Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=O)[CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Temperature: 0 °C

Procedure:
An alternative procedure to prepare compound B from compound A is as follows: Compound A (1.0 g) in 25 ml dry methylene chloride and 10 ml of 2.5 N NaOH was cooled to 0° C. and treated with 0.25 ml of acetyl chloride dropwise. After 2 hours the solution was allowed to warm up to room temperature and stirring was continued overnight. The solution was treated with distilled water and extracted with methylene chloride. The methylene chloride layer was separated, dried over anhydrous sodium sulfate, filtered and evapotated to give 1.33 g of crude amide reaction product, which was purified by flash column (silica, methylene chloride:methanol:25% NH4OH 90:9:1) to yield 0.7 g of 2-(4-fluorophenyl)-5-(N-acetylpiperidin-4-yl)-3-(4-pyridyl)pyrrole. This amide was dissolved in 15 ml of tetrahydrofuran and treated with 3 ml of 1M lithium aluminum hydride (LAH) in THF under an atmosphere of nitrogen at room temperature. After completion of addition of LAH, the solution was refluxed for two hours, cooled to 0° C., quenched with water (0.19 ml) and 2.5 N NaOH (0.19 ml) and filtered. The filtrate was dried over sodium sulfate, filtered, evaporated and purified by flash column as shown above to give compound B (0.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][S:7]O)=[CH:4][CH:3]=1.O1CCCC1.[CH2:16]([O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20])[CH3:17]>C(N(CC)CC)C>[C:19]([NH:21][C:22](=[S:23])[S:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)([O:18][CH2:16][CH3:17])=[O:20]
Reactant: OSCc1ccc(Cl)cc1
Reactant: CCOC(=O)N=C=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)SCc1ccc(Cl)cc1
Yield: 88.5 %

Procedure:
A mixture of 158.6 g of p-chlorobenzylthio alcohol, 800 ml of tetrahydrofuran, 5 ml of triethylamine and 131.6 g of ethoxycarbonyl isothiocyanate was refluxed for 21/2 hours and was then concentrated to dryness. The residue was washed with petroleum ether to obtain 233 g of p-chlorobenzyl N-carbethoxy-dithiocarbamate melting at 80° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1.[NH4+:18].[OH-]>CN(C)C=O.O>[Cl:7][C:8]1[C:13]([C:14]([NH2:18])=[O:15])=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Oxalyl chloride (7.70 mL, 88.3 mmol) was added over 1 hour to a suspension of 4,6-dichloronicotinic acid (8.47 g, 44.1 mmol) in dimethylformamide (200 mL) at room temperature. The reaction mixture was stirred for an additional 3 hours at room temperature then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) followed by the dropwise addition of NH4OH (8.3 mL, 130 mmol) over 30 minutes [Note: reaction is exothermic upon addition of NH4OH and care was taken to control the rate of addition so that the reaction temperature did not exceed 25° C.]. The reaction mixture was stirred for an additional 1 hour at room temperature then diluted with water (600 mL) and extracted with EtOAc (4×600 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light brown solid (8.05 g, 95% yield). This material was carried forward without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(NC(=O)OCCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccccc2)=CC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccccc2)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Yield: 94.5 %

Procedure:
Methyl 4-[(1,1-dimethyl-3-phenyl-1H-indene-5-carbonyl)amino]benzoate (359 mg, 0.90 mmol) was stirred with 4.5 mL of 2N NaOH in 5 mL of methanol and 5 mL of tetrahydrofuran for 10 hours. The solution was acidified with 1N HCl and concentrated under reduced pressure. After addition of 15 mL of water, the mixture was extracted with ethyl acetate (15 mL×3). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was triturated in etherhexane to give 326 mg (94% yield) of the title compound as solids; 1H-NMR (DMSO-d6) δ1.39 (s, 6H), 6.68 (s, 1H), 7.39-7.53 (m, 3H), 7.64-7.68 (m, 3H), 7.85-7.97 (m, 6H), 10.54 (s, 1H), 12.75 (bs, 1H); MS m/e 384 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])[NH:28][C:27]=1[C:37]([OH:39])=O.[NH2:40][CH2:41][C:42]1[C:43]([F:59])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:53]#[N:54])[C:45]([Cl:48])=[CH:46][CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH:34]2[CH2:35][CH2:36]2)=[O:32])[NH:28][C:27]=1[C:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([C:53]#[N:54])[CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:43]=1[F:59])=[O:39]
Reactant: O=C(NC1CC1)c1cc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(=O)NC4CC4)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 3-chloro-5-[(cyclopropylamino)carbonyl]-1H-pyrrole-2-carboxylic acid (0.037 g, 0.161 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. The residue was subjected to silica gel column chromatography (EtOAc/hexanes) to afford an impure solid. A second purification by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) afforded the title compound (0.0098 g, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10-8.26 (m, 1H), 7.82 (br. s., 1H), 7.39-7.62 (m, 5H), 7.33 (d, 1H), 6.35 (br. s., 1H), 4.42 (br. s., 2H), 2.62-2.79 (m, 1H), 0.61 (d, 2H), 0.45 (br. s., 2H). LCMS: m/z 521.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].S(OC)(OC)(=O)=O.[C-:23]#[N:24].[K+]>O>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([C:23]#[N:24])=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2ccc[n+]([O-])c2c1N
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1sc2ccc(C#N)nc2c1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
3-Amino-2-carbomethoxythieno[3,2-b]pyridine-4-oxide (3.1 g, 13.8 mmol) is stirred mechanically under N2 at 25° C. as dimethyl sulfate (1.3 mL, 14 mmol) is added dropwise. After stirring at 80° C. for 2 h, the reaction is cooled to 250C and the resulting solid is washed with acetone (50 mL) is added. The solid is dissolved in 10 mL H2O and is added dropwise to a 0° C. solution of KCN (2.7 g, 41 mmol) in H2O (10 mL). After stirring at 25° C. 18 h. The reaction was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, concentrated, and chromatographed (CH2Cl2). 1.5 g (47%) of the title compound was obtained: 1H NMR (300 MHz, CDCl3) δ3.94 (s, 3H), 6.25 (bs, 2H), 7.70 (d, 1H), 8.20 (d, 1H); MS (DCI/NH3) m/e 234 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:22])C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:22])=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6.985 g 1-benzyloxy-2-tert-butyl-4-methyl-benzene (27 mmol) and 115 g ammoniumcer (IV)-nitrate in 1000 ml acetic acid (50% v/v) was stirred at 90° C. for one hour. After cooling down to RT, the reaction mixture was extracted with AcOEt/heptane 1:9, dried over magnesium sulfate, filtered off and concentrated under vacuo. The residue was purified by flash column chromatography (heptane/AcOEt 95/5 to 90/10) to give 3.48 g of an orange solid. MS (ISP) 269.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CCCCOc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-butoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized from ethanol (22%, white crystals). HPLC-MS m/z=300.1 (M+1), Rt: 5.20.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([CH3:32])=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([CH3:32])=[CH:26][C:23]=1[CH:24]([OH:25])[C:9]#[C:8][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1cc(OC)c(C=O)cc1C
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cc(OC)c(C(O)C#Cc2ccccc2)cc1C
Yield: 89 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,4-dimethoxy-5-methyl-benzaldehyde (1.00 g, 5.55 mmol) was reacted to give the title compound (1.39 g, 89%). 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.30 (m, 6H), 6.61 (s, 1H), 5.79-5.70 (m, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][C:28]([NH2:30])=[O:29].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: NC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC(=O)CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 225 mg; 0.66 mmol), 3-bromopropanamide (302 mg; 1.99 mmol), KI (20 mg; 0.12 mmol) and K2CO3 (274 mg; 1.98 mmol) in CH3CN (20 mL) and DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to r.t., filtered, and concentrated to afford 272 mg (100%) of the title compound as a white solid, which was used directly without further purification.
Reaction SMILES: [CH2:1]([C:3]([OH:9])([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C:3]([O:9][Si:18]([CH3:21])([CH3:20])[CH3:17])([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2]
Reactant: C#CCC(O)(CC)CC
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC(CC)(CC)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-ethyl-3-hydroxy-5-hexyne (12.6 g) (WO 93/19044), triethylamine (67 ml) and DMAP (0.47 g) in dichloromethane (150 ml) was added, with stirring at 0° C., trimethylchlorosilane (38 ml), during 10 min. Stirring was continued at 0° C. for 15 min. and at 25° C. for 45 min. The reaction mixture was worked up, and the crude product was purified by distillation in vacuo to give the title compound as an oil, b.p. 83-85° C./25 mm Hg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.C(N(CC)CC)C>[C:6]1([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16][CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(CCO)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 62 cm3 of methanesulphonyl chloride in 100 cm3 of dichloromethane is added over 10 minutes to a solution, cooled to -20° C., of 95 g of 3,3-diphenyl-l,5-pentanediol (prepared according to P. EILBRACHT et al., Chem. Ber. 118, 825-839 (1985)) in 950 cm3 of dichloromethane and 113 cm3 of triethylamine. After stirring for 2 hours at 20° C., the reaction mixture is washed with twice 500 cm3 of water, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is crystallized from ethyl ether, the crystals are washed with ethyl ether, drained and dried. 140 g of 3,3-diphenyl-l,5-bis(methanesulphonyloxy)pentane are obtained in the form of white crystals; melting point 99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]3)=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=1)=[CH:9][C:8]([Br:33])=[CH:7][CH:6]=2.[H-].[Na+].Br[CH2:37][C:38](OCCCC)=[O:39]>CN(C=O)C>[Br:33][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:38](=[O:39])[CH2:37][N:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:24]5)=[C:15]([C:29]([F:31])([F:30])[F:32])[CH:14]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: COC(=O)C1CCN(c2ccc(Nc3c(N)cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Reactant: CCCCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc(N3CC(=O)Nc4cnc5ccc(Br)cc5c43)cc2C(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of compound 8.3 methyl 1-(4-(3-amino-6-bromoquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (60 mg, 0.115 mmol, 1 equiv.) in anhydrous DMF (3 mL) at 0° C. was added sodium hydride (60%, 5.0 mg, 0.126 mmol, 1.1 equiv.). After the mixture solution was stirred for 15minutes, tent-Butyl bromoacetate (19 mL, 0.126 mmol, 1.1 equiv.) was added. The resulting mixture was stirred overnight at room temperature under argon. Upon quenching with water, the mixture was concentrated under vacuum, diluted with EtOAc (20 mL), and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (CH2Cl2:MeOH=35:1) to afford the desired product 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (61 mg; 94%). LC-MS (M+H): 563.15
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH:40][C:41]2[CH:46]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:44]=[C:43]([O:56][CH3:57])[CH:42]=2)(=[O:39])=[O:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)(=[O:38])=[O:39])[CH:42]=[C:43]([O:56][CH3:57])[CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added 1-(4-fluorophenyl)-N-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (138 mg, 0.33 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 273 μl of a 2M aqueous solution of cesium carbonate in dioxane (5 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0 to 80%, hexane-ethyl acetate) to give 155 mg (85% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH2:15][CH2:16][CH2:17][Cl:18])=[O:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br>C(O)(=O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH:15]([Br:19])[CH2:16][CH2:17][Cl:18])=[O:14])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCCCl)c1ccc(-c2ccccc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(c1ccc(-c2ccccc2)cc1)C(Br)CCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
246 g (0.95 mol) of 3-chloropropyl 4-phenylphenyl ketone in 380 ml of glacial acetic acid were placed in a reaction flask and 152 g (0.95 mol) of bromine were added dropwise at 30° C., the reaction commencing with dissolution and decolorization. After 1 hour, a thick precipitate deposited. The mixture was stirred for a further 4 hours at room temperature in order to complete the reaction. The crystals produced were filtered off under suction, washed with water, dissolved in dichloromethane, washed by shaking with NaHCO3 solution and water and dried, and 250 g (78% of theory) of the title substance were obtained as colorless crystals of melting point 85°-88° C.
Reaction SMILES: C(O)C.[CH:4]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)([CH3:6])[CH3:5].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(N(CC)CC)C>[CH2:18]([O:17][C:15]([CH2:14][N:10]1[CH2:11][CH2:12][N:7]([CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)CCl
Reactant: CC(C)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CN1CCN(C(C)C)CC1
Yield: 68.3 %

Procedure:
One hundred milliliters of an ethanol solution containing 7 g of 1-isopropylpiperazine, 6.2 g of ethyl chloroacetate and 9.2 m of triethylamine was heated and refluxed for 4 hours. After being concentrated under reduced pressure, the resulting mixture was added with ethyl acetate. Insoluble matter was removed by filtration. Thereafter, the residue was purified by silica gel chromatography (eluent: a 20:1 mixture of chloroform and methanol) to obtain 7.4 g of 1-ethoxycarbonylmethyl-4-isopropylpiperazine as a light brownish oily substance.
Reaction SMILES: [CH2:1]([OH:12])[C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([OH:12])/[CH:2]=[CH:3]\[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCC#CCC#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CCCCC/C=C\C/C=C\CO
Reaction time: 7 h
Yield: 69.6 %

Procedure:
2,5-undecadiyn-1-ol (1.5 g) in absolute ethanol (15 ml) was reduced with Lindlar catalyst (0.33 g) in the presence of quinoline (0.1 ml) at 25° C., 1 atm., for 7 h. The uptake of hydrogen stopped at 420 ml (theoretical 428 ml). The solution was filtered, and the solvent was evaporated to give 1.5 g of crude product which was then purified by column chromatography on silica gel (50 g). Elution with ether-petroleum ether (1:4 parts by volume) gave 1.07 g of (Z,Z)-2,5-undecadien-1-ol as an oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]34[CH2:21][CH:16]5[CH2:17][C:18]([NH2:20])([CH2:19]3)[CH:14]([CH2:15]5)[CH2:13]4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]#[N:38])=[O:31]>CS(C)=O.CCOC(C)=O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]34[CH2:21][CH:16]5[CH2:17][C:18]([NH:20][CH2:29][C:30]([N:32]6[CH2:36][CH2:35][CH2:34][C@H:33]6[C:37]#[N:38])=[O:31])([CH2:19]3)[CH:14]([CH2:15]5)[CH2:13]4)=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: NC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.41 g, 1.5 mmol) and K2CO3 (0.62 g, 4.5 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.26 g, 1.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a (1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.2 g) in 32% yield as off-white solid. m/z (M+1) 415; 1H NMR (CDCl3) 300 MHz δ 7.38-7.26 (m, 4H), 7.10-7.05 (m, 2H), 6.36-6.32 (m, 2H), 4.84-4.78 (m, 1H), 3.75-3.40 (m, 2H), 3.50 (s, 2H), 2.50-2.42 (m, 1H), 2.38-2.28 (m, 2H), 2.25-2.0 (m, 6H), 2.0-1.70 (m, 7H).