Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=O)=[C:4]([S:25][CH3:26])[N:3]=1.C(=O)(O)[O-].[K+].Cl.[NH2:33][OH:34]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[N:33][OH:34])=[C:4]([S:25][CH3:26])[N:3]=1
Reactant: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=NO
Temperature: 60 °C
Yield: 28.8 %

Procedure:
To a round bottom flask was added 2-(2-amino-5-formyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (50.0 mg, 0.13 mmol, 1.0 mmol), MeOH (2.0 mL), potassium bicarbonate (51.0 mg, 0.51 mmol, 4.0 eq.), and hydroxylamine HCl (35.6 mg, 0.51 mmol, 4.0 eq.). The reaction was heated to 60° C. for 72 hrs before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give crude 2-[2-amino-5-(hydroxyimino-methyl)-6-methylsulfanyl-pyrimidin-4-ylamino]-N-(3-trifluoromethyl-phenyl)-acetamide as an oil. The product was then precipitated out with 3 mL water and 0.5 mL of ACN, filtered and rinsed with 2 mL of (1:2 ACN: H2O) to give pure 2-[2-amino-5-(hydroxyimino-methyl)-6-methylsulfanyl-pyrimidin-4-ylamino]-N-(3-trifluoromethyl-phenyl)-acetamide as a solid (15.0 mg, 29%). LC/MSD (HP Series 1100 MSD): Expected MW: 400, Observed M+H, 401.1, Retention time: 1.48 min. ANALYTICAL HPLC: >80%, Retention time: 2.89 min (8 minute run). 1H-NMR (d6-DMSO): 10.98 (s, 1H), 10.50 (s, 1H), 8.40 (t, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.77 (d, 1H), 7.58 (t, 1H), 7.40 (d, 1H), 5.90 (br s, 2H), 4.36 (d, 2H), 2.40 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:30]([OH:34])[CH2:31][CH2:32][CH3:33]>O1CCOCC1.CN(C=O)C>[CH2:30]([O:34][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCCCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-mopholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and butanol in dioxane and DMF. ES-MS m/e (%): 465 (M+Na+, 40), 443 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18](=[N:20]O)[CH3:19])=[CH:9]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]([NH2:20])[CH3:19])=[CH:9]1
Reactant: CC(Cc1cn(-c2ccccc2Cl)c2ccccc12)=NO
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(N)Cc1cn(-c2ccccc2Cl)c2ccccc12

Procedure:
0.052 mole of 1-(2-chlorophenyl)-3-(2-hydroxyiminopropyl)indole is dissolved in 150 ml of dry tetrahydrofuran. 6 gms of lithium aluminium hydride are slowly added whilst refluxing for 3.5 hours. The reaction mixture is then poured on to a mixture of ice and ammonia and the product extracted with ether. The ethereal extract is treated with an N hydrochloric acid solution. The latter is then rendered alkaline with N soda solution. The turbid substance formed is extracted with ether, washed with water and dried. On removing the solvent the primary amine is obtained which, after recrystallisation from di-isopropyl ether, had a melting point of 79°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:12][C:9]1[C:8]([O:10][CH3:11])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N)cc(OC)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1cc(N)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 62.7 %

Procedure:
3,5-Dimethoxyaniline (7.55 g) was dissolved in CH2Cl2 (100 mL) under N2 and the solution was cooled to −78° C. A solution of tetrabutylammonium tribromide (25 g) in CH2Cl2 (100 mL) was added and the mixture was stirred at that temperature for 45 min. The mixture was allowed to warm up to room temperature, stirred for 1.5 h and extracted with 1N HCl. The extract was neutralized with 3 N NaOH and extracted with AcOEt. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/AcOEt 4:1 to 2:3) to give 4-bromo-3,5-dimethoxyaniline (3.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:24][CH:13]([N:14](CC4C=CC=CC=4)[CH:15]2[CH3:16])[CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:24][CH:13]([NH:14][CH:15]2[CH3:16])[CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCCC(C2)N(Cc2ccccc2)C3C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc(C23CCCC(C2)NC3C)c1
Yield: 95.2 %

Procedure:
A mixture of 7.21 g of 1-(3-methoxyphenyl)-6-benzyl-7-methyl-6-azabicyclo[3,2,1]octane, 2.2 g of colloid palladium and 165 ml of acetic acid is shaken at room temperature for 2 hours in a hydrogen atmosphere under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is then evaporated to remove solvent. Water is added to the residue, and the aqueous mixture is made alkaline with ammonia. Then, the aqueous mixture is extracted with ether. The ether extract is dried and evaporated to remove solvent. 4.94 g of 1-(3-methoxyphenyl)-7-methyl-6-azabicyclo[3,2,1]octane are obtained. Hydrochloride: M.p. 174°-176°C(recrystallized from a mixture of acetone, ethanol and ether).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[NH:15][C:14]([C:16]([O-:18])=[O:17])=[CH:13][C:12](=O)[C:9]=3[CH:10]=2)[NH:5][C:4]([C:20]([O-:22])=[O:21])=[CH:3]1.[OH:23][C:24]([NH+:27]([C:29]([OH:32])([OH:31])[OH:30])[CH3:28])([OH:26])[OH:25].[OH:33][C:34]([NH+:37]([CH3:42])[C:38]([OH:41])([OH:40])[OH:39])([OH:36])[OH:35].OC(NC)(O)O>>[N:5]1[C:6]2[C:11](=[CH:10][C:9]3[CH:12]=[CH:13][C:14]([C:16]([O-:18])=[O:17])=[N:15][C:8]=3[CH:7]=2)[CH:2]=[CH:3][C:4]=1[C:20]([O-:22])=[O:21].[OH:23][C:24]([NH+:27]([C:29]([OH:32])([OH:31])[OH:30])[CH3:28])([OH:26])[OH:25].[OH:33][C:34]([NH+:37]([CH3:42])[C:38]([OH:41])([OH:40])[OH:39])([OH:36])[OH:35]
Reactant: O=C([O-])c1cc(=O)c2cc3c(=O)cc(C(=O)[O-])[nH]c3cc2[nH]1
Agent: CNC(O)(O)O
Agent: C[NH+](C(O)(O)O)C(O)(O)O
Product: O=C([O-])c1ccc2cc3ccc(C(=O)[O-])nc3cc2n1

Procedure:
To a solution of 5 gm. of di(tris-hydroxymethyl) methylammonium 10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[4,3-g]quinoline-2,8-dicarboxylate in 100 ml. of water is added 2.0 g. of 5% palladium-on-charcoal catalyst and 5.0 g. of magnesium oxide. The resulting mixture is hydrogenated at an initial pressure of 3 atmospheres of hydrogen until 1 mole of hydrogen has been absorbed. The mixture is filtered and the filtrate acidified by the addition of dilute hydrochloric acid. The resulting precipitate is removed by filtration. The 1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylic acid obtained is converted to di(tris-hydroxymethyl)methylammonium 1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate by adding two equivalents of (tris-hydroxymethyl)methylamine in aqueous solution. The crystalline product is recovered after addition of methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([O:20][Si](C(C)(C)C)(C)C)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[N:33][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[N:33][CH:34]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of methyl 5-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)pyridine-2-carboxylate (475 mg, 0.88 mmol) in THF (2.0 mL) was added 1.0M solution of TBAF in THF (5 mL, 5.0 mmol) and the resulting solution stirred for an 30 minutes at room temperature. The mixture was concentrate under vacuum and the residue taken up in dichloromethane (50 mL). The solution was washed with water (50 mL) and brine (50 mL). The organics were then dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified vial preparative TLC plate (2×1000 μM) eluting with 80% ethyl acetate in hexane to afford the title compound as a white foam (334 mg, 89%). LC-MS: C24H30N2O5 calculated 426.24 found m/z (ES) 427.2 (MH)+ and 327.2 (M-Boc)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[NH:5][CH:6]=1.CN(C=O)C.CC(C)([O-])C.[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:6]=1
Reactant: O=C(O)c1cc(Cl)c[nH]1
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(Cl)cn1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.2 %

Procedure:
To a mixture of 4-chloro-1H-pyrrole-2-carboxylic acid (0.20 g) and DMF (2.0 mL) was added potassium tert-butoxide (0.31 g) under ice-cooling, followed by stirring at room temperature for 15 minutes. To the reaction mixture was added 1-bromomethyl-4-chlorobenzene (0.29 g) under ice-cooling, followed by stirring at room temperature for 14 hours. To the reaction mixture was added water at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-chloro-1-(4-chlorobenzyl)-1H-pyrrole-2-carboxylic acid (0.06 g).
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:20]([O:19][CH2:18][N:6]1[C:2]([I:1])=[C:3]([CH3:7])[CH:4]=[N:5]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1cn[nH]c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnn(COCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-iodo-4-methyl-1H-pyrazole (0.5 g, 2.4 mmol, CAS RN 24086-18-8) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (342 mg, 450 μL, 2.64 mmol) and benzyl chloromethyl ether (460 mg, 407 μL, 2.64 mmol, CAS RN 3587-60-8) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes and then poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL CH2Cl2. The layers were separated and the aqueous layer was extracted a second time with 30 mL CH2Cl2. The organic layers were washed with 30 mL brine, dried with MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). Colorless oil (610 mg, 77%). MS (ESI): m/z=329.014 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([CH:17]=[O:18])[CH:3]=1.[Cl:19]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:5]=[C:4]([CH:17]=[O:18])[C:3]=1[Cl:19]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: Nc1cc(C=O)nc(Cc2ccc(F)cc2)c1F
Solvent: CC#N
Product: Nc1c(F)c(Cc2ccc(F)cc2)nc(C=O)c1Cl
Yield: 136.7 %

Procedure:
Using the procedure for Example 15, 4-amino-5-fluoro-6-(4-fluorobenzyl)-picolinaldehyde (0.5 g, 2.014 mmol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.218 g, 1.108 mmol) and CH3CN (20 mL) gave 4-amino-3-chloro-5-fluoro-6-(4-fluorobenzyl)picolinaldehyde (428 mg, 73.7%) as an orange solid: mp 109-111° C.; 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.28 (m, 3H), 6.97 (m, 2H), 4.84 (s, 2H), 4.14 (d, J=3.1 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −116.40, −139.04; 13C NMR (101 MHz, CDCl3) δ 190.27, 162.96, 160.53, 148.18, 145.80, 145.67, 145.61, 143.17, 139.85, 139.72, 133.24, 130.38, 130.31, 115.47, 115.26, 37.10, 37.08; EIMS m/z 282.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[NH:12][C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2nnnn2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, ethyl(rac)-7-(4-cyanophenyl)-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (600 mg, 1.9 mmol) was stirred in abs. dichloromethane (450 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (1.10 g, 5.8 mmol, 3 eq.), anhydrous copper(II) acetate (1.05 g, 5.8 mmol, 3 eq.), abs. pyridine (1.25 ml, 15.5 mmol, 8 eq.) and triethylamine (0.59 g, 5.8 mmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (0.37 g, 1.9 mmol, 1 eq.), anhydrous copper(II) acetate (0.35 g, 1.9 mmol, 1 eq.) and abs. pyridine (0.63 ml, 7.73 mmol, 4 eq.) were then added, and the mixture was stirred at RT for a further 12 h. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and methanol and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless amorphous solid (404.6 mg, 46% of theory).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CON(C)[C:39]([C:41]1[S:42][CH:43]=[C:44]([CH3:46])[N:45]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1nc(C)cs1
Product: Cc1csc(C(=O)c2nc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(Cl)c2F)n1

Procedure:
Starting material: (2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N,4-dimethylthiazole-2-carboxamide.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([O:7]C)=O)(=O)[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O>[CH2:9]([C:4]1[C:5](=[O:7])[N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][C:1]=1[CH3:2])[CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCC(C(C)=O)C(=O)OC
Reactant: Nc1ccccn1
Solvent: O
Product: C=CCCc1c(C)nc2ccccn2c1=O

Procedure:
Heat a mixture of 5.7 g of methyl 2-acetyl-5-hexenoate, 3.15 g of 2-aminopyridine and 0.65 g of polyphosphoric acid at 160° C. for 2 hours. Then add, in the cold state, 30 ml of water and extract the mixture using dichloromethane. The residue obtained after evaporating off the solvent is purified by chromatography on silica gel, using a mixture of dichloromethane/methanol: 98/2 as eluant.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:30]([OH:34])[CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][CH2:30][O:34][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCO
Product: OCCCOCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In the same manner as in step b) in Example 2, 674 mg of the title compound was prepared from 665 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole prepared in step a) in Example 2 and 3 ml of 1,3-propanediol.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[O:27][CH2:26][CH2:25][O:24]4)=[CH:19][CH:18]=3)[C:13]=2[C:28]=1[CH3:29])C1C=CC=CC=1>CCCCCC>[O:24]1[CH2:25][CH2:26][O:27][CH:23]1[C:20]1[CH:19]=[CH:18][C:17]([CH:14]2[C:13]3[C:28]([CH3:29])=[C:9]([NH2:8])[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=3[O:16][CH2:15]2)=[CH:22][CH:21]=1
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)C(c1ccc(C3OCCO3)cc1)CO2
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C3OCCO3)cc1)CO2
Yield: 87 %

Procedure:
Using N-benzyl-3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 284, the title compound was synthesized in the same manner as in Reference Example 30. Yield 87%. Melting point: 125-136° C. (hexane).
Reaction SMILES: [CH3:1][C@@:2]1([OH:22])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]([C:20]#[CH:21])=[CH:11]1.[H][H]>C1COCC1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][C@@:2]1([OH:22])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]([CH:20]=[CH2:21])=[CH:11]1
Reactant: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(N)c12
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Product: C=Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(N)c12
Reaction time: 168 h
Yield: 75 %

Procedure:
The acetylene product prepared above was dissolved in 3 mL THF and 22 mg of Lindlar's catalyst was added. The solution was stirred at ambient temperature under 1 atm of hydrogen (via balloon) for 7 days. The balloon was recharged with hydrogen at the beginning of each day. After 7 days, the reaction was filtered through celite to remove catalyst, concentrated in vacuo, and purified by reverse phase HPLC on Phenominex column (250×20 mm) using a gradient of acetonitrile in water from 0 to 30% over 30 min at 10 mL/min to yield 30 mg (75% yield) of the title compound;
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16]([C:18]2[CH:19]=[C:20]([C:24](=O)[CH3:25])[CH:21]=[CH:22][CH:23]=2)=[CH:17][C:9]=1[CH2:8][CH2:7]3.Cl.[NH2:28][OH:29].N1C=CC=CC=1>C(O)C>[CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16]([C:18]2[CH:19]=[C:20]([C:24](=[N:28][OH:29])[CH3:25])[CH:21]=[CH:22][CH:23]=2)=[CH:17][C:9]=1[CH2:8][CH2:7]3
Reactant: CC(=O)c1cccc(-c2ccc3c(c2)CCC24CN(C)CC2CCC34)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1cccc(-c2ccc3c(c2)CCC24CN(C)CC2CCC34)c1
Yield: 18.8 %

Procedure:
1-[3-(8-Methyl-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-2-yl)-phenyl]-ethanone (Example 2)(10.0 mg, 0.028 mmol), hydroxylamine hydrochloride (2.9 mg, 0.042 mmol), and pyridine (226 μL, 0.28 mmol) were heated in ethanol (1 mL) at 80° C. for 3 h. The mixture was quenched with water (1 mL), extracted with CH2Cl2 (2 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 1.9 mg (18.3%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2=[CH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[CH:12]=[C:2]12.C([Li])(C)(C)C.[CH3:18][Sn:19](Cl)([CH3:21])[CH3:20]>O1CCCC1>[CH3:18][Sn:19]([CH3:21])([CH3:20])[C:5]1[S:1][C:2]2=[CH:12][C:11]3[CH:10]=[C:9]([Sn:19]([CH3:21])([CH3:20])[CH3:18])[S:8][C:7]=3[CH:6]=[C:3]2[CH:4]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc2cc3sccc3cc2s1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2cc3sc([Sn](C)(C)C)cc3cc2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A dry 1 L three-neck round bottom flask was flushed with N2 and was charged with benzo[1,2-b:4,5-b′]dithiophene (5.20 g, 26.3 mmol) and anhydrous tetrahydrofuran (THF) (300 mL, 0.01 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 1.3 M solution of tert-butyl lithium in hexanes (53.0 mL, 68.8 mmol) was added dropwise via deoxygenated syringe. After 30 minutes of stirring at −78° C., the solution was chilled to 0° C. and stirring was continued for 5 minutes, at which point the reaction mixture was cooled back to −78° C. A 1 M solution of trimethyltin chloride (105 mL, 100 mmol) in hexanes was added to the reaction flask dropwise and stirring continued for 30 minutes at −76° C. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. As the reaction was completed, cool DI water (50 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 300 mL of cool water and extracted with MTBE (300 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified by precipitation into methanol from a THF solution to yield white solid (12.0 g, 88%).