Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]3)[NH:13][CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]3)[N:13]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COc1cccc(C=O)c1
Reactant: c1cc2[nH]ncc2cc1NC12CCC(CC1)NC2
Product: COc1cccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2CC3)c1

Procedure:
Reaction of Intermediate 26 with 3-methoxybenzaldehyde affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[OH:12].[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>C(Cl)Cl.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[O:12][CH3:19]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1c(Cl)ccc(O)c1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 1 h

Procedure:
A solution of 155.4 g of 2,4-dichloro-3-nitrophenol in 2 l of methylene chloride is treated with 16.9 g of benzyltrimethylammonium chloride. There is added thereto a solution of 44.8 g of sodium hydroxide in 1.8 l of water and, while stirring vigorously, 143 ml of dimethyl sulfate. After 1 hour, the organic phase is separated, washed with water, dried and evaporated in vacuo. There is obtained 2,4-dichloro-3-nitroanisole of melting point 97°-99° (hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1.CN(C)C=O>[CH:33]1([NH:39][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NC1CCCCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
11.15 g (0.05 mol) of N-benzyloxycarbonyl-L-alanine were dissolved in 75 ml of dry tetrahydrofuran and the mixture was cooled to -10° C. 6.35 ml (0.05 mol) of N-ethylmorpholine were added followed by 6.5 ml of isobutyl chloroformate and the solution obtained was stirred at -10° C. for 20 minutes. A solution of 6.05 ml of cyclohexylamine in 75 ml of tetrahydrofuran was then added and the resulting solution was stirred at 0° C. After 30 minutes the mixture solidified and 30 ml of dimethylformamide were added. After stirring for a further 1 hour at 0° C., the solvent was removed by evaporation, water was added and the solid filtered off. The solid was washed with 150 ml of 1-N hydrochloric acid, 150 ml of water, 150 ml of 5% sodium bicarbonate solution and 150 ml of water and then dried in vacuo. Recrystallisation from ethyl acetate yielded 11.7 g (77%) of N-benzyloxycarbonyl-L-alanine cyclohexylamide of melting point 163°-164° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][N:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]CC3C=CC=CC=3)[CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:30])[CH3:2]>CO.[C].[Pd]>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:30])[CH3:32]
Reactant: CCN(CC)CCN1C(=O)Nc2ccccc2C1c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCN1C(=O)Nc2ccccc2C1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
To a solution of 2.0 g (4.66 mmol) of 3-[2(diethylamino)ethyl]-4-(3-benzyloxyphenyl)-3,4-dihydro-2(1H)-quinazolinone in 100 mL of methanol was added 200 mg of 5 % palladium-carbon, and the mixture was stirred for 5 hours under a hydrogen atmosphere at ambient temperature. The reaction mixture was filtered through cerite, and the filtrate was concentrated in vacuo. The crystals formed was recrystallized from methanol to give 1.30 g (3.83 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzoic acid (2 g) and triethylamine (1.4 g) in dichloromethane (40 ml) were added decanoylchloride (2.7 g) and dimethylaminopyridine (0.2 g). The solution was stirred at room temperature for about 20 hours. To the solution was added dilute aqueous hydrochloric acid solution and the organic layer was separated by a funnel. The layer was distilled to remove the solvent. The residue was washed with n-hexane and dried to obtain the titled compound (about 2.8 g).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].C(=O)([O-])O.[Na+].Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>[Br-].[K+].C(Cl)Cl>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: CO[C@H]1CCCC[C@@H]1O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: CO[C@H]1CCCCC1=O
Temperature: 0 °C
Yield: 98.1 %

Procedure:
To a 1 liter 4-necked flask, (1S,2S)-2-methoxycyclohexanol (53.57 g,0.411 mol) and methylene chloride (250 ml) were placed, and subsequently, 2,2,6,6-tetramethyl-1-piperidinyloxy free radical(1.28 g, 0.008 mol), potassium bromide (1.47 g, 0.0123 mol), and 8%-sodium hydrogencarbonate solution (52 ml, 0.0494 mol) were added and cooled to 0° C. To this mixture, 3.1N sodium hypochlorite solution (254 ml, 0.787 mol) was added dropwise over a period of 6 hours while maintaining a temperature of 0° C. to 5° C. After the disappearance of the raw material (1S,2S)-2-methoxycyclohexanol was confirmed by gas chromatography, sodium sulfite (5.36 g, 0.0425 mol) was added to the mixture to perform fractionation. Distillation was then performed, and the aqueous phase was subjected to extraction with two 25 ml portions of methylene chloride. The solvent was distilled off under a reduced pressure, and further distillation was performed to obtain (2S) -2-methoxycyclohexanone (51.67 g). The yield was 95%, the boiling point and optical purity of the product were 84° C./24 mmHg and 100%e.e., respectively. Incidentally, the gas chromatography for confirming the disappearance of (1S,2S)-2-methoxycyclohexanol was performed using the following apparatus and conditions.
Reaction SMILES: [CH:1](OCC)(OCC)[O:2]CC.[NH2:11][C:12]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:21]([F:31])[CH:20]=2)[O:14][N:13]=1>>[CH:1]([NH:11][C:12]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:21]([F:31])[CH:20]=2)[O:14][N:13]=1)=[O:2]
Reactant: CCOC(OCC)OCC
Reactant: Nc1noc(CCc2ccc(-c3ccccc3)c(F)c2)n1
Product: O=CNc1noc(CCc2ccc(-c3ccccc3)c(F)c2)n1
Yield: 83 %

Procedure:
To triethyl orthoformate (6 ml) was added 3-amino-5-(2-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (0.10 g, 0.35 mmol). After the mixture was refluxed for 20 h, the mixture was evaporated under reduced pressure to a residue, which was extracted with chloroform after water was added. The extracts were dried with anhydrous potassium carbonate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-formylamino-5-(2-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (0.091 g, 83% yield): NMR(CDCl3)δ 1.86(d, 3H), 4.40(q, 1H), 7.00-7.65(m, 8H), 9.06(broad, 2H) ppm; IR(nujol) 3275, 1740, 1580 cm-1 ; mass m/e 311 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([NH:30][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (25 g, 0.10 mol) in N,N-dimethylformamide (DMF) (130 mL) was cooled to 0° C. Triethylamine (17.2 mL, 0.123 mol) and benzylamine (11.2 mL, 0.10 mol) were sequentially added, and the reaction was stirred at ambient temperature overnight. The reaction was poured into water (1 L), and the suspension was stirred for 30 minutes at ambient temperature. The resulting precipitate was isolated by filtration and washed with water to provide 31.92 g of N-benzyl-2-chloro-3-nitroquinolin-4-amine as a bright yellow powder.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][N:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)(=O)C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:18])([CH3:19])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCOC(C)=O)C(C)(C)CCC3(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc([Se]c3ccc(C(=O)O)cn3)c(OCCO)cc21

Procedure:
In a manner similar to that of Example 2, by reaction of 419 mg (0.81 mmol) of ethyl 6-[3-(2-acetoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl]nicotinate with 320 mg (8 mmol) of sodium hydroxide in a THF/ethanol mixture (4 ml/4 ml), 273 mg (75%) of a white powder are obtained. m.p.: 170° C.
Reaction SMILES: [OH:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:16](#[N:20])[CH2:17][C:18]#[N:19].C(NCC)C>C(O)C>[NH2:20][C:16]1[O:1][C:2]2[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=2[C:17]=1[C:18]#[N:19]
Reactant: N#CCC#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(O)C1
Solvent: CCO
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N1CCc2c(oc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
tert-Butyl 3-hydroxy-4-oxopiperidine-1-carboxylate from Example 45A (3.88 g, 64% purity, 11.5 mmol) was dissolved in ethanol (10 mL), and propanedinitrile (758 mg, 11.5 mmol) was added. Within 10 min, diethylamine (0.84 g, 11.5 mmol) was added dropwise, whilst the temperature was kept below 30° C. Subsequently, the reaction mixture was stirred for 20 h at rt. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1). The product was triturated with petroleum ether/tert-butyl methyl ether (3:1) to yield 1.45 g (47%) of the title compound as yellow crystals.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH:22]=O)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12.[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[CH2:33][N:34]([CH3:36])[CH3:35])[C:28]#[N:29].CC(O)=O.[BH4-].[Na+].Cl>ClCCCl>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:11]=[C:12]([CH2:22][NH:24][C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=4[CH2:33][N:34]([CH3:36])[CH3:35])[C:28]#[N:29])[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CN(C)Cc1ccc(C#N)cc1N
Reactant: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3ncnn3c2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cccc(-c2[nH]c(CNc3cc(C#N)ccc3CN(C)C)nc2-c2ccc3ncnn3c2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
To a stirred solution of 4-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazole-2-carbaldehyde (0.50 g, 1.64 mmol) in 1,2-dichloroethane (30 mL) were added 3-amino-4-((dimethylamino)methyl)benzonitrile (0.43 g, 2.46 mmol) and AcOH (0.20 g, 3.29 mmol), and the mixture was heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous MeOH (30 mL). To a methanolic solution at 0° C. was added NaBH4 (0.25 g, 6.57 mmol), and then the mixture was allowed to warm to room temperature and stirred for an additional 3 h. The pH of the reaction mixture was adjusted to 7-8 at 0° C. with 1 N HCl, and then MeOH was removed under reduced pressure. The aqueous mixture was extracted with CH2Cl2 (2×50 mL), and the CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:19 (v/v)) as eluent to give the titled compound (0.60 g, 79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.36 (s, 1H), 7.86 (dd, 1H, J=9.2, 1.6 Hz), 7.78 (dd, 1H, J=9.2, 0.8 Hz), 7.47 (t, 1H, J=7.6 Hz), 7.23 (br d, 1H, J=7.6 Hz), 7.09 (d, 1H, J=7.6 Hz), 7.01 (d, 1H, J=7.6 Hz), 6.98 (dd, 1H, J=7.6, 1.6 Hz), 6.93 (br s, 1H), 4.59 (s, 2H), 3.63 (s, 2H), 2.53 (s, 3H), 2.33 (s, 6H); MS (ESI) m/z 464.23 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.IC.[CH3:16]N1C=CC(C2C=CC=CC=2)=N1>C1COCC1.O>[CH3:16][N:10]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:13][CH:12]=[N:11]1
Reactant: Cn1ccc(-c2ccccc2)n1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cn1nccc1-c1ccccc1
Yield: 95 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.83 g, 20.8 mmol) is suspended in THF (45 ml) and stirred under a nitrogen atmosphere. 3-Phenyl pyrazole (2.5 g, 17.3 mmol dissolved in THF, 15 ml) is added slowly, stirred for 30 minutes then iodomethane (1.3 ml, 20.8 mmol) added and stirred for 3 hrs. The reaction is added to water and extracted twice with ethyl acetate. The combined organic extracts are ished with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 40% ethyl acetate in hexane) to elute the title compound. Obtained is a mixture of 1-methyl-3-phenyl-1H-pyrazole and 1-methyl-5-phenyl-1H-pyrazole (2.6 g, 95% yield).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH2:16][CH3:17])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:18])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[Cl:18][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([C:3]#[N:4])[CH3:19])[C:14]=2[O:15][CH2:16][CH3:17]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CCOc1c2ccc(Cl)cc2nn1CC(C)(N)C#N
Product: CCOc1c2ccc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (108 mg, described in Example 122) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (96 mg, 51%). MS (ES): M/Z [M+H]=483. 1H NMR: (400 MHz, CHLOROFORM-d): 1.59 (t, J=7.0 Hz, 3H), 1.91 (s, 3H), 4.50 (d, J=14.2 Hz, 1H), 4.63-4.81 (m, 2H), 4.83 (d, J=14.2 Hz, 1H), 6.92 (dd, J=9.1, 1.7 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.90-7.99 (m, 2H) and 9.15 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: C[O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:5][CH2:4]1>I.O>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:6]1[CH2:7][CH2:8][CH:3]([OH:2])[CH2:4][CH2:5]1
Reactant: COC1CCC(c2nc3ccccc3s2)CC1
Agent: I
Solvent: O
Product: OC1CCC(c2nc3ccccc3s2)CC1
Yield: 80 %

Procedure:
A solution of 2-(4-methoxy-cyclohexyl)-benzothiazole (1.2 g, 5.15 mmol) in HI (35%)(12 mL) was heated to 90° C. for 1 h. Then the reaction mixture was diluted with water (20 mL), extracted with EtOAc (2×) and the separated organic layer was washed with brine (2×), dried over Na2SO4, and concentrated to give the desired product (960 mg, 4.12 mmol, 85% yield) as brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].CCN(CC)CC.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C=O
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A solution of (3-methyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (1.613 g, 6.060 mmol) in dimethylsulfoxide (DMSO, 12.0 mL) is treated with Et3N (5.50 mL, 39.460 mmol) and pyridine-sulfur trioxide (2.902 g, 18.235 mmol) in a cold water bath. The bath is removed after 3 min. and the reaction is stirred overnight. The reaction mixture is poured into H2O (50 mL) and extracted with EtOAc (3×50 mL). Combined organic extracts are dried over MgSO4, filtered, and conc. The residue is loaded onto silica gel and eluted with hexanes using a gradient from 5% EtOAc to 33% EtOAc to provide 3-methyl-4′-trifluoromethyl-biphenyl-4-carbaldehyde (1.221 g, 76%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]#[N:15])=[C:12]([CH3:16])[O:11][N:10]=1.C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]#[N:15])=[C:12](/[CH:16]=[CH:22]/[N:23]([CH3:25])[CH3:24])[O:11][N:10]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C#N
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)/C=C/c1onc(-c2c(F)cccc2Cl)c1C#N

Procedure:
To a solution of 1.5 g (6.3389 mmol) 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonitrile in 100 mL dry toluene, were added 2.10 g (12.6779 mmol) tert-Butoxy-bis(dimethylamino)methane. The reaction mixture was heated under reflux for 12 h. The mixture was concentrated in vacuo and was dried in the high vacuum. Petroleum ether was added to the crystallized residue. The product was collected by filtration and 1.791 g (yield of theory: 95.9%) of clean product were obtained. Result of LC/MS MH+: 292.0; 1H NMR (DMSO-d6; CCl4): 2.93 (3H, s, N—CH3), 3.17 (3H, s, N—CH3), 5.15-5.20 (1H, d, C2H2), 7.74-7.78 (1H, d, C2H2), 7.45-7.52 (1H, dd, CH-arom.), 7.57-7.59 (1H, d, CH-arom.), 7.65-7.71 (1H, d, CH-arom.)
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.[ClH:11]>>[Cl:11][CH2:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: Cl
Reactant: O=c1[nH]cc(CO)c(=O)[nH]1
Product: O=c1[nH]cc(CCl)c(=O)[nH]1

Procedure:
A solution of 1.4 g. (0.010 mole) of 5-hydroxymethyl uracil in 12.5 ml. of concentrated hydrochloric acid was prepared. A colorless precipitate (5-chloromethyl uracil) formed within two minutes and after about ten minutes the precipitate was collected by filtration, washed rapidly with ice cold water, dried and then suspended in 10 ml. of dimethylformamide.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)Cl.S(Cl)(Cl)=O.[CH2:20]([C:22]1[C:30]2[C:29]([NH2:31])=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]([CH2:32][C:33]2[C:34]([O:40][CH3:41])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)[N:23]=1)[CH3:21]>C1COCC1.ClCCCl>[CH2:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[NH:31][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[N:24]([CH2:32][C:33]2[C:34]([O:40][CH3:41])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)[N:23]=1)[CH3:21]
Reactant: CCc1nn(Cc2ccc(C)nc2OC)c2cccc(N)c12
Reactant: O=C(O)c1cnc2ccccn12
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCc1nn(Cc2ccc(C)nc2OC)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
To imidazo[1,2-a]pyridine-3-carboxylic acid (118 mg, 0.729 mmol) was added a mixture of 3:1 DCM/thionyl chloride (4 mL). The mixture was stirred at ambient temperature for 3 hours and then concentrated to a residue under N2 stream. The residue was dried under high vacuum for 30 minutes. 3-Ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine (108 mg, 0.364 mmol) in THF/DCE (1:1; 8 mL) was added to the dry acid-chloride residue. The reaction mixture was heated at 75° C. for 30 minutes. The mixture was concentrated under reduced pressure and diluted with DCM. The solution was washed with saturated NaHCO3 aqueous solution, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5% MeOH 0.5% NH4OH in DCM to give the product (57.6 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:16]1([CH2:21][C@H:22](O)[CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CO.C(Cl)Cl>[N:16]1([CH2:21][C@@H:22]([O:1][C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C1CCCc2c1ccc(O)c2[N+](=O)[O-]
Reactant: CC(C)[C@@H](O)Cn1ccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)[C@@H](Cn1ccnc1)Oc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 6-hydroxy-5-nitro-1-tetralone (0.888 g, 4.29 mmol) in dry THF (10 mL) was added (R)-1-imidazol-1-ylmethyl-2-methyl-propanol (0.737 g, 4.78 mmol) followed by triphenylphospine (1.26 g, 4.78 mmol). After approximately 10 min, diethylazodicarboxylate (0.75 mL, 4.78 mmol) was added slowly. The reaction was allowed to stir at RT for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (SiO2, 20% acetone/CH2Cl2 then 5% MeOH/CH2Cl2) afforded the title compound as a foam (1.02 g, 2.97 mmol, 69%). The structure was confirmed by NMR and mass spectrometry. MS m/z 344 (M++H). 2. 5-Amino-6-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-3,4-dihydro-2H-naphthalen-1-one