37][CH:36]=[N:35]4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cccn3)c1)=N2

Procedure:
The title compound was prepared from {5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M119) (0.49 g, 0.85 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (324 mg, 83%).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:7]2[C:8]3[CH:9]=[C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=O)[NH:12][C:13]=3[CH:14]=[CH:15][C:6]2=[N:5][N:4]=1.O=P(Cl)(Cl)[Cl:26]>C(#N)C>[Cl:26][C:11]1[N:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:7]1[C:3]([CH:2]([F:23])[F:1])=[N:4][N:5]=[C:6]1[CH:15]=[CH:14]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc3nnc(C(F)F)n3c2cc1-c1ccccc1
Solvent: CC#N
Product: FC(F)c1nnc2ccc3nc(Cl)c(-c4ccccc4)cc3n12
Temperature: 140 °C

Procedure:
A mixture of 1-(difluoromethyl)-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridin-7(6H)-one (10-1) (19 g, 61 mmol) and POCl3 (28 mL, 304 mmol) in acetonitrile (95 mL) was heated under microwave irradiation at 140° C. for 2 hours. The solvent was removed under reduced pressure, and to the residue was added water. The resulting solid was collected by filtration to give 7-chloro-1-(difluoromethyl)-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridine (10-2) as pale yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[O:24]=[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][C:14]=2[CH:1]=1)[CH2:16][CH:17]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccccc1)c1ccc2c(ccc3ccccc32)c1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc2c(ccc3ccccc32)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(2-phenanthrenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-oxo-3-(2-phenanthrenyl)-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>C(#N)C.O>[CH2:10]([NH:14][CH2:15][CH2:16][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCC
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CC#N
Product: CCCCNCCc1cc(Cl)nc(C)n1
Yield: 99.7 %

Procedure:
A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10 mmol) in 5 ml of acetonitrile was treated with N-butyl-ethyl-amine (2.000 g, 20 mmol) and heated at reflux for 0.5 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 2.271 g (100%) of title compound as a light-brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.13 (t, 3H), 1.22-1.36 (m, 2H), 1.45-1.6 (m, 2H), 2.43 (s, 3H), 3.25-3.60 (m, 4H), 6.15 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[C:9]([CH3:15])[CH:8]=[C:7]2O)[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[CH:8]=[C:9]([CH3:15])[N:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([CH3:14])=[N:12]2
Reactant: CCOc1cc2c(O)cc(C)nc2nc1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(Cl)cc(C)nc2nc1C
Temperature: 95 °C

Procedure:
6-Ethoxy-2,7-dimethyl-1,8-naphthyridin-4-ol (2.77 g) was added to phosphorus oxychloride (25 ml) at ambient temperature. The mixture was then heated at 95° C. for 1 hour. The mixture was worked up as described in example B1 to give 5-chloro-3-ethoxy-2,7-dimethyl-1,8-naphthyridine, m.p. 144°-7° C.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:9](=[O:20])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2F)[C:7]#[N:8])[CH2:3][CH2:2]1.[H-].[Na+].CCCCCC>O1CCOCC1>[CH:1]1([N:4]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13]([F:17])[C:14]=3[F:16])[C:9](=[O:20])[C:6]([C:7]#[N:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: N#CC(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1COCCO1
Product: N#Cc1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A solution of 3-cyclopropylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (12.0 g) in dioxane (60 ml) is added dropwise to a suspension of sodium hydride (1.9 g, in oil, 55-65 w/w%) in dioxane (40 ml) while maitainig the internal temperature between 16° C. and 18° C. on an ice bath. The mixture is stirred for 6 hours with heating while keeping the internal temperature around 45° C. The reaction mixture is poured into hexane (300 ml), and the resulting precipitate is filtered and washed with hexane and water to yield 1-cyclopropyl-3-cyano-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline (10.2 g) as a colorless powder, m.p. 217°-218° C.