Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1CCC(N2C3N=CN=C(Cl)C=3C=C2)CC1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[C:26]2[C:33]([C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=3)=[O:35])=[CH:32][N:31]([CH:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[C:27]=2[N:28]=[CH:29][N:30]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:46][CH2:47][CH:43]([N:31]2[C:27]3[N:28]=[CH:29][N:30]=[C:25]([NH2:24])[C:26]=3[C:33]([C:34](=[O:35])[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=3)=[CH:32]2)[CH2:44][CH2:45]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3c(Cl)ncnc32)CC1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(N)c3)c3c(N)ncnc32)CC1

Procedure:
The title compound was prepared from 4-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylic acid tert-butyl ester by procedures analogous to those described for the preparation of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone. MS: 437.5 (MH+); HPLC Rf: 5.18 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C(O)C>O>[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:13])[N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=1
Reactant: CCCCN
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Solvent: CCO
Solvent: O
Product: CCCCN1C(=O)c2ccc(O)cc2C1=O

Procedure:
In a 250-ml round bottom flask were placed 20.5 g (112.6 mmols) of 4-hydroxyphthalic acid, 8.2 g (112.6 mmols) of n-butylamine and 100 ml of absolute ethanol. After mixing, the resulting mixture generated heat gently. The mixture was sufficiently stirred until the solids were completely dissolved. The alcohol was distilled off under reduced pressure, after which the viscous liquid thus obtained was heated at 180° C. for about 3 hours with continuous extraction of water. After cooling, the residue was solidified. The solidified residue was dissolved in an ethyl acetatebenzene (1:1 by volume) mixed solvent, and the resulting solution was washed with water, an aqueous sodium carbonate solution and then water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and then cooled to obtain powder crystals having a slightly yellowish white color. The crystals were collected by suction filtration and dried. Yield: 18.5 g (75%), m.p. 126°-127° C. The product was determined to be 4-hydroxy-N-n-butylphthalimide by investigation of its structure by NMR and infrared absorption spectrum.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:3]1=[O:19].[H-].[Na+].Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][N:24]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([C:23]2[N:24]=[CH:25][C:26]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][N:28]=2)([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:3]1=[O:19]
Reactant: CN1C(=O)C(C(=O)OCc2ccccc2)CC1(C)C
Reactant: Clc1ncc(C#Cc2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(C(=O)OCc2ccccc2)(c2ncc(C#Cc3ccccc3)cn2)CC1(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 79.6 %

Procedure:
A solution of (RS)-benzyl 1,5,5-trimethyl-2-oxopyrrolidine-3-carboxylate (206 mg, 787 μmol) in 4 ml of dry DMF was purged with argon and cooled to 0° C. Then a 60% suspension of sodium hydride (31.5 mg, 0.79 mmol) was added and the mixture was stirred for 40 min at room temperature whereby a white suspension was formed. Then 2-chloro-5-(phenylethynyl)pyrimidine (CAS: [1051388-40-9]) (130 mg, 606 μmol) was added, the mixture was stirred for 30 min at 80° C., and then quenched by addition of 1 ml of saturated ammonium chloride solution. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue (440 mg, yellow oil) was taken up in ethyl acetate, adsorbed onto 3 g of silicagel and loaded onto a 20 g prepacked flash chromatography column. After elution with a 10% to 60% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 212 mg (80%) of the title compound as a light yellow waxy solid, MS: m/e=440.3 (M+H+).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH:9]1([N:12]([CH3:22])[S:13]([N:16]2[CH:20]=[CH:19][N+](C)=C2)(=[O:15])=[O:14])[CH2:11][CH2:10]1.[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=C(N)C=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[CH:9]1([N:12]([CH3:22])[S:13]([NH:16][C:20]2[CH:19]=[C:40]3[C:35](=[CH:36][CH:37]=2)[N:34]=[C:33]([NH:32][C@H:23]2[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]2)[CH:42]=[CH:41]3)(=[O:14])=[O:15])[CH2:10][CH2:11]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN(C1CC1)S(=O)(=O)n1cc[n+](C)c1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(C1CC1)S(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with step C of the general method described in example 76 from 3-(cyclopropyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium trifluoromethanesulfonate and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=409.7 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[S:7])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[S:7][CH:18]([C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: NNC(=S)c1ccc(Cl)cc1
Solvent: CCO
Product: Clc1ccc(C2=NNC(c3cccnc3)S2)cc1
Reaction time: 1 h

Procedure:
39.2 g of p-chlorothiobenzoic acid hydrazide are dissolved in 350 ml of ethanol. Under nitrogen, 21.4 g of pyridine-3-aldehyde (dissolved in 20 ml of ethanol) are added dropwise to this solution. The reaction temperature is kept at 20° C. by cooling. When the addition is complete, the reaction mixture is stirred for 1 hour at reflux temperature and subsequently filtered through finely particulate diatomaceous earth. The filtrate is concentrated to three quarters of its initial volume and the precipitated product is isolated by filtration, washed with hexane and dried, affording the title compound of the formula ##STR8## with a melting point of 106°-108° C. (compound 1.1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[CH:23][CH:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1cccn1

Procedure:
Using general procedure 3, [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.15 g, 0.59 mmol) and pyrazole (0.194 g, 2.85 mmol) gives the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([CH3:19])([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=2[CH:10]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([CH3:18])([CH3:19])[C:15]([CH3:17])=[CH:16][C:11]=2[CH:10]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1=Cc2cc(Sc3ccccc3O)ccc2OC1(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1=Cc2cc(Sc3ccccc3O[Si](C)(C)C(C)(C)C)ccc2OC1(C)C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
6-(2-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.1 g) (see Preparation 10) was dissolved in dry dimethylformamide (2 ml) and imidazole (0.55 g) and tert-butyldimethylsilyl chloride (0.61 g) were added. The flask was fitted with a calcium chloride drying tube and the mixture stirred at 40° C. for 90 minutes. Water was added and the mixture was extracted with diethyl ether. The organic extract was washed with aqueous sodium hydrogen carbonate solution (×2), dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product was chromatographed on silica using 4:1 hexane: dichloromethane as the eluent to yield 6-(2-tert-butyidimethylsilyloxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.43 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[O:7])=[CH:4][CH:3]=1.[CH3:19]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([O:16][CH3:19])=[O:15])=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(c1ccc(Br)cc1)[C@H]1CCCC[C@H]1C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
To a solution of cis-2-(4-bromobenzoyl)-1-cyclohexanecarboxylic acid (4.0 g, 12.85 mmol) in MeOH (50 mL) was added 2,2-dimethoxypropane (2.01 g, 19.28 mmol) and HCl (4.0 M in dioxane, 1.20 mL). The resulting solution was stirred at 40° C. for 3 days, and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 3 to 6% ethyl acetate in hexanes to afford methyl cis-2-(4-bromobenzoyl)cyclohexane-carboxylate (1.76 g, 42%). LC-MS ret. time 3.40; m/z 326 (MH+); 1H NMR (400 MHz, CD2Cl2) δ 1.35-1.51 (m, 3H), 1.72-1.86 (m, 2H), 1.91-2.05 (m, 2H), 2.11-2.20 (m, 1H), 2.74 (m, 1H), 3.58 (s, 3H), 3.82 (q, 1H), 7.62 (m, 2H), 7.73 (m, 2H).
Reaction SMILES: [CH:1]([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([NH2:18])=O)=[CH:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:7][CH:6]=1)=[O:2].CS(Cl)(=O)=O.Cl>N1C=CC=CC=1>[CH:1]([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]#[N:18])=[CH:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:7][CH:6]=1)=[O:2]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)sc2-c2ccc(NCC=O)cc2)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)sc2-c2ccc(NCC=O)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A mixture of 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide (0.3 g) and methanesulfonyl chloride (0.5 g) in pyridine (1.5 ml) was stirred at 50° C. for 3 hours. The mixture was poured into dilute hydrochloric acid. The precipitates were collected and washed with water to give 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonitrile (0.25 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:15]=[CH:14][N:13]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:12]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)[N:15]=[CH:14][N:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccccc3Br)ncn2)cc1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a solution of 2-bromophenol (2.595 g, 15 mmol, Aldrich) in anhydrous DMF (20 mL) was added NaH (0.68 g, 17 mmol, 60% suspension in mineral oil, Aldrich) in small portions with stirring at room temperature. The reaction mixture was stirred for 0.5 h at room temperature and 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (2.586 g, 10 mmol) was added in one portion. The reaction mixture was stirred for 18 h at room temperature and most of the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with 1N NaOH (2×) and H2O, dried over Na2SO4, filtered and concentrated in vacuum. The residue was recrystallized from EtOAc/hexane to give 3.21 g (81%) of the title compound. MS (ESI, pos. ion) m/z: 397 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:20])([CH3:19])[CH2:7][CH2:8][N:9]2[C:12](OC(C)(C)C)=O)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:11]=2)[C:6]([CH3:20])([CH3:19])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C)c2ccc(N)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(C)(C)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 7-amino-4,4-dimethyl-2,3-dihydroquinoline-1-carboxylate (100 mg, 0.36 mmol) in THF (2.2 mL) under an inert atmosphere was added LiAlH4 (1.8 mL of 1 M, 1.8 mmol) dropwise. The reaction mixture was heated to reflux and stirred for 4 h. The reaction was cooled to room temperature and quenched with of 0.4 M NaOH solution (0.6 mL), the aqueous layer was extracted with DCM, dried over Na2SO4, filtered and concentrated to an orange oil. The residue was purified via reverse phase HPLC. LC/MS: m/z 191.5 (M+H)+ at 0.92 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:15]1[CH:32]=[CH:31][C:18]([C:19]([N:21]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=1[Cl:33].Cl>N1C(C)=CC(C)=CC=1C>[Cl:33][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][C:15]=1[O:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:19]([N:21]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[CH:22]([CH3:24])[CH3:23])=[O:20]
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CC(C)N(C(=O)c1ccc(Br)c(Cl)c1)C1CCCCC1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2Cl)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-3-chloro-N-cyclohexyl-N-isopropylbenzamide (1.43 g, 4.0 mmol) in 2,4,6-collidine (20 mL) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: O=c1cc(N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc[nH]1

Procedure:
6-[4-(3,4-Dichloro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,4-dichlorobenzaldehyde. Mass spectrum (ES) MH+=339.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=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>[Cl:1][C:2]1[C:7]([CH:9]2[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)C1CC1
Reactant: Clc1ncccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1ncccc1C1CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-chloro-3-iodopyridine (2.39 g, 9.98 mmol), cyclopropylboronic acid (860 mg, 10 mmol) and potassium carbonate (4.14 g, 30.0 mmol) in 1,4-dioxane (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.16 g, 1.00 mmol). The reaction mixture was stirred at 120° C. for 4 hours, then diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (Gradient: 10% to 30% ethyl acetate in petroleum ether) to afford the product as a colorless oil. Yield: 1 g, 6 mmol, 60%. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=4.7, 1.8 Hz, 1H), 7.24-7.28 (m, 1H), 7.14 (br dd, J=7.6, 4.8 Hz, 1H), 2.12-2.21 (m, 1H), 1.04-1.11 (m, 2H), 0.67-0.72 (m, 2H).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([P:26]([CH3:31])(=[O:30])[O:27][CH2:28][CH3:29])=[CH:22][CH:21]=4)[CH:16]=3)=[CH:13][N:12]=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([P:26]([CH3:31])(=[O:30])[O:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[CH:16]=2)=[CH:13][N:12]=[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:10]=1
Reactant: CCOP(C)(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(C)(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.7 %

Procedure:
To a solution of compound 38-f (440 mg, 0.80 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (2 mL). After being stir for 10 h at room temperature, the reaction mixture was concentrated under reduce pressure and the residue was purified by pre-TLC (DCM:methanol=15:1) to afford compound 38-g (320 mg, 94%). 1H NMR (300 MHz, CD3OD) δ 8.79-8.80 (m, 1H), 8.71 (s, 1H), 8.38-8.41 (m, 1H), 8.10-8.12 (m, 3H), 7.89-7.93 (m, 2H), 7.67-7.72 (m, 2H), 3.91-3.96 (m, 2H), 1.67-1.72 (d, J=14.4 Hz, 3H), 1.18-1.22 (m, 3H). LC-MS 423 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].ClCCl.[N:21]1C2C(=CC=CC=2)C=C[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:22]#[N:21])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: c1ccc2ncccc2c1
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)Cc1cc(C#N)ccc1-2

Procedure:
A mixture of 2-acetyl-7-bromofluorene (13.2 g.) and cuprous cyanide (8.2 g.) in quinoline (40 ml.) was heated to reflux for 40 minutes, cooled to 100° and poured into a mixture of ice-cold dilute aqueous ammonia and dichloromethane. The organic layer was separated, filered to remove a yellow solid, washed with N-hydrochloric acid, dried over sodium sulphate and evaporated. The residual solid was recrystallised from ethanol containing a small amount of dimethylformamide to give 2-acetyl-7-cyanofluorene m.p. 182°-186° .
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]2[C:8]3[CH:9]=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][C:13]=3[CH2:14][CH:3]12.C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1>>[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]2[C:8]3[CH:9]=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][C:13]=3[CH2:14][C@H:3]12
Reactant: N#Cc1ccc2c(c1)C1CCCNC1C2
Agent: Cl
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Product: N#Cc1ccc2c(c1)[C@H]1CCCN[C@H]1C2

Procedure:
reacting the HCl salt of 2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile with base followed by di-benzoyl-d-tartaric acid to provide (4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½ D-DTBA:
Reaction SMILES: F[C:2]1[CH:3]=CC(O[C@H]2CC[C@H](C(O)=O)CC2)=N[CH:7]=1.C(Cl)(=O)C(Cl)=O.COC(C1C=C(C=CC=1)O[C@H]1CC[C@H](C([N:40](C)[C:41]2[CH:61]=[CH:60][C:44]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:48](C)[CH2:47]3)=[C:43]([CH3:62])[CH:42]=2)=O)CC1)=O.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH:2]([NH:40][C:41]1[CH:61]=[CH:60][C:44]([CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:50][CH2:51]2)=[C:43]([CH3:62])[CH:42]=1)([CH3:3])[CH3:7]
Reactant: COC(=O)c1cccc(O[C@H]2CC[C@H](C(=O)N(C)c3ccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c(C)c3)CC2)c1
Reactant: O=C(O)[C@H]1CC[C@H](Oc2ccc(F)cn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC(C)C)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl trans-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarboxylate (511 mg, 1.73 mmol) produced in (15B) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere for 2 hours. After toluene (10 mL) was added to the reaction solution, the solvent was distilled off under reduced pressure, followed by drying, whereby trans-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarboxylic acid was obtained as a colorless oil (310 mg, yield: 74%). The obtained trans-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarboxylic acid (310 mg, 0.892 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (235 μL, 2.68 mmol) and a catalytic amount of dimethylformamide were added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The residue obtained by distilling off the solvent in the reaction solution under reduced pressure was dissolved in dichloromethane (15 mL), and tert-butyl 4-[4-(isopropylamino)-2-methylbenzyl]piperazine-1-carboxylate (113 mg, 0.325 mmol) produced in (5A) and triethylamine (125 μL, 0.892 mmol) were added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:34]=[C:33]3[C:29]([CH2:30][C:31](=[O:35])[NH:32]3)=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:30]1[C:29]2[C:33](=[CH:34][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)=[CH:27][CH:28]=2)[NH:32][C:31]1=[O:35])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc(C(C)C)c(OC)c(C(C)C)c2)c1

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-(3-ethoxyphenyl)-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-(3-ethoxyphenyl)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [N+:1]([O:4][C@H:5]([CH3:16])[CH2:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])([O-:3])=[O:2].B(F)(F)F.CCOCC>C(Cl)Cl>[N+:1]([O:4][C@H:5]([CH3:16])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2]
Reactant: C[C@H](CCCC(=O)OC(C)(C)C)O[N+](=O)[O-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](CCCC(=O)O)O[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of crude (R)-tert-butyl 5-nitrooxyhexanoate (31 mmol) in CH2Cl2 (50 mL) at 0° C., was added BF3.Et2O (5.1 mL, 40 mmol). After 1 hour, the mixture was then washed with brine, dried over Na2SO4, and the volume of the solvent reduced. The resultant solution was used in the following step without further purification.