Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:71])[C@@H:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28]([N:68]5[CH2:69][CH2:70][C@@H:66]([N:65]([CH3:71])[CH3:64])[CH2:67]5)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(C(=O)c2ccc3c(c2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a stirred solution of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid (82 mg; 0.19 mmol) in DMF (5 ml) was added HATU (103 mg; 0.27 mmol), DIPEA (50 μl; 0.27 mmol) and (R)-(+)-3-(dimethylamino)pyrrolidine (50 μl; 0.38 mmol). The reaction mixture was stirred at room temperature for 4 h upon which time it was diluted with EtOAc (20 ml) and washed successively with satd. NaHCO3 (20 ml) and brine (2 20 ml). The organic layer was dried (Na2SO4), concentrated and purified by prep. LCMS to give 418 as an off-white solid (53 mg; 53%). δH (400 MHz, CDCl3) 1.80-1.95 (m, 1H), 2.03-2.15 (br m, 1H), 2.24 (br s, 3H), 2.35 (br s, 3H), 2.62-2.85 (br m, 1H), 3.16 (br s, 2H), 3.30-4.00 (m, 4H), 4.33 (br s, 2H), 6.92-7.20 (m, 4H), 7.40 (br s, 1H), 7.51-7.61 (m, 1H), 7.77 (s, 1H), 8.11 (s, 1H). [M+H]+: 522
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11](Br)=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCn1c(=O)c2[nH]c(Br)nc2n(CCCC)c1=O
Product: CCCCn1c(=O)c2[nH]c(N3CCCC3)nc2n(CCCC)c1=O

Procedure:
The title compound was prepared from 1,3-di-n-butyl-8-bromo xanthine (1 g, 0.0029 ml) and pyrrolidine (0.041 g, 0.0057 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH2:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])=[CH:6][C:5]=1[C:13]([F:14])([F:16])[F:15]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cc(OC)c(N)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a stirred solution of 5-methoxy-4-amino-2-trifluoromethyl-benzoic acid methyl ester (552 mg, 2.22 mmol) in 6.6 mL CH2Cl2 at 0° C. under nitrogen was added pyridine (180 μL, 2.22 mmol) followed by p-nitrophenyl chloroformate (448 mg, 2.22 mmol) as a solid. After stirring for 1 hour, the reaction was diluted to 30 mL with CH2Cl2 and washed 2×30 mL with 2N HCl and 1×30 mL with H2O. The organics were dried (MgSO4), filtered and concentrated to the p-nitrophenyl carbamate which was isolated as a white foam (878 mg, 96%). 1H-NMR (400 MHz, CDCl3) S 8.57 (br s, 1H), 8.30 (d, 2H), 7.77 (br s, 1H), 7.40 (d, 2H), 7.37 (s, 1H), 4.03 (s, 3H), 3.94 (s, 3H)
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:5](=[O:7])[CH3:6].[I:16][CH3:17]>CCOC(C)=O>[I-:16].[CH3:15][N+:2]([CH3:17])([CH3:1])[CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:5](=[O:7])[CH3:6]
Reactant: CI
Reactant: CC(=O)C(CN(C)C)c1ccc(C)cc1
Solvent: CCOC(C)=O
Product: CC(=O)C(C[N+](C)(C)C)c1ccc(C)cc1
Product: [I-]

Procedure:
A mixture of 4-methylphenylacetone (3.01 g), paraformaldehyde (0.489 g) and dimethylamine hydrochloride (1.49 g) in MeOH (2 ml) is stirred under reflux for 3 h. The reaction mixture is diluted with 20 ml of water and the product is extracted with two portions of ether. After addition of 1 M aqueous NaOH solution, the aqueous layer is extracted with two more portions of ether. The combined organic layers are dried (Na2SO4) and the solvent is evaporated to obtain 4-dimethylamino-3-p-tolyl-butan-2-one (compound of formula VI) as a yellowish liquid, MS (ISP) 206.2 (M+H)+. 4-Dimethylamino-3-p-tolyl-butan-2-one is dissolved in AcOEt (17 ml) and iodomethane (1.46) is added. After 1 h the formed solid is collected by filtration, washed with AcOEt and dried on the vacuum. 2.61 g of trimethyl-(3-oxo-2-p-tolyl-butyl)-ammonium iodide are obtained as an off-white solid, MS (ISP) 220.3 M+.
Reaction SMILES: [N:1]([C:4]1[C:13]([Br:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[CH:6][C:5]=1[F:37])=[N+]=[N-].C(O)(=O)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[C:13]([Br:14])=[C:12]2[C:7]([C:8](=[O:36])[C:9]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:10][N:11]2[C:15]2[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:18]([F:29])=[CH:17][C:16]=2[F:30])=[CH:6][C:5]=1[F:37]
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N=[N+]=[N-])c(F)cc2c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N)c(F)cc2c1=O
Yield: 68.1 %

Procedure:
Ethyl 7-azido-8-bromo-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (650 mg) was dissolved in methanol (20 ml). An acetic acid suspension (3 ml) of 20% palladium hydroxide (100 mg) was added to this solution, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After palladium hydroxide was removed by filtration, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; chloroform) to obtain the title compound (423 mg) as a liver-colored amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[CH2:20])=[N:17][CH:18]=1>>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:20][CH2:19][C:16]3[CH:15]=[CH:14][C:13]([C:12]([F:22])([F:11])[F:21])=[CH:18][N:17]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: C=Cc1ccc(C(F)(F)F)cn1
Reactant: Nc1ccc2c(c1)CCC2
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)CCC3)nc1

Procedure:
In analogy to the procedure described for the synthesis example 25 (step 1), the title compound Indan-5-yl-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 307.2 [M+H]+) was prepared from 5-amino-indan instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:21])=[O:20]
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Product: Cn1cccc1CCNS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and 2,4,5-trichlorobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4](=[O:15])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:23][S:24]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:4](=[O:15])[CH2:3]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1=O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65981.7 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of tert-butyl 4-hydroxy-2-oxopiperidine-1-carboxylate (1.00 g, 4.65 mmol) in dichloromethane (30 mL). Triethylamine (1.03 mL, 7.42 mmol) and 4-dimethylaminopyridine (0.057 g, 0.47 mmol) were added, and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.47 mL, 6.05 mmol) was added dropwise and the resulting solution stirred for 1 h at room temperature. The reaction mixture was washed with water (2×10 mL) and 0.1 M aqueous HCl solution (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford tert-butyl 4-(methylsulfonyloxy)-2-oxopiperidine-1-carboxylate (0. 900 g, 66%) as a brown solid. MS (ESI, pos. ion) m/z 294 [M+H]+.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16]Br>C(O)C>[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([S:10][CH2:16][C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[N:4]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: Nc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(O)nc(SCc2c(F)cccc2F)n1
Temperature: 22 °C

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (1.61 g, 10.0 mmol) is suspended in 50% ethanol (10 ml), then treated with solid sodium hydroxide (440 mg, 11.0 mmol) and stirred until the solid dissolved. 2,6-Difluoro-benzyl bromide (2.17 g, 10.5 mmol) is added and the reaction heated to reflux for 1.5 hrs. After cooling to 22° C., the solid is collected, washed with water, then air dried. The title compound is recrystallized from ethanol, mp 245-246° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[O:22]1[C:26]2[CH2:27][NH:28][CH2:29][CH2:30][C:25]=2[CH:24]=[CH:23]1>CCOCC.CS(Cl)(=O)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][C:25]3[CH:24]=[CH:23][O:22][C:26]=3[CH2:27]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCc1ccccc1
Reactant: c1cc2c(o1)CNCC2
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: c1ccc(CCCCCCN2CCc3ccoc3C2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 0.39 g (2.2 mmol) of 6-phenylhexan-1-ol and 0.38 ml (2.7 mmol) of triethylamine in 20 ml of ether, methanesulfonyl chloride was added dropwise under ice-cooling, followed by stirring for 10 minutes. The ether solution was washed with water and saturated aqueous sodium chloride, after which it was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The residual oil (crude 6-phenylhexyl methanesulfonate) was dissolved in 30 ml of acetonitrile; 0.289 g (1.811 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride and 0.76 ml (5.4 mmol) of triethylamine were added, followed by refluxing for 3 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](N1C2C=CC=CC=2OCC1)=[O:4].C(Cl)Cl.ICl.S(=O)(O)[O-].[Na+].[OH2:27]>C(O)(=O)C>[F:16][C:2]([F:1])([F:15])[C:3]([O:4][C:3](=[O:4])[C:2]([F:16])([F:15])[F:1])=[O:27]
Reactant: O=C(N1CCOc2ccccc21)C(F)(F)F
Reactant: O
Agent: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reaction time: 0.75 h

Procedure:
A mixture of 0.5 g (2.16 mmol) of this 4-(trifluoroacetyl)-3,4-dihydro-2H-1,4-benzoxazine, 20 ml of glacial acetic acid and 5 ml of methylene chloride was cooled to 10° in an ice bath. A solution of 1 ml of iodine monochloride in 1 ml of acetic acid was added slowly over a period of 5 minutes Following the addition, the mixture was stirred for 45 minutes and was then diluted with water and a aqueous solution of sodium bisulfite. The product was extracted with ether. The extracts were washed with water, dried and evaporated. Crystallization of the residue from hexane yielded colorless crystals with m.p. 78°-80°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH:20]=[CH:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)CC.Cl.[Cl-].[Na+].O.[C:44]([CH3:54])(OCC)([O:48]CC)[O:45][CH2:46][CH3:47]>>[CH2:46]([O:45][C:44](=[O:48])[CH2:54][CH:21]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][CH2:7][C:6]2[CH:33]=[CH:34][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1)[CH3:47]
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3cnc4ccccc4n3)n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Temperature: 150 °C
Yield: 48 %

Procedure:
A solution of the allylic alcohol 22-3 (0.26 g, 0.57 mmol) in (EtO)3CMe (10 mL) was treated with 100 μL of a 1 mL solution of (EtO)3CMe containing 10 μL of propionic acid. The yellow solution was heated at 150° C. for 90 minutes. The solution was cooled to room temperature and poured into 1N HCl/brine. The mixture was extracted with CHCl3, dried, concentrated, and purified on silica gel (90:5:5 CHCl3:EtOAc:MeOH) to give 0.143 g (48%) of 22-4.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCN(CC)CC.C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][C:10]1[C:5]2[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:2]([C:38]#[C:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:7][C:6]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C#Cc2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
(see, e.g., Dai, W., et al., Org Lett 2006, 8, 4665-7). A mixture of 50 (95 mg, 0.22 mmol), Pd(PPh3)2Cl2 (16 mg, 0.02 mmol), and CuI (8.6 mg, 0.04 mmol) in Et3N (0.5 mL) and dry THF (1 mL) was added dropwise to a solution of phenylacetylene (40 μL, 0.36 mmol) in Et3N (0.5 mL) under nitrogen at room temperature. Reaction mixture was heated to 60° C. and stirred overnight then diluted with EtOAc (10 mL) and washed with saturated aqueous NH4Cl (15 mL×2) and brine (15 mL). The organic layer was dried (Na2SO4), filtered, concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel to give the title compound (33 mg, 31%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.68-7.63 (m, 2H), 7.42-7.37 (m, 3H), 7.35-7.29 (m, 4H), 7.08 (t, J=7.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 5.68 (s, 2H), 4.50 (q, J=7.1 Hz, 2H), 2.72 (s, 3H), 1.47 (t, J=7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.08, 157.02, 156.83, 152.00, 141.84, 141.44, 133.56, 132.20, 131.77, 129.69, 129.47, 129.36, 128.45, 123.28, 121.86, 121.06, 118.94, 118.81, 110.56, 90.88, 88.87, 62.09, 49.81, 16.24, 14.26.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:14].O>CCOCC>[CH3:1][C:6]1([OH:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:5]1[CH3:4]
Reactant: C[Mg]Br
Reactant: CC1Cc2ccccc2C1=O
Solvent: CCOCC
Solvent: O
Product: CC1=Cc2ccccc2C1(C)O

Procedure:
A 200 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, methylmagnesium bromide (3.0 mol/l ether solution) (16.9 ml, 50.7 mmol) and dehydrated ether (50 ml) were introduced. To the flask, a solution of 2-methyl-1-indanon (3.70 g, 25.3 mmol) in dehydrate ether (20 ml) was dropwise added at room temperature with stirring. Then, the reaction mixture was stirred for 2 hours and poured into cold water. The resultant mixture was introduced into a separatory funnel to separate an organic phase. The aqueous phase was extracted by ether (100 ml×3) and a combined organic phase was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 1,2-dimethyl-1-hydroxy-indene. The compound thus obtained was dissolved in toluene (30 ml) and, thereto, 0.1 g of p-toluenesulphonic acid was added. The reaction mixture was refluxed for 3 hours to remove water. The organic phase thus obtained was introduced into a separatory funnel and washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After removing a solvent, it was purified by column chromatography (developer; hexane) to obtain 2.70 g (GC 94%) of a pale yellow solution (yield: 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=[CH:26][CH:27]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:30][CH3:31])[N:9]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38]COC[CH2:34]1.CNC.C1C[O:45]CC1>>[CH2:30]([N:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=4)=[CH:21][C:14]=23)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:45])[N:33]([CH3:32])[CH3:34])=[CH:7][CH:6]=2)=[N:9]1)[CH3:31]
Reactant: CN1CCOCC1
Reactant: C1CCOC1
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CO)c4)cc23)c(-c2ccc(N)cc2)n1
Agent: CNC
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CO)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred solution of (3-{4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}phenyl)methanol (16.13 g, 39.4 mMol) in THF (400 mL) was added NMM (4.5 mL, 40.9 mMol) followed by p-nitrophenylchloroformate (7.9 g, 39.2 mMol). (The reaction quickly became a fine suspension.) After stirring for 1 h at RT, a solution of 2.0 M dimethylamine in THF (200 mL, 400 mMol) was added. The reaction was stirred an additional 1 h at RT then concentrated to dryness under vacuum. The residue which remained was triturated with a cold solution of aq. 1 N NaOH (100 mL) in ice water (200 mL), filtered, washed with cold water (100 mL), and dried under vacuum. Purification by flash chromatography on silica gel (2 to 10% MeOH/CHCl3) gave the title product (16.67 g, 85% pure containing ˜15% starting aniline by LCMS, 75%) as a yellow solid: MS (ES) m/e 481.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 12.14 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.07 (d, J=4.8 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.41 (m, 1H), 7.29 (m, 1H), 7.28 (d, J=8.6 Hz, 2H), 6.79 (s, 1H), 6.78 (d, J=4.8 Hz, 1H), 5.26 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.27 (q, J=7.3 Hz, 2H), 2.91 (s, 6H), 1.51 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC#N
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccccc1
Yield: 104.4 %

Procedure:
A solution of 2.55 g of benzaldehyde, 2.46 g of ethyl cyanoacetate, 0.3 ml of acetic acid and 0.3 ml of piperidine in 20 ml of dry benzene was heated under reflux for 16 hours while removing water formed during the reaction by using a molecular sieve. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 4.57 g of 2-cyano-3-phenylpropenoic acid ethyl ester as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCOCC>CN(C=O)C>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@:4]1([OH:16])[CH3:17])(=[O:28])=[O:27]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a mixture of (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (4.66 g, 19.4 mmol)) and Et3N (7.01 mL, 50.4 mmol)) in DMF (40 mL) was added methanesulfonyl chloride (2.66 g, 23.3 mmol) dropwise at 0° C. After stirring at room temperature for 3 h, ether (400 mL) was added. The organics were washed with 1N HCl (20 mL), saturated aqueous sodium bicarbonate (20 mL), brine (2×20 mL), dried (Na2SO4), and concentrated to give ((1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)methyl methanesulfonate (12) (5.90 g, 96%) as a light yellow sticky mass.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([F:11])=[C:6]([CH2:12][NH:13]C(OC(C)(C)C)=O)[CH:5]=1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([F:11])=[C:6]([CH2:12][NH2:13])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(F)c(CN)c1
Reaction time: 8 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid methyl ester (4.25 g, 13.4 mmol) in CH2Cl2 (70 mL) was added TFA (10.3 mL, 134 mmol), and stirring was continued at RT overnight. Methanol was then added to the reaction mixture, and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure to afford the title compound as a beige solid. MS (LC/MS): 218.0 [M+H]+; tR (HPLC conditions c): 3.10 min. The material thus obtained was used in the next reaction step without further purification.