Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:14][CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].C(O)C.[CH3:19][NH:20][CH3:21]>C(OCC)C.O>[CH3:19][N:20]([CH3:21])[CH:2]([CH2:14][CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: CCC(Br)C(=O)Nc1c(C)cccc1C
Reactant: CNC
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCC(C(=O)Nc1c(C)cccc1C)N(C)C
Yield: 47.9 %

Procedure:
A mixture of 7.7 g (28.5 mmoles) of N-(2-bromo-butyryl)-2,6-dimethyl-aniline, 70 ml of ethanol and 20 ml of a 33% aqueous dimethyl amine solution is heated in a bomb at 100°-110° C. for 6 hours. The mixture is cooled, diluted with 150 ml of diethyl ether and 40 ml of water, the phases are separated, and the aqueous phase is extracted twice with 25 ml of diethyl ether, each. The etheral solutions are combined, washed thrice with 35 ml of 1 n aqueous hydrochloric acid, each, the aqueous acidic solutions are combined, rendered alkaline (pH=9) with concentrated aqueous ammonia, and extracted thrice with 40 ml of 1,2-dichloroethane, each. The dichloroethane solutions are combined, washed thrice with 20 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The oily residue, weighing 7.1 g, is triturated with diisopropyl ether to obtain 4.1 g of crude product, which is recrystallized then from ethyl acetate. 3.2 g (47.9%) of pure N-(2-dimethylamino-butyryl)-2,6-dimethyl-aniline are obtained; m.p.: 155°-157° C.
Reaction SMILES: C1([O:4][S:5](=[O:8])(=[O:7])[NH2:6])CC1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]>>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:6][S:5](=[O:8])(=[O:7])[O-:4].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][S:5](=[O:7])(=[O:4])[NH2:6]
Reactant: NS(=O)(=O)OC1CC1
Reactant: Oc1ccccc1F
Product: NS(=O)(=O)Oc1ccccc1F
Product: O=S(=O)([O-])Nc1ccccc1F

Procedure:
2-Fluorophenylsulfamate was synthesized according to the method presented in the synthesis of Sulfamic acid cyclopropyl ester in Example 1 with the exception of utilizing 2-fluorophenol to obtain sulfamic acid 2-fluoro-phenyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
23.8 g of 4-cyanophenol in 150 ml of dimethylformamide were added dropwise to a stirred suspension of 6 g of 80% sodium hydride in 100 ml of dimethylformamide and the mixture was then stirred for a further 1 hour. 39 g of ethyl bromoisobutyrate were added dropwise and the mixture was heated to 100° C. for 76 hours. The solvents were removed by evaporation and the residue was partitioned between diethyl ether and water. The organic phase was washed in succession with 2M sodium hydroxide solution and sodium chloride solution and then evaporated to give 9.4 g of ethyl 2-(4-cyanophenoxy)-2-methylpropionate in the form of a colourless viscous liquid of boiling point 115°-117° C./0.05 mmHg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].C(N(CC)CC)C.C1COCC1>C(OCC)C>[C:17]([O:16][C:12]([NH:13][NH:14][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSc1ncc(C#N)c(NNC(=O)OC(C)(C)C)n1
Reaction time: 22 h
Yield: 83 %

Procedure:
4-Chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (prepared as described in US2003158218, 0.509 g, 2.74 mmol), tert-butyl carbazate (tert-butoxycarbonyl hydrazine, 0.403 g, 3.05 mmol) and triethylamine (0.57 mL, 4.1 mmol) were added to 25 mL THF. The reaction mixture was stirred 22 hours, and then 25 mL diethyl ether was added and the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and the resulting oil was chromatographed through silica (0%-33% EtOAc in hexanes) to give 0.64 g of N′-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-hydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([NH:72][CH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1)[CH:70]=[CH2:71]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:14]([C:15](=[O:16])[N:72]([CH2:69][CH:70]=[CH2:71])[CH:73]2[CH2:77][CH2:76][CH2:75][CH2:74]2)[CH:13]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCNC1CCCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a strrred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.039 g), TBTU (0.064 g) and HOBt (0.027 g) in DMF (1 ml) was added DIPEA (0.036 ml) followed by N-allylcyclopentylamine (0.029 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.030 g) obtained by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@:14]2([CH2:27]O)[CH3:26])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CC(C)([O-])C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O.CCOC(C)=O>[Si:19]([O:18][C@H:15]1[C@:14]2([CH3:26])[N:13]([C:11](=[O:12])[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=3[CH3:29])[CH2:27]2)[CH2:17][CH2:16]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21]
Reactant: Cc1c(NC(=O)N2CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@]2(C)CO)ccc(C#N)c1Cl
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(N2C[C@]3(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN3C2=O)ccc(C#N)c1Cl
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
To a solution of (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-hydroxymethyl-2-methylpyrrolidine-1-carboxylic acid (3-chloro-4-cyano-2-methyl-phenyl)-amide (58D) (43 mg, 0.10 mmol) in THF (1 mL) at 0° C. was added a 1 M solution of potassium tert-butoxide in THF (0.24 mL, 0.24 mmol) followed by a solution of p-toluenesulfonyl chloride (22 mg, 0.12 mmol) in THF (0.5 mL). After 10 min, additional potassium tert-butoxide (50 □L) and p-toluenesulfonyl chloride (3 mg) were added. After another 10 min, the reaction was diluted with water and EtOAc and the layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated and purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 12 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (17 mg). LC/MS m/z 420 [M+H]+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]([S:35][CH3:36])[N:32]=[C:31]([C:37]([NH:39][O:40][CH3:41])=[O:38])[CH:30]=2)[CH2:25][CH2:24]1)=[O:21]>C(Cl)Cl>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[C:33]([S:35]([CH3:36])=[O:9])[N:32]=[C:31]([C:37]([NH:39][O:40][CH3:41])=[O:38])[CH:30]=2)[CH2:25][CH2:24]1)=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(SC)n1
Solvent: ClCCl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)n1
Yield: 26.3 %

Procedure:
mCPBA (70%, 86 mg, 0.35 mmol) was added to a suspension of 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-N-methoxy-2-(methylthio)pyrimidine-4-carboxamide (Example 8, 166 mg, 0.35 mmol) in DCM (12 ml) at 0° C. and the resultant mixture was stirred for 2 h. The reaction mixture was diluted with DCM (50 ml), washed with Na2SO3 solution (5%, 10 ml), dried over Na2SO4, filtered and concentrated under vacuum. Purification by reversed-phase HPLC (water/acetonitrile gradient, 10-95%) gave 45 mg of the title product.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]=2.[ClH:20].N([O-])=O.[Na+].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>CC(C)=O.O>[CH2:13]([O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH2:27][CH:26]([Cl:20])[C:25]([O:29][CH3:30])=[O:28])[CH:3]=[N:4]2)=[CH:9][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1
Reactant: C=CC(=O)OC
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(Cl)Cc1cnc2cc(OCc3ccccc3)ccc2c1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
The above 3-amino-7-benzyloxyquinoline (2.3 g, 9.2 mmol.) was dissolved in a mixture of acetone and water (25 mL and 6 mL). Under chilling with ice, to the solution was added concentrated hydrochloric acid (2.5 mL). The reaction temperature was set to a temperature of lower than 5° C. The reaction mixture was stirred at 5° C. for 20 minutes after addition of aqueous sodium nitrite solution (833 mg (12 mmol.)/1.6 mL) for 5 minutes. After the stirring was complete, methyl acrylate (6 mL, 67.5 mmol.) was added for 5 minutes. Then, cuprous oxide (120 mg) was gradually added, and the reaction temperature was set to 37° C. Under the condition, the reaction mixture was vigorously stirred. After the completion of reaction was confirmed, acetone was distilled off. To the residue were added ethyl acetate and concentrated aqueous ammonia, so that the aqueous portion reached pH 7. The organic portion was recovered, washed with water, and dried over anhydrous sodium sulfate. The dried mixture was filtered, and the filtrate was placed under reduced pressure to distill off ethyl acetate. The residue was purified by column chromatography (hexane/ethyl acetate=2/1), to give 1.65 g of the desired compound as a pale yellowish white crystalline product (yield 51%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9](C(OC(C)(C)C)=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)cn(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(-c3ccccc3)c[nH]c2c1
Reaction time: 3 h

Procedure:
To a solution of 1-tert-butyl 6-methyl 3-phenyl-1H-indole-1,6-dicarboxylate 16a (4.04 mmol, 1.42 g) in CH2Cl2 (8 mL) was added 6 mL of TFA. The resulting solution was stirred for 3 h. The mixture was then concentrated and washed with hexanes to afford 16b.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[NH:5]1.CS(C)=O>O>[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:5]1[CH2:23][CH2:22][CH2:6][CH2:7][OH:21]
Reactant: N#Cc1ccc(N2C(=O)NC3(CCOCC3)C2=O)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2C(=O)N(CCCCO)C3(CCOCC3)C2=O)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 179 %

Procedure:
55 mg of 50% sodium hydride were introduced and 340 mg of the product of Example 2 and 25 ml of dimethylsulfoxide were added dropwise over 25 minutes. Rinsing was carried out with 0,5 ml of dimethylsulfoxide and 20 minutes after the release of hydrogen had stopped, 0.41 g of 4-iodobutoxy-trimethyl-silane was added. The mixture was allowed to react for 18 hours at ambient temperature and the reaction medium was then poured into 10 ml of water. Extraction was carried out 4 times with ether and the organic phase was washed with water, then with salt water, dried and taken up in a mixture of 10 ml of methanol and 1 ml of 2N hydrochloric acid. After 30 minutes, the mixture was poured into 20 ml of saturated sodium chloride solution and extraction was carried out 3 times with chloroform, followed by drying. Purification was carried out on silica with methylene chloride-acetone 8-2 as eluant to obtain 369 mg of the expected product (friable white foam).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[CH3:5][O-:6].[Na+].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][CH:18]=1)O[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13]/[C:12]/2=[N:25]/[C:26]#[N:27]>CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:26]([NH2:27])=[N:25]3)[CH2:13][CH:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:6][C:5]2=[CH:17][CH:18]=1
Reactant: CNO
Reactant: C[O-]
Reactant: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
To a solution of methylhydroxylamine HCl salt (26 mg, 0.307 mmol) in anhydrous MeOH (10 mL) was added NaOMe (25 wt. % in MeOH, 0.07 mL, 0.276 mmol), followed by (Z)—N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide (100 mg, 0.307 mmol). After stirring for 10 minutes, the solvent was removed in vacuo. The residue was dissolved in DCM (20 mL). The mixture was filtered, and the solvent was removed in vacuo to give 6-bromo-2′methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazol)-3′-amine (100 mg, 87%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
Pd(OAc)2 (0.031 g, 0.136 mmol) was added to a solution of 5-methoxy-1H-indole (0.2 g, 1.359 m mol) and phenylboronic acid (0.249 g, 2.038 mmol) in acetic acid (2 mL) followed by copper (II) acetate (0.025 g, 0.138 mmol), and the mixture was stirred at 25° C. for 2 h under oxygen atmosphere. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using 10% ethyl acetate in hexane to afford title compound (0.08 g, 24%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 11.3 (s, 1H), 7.82 (d, J=7.2 Hz, 2H), 7.44 (t, J=7.2 Hz, 2H), 7.32-7.26 (m, 2H), 7.02 (d, J=2.4 Hz 1H), 6.81 (d, J=1.2 Hz, 1H), 6.74 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H) 3.78 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][C:3]=1[CH3:13].[CH2:14]([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][C:3]=1[CH3:13])(=[O:24])[CH3:23].[C:22]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:11])([CH3:12])[C:9]#[N:10])=[C:6]([CH3:14])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: [Li]CCCC
Reactant: Cc1cc(C(C)(C)C#N)ccc1Br
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(C(C)(C)C#N)c(C)c1
Product: CC(=O)c1ccc(C(C)(C)C#N)cc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
To a stirred solution of 2-(4-bromo-3-methylphenyl)-2-methylpropanenitrile (5.0 g, 21.0 mmol) in anhydrous THF (75 mL) at −100° C. is added n-butyllithium (2 M in c-hexane) (21 mL, 42 mmol). This reaction mixture is stirred at that temperature 5 min., then N-methoxy-N-methyl-acetamide (4.33 g, 42 mmol) is added. The solution is then warmed up to room temperature over 1 h. Acidic brine (30 mL of brine, 15 mL of 3% HCl aq) is then slowly added and the solution is extracted with EtOAc (3×100 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified on silica gel using a 0 to 30% gradient of EtOAc in heptane to provide the expected product 2-(4-acetyl-2-methylphenyl)-2-methylpropanenitrile (1.0 g, 24%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.71 (s, 6H) 2.53 (s, 3H) 2.56 (s, 3H) 7.30-7.38 (m, 2H) 7.70 (d, J=8.01 Hz, 1H)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=[O:2].C[Li].[CH2:14](OCC)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH:1]([OH:2])[CH3:14])[CH:8]=[CH:9]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CCOCC
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cccc2cc[nH]c12
Yield: 94.5 %

Procedure:
Add 7-formylindole (1.0 g, 6.89 mmol) in anhydrous tetrahydrofuran (15 ml) dropwise to a solution of 1.4M methyllithium in diethyl ether (12.2 ml, 17.1 mmol) at −78° C. After 15 minutes add saturated aqueous sodium bicarbonate (15 ml). Dilute with 1:1 ethyl acetate:diethyl ether, wash with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure to provide desired compound (1.05 g, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NCC(O)CO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(O)CO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 3-amino-1,2-propanediol (45 ml) and triethylamine (150 mg) were added to pyridine (500 mg), and the mixture was stirred at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (60 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1.5 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (107 mg) as a colorless powder.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9](Cl)=[C:10]([CH3:16])[C:11]=2[CH3:15])[N:6]=1.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CO>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([CH3:16])[C:11]=2[CH3:15])[N:6]=1
Reactant: Cc1c(Cl)nc2nc(N)ccc2c1C
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(Sc2ccccc2)nc2nc(N)ccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
13 g of a 30% strength methanolic sodium methylate solution is introduced into 5.0 g (24 mmol) of 2-amino-7-chloro-5,6-dimethyl-1,8-naphthyridine and 8.0 g (72 mmol) of thiophenol in 100 ml of anhydrous methanol. The mixture is boiled under reflux for 3 hours and stirred overnight at room temperature. 200 ml of water is added, the mixture is stirred for 1 hour, and the precipitated solid is filtered off, washed with a small amount of methanol and dried under reduced pressure. There is obtained 4.7 g of a pale yellow solid.
Reaction SMILES: [Cl-:1].[K+].[Pt+2:3].[Cl-:4].[Cl-].[NH2:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1>O>[Pt+2:3].[Cl:1][C@H:8]1[C@@H:7]([NH2:6])[CH2:11][CH2:10][N:9]1[Cl:4]
Reactant: [Cl-]
Reactant: NC1CCNC1
Agent: [Pt+2]
Agent: [K+]
Solvent: O
Product: N[C@H]1CCN(Cl)[C@H]1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 67.9 %

Procedure:
To a solution of platinum (II) potassium chloride (12.2 g) in water (800 ml) is added (3RS)-3-aminopyrrolidine (2.5 g), and the mixture is stirred at room temperature for 19 hours. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added a small amount of water, and the resulting crystals are separated by filtration and washed with water and acetone to give cis-dichloro-(3RS)-3-aminopyrrolidine platinum (II) (6.9 g) as pale yellow crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:17]([C:18]5[C:23]=3[C:22]=2[CH:21]=[CH:20][CH:19]=5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>CCCCCC.O1CCCC1>[CH:9]1[C:8]2=[C:22]3[C:21]([C:5]4[C:4]2=[CH:3][CH:2]=[CH:7][CH:6]=4)=[CH:20][CH:19]=[CH:18][C:23]3=[C:11]([C:12]2[CH:13]=[C:14]([B:29]([OH:34])[OH:30])[CH:15]=[CH:16][CH:17]=2)[CH:10]=1
Reactant: Brc1cccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A flask was charged with 9.2 g of 3-(3-bromophenyl)fluoranthene and 129 mL of tetrahydrofuran. After cooling the reaction solution to −70° C., 17.2 mL of a 1.65 M hexane solution of n-butyllithium was added dropwise to the reaction solution. The mixture was stirred at −70° C. for 2 hours. After the dropwise addition of 17.7 mL of triisopropyl borate to the reaction solution, the reaction solution was stirred at −70° C. for 1 hour. The reaction solution was then stirred for 5 hours while heating the reaction solution to room temperature. After the addition of 2 M hydrochloric acid to the reaction solution so that the reaction solution had a pH in the acidic region, the reaction solution was extracted with ethyl acetate. After removing the aqueous phase, the organic phase was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering the organic phase, the solvent was evaporated under reduced pressure. The residue was washed with a hexane-ethyl acetate mixture to obtain 7.9 g of the target 3-(fluoranthen-3-yl)phenylboronic acid (yield: 95%).