Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1.Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][C:14]1([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:16][CH2:17][O:13]1
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)C1CCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C1(Cc2cccc(OC)c2)CCCO1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 4.44 g of diisopropylamine in 20 ml of tetrahydrofuran were sequentially added 26 ml of 1.6 M solution of n-butyllithium in hexane, 5.30 g of methyl tetrahydro-2-furancarboxylate in 20 ml of tetrahydrofuran and 8.85 g of 1-bromomethyl-3-methoxybenzene in 25 ml of tetrahydrofuran at −70° C. under an atmosphere of nitrogen gas. After warming to room temperature, 100 ml of 1N hydrochloric acid and 200 ml of ethyl acetate were added. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 6.01 g of the title compound from the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C.[Li+].[Cl-].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C1(C=CC(O)=CC=1)O>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zn+2].CO>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCCCCCCO
Agent: CC(=O)/C=C(/C)[O-]
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Solvent: CO
Product: C=C(C)C(=O)OCCCCCCCCCC
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a 1 liter flask equipped with an agitator, thermometer and a Vigreux fractionating column were added 188 g (1.88 mol) of methyl methacrylate (MMA), 59.4 g (0.376 mol) of n-decyl alcohol, 1.25 mol % of zinc acetylacetonate, 1.25 mol % of LiCl and 0.75 g of phenothiazine, and 0.62 g of hydroquinone free radical polymerization inhibitor. The mixture was heated to reflux at atmospheric pressure while an azeotropic mixture of MMA and methanol was removed from the upper part of the fractionation column. The reaction was continued in this manner for approximately five hours. After vacuum filtration of the catalyst and inhibitors, the excess of MMA was removed under vacuum and the resulting n-decyl methacrylate (DMA) was isolated (84.3 grams, 99.1% yield) and analyzed. Gas-liquid chromatographic (GLC) analysis showed 99% conversion of 1-decanol to DMA of 98% purity.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: CCOC(=O)C1(N)CCC1
Agent: Cl
Product: CCOC(=O)C1(NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)CCC1
Yield: 77 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and ethyl 1-aminocyclobutanecarboxylate hydrochloride. Yield 77%, colorless liquid. MS 364 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][C:29]#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O=[C:41]1COC2N=C(C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)C(C3C=CC=CC=3)=CC=2N1.BrCC(C)C>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH:28]([CH3:29])[CH3:41])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Solvent: CC(C)CBr
Product: CC(C)CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 1-bromo-2-methylpropane (87 mg, 0.636 mmol) to afford the title compound (78 mg). LCMS (method D) RT=1.73 min, M+H=528.2
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[S:13](Cl)(=[O:15])=[O:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:25]2[CH2:28][CH:27]([NH2:29])[CH2:26]2)=[CH:20][CH:19]=1>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:25]2[CH2:26][CH:27]([NH:29][S:13]([C:9]3[S:8][CH:12]=[CH:11][CH:10]=3)(=[O:15])=[O:14])[CH2:28]2)=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccs1
Temperature: 25 °C
Reaction time: 68 h
Yield: 66.2 %

Procedure:
69.3 mm3 of triethylamine and 110 mg of thien-2-ylsulfonyl chloride are successively added, at room temperature and under an argon atmosphere, to a solution of 61.4 mg of 1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylamine in 3 cm3 of dichloromethane. After stirring for 68 hours at room temperature, the reaction mixture is introduced into a Bond Elut® SCX cartridge (3 cm5/500 mg), eluting successively with twice 2 cm3 of dichloromethane and then twice 2 cm3 of a 1 M solution of ammonia in methanol. The ammoniacal fractions are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is dissolved in 5 cm3 of dichloromethane, washed with three times 3 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 60 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}thien-2-ylsulfonamide are thus obtained in the form of a cream-colored foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.77 (split t, J=7 and 2 Hz: 2H); 3.40 (split t, J=7 and 2 Hz: 2H); 4.06 (mt: 1H); 4.21 (s: 1H); from 4.85 to 5.25 (broad unresolved complex: 1H); 7.06 (t, J=4.5 Hz: 1H); from 7.15 to 7.35 (mt: 8H); 7.58 (mt: 2H)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[CH3:21][O:20][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([O:8][CH3:7])[C:17]=1[O:18][CH3:19])[C:12]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:13]
Reactant: C1COCCN1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2CCOCC2)cc(OC)c1OC
Reaction time: 3 h
Yield: 86 %

Procedure:
Morpholine (0.8 mL) was slowly added to a solution composed of toluene (10 mL) and 3,4,5-trimethoxybenzoyl chloride (1.1 g). The reaction was accompanied by evolution of heat and precipitation of morpholine hydrochloride. After 3 hours, the solution was filtered and concentrated in vacuo to afford a white solid which was recrystallized from ethanol to afford colorless needles (1.2 g, 86%): m.p. 119.8-120.7° C., lit3c m.p. 120-121° C.; EIMS m/z 281 (M+), 266, 195; 1H NMR δ 6.63 (2H, s, H2,6), 3.87 (6H, s, OCH3×2), 3.86 (3H, s, OCH3), 3.70 (8H, bs, CH2×4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8](/[CH:33]=[C:34](/[C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)\[CH3:35])[C:9]=2[CH:10]=1
Reactant: CN1CCc2[nH]c3cc(Cl)ccc3c2C1
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3ccc(Cl)cc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 85 °C

Procedure:
7-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 0.90 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (17 mg, 0.09 mmol), L-proline (20 mg, 0.18 mmol) and potassium phosphate (380 mg, 1.8 mmol) were added and the reaction mixture was stirred for min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (230 mg, 1.09 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.78 (m, 2H), 7.52 (d, 1H), 7.30 (m, 3H), 7.16 (d, 1H), 7.10 (s, 1H), 4.30 (m, 2H), 3.0 (s, 3H), 2.82 (m, 4H), 1.85 (s, 3H).
Reaction SMILES: O=C1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4](=[O:21])O1.Cl.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][O:29][NH2:30])=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C.O>CN(C=O)C>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][O:29][NH:30][C:4](=[O:21])[C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=2[NH:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Reactant: NOCc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNc2ccccc2C(=O)NOCc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To a stirred mixture of 4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-benzonitrile (Preparation 7D, 319 mg) and O-(4-chloro-benzyl)-hydroxylamine hydrochloride (preparation 9, 267 mg) in DMF (10 ml) was added N-ethyldiisopropylamine (0.4 ml). The reaction mixture was heated to 100° C. and stirred for 17 hours. The mixture was cooled to room temperature and water was added. The pale brown precipitated material was isolated by filtration and re-crystallised from ethanol and gave the title compound as a white solid material. 13C-NMR (DMSO-d6) δ 148.2, 145.9, 135.1, 132.8, 132.5, 132.3, 130.6, 128.2, 128.0, 127.7, 118.8, 114.8, 113.2, 111.4, 109.5, 75.9, 45.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[C:5]([N+:17]([O-])=O)[CH:4]=2.[OH-].[Na+]>C(O)(=O)C.[Pd]>[NH2:17][C:5]1[CH:4]=[C:3]2[C:8]([N:9]=[C:10]3[C:15](=[C:2]2[NH2:1])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=1
Reactant: Nc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc2nc3c(c(N)c2c1)C(=O)CCC3

Procedure:
In 250 ml of glacial acetic acid was dissolved 4.43 g of 9-amino-3,4-dihydro-7-nitroacridin-1(2H)-one and 0.44 g of 10% Pd/C was added. The mixture was put in a 500 ml hydrogenation vessel (Parr) and was shaken under 55 psig (initial) H2. The uptake of H2 was 3 eq before the reaction was complete. The reaction was poured into ice and made basic with 10% NaOH. The precipitate was filtered and dissolved in MeOH. The insoluble Pd/C catalyst was filtered off and the filtrate was diluted with toluene and concentrated until crystallization occurred. The yield was 2.84 g (73%) of a solid, melting point 310° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[NH4+]>CO.O>[F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[N:15][OH:16]
Reactant: NO
Reactant: O=Cc1ccnc(C(F)(F)F)c1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: ON=Cc1ccnc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-2-trifluoromethyl-pyridine-4-carbaldehyde (0.495 g, 2.05 mmol) in MeOH (17.6 mL) and water (2.9 mL) were added hydroxylamine hydrochloride (0.214 g, 3.08 mmol) and ammonium acetate (0.474 g, 6.15 mmol), and the resulting mixture was stirred at RT overnight. Volatile were removed in vacuo, and the residue was suspended in CH2Cl2/MeOH 9:1. The precipitate was filtered off, washed with CH2Cl2 and dried to afford the title compound as a white solid. MS (LC/MS): 209.0 [M+H]+; tR (HPLC conditions c): 4.28 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:22][C:23]([F:26])([F:25])[F:24])[CH:3]=1.C([N:29](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([NH2:29])=[O:20])[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:22][C:23]([F:26])([F:25])[F:24])[CH:3]=1
Reactant: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of trans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid (7.14 g, 15.5 mmol) and triethylamine (2.35 mL, 16.9 mmol) in THF (25 mL) was cooled to 0° C. To the mixture was added ethyl chloroformate (1.62 mL, 17 mmol) in THF (5 mL) over 10 min. After stirring at 0° C. for 15 min, aqueous ammonia (27 mL) was added dropwise and the mixture was stirred at ambient temperature for 2 hr. The mixture was concentrated under reduced pressure and the concentrate was treated with water to give a solid. The solid was filtered and washed with water and hexanes to give trans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid amide as a white solid (4.2 g, 59%).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH3:1][C:2]1[CH:13]=[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH2:19][CH3:20])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2cc(C(=O)O)ccn2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccn2nc(C)cc2c1

Procedure:
2-Methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (723 mg) was dissolved in 10% sulfuric acid/ethanol (20 ml) and the mixture was refluxed under heating for 2.5 hr. The reaction mixture was neutralized under ice-cooling, extracted with ethyl acetate and dried over magnesium sulfate. The residue was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the objective compound (707 mg) as a pale-brown powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([Br:14])=[CH:12][S:11][C:8]2=[CH:9][N:10]=1)=[O:4].CO.[OH-].[Na+]>O>[Br:14][C:13]1[C:7]2[C:8](=[CH:9][N:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[S:11][CH:12]=1
Reactant: COC(=O)c1cc2c(Br)csc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(Br)csc2cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Methyl-3-bromothieno[2,3-c]pyridine-5-carboxylate (635 mg, 2.33 mmol) is combined with 25 ml MeOH. The mixture is treated with 2N NaOH (3 ml, 6 mmole) and 3 ml H2O and the reaction is stirred 4 h at rt. The volatiles are removed in vacuo and the residue is combined with 5 ml H2O. The pH of the mixture is adjusted to 3.5 with 10% aqueous HCl. The tan precipitate is collected, washed with water, and is dried in vacuo at 50° C. to afford 475 mg (79%) of 3-bromothieno[2,3-c]pyridine-5-carboxylic acid as a tan solid. MS (ESI): 257.9.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])[CH:11]=1)[CH2:6][CH2:7][CH3:8].[BH4-].[Na+]>CS(C)=O>[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])[CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOc1cccc(/C=C/[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCCOc1cccc(CC[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To an acetic acid (3.9 mL) and dimethyl sulfoxide (67 mL) solution of 1-butoxy-3-((E)-2-nitro-vinyl)-benzene (3.92 g, 17.7 mmol) described in Manufacturing Example 65-1-2 was added sodium borohydride (1.07 g, 28.3 mmol) at room temperature while cooling appropriately. This mixture was stirred for 4 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (2.29 g, 58%).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[F:9][C:10]1[CH:11]=[C:12]([C:17]2[O:18][C:19](=[O:22])[CH2:20][N:21]=2)[CH:13]=[CH:14][C:15]=1[F:16].O.[OH-].[Li+]>C1COCC1.O>[F:9][C:10]1[CH:11]=[C:12]([C:17]2[N:8]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[C:20]([C:19]([OH:22])=[O:18])[N:21]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: O=C1CN=C(c2ccc(F)c(F)c2)O1
Reactant: COC1=NCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc(F)c(F)c2)n2c1CCCC2
Temperature: 90 °C
Yield: 70.2 %

Procedure:
6-methoxy-2,3,4,5-tetrahydropyridine (0.431 g, 3.80 mmol) was dissolved in THF (5 mL) in a 40 mL screw-cap vial and 2-(3,4-difluorophenyl)oxazol-5(4H)-one (0.75 g, 3.80 mmol) in THF (5 mL) was added, producing an orange solution. The vial was capped and heated to 90° C. for 3 hours. THF was removed under reduced pressure and the residue was dissolved in MeOH (10 ml) and lithium hydroxide monohydrate (0.479 g, 11.41 mmol) in water (1 mL) was added. The reaction was heated to 90° C. for 3 hours. MeOH was removed by evaporation under reduced pressure. The remaining aqueous solution was diluted with water (5 mL) and acidified to pH 2 with 5M HCl. The solution was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to yield the desired product as a brown oil (742 mg, 71%) that was used without further purification. LCMS (+ESI) m/z: 279.3 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:12]=[N:11]2)=[CH:7][CH:6]=1)(=O)C.O.[OH-].[Li+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[OH:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:12]=[N:11]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(Cn2ncc(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(F)cc3)c2=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccc(O)cc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (0.2 g, 4.06 mmol) (Example 114) in THF (20 mL) was treated with a solution of lithium hydroxide monohydrate (0.05 g, 1.22 mmol) in water (5 mL). Methanol (2 mL) was added to provide a homogeneous solution which was stirred at room temperature overnight. The reaction mixture was then acidified with 10% aqueous citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to provide a white foam which was purified by column chromatography (silica gel, 65:35 hexanes/ethyl acetate). Product fractions were combined and concentrated in vacuo. The residue was crystallized from ethyl acetate/hexanes (yield: 195 mg, 70%). mp 225–226° C. 1H NMR (300 MHz, CDCl3) δ 3.05 (s, 3H), 4.86 (s, 1H), 5.33 (s, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.95 (t, J=9 Hz, 2H), 7.15 (dd, J=9 Hz, 5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.87 (d, J=8.5 Hz, 2H). MS (DCI/NH3) m/z 451 (M+H)+. Anal. calc. for C24H19FN2O4S: C, 63.99; H, 4.25; N, 6.22. Found: C, 63.73; H, 4.16; N, 6.11.
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C@H:6]([OH:8])[CH3:7].[C:15]([O-])(=[O:19])[CH2:16]CC.C(OC(=O)C)(=O)C.N1C=CC=CC=1>>[C:15]([O:8][C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@H:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:7])(=[O:19])[CH3:16]
Reactant: CCCC(=O)[O-]
Reactant: CC(C)=CCC[C@@H](C)C/C=C/[C@@H](C)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H](C)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99 %

Procedure:
A flame-dried 100 mL, three necked flask with magnetic stirring bar was charged under argon with 2.0 g (10.2 mmol) of (2R,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol [(2R,6R)/(2S,6R)=90:10 by GC diastereomer analysis of butyrate derivative]. Then, after cooling in an ice-bath, 1.5 g (1.4 mL, 15 mmol) of acetic anhydride, 1.58 g (1.6 mL, 20 mmol) of dry pyridine and 12.3 mg (0.1 mmol) of 4-N,N-dimethylaminopyridine were added, and the reaction was stirred for 75 minutes at ambient temperature. Work-up as described in Example 9 followed by Kugelrohr distillation at ca. 110° C./0.25 mm afforded 2.35 g (99%) of (2R,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol acetate as colorless liquid; GC purity 90%; [α]D25 =+47.17° (5.3% in CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](O)=[O:8].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:2]2[NH:1][C:7](=[O:8])[C@@H:6]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][O:4][C:3]=2[CH:18]=1
Reactant: Cc1ccc(N)c(OC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
(S)-3-(2-amino-5-methylphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (3.85 g, 12.4 mmol, Eq: 1.00) and EDCI (2.38 g, 12.4 mmol, Eq: 1.00) were dissolved in DMF (50 mL) and the mixture was stirred at RT for 3 h. The mixture was diluted with EtOAc and washed with water, brine and the organic solution dried over Na2SO4. The mixture was filtered, concentrated and the residue was purified by silica gel chromatography to afford (S)-tert-butyl 8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (2.51 g, 69%) as an off white foam.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15](=[N:20][C:21]#[N:22])OCCC)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32]>CO>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15](=[N:32][CH2:31][CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])[NH:20][C:21]#[N:22])[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCOC(=NC#N)c1cncc(NCc2ccccc2)c1
Reactant: NCCc1ccccc1Cl
Solvent: CO
Product: N#CNC(=NCCc1ccccc1Cl)c1cncc(NCc2ccccc2)c1
Reaction time: 1.75 h
Yield: 84.2 %

Procedure:
To a solution of propyl 5-benzylamino-N-cyano-3-pyridinecarboximidate (114 mg, 0.38 mmol) in methanol (2 ml) was added 2-(2-chlorophenyl)ethylamine (72 mg, 0.46 mmol), and the mixture was stirred for 105 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (Wako Gel C-200, 20 g; eluted with chloroform:methanol=200:1) and further crystallized from diethyl ether to give the title compound (126 mg, 0.32 mmol) as colorless crystals in the yield of 85%.