Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:26]([F:29])([F:28])[F:27])=[CH:10]\[C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=[S:32])C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([SH:32])([C:26]([F:28])([F:27])[F:29])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: CC(O)=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 5-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-[1,2,4]triazol-1-yl-benzonitrile (100 mg) was added thioacetic acid (6 eq.) and triethylamine (4 μL). To dissolve the suspension more thioacetic acid (400 μL) was added. The solution was stirred under argon at room temperature for 20 hours. To this mixture was added a minimum of dichloromethane and then isolute. The suspension was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 5-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-[1,2,4]triazol-1-yl-benzonitrile (108 mg).
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:16])/[CH2:8]OC1CCCCO1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:16])/[CH2:8][Br:18])(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)OC/C=C(\C)COC1CCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)OC/C=C(\C)CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 460 mg (2.0 mmol) of (E)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-enyl acetate in 20 ml of CH2Cl2 was added a solution of 1.33 g (4 mmol) of CBr4 in 10 ml of CH2Cl2. The solution was cooled to 0° C. and a solution of 1.05 g (4 mmol) of triphenylphosphine was added dropwise. The solution was allowed to warm up to room temperature for 6 hours and stirred at the same temperature for further 1 hour. The precipitate was filtered and the filtrate was evaporated. The residue was purified by chromatography on silica gel using Heptane/EtOAc (8/2) as eluent. 314 mg (1.52 mmol, 76%) of (E)-4-bromo-3-methylbut-2-enyl acetate were isolated as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[Cl:27][CH2:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (100 mg, 0.286 mmol) and THF (1 mL) was added chloroacetyl chloride (0.0230 mL, 0.286 mmol). The solution was stirred at ambient temperature for 1 hour. The crude mixture was then concentrated and used without further purification. LCMS: m/z 424 (M+H)+.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1.[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.33 h

Procedure:
To 1.7 mL (3.0 g, 30.6 mmol, 18M) H2SO4 at 5iC (ice-NaCl bath) was slowly added 783.0 mg (4.49 mmol) of 3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. A solution of HNO3 (426.7 mg 6.88 mmol, 0.43 mL, 16M), and 1.31 g (0.013 mol, 0.74 mL, 18 M) of H2SO4 were slowly added. After 20 min, ice was added and the resulting mixture was extracted with EtOAc. The combined extracts were concentrated under reduced pressure to give a yellow oil from which the title compound, a pale yellow solid, was isolated by column chromatography (10% EtOAC/hexanes).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[N:4][C:5]([F:18])=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.Cl[S:21]([OH:24])(=[O:23])=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:19])=[N:4][C:5]([F:18])=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:21]([OH:24])(=[O:23])=[O:22])[CH:10]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(Oc2c(Cl)c(F)nc(F)c2Cl)cc1
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)c(F)nc(F)c2Cl)cc1S(=O)(=O)O
Yield: 70 %

Procedure:
3,5-Dichloro-2,6-difluoro-4-(4-methoxyphenoxy)pyridine (1.5 g, 4.9 mmol) and chlorosulfonic acid (0.39 ml, 5.8 mmol) were stirred in 5 ml of methylene chloride overnight. The resulting solid-was filtered and washed with cold CH2Cl2. Compound 43a was obtained as solid in 70% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:24](O)=[O:25])=[N:21][NH:22][CH:23]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:20]3[C:19]([Cl:18])=[CH:23][NH:22][N:21]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1n[nH]cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3n[nH]cc3Cl)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 4-chloro-1H-pyrazole-3-carboxylic acid (CAS 84547-87-5) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=370.1 [M+H]+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Si]([N:12]=[N+:13]=[N-:14])(C)(C)C>CCOCC>[CH2:5]([C:6]1[N:12]=[N:13][NH:14][CH:7]=1)[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CCCCCC
Solvent: CCOCC
Product: CCCCCc1c[nH]nn1
Temperature: 155 °C

Procedure:
##STR10## 1-heptyne (9.6 g) and Me3SiN3 (7.8 g) were sealed into a heavy-walled glass reactor at -70° C. and 0.6 mm Hg. The mixture was heated at 155° C. for 48 hrs., cooled and dissolved in Et2O. The Et2O was treated exactly as in Example 2. The product was distilled, bp 89-94/0.2 mm to give 7.2 g (76%) water white liquid whose NMR spectrum and elemental analysis confirm its structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[O:32]1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:31]1[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33](=[O:40])[O:32]1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=C1OC(Br)c2ccccc21
Product: O=C1OC(Oc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c2ccccc21

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-Bromo-3H-isobenzofuran-1-one following the procedure of Example 478: MS (ESI) m/z 526; HRMS: calcd for C31H18F3NO4+H+, 526.12607; found (ESI, [M+H]+), 526.1287.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[N:19]3[C@H:14]([CH2:15][CH2:16][CH2:17][C:18]3=[O:20])[CH2:13][C@@H:12]3[O:21][C@H:11]23)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C([BH-](CC)CC)C.[Li+].O.C(OCC)(=O)C>C1COCC1>[OH:21][C@H:11]1[CH2:12][CH2:13][C@@H:14]2[N:19]([C:18](=[O:20])[CH2:17][CH2:16][CH2:15]2)[C@@H:10]1[C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1
Reactant: O=C1CCC[C@@H]2C[C@@H]3O[C@@H]3[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC[C@@H]2CC[C@H](O)[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A solution of (1aR*,2R*,6aR*,7aS*)-2-(3,4,5-trifluorophenyl)octahydro-1-oxa-2a-aza-cyclopropa[b]naphthalen-3-one (123 mg) in THF (4.0 mL) was cooled to −78° C. Lithium triethyl borohydride (1 M solution in THF, 620 μL) was added to the reaction solution, which was then stirred at 0° C. for one hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 125 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.[Mn]([O-])(=O)(=O)=[O:14].[K+].[OH2:19]>C(O)(C)(C)C>[C:7]1([C:6]2[C:2]([C:1]([OH:14])=[O:19])=[N:3][NH:4][CH:5]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1n[nH]cc1-c1ccccc1
Reactant: O
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)c1n[nH]cc1-c1ccccc1

Procedure:
A solution of 3-methyl-4-phenylpyrazole (1.00 g) in tert-butanol (15 ml) and water (25 ml), at 60° C., was treated portionwise potassium permanganate (5.47 g). The temperature was then slowly elevated to 90° C. and maintained at that temperature for 5 hours. The mixture was then cooled and filtered through a pad of celite. The filtrate was concentrated and the pH was adjusted to 10 to 14 by addition of 5N aqueous sodium hydroxide solution. This mixture was washed twice with ethyl acetate. The aqueous layer was then acidified to pH 3 to 5 and then extracted four times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated to yield 4-phenyl-1H-pyrazole-3-carboxylic acid (0.512 g) as a white solid, which was used without further purification. MS:189 (M+H)+. HPLC (METHOD B): RT=2.48 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:6])[CH3:5])[CH3:2].Br[CH2:8][CH2:9][C@H:10]([CH3:22])[CH2:11][CH2:12][CH2:13][C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19].[CH2:23]([OH:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:6])[CH:5]([C:23](=[O:25])[CH3:24])[CH2:8][CH2:9][C@H:10]([CH3:22])[CH2:11][CH2:12][CH2:13][C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCBr
Reactant: CCO
Product: CCOC(=O)C(CC[C@H](C)CCC[C@H](C)CCCC(C)C)C(C)=O
Temperature: 0 °C

Procedure:
To 2.3 ml of a solution of 1.01-N sodium ethylate in ethanol in a flask provided with reflux condenser and calcium chloride tube are added dropwise 300 mg (2.3 mmol) of acetic acid ethyl ester and subsequently 671 mg (2.3 mmol) of (3R,7R)-1-bromo-3,7,11-trimethyldodecane in 2 ml of ethanol. This mixture is boiled under reflux for 15 hours while stirring. After cooling, so much ice water is added that the separated salt is just dissolved, the organic phase is separated in a separating funnel and shaken out four times with methylene chloride. After drying the combined organic phases over magnesium sulphate and distillation of the solvent, there are obtained 755 mg of crude (5R,9R)-2-acetyl-5,9,13-trimethyltetradecanoic acid ethyl ester. For analytical purposes a sample of the crude (5R,9R)-2-acetyl-5,9,13-trimethyl-tetradecanoic acid ethyl ester is chromatographed on a preparative silicagel plate with toluene/hexane/acetic acid ethyl ester = 30:10:3 and the thus obtained pure (5R,9R)-2-acetyl-5,9,13-trimethyl-tetradecanoic acid ethyl ester is distilled at 150°/0.03 Torr; [α]36520 = -4.0° (c = 1.04; CHCl3).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-:14].[Cs+].[Cs+]>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[C:2]([OH:14])([CH3:1])[C:8]([OH:10])=[O:9])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(O)C(=O)O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of 3.52 g (20 mmol) diethyl methylmalonate in 40 ml dimethylformamide were added 13.1 g (40 mmol) cesium carbonate. The suspension was stirred at room temperature and air was bubbled in for 1 hour. The mixture was poured into water and extracted with ethylacetate. Extraction at pH 1 with ethylacetate yielded 2.28 g (70%) 2-hydroxy-2-methyl-malonic acid monoethyl ester, light yellow liquid, MS m/e (%): 161.0 (M−H, 100).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[OH-].[K+].[CH3:23]I>O1CCCC1>[CH:18]1([CH2:17][O:16][C:10]2[CH:9]=[C:8]([C:2]3([CH3:1])[O:6][C:5](=[O:7])[N:4]([CH3:23])[CH2:3]3)[CH:13]=[CH:12][C:11]=2[O:14][CH3:15])[CH2:20][CH2:19]1
Reactant: COc1ccc(C2(C)CNC(=O)O2)cc1OCC1CC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CN(C)C(=O)O2)cc1OCC1CC1
Yield: 40.4 %

Procedure:
500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone, 113 mg (2.0 mmol) of potassium hydroxide, and 0.15 ml (2.2 mmol) of methyl iodide were stirred in 4 ml of tetrahydrofuran for 4 hours at room temperature. The reaction mixture was filtered, the filtrate combined with 30 ml of water and then extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over sodium sulfate, filtered, and concentrated (390 mg of a yellow oil). By PSC separation with methylene chloride/ether (1:1), 212 mg of 5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3,5-dimethyl2-oxazolidinone was obtained as an oil.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21]Br)=[CH:19][C:14]=2[O:13][C:12]1=[O:23]>>[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH3:9])=[CH:19][C:14]=2[O:13][C:12]1=[O:23]
Reactant: CNCc1ccccc1
Reactant: Cn1c(=O)oc2cc(CCBr)ccc21
Product: CN(CCc1ccc2c(c1)oc(=O)n2C)Cc1ccccc1
Yield: 65 %

Procedure:
By following the procedure indicated in Example 6, but starting from 0.04 mol (4.90 g) of N-benzyl-N-methylamine and 0.02 mol (5.10 g) of 3-methyl-6-(2-bromoethyl)-benzoxazolinone, 3.85 g of the title compound having a melting point of 72°-73° C. were obtained after recrystallisation from hexane.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].[CH:16](=[O:18])[CH3:17].[Cl:19]CCl>[Cl-].[Zn+2].[Cl-]>[Cl:19][CH:16]([O:18][C:3](=[O:4])[C:2]([CH3:1])([CH3:15])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:17]
Reactant: CC=O
Reactant: CC(C)(COCc1ccccc1)C(=O)Cl
Reactant: ClCCl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(Cl)OC(=O)C(C)(C)COCc1ccccc1
Yield: 5 %

Procedure:
Following the general procedure for the synthesis of 1-chloroalkyl carboxylic esters of Description 21, 3.7 g (16.5 mmol) of 2,2-dimethyl-3-(phenylmethoxy)propanoyl chloride (26c) was reacted with 1.4 mL (1.1 g, 25 mmol) of acetaldehyde in 70 mL of anhydrous dichloromethane (DCM) in the presence of 0.25 g (1.8 mmol) of zinc chloride (ZnCl2). After work-up and isolation, the product was further purified by silica gel column chromatography using methyl tert-butyl ether (MTBE) and n-heptane (Hptn) mixtures as eluent (MTBE/Hptn=1:9) to provide 0.21 g (5% yield) of the title compound (26) as a yellow oil. Rf=0.24 (MTBE/Hptn=1:9). 1H NMR (400 MHz, CDCl3): δ=1.17 (s, 6H), 1.44 (d, J=5.6 Hz, 3H), 3.54 (s, 2H), 4.50 (s, 2H), 6.87 (q, J=5.6 Hz, 1H), 7.26-7.33 (m, 5H) ppm. The analytical data was consistent with the proposed structure.
Reaction SMILES: CS[CH2:3][C:4]1[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:16][C@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][CH3:19])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.[CH:32]1C=C(Cl)C=C(C(OO)=O)C=1.[S:43]([O-:47])([O-])(=[O:45])=S.[Na+].[Na+].O>C(Cl)Cl>[CH3:32][S:43]([CH2:3][C:4]1[C:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:16][C@H:17]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][CH3:19])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:47])=[O:45]
Reactant: O=S([O-])([O-])=S
Reactant: CC[C@H](NC(=O)c1c(CSC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(CS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a stirring solution of 3-[(methylthio)methyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (9) (800 mg, 1.87 mmol) at 0° C. was added MCPBA (900 mg, 70-75%, 4.31 mmol), the cooling bath removed, and reaction allowed to stir for 1 h. Additional MCPBA (100 mg) was added and reaction heated briefly to 40° C., then allowed to cool. Sodium thiosulfate (Na2S2O3.5H2O-1.5 g) and H2O (10 mL) were added and suspension stirred vigorously for 10 min., diluted with CH2Cl2, washed with aqueous 0.3 N NaOH, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-25% EtOAc/CH2Cl2) to give the desired product (630 mg, 73% yield) as a solid. 1HNMR (300 MHz, CDCl3, 52° C.) δ 8.12 (d, J=8.4 Hz, 1H), 7.83-7.68 (m, 2H), 7.61 (d, J=7.7 Hz, 2H), 7.56-7.26 (m, 10H), 5.22 (q, J=7.6 Hz, 1H), 4.74 (d, J=12.3 Hz, 2H), 2.31 (s, 3H), 2.20-1.88 (m, 2H), 1.00 (t, J=7.4 Hz, 3H); LCMS: m/z 459 (MH+).
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.O.[NH2:14][NH2:15]>C(O)C>[NH:14]([CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)[NH2:15]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(NN)C1
Temperature: 85 °C
Yield: 94.4 %

Procedure:
tert-Butyl 3-iodoazetidine-1-carboxylate (142 g, 0.50 mol) and hydrazine hydrate (245.2 mL, 5.02 mol) were mixed in ethanol (284 mL) and the reaction mixture was heated to 85° C. for 48 hours under nitrogen. The reaction mixture was cooled and the ethanol was removed in vacuo. The residue was partitioned between water (200 mL) and dichloromethane (300 mL), the water layer was re-extracted with dichloromethane (2×200 mL), the combined organics were dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a colourless oil (88.37 g). This compound was used immediately in the next step without purification.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH:23]([N+:34]#[C-:35])S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CO>O1CCOCC1.O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[N:34]=[CH:35][O:14][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=2)[N:9]=1
Reactant: [C-]#[N+]C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)c1nnc2ccc(C=O)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)c1nnc2ccc(-c3ocnc3-c3cc(F)ccc3F)nn12
Temperature: 80 °C
Yield: 71.8 %

Procedure:
To a solution of 3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carbaldehyde (0.150 g, 0.789 mmol, Preparation #2) in 1,4-dioxane (3 mL) was added 1,4-difluoro-2-(isocyano(tosyl)methyl)benzene (0.202 g, 0.657 mmol, Preparation #4), K2CO3 (0.218 g, 1.58 mmol) and MeOH (3.00 mL). The reaction mixture was heated to about 80° C. for about 3 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient; 1:1 to 0:1) to give the title compound (0.161 g, 71% yield). LC/MS (Table 1, Method a) Rt=2.20 min; MS m/z: 342.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:11])[CH2:3][CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].CO.CCN(CC)CC>C(Cl)Cl>[OH:11][CH:2]([CH2:3][CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:1]
Reactant: CCCCC(=O)CCC(C)=O
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC(=O)CCC(C)O
Yield: 65.2 %

Procedure:
A 100-ml stainless steel autoclave purged with nitrogen in advance was charged with 5 g (0.032 mol) of 2,5-nonanedione and 10 ml of methanol. A solution of 0.144 g (0.08 mmol) of Ru2Cl4 ((R)-T-BINAP)2 (NEt3) in 2 ml of methylene chloride was added thereto, thereby conducting reaction at a reaction temperature of 50° C. for 20 hours under a hydrogen pressure of 50 kg/cm2. After distilling off the solvent, the residue was purified by column chromatography on a silica gel using a developing solvent of hexane/ethyl acetate (4/1) to obtain 3.3 g of (-)-2-hydroxynonane-5-one (yield: 65.6%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21].C[O-].[Na+].C(O)(C)C>O>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=2)[N:1]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[N:21]=1
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: N#Cc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc2nc(-c3ccccn3)nc(N)c2cc1OC

Procedure:
8.9 g. (0.05 mol) of 6-aminoveratronitrile, 5.2 g. (0.05 mol) of 2-pyridine carbonitrile and 5.4 g. (0.1 mol) of sodium methoxide in 250 ml. of isopropanol are refluxed for 48 hours under a nitrogen atmosphere. The reaction mixture is then decomposed with water and the isopropanol is distilled off. 80 ml. of diethyl ether and 80 ml. of water are added and the layers are separated. The water is distilled off from the aqueous layer and the residue is dissolved in 100 ml. of chloroform. The solution is filtered and the chloroform is distilled off. The residue is crystallized from toluene to give 4-amino-6,7-dimethoxy-2-(2-pyridyl)quinazoline, m.p. 248° - 251°C. The base is converted into the monohydrochloride, and the salt after crystallization from a mixture of water and isopropanol, melts above 310°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[H-].[Na+].Cl.[CH3:16][CH:17]([CH3:20])[CH2:18][OH:19]>>[Br:1][C:2]1[C:3]([O:19][CH2:18][CH:17]([CH3:20])[CH3:16])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: CC(C)CO
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(OCC(C)C)c(Br)c[n+]1[O-]
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a solution of 5-bromo-2-methyl-4-nitropyridine 1-oxide (4.10 g) in 2-methyl-1-propanol (80 mL) was added 60% sodium hydride (2.69 g) at 0° C., and the mixture was stirred for 2 hr. 6N Hydrochloric acid was added to the reaction mixture, and the resulting brown solid was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (3.40 g) as a pale-yellow solid.