Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([C:2]2[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]3[C:12]4[CH:19]=[N:18][N:17]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=5)[C:13]=4[CH:14]=[N:15][CH:16]=3)=[O:10])=[CH:5][N:6]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: O=C(NCc1cnc(Br)s1)c1cncc2c1cnn2-c1ccc(F)cc1
Product: O=C(NCc1cnc(N2CCOCC2)s1)c1cncc2c1cnn2-c1ccc(F)cc1

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2-bromo-thiazol-5-ylmethyl)-amide (80 mg, 0.21 mmol) in morpholine (2 mL) was heated at 140° C. for 72 hours in a sealed tube. The mixture was partitioned between EtOAc (20 mL) and saturated aqueous ammonium chloride (20 mL). The organic layer was separated and washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane. The purification was repeated using the same conditions listed above. The material from the purification was diluted with dichloromethane (1 mL) followed by hexanes (5 mL) and filtered to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][CH3:35]>CC(C)=O>[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH3:30])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCCCNC
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCOS(C)(=O)=O
Solvent: CC(C)=O
Product: CCCCN(C)CCCn1c(C(=O)OCC)c2ccc(Cl)cc2c1-c1ccccc1
Product: Cl

Procedure:
A solution of 4.36 g. of 5-chloro-2-{3-[(methylsulfonyl)oxy]propyl}-3-phenylisoindole-1-carboxylic acid ethyl ester in 40 ml. of acetone is treated with 10 ml. of N-methylbutylamine and boiled at reflux for 5 hours. The mixture is then concentrated to dryness under reduced pressure and the residue partitioned between 50 ml. of water and 50 ml. of ether. The ethereal phase is treated with 30 ml. of 0.5-N hydrochloric acid and the mixture thoroughly shaken. After cooling in an ice-bath, the crystallized hydrochloride is removed by filtration under vacuum, dried and recrystallized from methylene chloride/ether, and there is obtained 2-[3-(butylmethylamino)propyl]-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 98°-101° C. (decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].Cl[C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C>ClC(Cl)C.C[C]1[C](C)[C](C)[C](C)[C]1C.C1CC=CCCC=C1.Cl[Ru]>[C:3]1([C:1]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:16][O:17][CH:2]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C#Cc1ccccc1
Agent: Cl[Ru]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Solvent: CCN(CC)CC
Solvent: C1=CCCC=CCC1
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1nocc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.1 %

Procedure:
Ethynylbenzene (0.300 mL; 2.73 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (0.455 g; 3.00 mmol) were dissolved in degassed dichloroethane (15 mL), chloro(1,5-cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium (II) (0.052 g; 0.136 mmol) and triethyl amine (0.476 mL; 3.41 mmol) were added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then filtered through a pad of silica gel and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 2 to 20% ethyl acetate in heptane) and by preparative HPLC method 3 to yield 0.030 g (5%) of the title compound as a solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:26])([F:25])[C:22](O)=O.C(N(CC)CC)C.[C:34]([NH2:53])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)(Cl)(Cl)[Cl:55]>>[F:20][C:21]([F:26])([F:25])[C:22]([Cl:55])=[N:53][C:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: FC(F)(F)C(Cl)=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
In a typical reaction, a mixture of about 3 equivalents of triphenylphosphine and trifluoroacetic acid in carbon tetrachloride are cooled to about 0° C. in an ice bath and a 20% excess of triethylamine is added. With continued cooling, about a 20% excess of tritylamine in carbon tetrachloride is slowly added. After completion of the addition, the mixture is heated to about 70° C. for several hours. After cooling, the reaction mixture is extracted with hexane and the solvent evaporated to provide crude 2,2,2-trifluoro-N-(trityl)-ethanimidoyl chloride.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:22][C:16]2([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: CN1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 56.7 %

Procedure:
A solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.58 mmol, 1 wt), 1-methylpiperazine (300 mg, 2.99 mmol), absolute ethanol (20 ml, 40 vol), activated 3 Å molecular sieves (500 mg), titanium (IV) isopropoxide (2.32 ml, 7.83 mmol) and STAB (1.43 g, 6.73 mmol) were reacted in accordance with the general procedure D. The isolated oil was purified by column chromatography on silica (20 g, 28.6 wt) eluting with DCM(95):MeOH(4):NH3(I) to give the title compound as a clear viscous oil (360 mg, 56%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.75 (dt2H), 3.60-3.47 (m, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.38 (s, 2H), 2.34-2.14 (m, 11H), 2.13-1.73 (m, 10H).
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.O1CCC[CH2:20]1.CC(C)([O-])C.[K+].S(OC)(OC)(=O)=O>C(OCC)(=O)C.O>[CH3:20][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: C1CCOC1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The title compound was prepared by taking tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (702 mg, 0.00269 mol) in Tetrahydrofuran (10 mL, 0.1 mol) at 0° C. and adding in Potassium tert-butoxide (15 mL, 0.015 mol). The reaction was stirred for 20 min and then Dimethyl sulfate (0.56 mL, 0.006 mol) was added and the temperature raised to ambient temperature. After stirring overnight the reaction mixture was poured into water and ethyl acetate. The organic layers were separated, dried and concentrated in vacuo to afford an oil which was used as-is (424 mg, 99%) MS calculated for C13H25NO5: (M+H) 276; found 276.1.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: Cc1ccoc1C
Reactant: BrCc1cccc(Br)c1
Solvent: C1CCOC1
Product: Cc1cc(Cc2cccc(Br)c2)oc1C
Yield: 91.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (5.00 g, 52.0 mmol), commercial 3-bromobenzylbromide (13.0 g, 52.0 mmol) and 2.5M n-BuLi/hexanes (20.8 mL, 52.0 mmol) in THF. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet. ether gave 12.63 g (85%) of the title compound. 1H NMR (DMSO-d6) δ1.85 (s, 3 H), 2.10 (s, 3 H), 3.86 (s, 2 H), 5.90 (s, .1 H), 7.21-7.30 (m, 2 H), 7.34-7.47 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:17]4=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]4[C@H:15]4[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]34)[CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Clc1ccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1Cl

Procedure:
Using 3,4-dichloro-1-bromobenzene and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 39 as a powder. 1H NMR(CDCl3, 300 MHz) δ 1.82-1.87 (m, 2H), 2.48-2.55 (m, 1H), 2.57-2.64 (m, 1H), 2.81-3.13 (m, 6H), 3.18-3.25 (m, 1H), 3.42-3.47 (m, 1H), 3.57-3.64 (m, 1H), 3.72 (s, 2H), 5.55 (s, 1H), 6.61-6.68 (m, 2H), 6.74 (s, 1H), 6.89 (d, 1H, J=3 Hz), 7.19 (d, 1H, J=9 Hz). LRMS (ES)+: 406 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:24].O>CC(C)=O>[Br:12][C:4]1[C:3]2[O:13][CH2:22][C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)([OH:24])[NH:1][C:2]=2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[CH:5]=1
Reactant: Nc1c(O)c(Br)cc(F)c1[N+](=O)[O-]
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1c(F)cc(Br)c2c1NC(O)(c1cccnc1)CO2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Amino-6-bromo-4-fluoro-3-nitrophenol (500 mg, 1.9 mmol) and potassium carbonate (780 mg, 5.7 mmol) were stirred in acetone (8 mL) for 5 minutes and 2-bromo-1-pyridin-3-ylethanone hydrobromide (530 mg, 1.9 mmol) was added as a solid over 5 minutes. The mixture was stirred at rt for 5 minutes and poured into water. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes gave the desired compound, 0.69 g, 99%. LCMS calculated for C13H10BrFN3O4 (M+H)+: m/z=370.1, 372.1. found: 370.0, 372.0.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH:18]1[CH:25]2[CH2:26][C:21]3([CH2:28][OH:29])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2>>[OH:29][CH2:28][C:21]12[CH2:20][CH:19]3[CH2:27][CH:23]([CH2:24][CH:25]([CH:18]3[NH:17][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH2:26]1)[CH2:22]2
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Product: O=C(NC1C2CC3CC1CC(CO)(C3)C2)c1cccc(Oc2ccccc2)c1

Procedure:
Prepared from 3-phenoxy benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 7.31-7.49 (m, 5H), 7.08-7.18 (m, 2H), 7.02 (d, 2H), 6.29-6.43 (m, 1H), 4.13-4.23 (m, 1H), 3.24 (d, 2H), 2.09-2.18 (m, 2H), 2.01 (br. s., 1H), 1.55-1.92 (m, 10H), 1.44 (d, 1H).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH2:25][NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>ClCCl>[C:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][N:26]([CH2:25][C:24]1[CH:37]=[CH:38][C:21]([Cl:20])=[CH:22][CH:23]=1)[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=[O:3])=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(Cl)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 37.9 %

Procedure:
Benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate (233 mg, 0.83 mmol) was added at room temperature to a solution of tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (235 mg, 0.83 mmol) and Hunig's base (0.2 mL, 1.2 mmol, 1.5 eq.) in dichloromethane (1.6 mL). The reaction was allowed to stir overnight. The reaction mixture was then concentrated to the crude product, which was purified by flash column chromatography to afford benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate as foam (167 mg, 38%). MS (ESI) m/e (M+H+) 531.
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][C:19](=O)[CH3:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].C(O)C.[CH:25]([NH2:28])([CH3:27])[CH3:26].[H][H]>[Pd].C(OCC)C>[C:1]([C:4]1([CH2:17][CH2:18][CH:19]([NH:28][CH:25]([CH3:27])[CH3:26])[CH3:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: CC(=O)CCC1(C(N)=O)c2ccccc2-c2ccccc21
Reactant: CC(C)N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)NC(C)CCC1(C(N)=O)c2ccccc2-c2ccccc21

Procedure:
A solution of 2.35 g. of 9-carbamoyl-9-(3-oxobutyl)fluorene from Example 2 in 200 ml. of ethanol containing 59.0 g. of isopropylamine and 2.0 g. of 5% palladium on charcoal was stirred for sixteen hours at 25° C. under 60 psi of hydrogen. The reaction mixture was filtered and the filtrate was concentrated to a volume of about 50 ml. The mixture was added to 200 ml. of diethyl ether and extracted with 6N hydrochloric acid. The aqueous acid extract was cooled, made alkaline by addition of 10% aqueous sodium hydroxide, and the alkaline solution was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water, dried and the solvent was removed by evaporation under reduced pressure to provide a solid. The solid was dissolved in fresh diethyl ether and hydrogen chloride was bubbled into the solution. The precipitated crystals which formed were collected by filtration, dried and identified as 829 mg. of 9-carbamoyl-9-(3-isopropylaminobutyl)fluorene hydrochloride. m.p. 204°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:18])[NH:15][CH2:16][CH2:17][C:12]=3[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10]2)=[CH:5][CH:4]=1.I[C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH3:35])([CH3:34])[C:32]#[N:33])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[C:32]([C:31]([CH3:35])([CH3:34])[C:28]1[CH:29]=[CH:30][C:25]([N:15]2[CH2:16][CH2:17][C:12]3[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:13]=3[C:14]2=[O:18])=[CH:26][CH:27]=1)#[N:33]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Reactant: CC(C)(C#N)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C(C)(C)C#N)cc1)C2=O
Temperature: 130 °C
Yield: 45.9 %

Procedure:
Part D. To a DMSO (4 mL, degassed) solution of ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.6 g, 1.9 mmol), and 2-(4-iodophenyl) 2-methylproprionitrile (0.6 g, 2.2 mmol), and K2CO3 (0.66 g, 4.8 mmol) and was added CuI (73 mg, 0.3 mmol). The reaction was heated to 130° C. for 18 h. The reaction was cooled, extracted with EtOAc, washed with H2O, and dried (MgSO4). Purification by chromatography on silica gel (1:1 hexanes/ethyl acetate) afforded the title compound 0.4 g (45.9%) of a pale yellow solid; Mass Spec (M+H)+ 459.3.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][CH:12]([CH3:15])[CH:13]=[CH2:14]>>[OH:4][C:3]([C:5]([F:8])([F:7])[F:6])([C:2]([F:10])([F:9])[F:1])[CH2:14][CH:13]=[C:12]([CH3:15])[CH3:11]
Reactant: C=CC(C)C
Reactant: O=C(C(F)(F)F)C(F)(F)F
Product: CC(C)=CCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 125 °C

Procedure:
A stirred mixture of hexafluoroacetone (235 g) and 3-methylbut-1-ene (100 g) was heated at 125° C. under a pressure of 17 atmospheres for a period of 20 hours. Distillation of the product mixture under reduced pressure yielded 5-hydroxy-2-methyl-6,6,6-trifluoro-5-trifluoromethylhex-2-ene as a mobile colourless liquid, b.p. 43° C./15 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][C:16]#[C:17][CH3:18])[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:30][N:31]=[C:32]=[O:33]>C(Cl)Cl>[CH3:30][NH:31][C:32](=[O:33])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][C:16]#[C:17][CH3:18])[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CC#CN=C1CCc2c1n(C)c1ccc(O)cc21
Reactant: CN=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC#CN=C1CCc2c1n(C)c1ccc(OC(=O)NC)cc21
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (3.4 g) in CH2Cl2 (15.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (326 mg) followed by the dropwise addition of methyl isocyanate (0.8 g) in CH2Cl2 (5.0 ml). The reaction was monitored via TLC and after 1.0 hour, the solution was concentrated and the crude product was purified via flash chromatography eluting with hexane/acetone (2:1). The product which precipitated out of the pure fractions was collected to give 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-yl methylcarbamate (1.2 grams) and the fractions were concentrated to give an additional 0.9 gram.
Reaction SMILES: Br[CH2:2][C:3]([F:15])=[CH:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[CH:4]=[C:3]([F:15])[CH2:2][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:25]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C=C(F)CBr)c1ccc(Cl)cc1
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C=C(F)Cc1ccc(F)c(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-bromo-4-(p-chlorophenyl)-2-fluoro-4-methyl-2-pentene, (Z)—(320.8 mg, 1.1 mmol), bis(dibenzylideneacetone)palladium(O) (Pd(dba)2, 31.6 mg, 0.055 mmol) in toluene (8 mL) is treated with potassium carbonate (608 mg, 4.4 mmol), degassed, treated with a solution of 4-fluoro-3-phenoxybenzeneboronic acid (331.8 mg, 1.43 mmol) in ethanol (2 mL), refluxed for 45 minutes, cooled to room temperature, and filtered through diatomaceous earth. The filtrate is diluted with ethyl acetate, and the resultant solution is washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a colorless liquid (401 mg, 91% yield) which is identified by NMR spectral analyses.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>CC(C)=O.C(Cl)Cl.O>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[CH:25]=[C:20]3[N:19]([CH:2]=2)[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reactant: Cc1ccccn1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(-c2cc3ccccn3c2)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (0.44 mmol) and 2-picoline (41 mg, 0.44 mmol) in acetone (2 mL) was heated to reflux for 3 h, diluted with CH2Cl2 (20 mL) and water (10 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:19 to 1:2) to afford 2-(3-methoxy-4-pyridin-2-ylphenyl)indolizine. 1H NMR (CDCl3, 300 MHz) δ 8.75 (m, 1H), 7.92 (m, 2H), 7.86 (d, 1H), 7.73 (dt, 1H), 7.65 (br s, 1H), 7.41 (dd, 1H), 7.38 (d, 1H), 7.30 (br s, 1H), 7.21 (m, 1H), 6.77 (s, 1H), 6.69 (dd, 1H), 6.49 (dt, 1H), 3.97 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz) δ 157.3, 156.0, 149.4, 137.3, 135.7, 133.7, 131.5, 129.1, 127.2, 125.1, 125.1, 121.6, 119.1, 119.1, 117.6, 110.8, 109.6, 109.2, 96.8, 55.7 ppm. MS (ESI) 301 (M)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH:2]=[CH2:3].C(C1CCCC([Cl:21])C1=O)(C)(C)C>>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([Cl:21])[C:5]1=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCC1CCCCC1=O
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Product: C=CCC1CCCC(Cl)C1=O

Procedure:
The chlorination of 2-allylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.