Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A solution of 4-chloro-3-nitrobenzoyl chloride (1.00 g, 4.99 mmol) in dry methylene chloride (20 mL) under a nitrogen atmosphere was treated with 2-amino-5-chloropyridine (643 mg, 4.99 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol), and the resulting mixture stirred at room temperature for 18 hours. The solvent was removed by rotary evaporation in vacuo, the residue taken up in ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate (50 mL), water (2×50 mL), and brine (50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 5% ethyl acetate/methylene chloride afforded the title compound as a dark yellow solid (660 mg, 42%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[Br:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>O1CCCC1.CCCCCC>[Br:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:37]=[CH:38][CH:39]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCCCCBr
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC=Cc1cccc(Br)c1
Reaction time: 0.25 h

Procedure:
To 14.7 gm of the Wittig salt prepared from 1-bromopentane and triphenylphosphine in 80 ml of tetrahydrofuran at 0° C. is added 22.5 ml of n-butyl lithium (1.6M) in hexane. The mixture is stirred for 15 minutes, and 3.8 ml of 3-bromobenzaldehyde is added. This mixture is stirred for 30 minutes; and after concentrating and diluting with ether, the solids are filtered off. Further concentration of the filtrate and chromatography over silica gel eluting with 3:2 hexane:ether yields pure 3-bromo-(1-hexenyl)benzene as a clear oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:29](=[O:30])[O:28][CH2:27][C:26]=1[N:31]1[CH2:35][CH2:34][C:33]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:32]1=[O:41].C([BH3-])#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Si:1]([O:8][CH2:9][CH:10]([N:38]1[CH2:39][CH2:40][C:33]2([C:32](=[O:41])[N:31]([C:26]3[CH2:27][O:28][C:29](=[O:30])[C:25]=3[CH3:24])[CH2:35][CH2:34]2)[CH2:36][CH2:37]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(CC(=O)CO[Si](C)(C)C(C)(C)C)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CC1=C(N2CCC3(CCN(C(CO[Si](C)(C)C(C)(C)C)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)-2-oxopropyl)-4-methylisobenzofuran-1(3H)-one (0.50 g, 1.5 mmol) in methanol (20 mL) was added 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17) (0.45 g, 1.8 mmol) and titanium(IV) isopropoxide (2.10 g, 7.5 mmol). After stirring at for room temperature 48 h, sodium cyanoborohydride (190 mg, 3.0 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water (10 mL), and the resulting inorganic precipitate was filtered off and washed with methanol (50 mL). The filtrate was then concentrated and the crude product was dissolved in ethyl acetate, filtered to remove the remaining inorganic solids, and concentrated. The residue was purified by flash column chromatography (0-10% methanol in dichloromethane) to give the title compound. LC-MS (ESI, m/z): 569 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[C:23]3[C:19]=2[CH2:20][CH2:21][CH2:22]3)=[CH:13][C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9](=[O:12])[NH:10][N:11]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[C:23]3[C:19]=2[CH2:20][CH2:21][CH2:22]3)=[CH:13][C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9](=[O:12])[NH:10][N:11]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1Cc1ccc(=O)[nH]n1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(O)c(Cc3ccc(=O)[nH]n3)c1)CCC2
Yield: 39.7 %

Procedure:
To a solution of 6-[2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzyl]-2H-pyridazine-3-one (704 mg) in acetic acid (10 mL) was added hydrobromic acid (48%, 10 mL). The mixture was heated at reflux temperature under an argon atmosphere overnight. After adding water, the reaction mixture was extracted with dichloromethane. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from a small amount of ethyl acetate to give the title compound (270 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc(O)nc(N)n2)cc1
Product: COc1ccc(-c2cc(Cl)nc(N)n2)cc1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 75 %

Procedure:
A mixture of compound 2-amino-6-(4-methoxy-phenyl)-pyrimidin-4-ol (18 g, 83 mol) obtained in step (ii) and phosphorus oxychloride (POCl3) (150 mL) was stirred at 100° C. under anhydrous condition for 5 to 8 hours. The initial turbidity disappeared after completion of the reaction and excess phosphorus oxychloride was then removed by distillation under low vacuum. The residue was diluted with aqueous sodium bicarbonate solution to reach the pH˜7-8. The white solid separated was filtered, washed with water, and dried under vacuum to afford the desired product (15 g). Yield: 75%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:27]=[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:11]([O:18][C:19]1[CH:27]=[C:22]2[CH2:23][N:24]([C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[O:7])[CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(COc2cc3n(n2)CCNC3)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCn2nc(OCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
4-Fluorobenzoyl chloride (0.36 mL, 3.04 mmol) was added to a stirred solution of 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.71 g, 2.53 mmol) and triethylamine (0.65 mL, 3.8 mmol) in DCM (25 mL) under nitrogen at 0° C. The mixture was stirred at room temperature for 16 hours, diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 2-(benzyloxy)-5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.73 g, 83% yield) as a white solid. C20H18FN3O2. 1H NMR (400 MHz, CDCl3) δ ppm 4.10 (br. s., 4H), 4.73 (br. s., 2 H), 5.18 (s, 2 H), 5.50 (br. s., 1 H), 7.10-7.19 (m, 2 H), 7.29-7.35 (m, 1 H), 7.35-7.41 (m, 2 H), 7.41-7.46 (m, 2 H), 7.46-7.51 (m, 2 H).
Reaction SMILES: Br[C:2]1[C:3]([C@@H:14]([NH:24][C:25](=[O:31])OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=[N:4]C(N2CC(O)(C)C2)=CC=1.Cl[C:33]1[N:38]=[C:37]([C@@H:39]([NH:49][C:50](=[O:67])[CH2:51][N:52]2[C:56]3[C:57]([F:62])([F:61])[C@@H:58]4[CH2:60][C@@H:59]4[C:55]=3[C:54]([C:63]([F:66])([F:65])[F:64])=[N:53]2)[CH2:40][C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=2)[C:36]([C:68]2[CH:69]=[CH:70][CH:71]=[C:72]3[C:76]=2[N:75]([CH3:77])[N:74]=[C:73]3[NH:78][S:79]([CH3:82])(=[O:81])=[O:80])=[CH:35][CH:34]=1.BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(Br)=CC=1>>[NH2:4][CH:3]1[CH2:14][N:24]([C:33]2[N:38]=[C:37]([C@@H:39]([NH:49][C:50](=[O:67])[CH2:51][N:52]3[C:56]4[C:57]([F:62])([F:61])[C@@H:58]5[CH2:60][C@@H:59]5[C:55]=4[C:54]([C:63]([F:66])([F:65])[F:64])=[N:53]3)[CH2:40][C:41]3[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=3)[C:36]([C:68]3[CH:69]=[CH:70][CH:71]=[C:72]4[C:76]=3[N:75]([CH3:77])[N:74]=[C:73]4[NH:78][S:79]([CH3:82])(=[O:81])=[O:80])=[CH:35][CH:34]=2)[C:25](=[O:31])[CH2:2]1
Reactant: Cn1nc(NS(C)(=O)=O)c2cccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Reactant: CC1(O)CN(c2ccc(Br)c([C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)n2)C1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)ccc1Br
Product: Cn1nc(NS(C)(=O)=O)c2cccc(-c3ccc(N4CC(N)CC4=O)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21

Procedure:
Compound 43B was prepared according to the method presented in the synthesis of compound 42G of Example 42 substituting N—((S)-1-(6-chloro-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (43A) for (S)-Atert-butyl (1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (42F). 1H NMR (400 MHz, methanol-d4) δ 8.69-8.34 (m, 2H), 7.91-7.67 (m, 2H), 7.38-6.89 (m, 1H), 6.93-6.52 (m, 1H), 6.48-6.14 (m, 2H), 5.39-4.92 (m, 1H), 4.84-4.70 (m, 2H), 4.69-4.33 (m, 2H), 4.27 (m, 1H), 3.48-2.72 (m, 10H), 2.62-2.28 (m, 2H), 1.61-1.27 (m, 1H), 1.08 (m, 1H). MS (m/z) 820.00[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C([N:20](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([NH2:20])=[O:17])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CCc1conc1-c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a mixture of 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (1.28 g), triethylamine (1.1 ml) and tetrahydrofuran (100 ml) was added ethyl chlorocarbonate (0.6 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (15 ml) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.91 g, yield 71%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 158–159° C.
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Cl[CH2:38][C:39]([N:41]([CH2:43][CH2:44][O:45][CH3:46])[CH3:42])=O>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]([CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=3[CH2:19]2)=[C:10]([NH:9][CH2:8][CH2:6][C:5]2[CH:35]=[CH:36][C:2]([O:1][CH2:38][CH2:39][N:41]([CH2:43][CH2:44][O:45][CH3:46])[CH3:42])=[CH:3][CH:4]=2)[CH:15]=1
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Product: COCCN(C)CCOc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 50.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)CO>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:17][CH:16]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: Nc1ccc(F)cc1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(F)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-4-fluorobenzene (12b, 91 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 2b (187 mg, 80%); mp: 197-199° C.; 1H NMR (300 MHz, CDCl3) δ 10.61 (s, 1H), 8.63 (brs, 1H), 8.24 (dd, J=4.4, 1.4 Hz, 1H), 7.98 (dd, J=, 8.0, 1.8 Hz, 1H), 7.64 (s, 1H), 7.63-7.58 (m, 2H), 7.41 (s, 1H), 7.23 (s, 1H), 6.98 (t, J=8.4 Hz, 2H), 6.88 (t J=8.4 Hz, 2H), 6.69-6.65 (m, 1H), 5.44 (s, 2H), 4.63 (d, J=5.5 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 421 [M+H]+. Yield: 80%
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[CH3:4][C:5](/[CH:12]=[CH:13]/[CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[K+].[BH4-].[Na+]>O>[CH2:1]([O:3][C:19]([CH3:20])([CH3:21])[CH2:18][CH2:17][CH2:16][CH:15]([CH3:22])[CH2:14]/[CH:13]=[CH:12]/[C:5]([CH3:4])=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C=C(C)/C=C/CC(C)CCC=C(C)C
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C=C(C)/C=C/CC(C)CCCC(C)(C)OCC
Reaction time: 8 h

Procedure:
Fifteen grams of mercuric acetate in 50 ml. of dry ethanol is added to 12 g. of trans ethyl 3,7,11-trimethyldodeca-2,4,10-trienoate in 30 ml. of dry ethanol cooled in an ice bath. The temperature is allowed to come to room temperature by standing overnight. Then the mixture is cooled to 0°, 10 g. of potassium hydroxide in 150 ml. of ethanol is added followed by addition of 1.0 g. of sodium borohydride in small portions. After about 30 minutes at 0°, water is added and mixture left at room temperature for 2 hours. The mixture is filtered, filtrate concentrated and extracted with ether. The ethereal extract is washed, dried, and evaporated to yield trans ethyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate which is purified by distillation or chromatography.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[S:12])=O)=[CH:3][CH:2]=1.Cl>[OH-].[Na+]>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11]([SH:12])=[N:10][N:9]=2)=[CH:3][CH:2]=1
Reactant: O=C(NNC(=S)Nc1ccccc1F)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccccc1-n1c(S)nnc1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
1-(Biphenyl-4-carbonyl)-4-(2-fluorophenyl)thiosemicarbazide (12.1 g) was suspended in aqueous 2 mol/liter sodium hydroxide solution (300 ml), and refluxed under heating for 3 hours. After the reaction solution was cooled to ambient temperature, the solution was neutralized under ice cooling with conc. hydrochloric acid. The precipitate was filtered and washed with water, to afford 5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole-3-thiol as pale yellow solid (11.2 g, 97%). The physico-chemical values are as follows.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([OH:24])[CH3:23])=[C:14]([F:25])[CH:13]=3)[CH2:9]1)=O)(C)(C)C>O1CCOCC1.Cl>[F:25][C:14]1[CH:13]=[C:12]2[C:17]([N:18]3[C@H:10]([CH2:11]2)[CH2:9][NH:8][CH2:20][C@H:19]3[CH3:21])=[N:16][C:15]=1[C@@H:22]([OH:24])[CH3:23]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)c([C@@H](C)O)nc3N21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](O)c1nc2c(cc1F)C[C@@H]1CNC[C@@H](C)N21
Yield: 69.9 %

Procedure:
A solution of 0.010 g (4R,9aR)-7-fluoro-6-[1-(R)-hydroxy-ethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 1 mL dioxane and 0.1 mL 2M hydrochloric acid was kept at room temperature for 30 min. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia (100:10:1) to yield 0.005 g 1-(S)-[(4R,9aR)-7-fluoro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl]-ethanol as a colorless gum.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[O:22])[C:19]([OH:21])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH3:23][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[O:22])[C:19]([O:21][CH3:23])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1sc(C)c(-c2ccc3c(c2)CCCO3)c1C(=O)C(=O)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(=O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]-2-oxoacetic acid (42a) (1.09 g, 3.43 mmol) in methanol (10 mL) was cooled to 0° C. Trimethylsilyldiazomethane 2N in diethyl ether (6.89 mL, 13.7 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The precipitate was filtered off and washed with cooled methanol (5 mL). The filtrate was concentrated in vacuo and the residue was dissolved in a minimum of methanol. The solution was sonicated for a few seconds and the precipitate was filtered and washed with cooled methanol. The precipitates were combined to provide the desired ester (42b) (820 mg, 2.48 mmol, 72% over two steps) as a beige solid, which was used without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][Si:11]([CH3:15])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:16]>CCO>[ClH:16].[CH3:14][Si:11]1([CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C[Si]1(C)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: C[Si]1(C)CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.6 %

Procedure:
To a solution of 4,4-dimethyl-1,4-azasilinane 3 (2.3 g, 10.5 mmol) in EtOH (20 mL), 6N hydrochloricacid (1.75 mL, 10.5 mmol) is added and the solvent is removed under reduced pressure. The reaction mixture is co-evaporated with EtOH (2×10 mL) and recrystallized from EtOH-diethyl ether. To a slurry of Pd/C (50 mg) in EtOH (15 mL) an ethanolic solution of above prepared HCl salt is added drop wise and stirred at 25° C. under hydrogen atmosphere for 20 h. The reaction mixture is filtered through celite and washed with 2×20 mL of MeOH. The filtrate is then concentrated under reduced pressure to give viscous oil which was triturated with diethyl ether to obtain the product 4 as a white solid (950 mg) in 70% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccc([N+](=O)[O-])cc1
Yield: 34.8 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro- 1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-nitroaniline (70 mg, 0.51 mmol) to give 80 mg of the title compound (35%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.65 (s, 1H), 8.23 (d, 2H, J=9.2 Hz), 7.30 (d, 2H, J=9.2 Hz), 7.24 (bs, 1H), 7.18 (bs, 1H), 5.20~5.29 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.68 (d, 2H, J=7.3 Hz), 2.11 (dm, 1H, J=13.5 Hz), 1.82~1.97 (m, 1H).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[CH3:47][S:48](Cl)(=[O:50])=[O:49].C(N(CC)CC)C>O1CCCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:42][CH:41]=2)=[N:17]1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 28 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.258 g, 0.43 mmol) in tetrahydrofuran (4.5 mL) was added methanesulfonyl chloride (0.05 mL, 0.64 mmol) and triethylamine (0.30 mL, 2.14 mmol). The final crude product was purified by preparative HPLC (10–100% acetonitrile to H2O, 20 min.) (0.042 g, 28% yield): 1H NMR (CD3OD) δ 7.93 (dd, 1H), 8.54 (br s, 1H), 8.29 (dd, 1H), 8.20 (m, 2H), 7.87 (dd, 1H), 7.62 (m, 2H), 3.23 (s, 3H); ES-MS (m/z) 355 [M+1]+.