Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][N:11]([CH:13]([N:16](C)C)[O:14]C)C.NC(N)=O>>[N:7]1[CH:8]=[CH:9][C:4]([C:1]2[CH:2]=[CH:10][NH:11][C:13](=[O:14])[N:16]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Reactant: COC(N(C)C)N(C)C
Agent: NC(N)=O
Product: O=c1nc(-c2ccncc2)cc[nH]1
Temperature: 85 °C

Procedure:
A mixture of 4-acetylpyridine (25 ml, 226.0 mmol) and bis(dimethylamino)methoxymethane (44 ml 293.8 mmol) was heated at 85° C. for 30 min followed by evaporation to dryness to recover a solid of 3-(dimethylamino)-1-(4-pyridyl)-3-propen-1-one. Its ethanolic solution (2.00 ml) was transferred into ethanolic 1.13 N sodium ethoxide (200 ml) containing urea (16.3 g, 271 mmol) The mixture was heated to reflux overnight, then cooled down to ice-bath temperature. The precipitate was filtered, dissolved in a minimal amount of water and the aqueous solution was washed with dichloromethane. The title compound was precipitated from the aqueous solution by neutralization with 6N hydrochloric acid and filtered. More material was obtained from the original reaction filtrate which was concentrated, diluted with a minimal amount of water and washed with dichloromethane. The aqueous solution was neutralized with 6N hydrochloric acid and the precipitate filtered. MS (m/z): 174.1 (M+H)+; C9H7N3O requir. 173.2.
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.[CH3:36][NH:37][CH2:38][CH:39]=[CH2:40].C(N(CC)CC)C.C(Cl)Cl>>[CH2:38]([N:37]([CH3:36])[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])[CH:39]=[CH2:40]
Reactant: C=CCNC
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(C)C[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.0002 mol), N-methylprop-2-en-1-amine (30 mg, 0.4 mmol), triethylamine (200 mg, 0.002 mol) and methylene chloride (6 mL, 0.09 mol) was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the mixture was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:13]([CH3:15])[CH3:14])=[C:4]([CH:6]=[C:7]([CH:10]([CH3:12])[CH3:11])[C:8]=1[OH:9])[OH:5].[Cl:16][CH2:17]OC>C(=S)=S>[Br:1][C:2]1[C:8]([OH:9])=[C:7]([CH:10]([CH3:11])[CH3:12])[C:6]([CH2:17][Cl:16])=[C:4]([C:3]=1[CH:13]([CH3:15])[CH3:14])[OH:5]
Reactant: COCCl
Reactant: CC(C)c1cc(O)c(C(C)C)c(Br)c1O
Solvent: S=C=S
Product: CC(C)c1c(O)c(CCl)c(C(C)C)c(O)c1Br

Procedure:
Two hundred seventy-three parts of 3-bromo-2,5-diisopropylhydroquinone is allowed to react with 130 parts of chloromethylmethyl ether and 80 parts of stannic chloride in 400 parts of carbon disulfide under general conditions set forth in "Organic Reactions", Vol. 1, p. 68 and 69. The reaction mixture is poured on ice, and the organic layer is separated and dried over anhydrous calcium sulfate. The solvent is allowed to evaporate and the residue is crystallized to give a pure sample of the title compound. Chloromethylation of the following monohalo- or dihalodialkylhydroquinones or resorcinols gives the corresponding chloromethyl derivatives.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:14][C:4]1[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCc1c(N)cc(Cl)cc1C(=O)OC
Temperature: 70 °C
Yield: 44.7 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-nitrobenzoate (6.18 g, 25.36 mmol) in Methanol (250 ml) at room temperature was added ammonium chloride (13.31 g, 253.65 mmol) followed by deionized Water (125 ml). The mixture was heated to 70° C. in air before the addition of iron (8.5 g, 152.19 mmol). The reaction turned to a dark color over the 2.5 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (250 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3(aq) (50 ml) and EtOAc (150 ml). The phases were separated and the organic phase was washed with saturated NaHCO3(aq) (2×50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 75:25 Heptane:EtOAc) to give 2.42 g (22%, 7% corrected yields) of methyl 3-amino-5-chloro-2-ethylbenzoate as a yellow oil. The product contains ˜25% ethyl ester and possible ˜15% 4-nitro products. The material was taken through the next step without further purification. LC-MS 31%, 2.00 min (3 minute LC-MS method), m/z=295.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.17 (d, J=2.1 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.87 (s, 3H), 3.86-3.81 (m, 2H), 2.74 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[Cl:17])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:17][C:10]1[CH:11]=[C:12]([CH:13]2[O:23][CH2:22][CH2:21][O:14]2)[CH:15]=[CH:16][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:18]([O-:20])=[O:19])[CH:4]=1
Reactant: Nc1ccc(Oc2ccc(C=O)cc2Cl)cc1[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc(Oc2ccc(C3OCCO3)cc2Cl)cc1[N+](=O)[O-]

Procedure:
4-[(4-Amino-3-nitrophenyl)oxy]-3-chlorobenzaldehyde (1.16 g, 5.3 mmol), ethylene glycol (5 ml) and p-toluenesulfonic acid (50 mg) in 150 mL of toluene was heated at 120 degrees centigrade with a Dean-Stark trap for 24 hours. The reaction mixture was diluted with ethyl acetate and washed twice with 1N NaOH. The organic layer was dried over MgSO4 and concentrated to give 4-{[2-chloro-4-(1,3-dioxolan-2-yl)phenyl]oxy}-2-nitroaniline. (M+1) 336.9, 2.60 min (LC/MS method B)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#N)=[CH:5][CH:4]=1.O.CC(O)=[O:16]>[Ni].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:16])=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(C=CC#N)cc1
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C=CC=O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To 2 g (12.6 mmol) 4-methoxycinnamonitrile in 10:10:20 ml H2O:HOAc:pyridine was added 5 g (47 mmol) NaH2PO2 (hypophosphite) followed by 2 g Ra-Ni. After stirring 3 hours at 50° C., the reaction mixture was filtered, extracted with CH2Cl2, washed with dilute HCl, washed with H2O and evaporated to give 0.7 g (35% yield) 4-methoxycinnamaldehyde, a yellow solid, m.p. 47° C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][N:12]([CH3:36])[CH:13]([CH2:34][CH3:35])[CH2:14][CH2:15][NH:16][C:17]1[CH:33]=[CH:32][C:20]2[N:21]=[CH:22][N:23](COCC[Si](C)(C)C)[C:19]=2[CH:18]=1.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:47]2[CH:48]=[C:49]([CH:52]=[CH:53][C:54]=2[O:55][CH3:56])[CH:50]=[O:51])=[CH:39][N:38]=1>C1COCC1>[CH3:36][N:12]([CH3:11])[CH:13]1[CH2:14][CH2:15][N:16]([C:17]2[CH:33]=[CH:32][C:20]3[N:21]=[C:22]([C:50]([C:49]4[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:47]([C:40]5[C:41]6[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=6)[CH:37]=[N:38][CH:39]=5)[CH:48]=4)=[O:51])[NH:23][C:19]=3[CH:18]=2)[CH2:35][CH2:34]1
Reactant: COc1ccc(C=O)cc1-c1cncc2ccccc12
Reactant: CCC(CCNc1ccc2ncn(COCC[Si](C)(C)C)c2c1)N(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)cc3[nH]2)cc1-c1cncc2ccccc12
Reaction time: 0.08 h
Yield: 17.1 %

Procedure:
To a cooled (−78° C.) 1M solution of lithium hexamethyldisilazane (0.88 mL, 0.88 mmol) in THF was added N3,N3-Dimethyl-N1-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazol-5-yl]-pentane-1,3-diamine (82 mg, 0.22 mmol) in 1 mL THF. Solution turned bright orange. After 5 min, the reaction mixture was treated with 3-isoquinolin-4-yl-4-methoxy-benzaldehyde (58 mg, 0.22 mmol) in 1 mL THF. After 20 minutes, the reaction mixture was removed from cold bath, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was then dissolved in DCM: TFA. After 1 hour, the reaction mixture was concentrated and purified by HPLC (Deltapak C18, acetonitrile: 0.1% trifluoroacetic acid), then neutralized using PL-HCO3 SPE to obtain 19 mg [6-(4-dimethylamino-piperidin-1-yl)-1H-benzoimidazol-2-yl]-(3-isoquinolin-4-yl-4-methoxy-phenyl)-methanone in 17% yield. MS m/z 506.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Cl)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[I-].[Na+].[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.Cl>C(#N)C>[Br:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:29]3[CH2:30][CH2:31][CH2:32][CH:28]3[CH3:27])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCCOc1ccc(-c2nc(CN3CCCCC3)c(Br)o2)cc1
Reactant: CC1CCCN1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nc(CN3CCCCC3)c(Br)o2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
A solution of 1-[(5-bromo-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl)methyl]piperidine i90 (0.39 g, 0.94 mmol, 1 eq) and 2-metlhylpyrrolidine (192 μl, 1.89 mmol, 2 eq) in acetonitrile (6 ml) is treated with sodium iodide (14 mg, 0.09 mmol, 0.1 eq) and stirred for 24 h at 90° C. 2-Methylpyrrolidine (100 μl, 1 mmol) is then added and the mixture is stirred for a further 24 h at 90° C. The mixture is then poured into 0.1 N hydrochloric acid (10 ml) and extracted with diethyl ether (10 ml). The aqueous phase is then treated with 1 N sodium hydroxide to reach pH 10 and extracted with dichloromethane (3×10 ml). The combined dichloromethane extracts are then dried over magnesium sulfate and concentrated to yield 370 mg of an orange oil which is purified by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 96:3.6:0.4) to yield 86 mg of 1-[(5-bromo-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl]piperidine 117.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[C:28]([F:30])[F:29]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[C:28]([F:30])[F:29])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: FC(F)=CCCCCCl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCCCCC=C(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
Under a nitrogen atmosphere a solution of 2.7 grams (0.0171 mole) of 4-chlorobenzoic acid in 100 ml of acetonitrile was stirred, and 2.6 grams (0.0171 mole) of DBU was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 15 minutes, and then 4.0 grams (0.017 mole) of 6-chloro-1,1-difluoro-1-hexene was added. The reaction mixture was then warmed to and stirred at reflux for 18 hours. The reaction mixture was cooled and was washed into a separatory funnel with diethyl ether. The reaction mixture was washed in turn with 50 ml of aqueous 10% hydrochloric acid, 50 ml of aqueous 10% sodium bicarbonate, and 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate nd filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure yielding 3.9 grams of 6,6-difluoro-5-hexenyl 4-chlorobenzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:34]([NH2:36])[CH3:35])[CH:20]=[N:21][C:22]=1[O:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:36]([CH:34]([C:19]3[CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[C:17]([CH3:16])[CH:18]=3)[CH3:35])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1Oc1ccc(C(F)(F)F)nc1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1ccc(C(F)(F)F)nc1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (160 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.73 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (290 mg, 0.86 mmol, Amine-41, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>O.CO.[Fe]>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[CH2:12][CH2:11][CH2:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CCCc2nccs2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(CCCc2nccs2)nc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of compound 138 (2.32 g, 9.3 mmol), NH4Cl (7.46 g, 140 mmol) and Iron Powder (5.19 g, 93 mmol) in water (100 mL) and CH3OH (100 mL) was stirred at 90° C. for 1 h. After cooling, the reaction mixture was filtered and the solid was washed by DCM. The filtrates were separated, the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 139 (2.0 g, 83%) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC.N#N>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([C:30]([O:32][CH2:33][CH3:34])=[CH2:31])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: CC(c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Temperature: 95 °C

Procedure:
A solution of 6-chloro-3-[1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (80 mg, 0.23 mmol) and tributyl(1-ethoxyvinyl)stannane (0.234 mL, 0.69 mmol) in 15 mL of DMF was purged with N2 for 30 min and then Pd(PPh3)4 (80 mg, 0.069 mmol) was added and the solution was heated at 95° C. overnight. After the reaction was complete, it was quenched with water, extracted with EtOAc three times. The organic layers were combined, washed with KF solution then brine, dried over Na2SO4. Solvent was evaporated and the crude (80 mg, 90%) was used in the next step without further purification. LCMS (method C): [MH]+=384.0, tR=4.67 min
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18]CCC)[CH:12]=[CH:11][C:10]=1[CH:24]1[CH:29]([CH3:30])[CH:28]([CH3:31])[CH2:27][C:26]([CH:33](Br)Br)([OH:32])[CH2:25]1)C1C=CC=CC=1.[CH2:36]([Li])[CH2:37][CH2:38][CH3:39]>O1CCCC1>[CH2:36]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:11][CH2:12][CH3:13])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH:29]([CH3:30])[CH:28]([CH3:31])[CH2:27][CH2:33][C:26](=[O:32])[CH2:25]1)[C:37]1[CH:14]=[CH:9][CH:10]=[CH:39][CH:38]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(O)(C(Br)Br)CC(C)C2C)c(OCc2ccccc2)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCC(C)C2C)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a -78° C. solution of 30.4 g (0.050 mole) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1-dibromomethyl-4,5-dimethylcyclohexanol in 150 ml of tetrahydrofuran is slowly added over a period of 2 hours 47.7 ml (0.105 mole) of n-butyllithium (2.2 M in hexane). The reaction solution is stirred 2 hours longer at -78° C. and 10 minutes at 0° C. and then quenched by pouring into 300 ml of ice cold 1 N hydrochloric acid. The quenched reaction is extracted with two 250 ml portions of ether, the combined extract washed with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 500 g of silica gel eluted with ether-pentane to yield the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.CO[CH:12]=[C:13]=[CH2:14]>CCOCC.[Cu]Br>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:14][C:13]#[CH:12])=[CH:4][CH:5]=1
Reactant: C=C=COC
Reactant: Clc1ccc(Br)cc1
Agent: [Cu]Br
Agent: [Mg]
Solvent: CCOCC
Product: C#CCc1ccc(Cl)cc1

Procedure:
Place 59 g (2.43 mole) of magnesium turnings into a four-neck flask equipped with mechanical stirrer under N2 atmosphere. Add 500 ml of anhydrous ether and then add a solution of 465 g (2.43 mole) of 1-bromo-4-chlorobenzene in 1000 ml of anhydrous ether dropwise while stirring. Stir one hour after the completion of addition. Transfer and add this Grignard reagent to a solution of 170 g (2.43 mole) of 1-methoxy-1,2-propanediene and 69 g of copper (I) bromide in 300 ml of anhydrous ether with cooling. Stir for another ten minutes after the completion of addition. Add saturated aqueous solution of ammonium hydroxide and decant ether solution. Wash the solid residue with ether (3×50 ml). Wash the combined ether solutions with 1N HCl, saturated aqueous sodium bicarbonate, and with H2O. Dry over magnesium sulfate, evaporate, and distill in vacuo to yield the title compound, b.p. 99°-105° C. (15 mmHg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[N:7]=[C:6]([NH2:18])[N:5]=1)=O.C(O)C.Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+]>O>[CH3:1][C:2](=[N:23][OH:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[N:7]=[C:6]([NH2:18])[N:5]=1
Reactant: NO
Reactant: CC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1nc(N)nc(N)c1-c1ccc(Cl)cc1

Procedure:
[2,6-Diamino-5-(p-chlorophenyl)-4-pyrimidinyl] methyl ketone (2.6 g.) was dissolved in 30 ml. of ethanol and hydroxylamine, hydrochloride (1.5 g.) and sodium acetate (2.5 g.) in 25 ml. of water was added and the mixture refluxed for 5 hours. After cooling a white precipitate separated; it was recrystallized from methanol to give 1.5 g. of the title product, m.p. 256°-259°.
Reaction SMILES: O.C([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:25]([O:27][CH3:28])[CH3:26])=[N:15][N:16]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH3:28][O:27][CH:25]([C:14]1[C:13]2[C:17](=[CH:18][C:10]([OH:9])=[CH:11][CH:12]=2)[N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1)[CH3:26]
Reactant: COC(C)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COC(C)c1nn(C2CCCCO2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
5% Palladium on carbon-STD-type-50% wet with water (79.5 mg; manufactured by N. E. Chemcat Corp.) and 6-(benzyloxy)-3-(1-methoxyethyl)-1-(tetrahydro-2H-pyran-2-yl)-indazole (195 mg) which can be prepared according to the method described in Reference example 25, etc. were dissolved in THF (5.6 mL; manufactured by Kanto Chemical Co., Inc.). After replacing the reaction system with hydrogen, it was stirred overnight at room temperature under hydrogen atmosphere. After replacing the reaction solution with nitrogen, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (167 mg).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3].[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH2:1]([C:4]1[C:13]([O:14][C:26]2[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: C=CCc1c(O)cc(C(=O)OC)cc1C(=O)OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Yield: 77.4 %

Procedure:
A mixture of dimethyl 4-allyl-5-hydroxyisophthalate (2.0 g, 7.99 mmol), 4-fluorophenyl methyl sulfone (2.1 g, 12 mmol), Cs2CO3 (5.2 g, 16 mmol) and CuI (400 mg, 2.1 mmol) in DMF (20 mL) was heated to for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via silica gel gradient chromatography eluted with EtOAc in hexanes (10/90 to 30/90) to afford the title compound (2.5 g, 78%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.83 (dd, J=6.69, 1.60 Hz, 2 H) 3.03-3.16 (m, 3 H) 3.93 (d, 6 H) 6.14-6.34 (m, 1 H) 6.63 (dd, J=16.11, 1.60 Hz, 1 H) 6.88-6.98 (m, 1 H) 6.97-7.09 (m, 2 H) 7.79 (d, J=1.70 Hz, 1 H) 7.87-8.01 (m, 2 H) 8.29 (d, J=1.70 Hz, 1 H); LC-MS (ESI)+m/z =405.00 (M+H)+.