Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]3[CH2:17][C@H:18]([OH:20])[CH2:19][C@H:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[H-].[Na+].I[CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]3[CH2:17][C@H:18]([O:20][CH2:28][CH3:29])[CH2:19][C@H:13]3[CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CCI
Reactant: O=S(=O)(c1ccc(Cl)c(C(F)(F)F)c1)N1CCN2C[C@H](O)C[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H]1C[C@H]2CN(S(=O)(=O)c3ccc(Cl)c(C(F)(F)F)c3)CCN2C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To (7R,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol (0.3 mmol, Example 187) in tetrahydrofuran (1 mL) at room temperature was added NaH (20 mg, 60% in mineral oil). After 15 minutes, iodoethane (0.39 mmol) was added. The mixture was stirred at 60° C. for 2 days. The mixture was partially purified by chromatography on silica gel (CH2Cl2/CH3OH=10:1) to give the title compound as an impure solid (77 mg). The product was purified by HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol (70:30 to 0:100 gradient over 16 minutes), flow rate 36 mL/minute, UV=220 nm) to give the title compound (20 mg, 16% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (m, 3H), 1.47 (m, 1H), 1.73 (m, 1H), 2.00 (m, 1H), 2.08 (m, 1H), 2.19 (m, 1H), 2.39 (m, 6H), 2.93 (m, 1H), 3.63 (m, 1H), 3.76 (m, 1H), 3.92 (m, 1H), 8.04 (m, 3H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=1[N:14]([C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:9][C:8]=1[N:14]([C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COC[C@H](C)N(C(=O)C(F)(F)F)c1cc(F)ccc1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC[C@H](C)N(C(=O)C(F)(F)F)c1cc(N2CCN(C)CC2)ccc1C(=O)OC(C)(C)C
Yield: 84.1 %

Procedure:
A solution of 4-fluoro-2-[((S)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester (2 g, 5.28 mmol) and N-methylpiperazine (5.86 mL, 52.8 mmol) in tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days. The solution was then evaporated, NaHCO3 satured solution was added and the mixture extracted with dichloromethane (3 times). The organic layer was washed with water, brine, dried over sodium sulfate filtered and evaporated to obtain a crude, which was purified by column chromatography on silica gel (dichloromethane-methanol 93:7). The title compound (2.04 g, 84%) was obtained as yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CO>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][N:22]3[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[C:8]3=[O:12])=[CH:25][C:26]=2[CH2:30][CH2:29]1
Reactant: NCc1ccc2c(c1)CCO2
Reactant: O=C(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 50 °C
Reaction time: 36 h
Yield: 82.1 %

Procedure:
A mixture of 6-fluoro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (1 g), 5-aminomethyl-2,3-dihydrobenzo[b]furan (1.1 g), triethylamine (1 ml) and methanol (10 ml) was stirred at 50° C. for 36 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added 4N-hydrochloric acid-ethyl acetate solution (5 ml) at room temperature and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.2 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][C:14]2=[O:17])=[CH:9][CH:8]=1)(=O)=O.[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[C:20]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCc2ccc(-c3ccccc3)cc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
While stirring a mixture comprising 15.32 g (52.06 mmol) of 7-trifluoromethanesulfonyloxy-3,4-dihydro-1(2H)-naphthalenone obtained in the Synthesis Example A-1, 12.7 g (104.12 mmol) of phenylboric acid, 10.8 g (78.09 mmol) of potassium carbonate and 450 ml of toluene at room temperature, nitrogen gas was bubbled thereinto for 30 minutes. Next, 1.81 g (1.57 mmol) of tetrakistriphenylphosphine palladium was added thereto. The mixture was slowly heated to thereby maintain the bulk temperature at about 90° C. After stirring at this temperature for 90 minutes, the reaction mixture was cooled and water was added thereto. The insoluble matters were filtered through celite and thoroughly washed with ethyl acetate. The organic phase was collected, washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water, 1N hydrochloric acid, water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. After successively eluting with hexane:ethyl acetate in a ratio ranging from 20:1 (v/v) to 12:1 (v/v), 9.53 g of the title compound was obtained as white crystals. Yield 82%.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[CH2:11]([N:18]=[N+:19]=[N-:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[CH2:11]([N:18]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 86.1 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.095 g, 0.603 mmol) was reacted with benzyl azide (0.096 g, 0.723 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol 2-ylamine hydrochloride (0.151 g, 86%) of a pale yellow solid. 1H NMR (300 MHz, D2O) δ 7.79 (s, 1H), δ 7.42-7.35 (m, 5H), δ 6.43 (s, 1H), δ 5.58 (s, 2H), δ 3.86 (s, 2H) ppm; 13C δ 145.4, 136.6, 136.4, 128.8, 128.7, 126.9, 126.8, 126.3, 124.1, 121.8, 109.6, 53.3, 24.1 ppm; HRMS (ESI) calcd for C13H6N6O (M+) 254.1352. found 254.1352.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:24]1[CH2:29][CH:28]=[C:27]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:23][C:19]1[C:17]2[O:18][CH:13]([CH2:12][N:24]3[CH2:25][CH:26]=[C:27]([C:30]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[NH:32][CH:31]=4)[CH2:28][CH2:29]3)[CH2:14][O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cccc(F)c3O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1cccc2c1OC(CN1CC=C(c3c[nH]c4ccccc34)CC1)CO2

Procedure:
[(2R)-8-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl 4-methylbenzenesulfonate (1.2 g, 3.5 mmole) was dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 30 mL) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.60 g, 3.0 mmole) added, followed by the addition of sodium bicarbonate (0.60 g, 7.1 mmole) and the mixture refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuum, and the residue partitioned between 400 mL each of methylene chloride and water. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue chromatographed on silica gel using 4% methanol in chloroform as eluant. The product fractions were combined and concentrated in vacuum to give 0.20 g (16%) of the (S)-enantiomer of the title compound as a yellow solid, m.p. 174–177° C.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1>>[O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([NH:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1)=[O:5]
Reactant: Cc1ccc(OC2CCN(C(=O)C(=O)O)CC2)cc1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)[nH]c4c3)CC2)cc1

Procedure:
The title compound is prepared from oxo-(4-p-tolyloxy-piperidin-1-yl)-acetic acid (Example 26b) and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 294° C. (isopropanol)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([C:27]3[N:31]=[CH:30][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)=[O:26])[CH:18]=1)=[O:14])[NH:7][C:6]2=[O:51])#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([C:27]3[N:31]=[CH:30][NH:29][N:28]=3)=[O:26])[CH:18]=1)=[O:14])[NH:7][C:6]2=[O:51])#[N:2]
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(CNC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(CNC(=O)c4nc[nH]n4)c3)[nH]c(=O)c2c1
Yield: 42.1 %

Procedure:
A solution of 6-cyano-4-oxo-N-({3-[({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]carbonyl}amino)methyl]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide (420 mg, 0.626 mmol), triethylsilane (0.105 mL, 0.657 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (10 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from IPE. The obtained powder was suspended in ethanol, and the suspension was stirred under heating for 2 hr to give the title compound as a white powder (113 mg, 42%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=C.CSC.[C:11]([NH:18][NH2:19])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(Cl)Cl>[C:11]([NH:18][N:19]=[CH:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C=CCCC(=O)O
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN=CCCC(=O)O
Temperature: -78 °C
Yield: 63 %

Procedure:
4-Pentenoic acid (10.00 g, 99.88 mmol) was dissolved in methylene chloride (150 mL), and the mixture was cooled to −78° C. under N2(g). Ozone was bubbled through the reaction mixture, and the course of the reaction was monitored by TLC. After TLC showed disappearance of the starting material (ca. 2.5 h), methyl sulfide (15.0 mL, 205.23 mmol) was added and the reaction mixture was allowed to warm to room temperature. Subsequently, solvent was removed under reduced pressure, and the residue was dissolved in THF (200 mL). BocNHNH2 (13.2 g, 99.88 mmol) was then added, and the reaction mixture was refluxed overnight under Ar(g). Solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, 6% v/v methanol in methylene chloride) to give BocNHN═CHCH2CH2CO2H as a white solid (13.60 g, 63%). HRMS (ESI) [M−H]− calcd for C9H15N2O4, 215.1032; found, 215.1035; 1H NMR (300 MHz, d6-DMSO) δ 12.16 (s, 1H), 10.45 (s, 1H), 7.30 (app bs, 1H), 2.45-2.30 (m, 4H), 1.41 (s, 9H); 13C NMR (100 MHz, d6-DMSO) δ 173.5, 152.4, 145.6, 78.9, 30.4, 28.1, 27.2.
Reaction SMILES: [CH2:1]([O:17][CH:18]([CH:20]1[CH2:22][O:21]1)[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>C(O)(=O)C>[CH2:1]([O:17][CH:18]([CH3:19])[CH:20]([OH:30])[CH2:22][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC(C)C1CO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCOC(C)C(O)CO
Reaction time: 0.5 h
Yield: 7520.1 %

Procedure:
A mixture of 30 g of [1-(hexadecyloxy)ethyl]oxirane, 0.2 g of p-toluenesulfonic acid and 200 ml of glacial acetic acid was refluxed for 4.5 hours, then the acetic acid was removed. Toluene was added and removed. The residue was dissolved in 225 ml of methanol and 13.44 g of sodium hydroxide in 14 ml of water was added. This mixture was stirred 1/2 hour, the solvent removed and the residue extracted twice with ether. The ether extracts were combined, washed with brine, dried and the solvent removed. The resulting oil was diluted via a Kugelrohr (200° C., 0.5 mm), giving 28.87 g of the desired compound as a white sticky solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(C1C=CC(C)=CC=1)(O[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])(=O)=O.[BH4-].[Na+]>CO.O>[CH2:19]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: c1cnc2ccncc2c1
Reactant: C=CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCCCN1CCc2ncccc2C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1,6-naphthyridine (6.5 g, 0.05 mol) and 4-pentenyl tosylate was heated at 80° C. for 6 hours. The reaction mixture was dissolved in methanol (300 ml) and water (100 ml). To the mixture, sodium borohydride (9.5 g, 0.25 mol) was added portionwise over the internal temperature range 0° to 20° C. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with ether. The organic layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The resulting residue was purified by alumina column chromatography (eluted successively with petroleum ether and ether) and distilled, bp. 110°-112° C./0.35 mmHg, to afford the Compound No. 15 (6.9 g, 68.6%) as a colorless oil.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[CH2:2].[CH2:8]([O:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:17]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:8]([O:15][C:16]1[CH:21]=[C:20](/[CH:2]=[CH:1]/[N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:19]=[CH:18][C:17]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=Cn1cncn1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CN(c2ccc(/C=C/n3cncn3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 110 °C

Procedure:
A mixture of 1-vinyl-1,2,4-triazole (0.100 g, 1.06 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.236 g, 0.531 mmol), palladium acetate (0.024 g, 0.107 mmol), triethylamine (0.295 mL, 2.09 mmol) in acetonitrile is heated in a microwave apparatus at 110° C. for 30 min. The mixture is filtered over Celite, washed with acetonitrile, and concentrated. The residue is purified by column chromatography using a gradient of 10-60% EtOH/water as eluent to afford the title compound: (M−1)−=410.
Reaction SMILES: [C:1]([C@@H:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)#[N:2].[CH3:18][C:19]1([CH3:32])[CH:21](/[CH:22]=[C:23](\[Cl:28])/[C:24](=[O:27])[O:25][CH3:26])[CH:20]1[C:29](O)=[O:30]>C1C=CC=CC=1>[CH3:18][C:19]1([CH3:32])[C@@H:21](/[CH:22]=[C:23](\[Cl:28])/[C:24](=[O:27])[O:25][CH3:26])[C@H:20]1[C:29]([O:17][C@H:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:30]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: COC(=O)/C(Cl)=C/C1C(C(=O)O)C1(C)C
Solvent: c1ccccc1
Product: COC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R, cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+62.5°±1.5° (c=1% in benzene).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[C:11]2[CH:10]=[C:9]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:8]3=[CH:7][C:6]=2[CH2:5][C:4]=1[CH3:20].[Li:22]CCCC>CCCCCC>[CH3:1][N:2]([CH3:21])[C:3]1[C:11]2[CH:10]=[C:9]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[C:8]3=[CH:7][C:6]=2[CH:5]([Li:22])[C:4]=1[CH3:20]
Reactant: [Li]CCCC
Reactant: CC1=C(N(C)C)c2cc3c(cc2C1)C(C)(C)CCC3(C)C
Solvent: CCCCCC
Product: [Li]C1C(C)=C(N(C)C)c2cc3c(cc21)C(C)(C)CCC3(C)C
Reaction time: 8 h
Yield: 93 %

Procedure:
3-(dimethylamino)-5,6,7,8-tetrahydro-2,5,5,8,8-pentamethyl-1H-benz(f)indene (2.11 g, 7.46 mmol) was stirred in hexane (75 mL) as n-BuLi (4.10 mL of 2.0 M solution in hexane, 8.20 mmol) was added slowly. This mixture was allowed to stir overnight during which time a pale yellow precipitate formed. After the reaction period the desired product was collected via filtration, washed with hexane, and dried under vacuum resulting in the isolation of a pale yellow solid which was used without further purification or analysis (2.00 g, 93 percent yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23](CC3C=CC=CC=3)[CH3:24])[C:12]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23]([C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:46])[CH3:24])[C:12]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 99.6 %

Procedure:
1.52 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.24 g of benzyloxycarbonyl chloride and 18 ml of benzene are treated in the same manner as described in Example 4-(2), whereby 1.64 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][NH2+:9][CH2:10][CH2:11]Cl)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:9]([CH2:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:10][CH2:11][S:26]1
Reactant: ClCC[NH2+]CC1CCCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: COc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([NH:42][C:43]([C:45]2([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:50][CH2:49][N:48]([C:51]3[C:52]4[CH:59]=[CH:58][NH:57][C:53]=4[N:54]=[CH:55][N:56]=3)[CH2:47][CH2:46]2)=[O:44])[CH2:39][CH2:40]O)=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:38]([NH:42][C:43]([C:45]2([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:46][CH2:47][N:48]([C:51]3[C:52]4[CH:59]=[CH:58][NH:57][C:53]=4[N:54]=[CH:55][N:56]=3)[CH2:49][CH2:50]2)=[O:44])[CH2:39][CH2:40][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCN2C(=O)c3ccccc3C2=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
Triphenylphosphine (158 mg) and phthalimide (22.11 mg) were added in one portion to a stirred solution of tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 36) (53 mg) dissolved in THF (10 mL) and cooled to 0° C. under argon. The resulting solution was stirred at 0° C. for 30 minutes. Diethyl azodicarboxylate (0.093 mL) was added dropwise at 0° C. under argon. The resulting suspension was stirred at 0° C. for 60 minutes and overnight at room temperature. The suspension was quenched with water. The THF was removed in vacuo and the aqueous phase extracted with DCM. The organic phase was dried and concentrated to provide crude product. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in DCM. The solvent was evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-(1,3-dioxoisoindolin-2-yl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate as a white solid (14.00 mg, 21.23%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7]([Cl:24])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:11]=1)[CH3:2].[CH2:26]([NH2:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7]([Cl:24])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][NH:28][CH2:26][CH3:27])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2C=O)cnc1Cl
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cnc(Cl)c(CC(=O)OCC)c1

Procedure:
[2-Chloro-5-(2-formyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and ethylamine (2M in THF) were reacted as described in Example 3, Step 3 to provide [2-chloro-5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.