Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8](C(OC(C)(C)C)=O)[N:7]=1)[CH3:3].[F:22][C:23]([F:35])([F:34])[S:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:3][CH:2]([N:4]([CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:23]([F:34])([F:22])[F:35])=[CH:26][CH:27]=1)=[O:33])[CH3:1]
Reactant: CC(C)NCc1nn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(Cc1n[nH]c2ncccc12)C(=O)Nc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To crude tert-butyl 3-[(propan-2-ylamino)methyl]-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (75 mg, 0.26 mmol) in 2 mL CH2Cl2 was added 4-(trifluoromethylthio) phenylisocyanate (57 mg, 0.26 mmol). The reaction was allowed to stir at ambient temperature for 16 h. To the reaction solution was added trifluoroacetic acid (1.0 mL, 1.35 mmol). The solution was allowed to stir at ambient temperature for 1 h, concentrated, and purified on a Gilson reverse phase preparatory instrument. The aqueous fractions were partitioned between saturated Na2CO3 and ethylacetate. The organics were washed with water and brine, dried over Na2CO3, filtered, and purified by silica gel chromatography to give 1-(1-methylethyl)-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}urea. 1H NMR (400 MHz, CDCl3): δ 11.69 (s, 1 H); 8.62 (dd, J=4.6, 1.5 Hz, 1 H); 8.54 (s, 1 H); 8.22 (dd, J=8.1, 1.5 Hz, 1 H); 7.51 (d, J=3.1 Hz, 4H); 7.24-7.21 (m, 1 H); 4.71 (s, 2 H); 4.61-4.51 (m, 1 H); 1.24 (d, J=6.8 Hz, 6 H. LCMS [M+H]+=410.1.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][C@H:21](OS(C)(=O)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[CH3:29][C@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1>>[CH3:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([N:3]3[CH2:4][CH2:5][C:6]4([CH2:7][CH2:8][O:9][CH2:10][CH2:11]4)[C:2]3=[O:1])=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Reactant: C[C@H]1CCCN1
Product: C[C@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 9 by condensing cis-methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and (S)-2-methylpyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: NCC(O)C(F)(F)F
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC(O)C(F)(F)F)cn1
Yield: 76 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (68 mg, 0.21 mmol) was converted, using 3-amino-1,1,1-trifluoro-2-propanol instead of 4-aminotetrahydropyran, to the title compound (69 mg, 76%) which was obtained as a white solid. MS: m/e=440.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15][N:16]([CH:20]1[CH2:22][CH2:21]1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH3:15][N:16]([CH:20]1[CH2:22][CH2:21]1)[C:17](=[O:18])[O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=1
Reactant: CN(C(=O)Cl)C1CC1
Reactant: COC(COc1ccc(O)cc1)OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COC(COc1ccc(OC(=O)N(C)C2CC2)cc1)OC
Temperature: 80 °C

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole), N-methyl-N-cyclopropylcarbamoyl chloride (0.08 mole), triethylamine (0.05 mole) and xylene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is stirred and heated at 80° C. for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then washed with water and dried over anhydrous magnesium sulfate. The dried solution is then filtered and stripped of solvent and unreacted starting materials to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-methyl-N-cyclopropylcarbamate as the residue.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH2:9][NH:10][CH:11]=O)[O:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH:1]1([C:4]2[N:8]=[C:7]([CH2:9][N+:10]#[C-:11])[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=CNCc1nc(C2CC2)no1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]Cc1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 3-cyclopropyl-5-formylaminomethyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged at 0° C. dropwise with POCl3 (60 mmol). The mixture was then left for 30 min. with stirring at 0° C., whereafter a solution of Na2CO3 (60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted, and the solution was evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.ClC1C=CC=[C:17]([C:21]([O:23]O)=[O:22])C=1>O1CCCC1>[C:21]([O:23][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1)(=[O:22])[CH3:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccccc2)cn1
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A mixture of 2-methyl-5-phenylpyridine (3.00 g), 3-chloroperbenzoic acid (4.79 g) and tetrahydrofuran (50 ml) was stirred at room temperature overnight, and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with tetrahydrofuran. A solution of the resulting colorless oily substance in acetic anhydride (50 ml) was added slowly to acetic anhydride (50 ml) heated at 130° C., which was stirred at 2 hours, and concentrated. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate solution, and with saturated aqueous sodium chloride solution, and then dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-phenyl-2-pyridylmethyl acetate (3.68 g, yield 92%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 71–72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9](C(N3CCCC3)=O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C[C:50](C1C=C(OC)C=CC=1O)=[O:51]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:51][CH3:50])=[CH:8][CH:7]=2)=[CH:47][CH:48]=1
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1

Procedure:
The title compound was synthesized in seven steps as described for Compound 204 except 2-hydroxy-5-methoxy acetophenone was used instead of Compound 18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([N:19]([CH3:21])[NH2:20])[CH:14]=[N:13]1.[CH3:22]OC(OC)N(C)C>CN(C)C=O>[CH3:21][N:19]1[C:15]2[C:14](=[N:13][N:12]([C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:9])[F:10])[CH:6]=[CH:7][C:2]=3[F:1])[C:17](=[O:18])[CH:16]=2)[CH:22]=[N:20]1
Reactant: COC(OC)N(C)C
Reactant: CN(N)c1cnn(-c2cc(C(F)(F)F)ccc2F)c(=O)c1
Solvent: CN(C)C=O
Product: Cn1ncc2nn(-c3cc(C(F)(F)F)ccc3F)c(=O)cc21

Procedure:
In 250 ml. of absolute dimethylformamide (dried over molecular sieves) under a nitrogen atmosphere, are dissolved 14.5 grams of 2-(2-fluoro-5-trifluoromethylphenyl)-5-(1-methylhydrazino)-3(2H)-pyridazinone. To this solution are added 11.4 grams of N,N-dimethylformamide dimethyl acetal and the solution is heated at 110°-120° C. overnight. The progress of the reaction is followed by thin layer chromatography. An additional 6.0 grams of N,N-dimethylformamide dimethyl acetal is added with continued heating to complete the reaction (about 20 hours). The reaction mixture is then evaporated to dryness in vacuo and then column chromatographed on silica gel, eluting with a mixture of benzene-chloroform (50/50), to obtain the title product. (m.p. 190°-195° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]Br)[CH:6]=[CH:7][CH:8]=1.[C-:13]#[C-:14].[Na+].[Na+].N>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:13]#[CH:14])[CH:6]=[CH:7][CH:8]=1
Reactant: [C-]#[C-]
Reactant: COc1cccc(CCCBr)c1
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCc1cccc(OC)c1

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride at 70° C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-(m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH:25]1([CH2:28][NH:29][CH2:23][C:20]2[CH:21]=[CH:22][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)[CH:19]=2)[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1-n1ccc(CNCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
Compound 167 (0.06 g, 0.19 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with cyclopropanemethylamine (50 μL, 0.57 mmol), acetic acid (63 μL, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain Compound 189 (0.01 g, 14%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3ccccc3)C2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)O
Yield: 100.1 %

Procedure:
A solution of ethyl (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate (750 mg) and 1N NaOH solution (4.1 ml) in MeOH (10 ml) and THF (10 ml) was stirred at 80-85° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture was AcOEt and H2O. The aqueous solution was adjusted to PH 5.4 with 5% HCl solution and resultant solution was evaporated in vacuo and the residue was dissolved in a MeOH and THF. The solvent was evaporated in vacuo and dried to give (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylic acid (693 mg).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([CH2:11][NH:12][C:13]([C:15]1[N:16]=[C:17]([C:33]#[N:34])[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=[O:14])([CH3:10])[CH2:8][CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:33]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=2)[C:24]([OH:25])=[C:15]([C:13]([NH:12][CH2:11][C:7]([CH3:10])([CH2:8][CH3:9])[C:6]([OH:35])=[O:5])=[O:14])[N:16]=1)#[N:34]
Reactant: CCC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-{[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-2-methyl-butyric acid tert-butyl ester (45 mg, 0.10 mmol) was dissolved in TFA (1.7 mL) and CH2Cl2 (1.7 mL). The resulting mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved again in CH2Cl2 (4 mL). The volatiles were removed again in vacuo to give the title compound in 36 mg. MS: (−) m/z 418.14 (M−1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.Cl.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[N:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:33]1([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[N:29][C:24]([C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[CH2:17][N:8]3[C:7]4[CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=4[S:10][C:9]3=[O:11])=[N:25][CH:26]=2)[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2s1
Reactant: ClCc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1sc2ccc(C(F)(F)F)cc2n1Cc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1
Temperature: 70 °C
Reaction time: 120 h

Procedure:
A suspension of 89 mg (0.405 mmol) of 5-trifluoromethyl-3H-benzothiazol-2-one, 150 mg (0.405 mmol) of 4-{2-[2-(3-chloromethylphenyl)pyrimidin-5-yl-oxy]ethyl}morpholine hydrochloride and 286 mg (2.02 mmol) of potassium carbonate in 8 ml of acetonitrile are stirred at 70° C. for 5 days. 30 ml of water are added to the reaction mixture, with a precipitate slowly forming. The precipitate is filtered off with suction, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc([N+](=O)[O-])c2ncccc2c1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc(N)c2ncccc2c1C
Yield: 77.4 %

Procedure:
In a similar fashion using route 6 general procedure 14, 5,6-dimethyl-8-nitroquinoline (Intermediate 43) (200 mg, 0.9 mmol), Raney nickel (40 mg, 20 wt), hydrazine hydrate (200 μl, 3.9 mmol) and MeOH (5 ml) gave the title compound (120 mg, 77%) which was used in the next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19]C)=[CH:14][C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[CH2:10][CH2:11][C:12]2[C:13]([CH3:21])=[CH:14][C:15]([OH:19])=[C:16]([CH3:18])[CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2cc(C)c(OC)cc2C)nc1
Product: CCc1cnc(N(CCc2cc(C)c(O)cc2C)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyl]pyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=2[CH:17]=1.B(Br)(Br)Br.C(OCC)C.O>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=2[CH:17]=1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2CCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1=Cc2cc(O)ccc2CCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To methyl 2-methoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (5.07 g, 21.8 mmol) dissolved in dichloromethane (100 ml) was added dropwise at −60° C. to −70° C. (inner temperature) boron tribromide (a 1 M solution in dichloromethane, 87 ml), and the resulting mixture was stirred for 5 hours while raising the temperature from −70° C. to room temperature. The reaction mixture was mixed with diethyl ether and water (100 ml) in the order, and was extracted with dichloromethane (100 ml, 50 ml×2). The combined organic layers were dried with anhydrous magnesium sulfate, and were then concentrated under reduced pressure. To the residue dissolved in methanol (150 ml) was added sulfuric acid (0.5 ml), and the resulting mixture was stirred under reflux with heating (100° C.) for 24 hours. The reaction mixture was concentrated under reduced pressure, was mixed with ethyl acetate (150 ml) and was washed with an aqueous saturated solution of sodium chloride (30 ml×3). After drying with anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure, diisopropyl ether was added to the residue and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (4.31 g, 19.7 mmol, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: Fc1ccc(CS)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccc(F)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 4-fluorobenzylsulfide. The title compound was obtained in 69% yield following oxidation. 1HNMR (CDC13) δ 2.46 (3H, s),4.62 (2H, s), 6.78 (1H, d, JH,H=11.98), 7.18-7.59 (9H aromatic+1H ethylenic).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29]>>[OH:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])=[CH:22][C:21]=1[CH3:29]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: Cc1cc(C=CC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1O

Procedure:
3-(4-Hydroxy-3,5-dimethylphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 4-hydroxy-3,5-dimethylbenzaldehyde according to general procedure B. The evaporation residue is washed with dichloromethane.
Reaction SMILES: CS[C:3](=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[CH:4]([CH3:6])[CH3:5].[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([C:21]([NH:23][NH2:24])=O)=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([C:21]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:3]([CH:4]([CH3:6])[CH3:5])=[N:24][N:23]=2)=[CH:17][CH:16]=1
Reactant: CSC(=Nc1ccccc1F)C(C)C
Reactant: NNC(=O)c1ccc(-c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)c1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Temperature: 25 °C
Yield: 67.6 %

Procedure:
N-(2-Fluorophenyl)-2-methylthiopropionimidate methyl ester (7.84 g) prepared in the Reference Example 1 and biphenyl-4-carboxylic acid hydrazide (5.25 g) were dissolved in N,N-dimethylformamide (50 ml), followed by addition of p-toluenesulfonic acid.monohydrate (941 mg), and stirred at 120° C. for 59 hours. After the reaction solution was cooled to ambient temperature, the resulting solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:chloroform-chloroform/methanol=100/1 to 50/1 to 20/1), to afford 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole as pale yellow solid (5.98 g, 68%). A part of the product was recrystallized from ethyl acetate, to afford the entitled compound as pale yellow crystal. The physico-chemical values are as follows.