Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
4-Hydroxy-2-methoxybenzaldehyde (408 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10 (v/v)), whereby the objective title compound was obtained as a white solid (801 mg, yield: 96%).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+:10]1C=CC=C[CH:11]=1.[NH+]1C=CC=CC=1.[Cl:22][C:23]1[S:48][C:26]2[NH:27][C:28]([C:30]([NH:32][CH:33]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH2:43][CH2:44][CH2:45][OH:46])[C:34]3=[O:47])=[O:31])=[CH:29][C:25]=2[CH:24]=1>CN(C=O)C>[Cl:22][C:23]1[S:48][C:26]2[NH:27][C:28]([C:30]([NH:32][CH:33]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH2:43][CH2:44][C:45]([NH:10][CH3:11])=[O:46])[C:34]3=[O:47])=[O:31])=[CH:29][C:25]=2[CH:24]=1
Reactant: c1cc[nH+]cc1
Reactant: O=C(NC1Cc2ccccc2N(CCCO)C1=O)c1cc2cc(Cl)sc2[nH]1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: CN(C)C=O
Product: CNC(=O)CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 24 h
Yield: 60.8 %

Procedure:
Pyridinium dichromate (329 mg, 0.88 mmol) was added to 2-chloro-N-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 43; 100 mg, 0.248 mmol) in DMF (3 mL) and the reaction was stirred for 24 hours. The reaction was diluted with EtOAC (20 mL) and filtered through celite. The filtrate was washed with 1M HCl (aq.) and the organic layer was dried (MgSO4), filtered and evaporated to afford the crude acid which was used without purification. Standard amide bond formation analogous to Method 3 except using methylamine (2.0 M in THF) as amine gave the title compound (65 mg, 61% over 2 steps) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][C:22](F)=[CH:23][C:24]=3[O:29][CH3:30])[N:19]=2)[CH:15]=[C:14]([CH3:32])[N:13]=1>CS(C)=O>[CH3:32][C:14]1[CH:15]=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][C:22]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:23][C:24]=3[O:29][CH3:30])[N:19]=2)[CH:17]=[C:12]([CH3:11])[N:13]=1
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(OCCN2CCCC2)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-pyrrolidin-1-yl-ethanol (1.15 g, 10 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.20 g, 5.0 mmol) was added in portions and the reaction mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.30 g, 1.0 mmol) and the reaction mixture was stirred at 75° C. for 16 hours. The reaction mixture was loaded onto a column and purified by column chromatography (silica gel 230-400 mesh; eluting with 5% 7.0 M ammonia in methanol solution in dichloromethane), to obtain the title compound as a white solid. Yield: 0.163 g (41.3%). MP 227-229° C. MS (ES) m/z: 395.15 (M++1). 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.25 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.66 (s, 6H), 2.63 (m, 4H), 1.83 (m, 4H).
Reaction SMILES: [C:1](#N)C.[NH2:4][C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]([OH:17])=[O:16])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O1CCCC1>[CH3:1][O:16][C:15]([C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:18])[CH:12]=2)[N:7]=[C:6]([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[C:5]=1[NH2:4])=[O:17]
Reactant: CC#N
Reactant: Nc1c(-c2ccc(I)cc2)nc2ccc(F)cc2c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1c(N)c(-c2ccc(I)cc2)nc2ccc(F)cc12
Reaction time: 1 h

Procedure:
To a solution of 400 ml of acetonitrile and 40 ml of tetrahydrofuran was added 4.0 g of 3-amino-6-fluoro-2-(4-iodophenyl)-4-quinolinecarboxylic acid and 2.0 g of cesium carbonate. The solution was stirred for 1 hour and 0.84 ml of methyl iodide was added. After stirring for an additional 12 hours, the volatiles were removed in vacuo and the residue dissolved in methylene chloride and ethyl acetate. The insoluble solids were removed by filtration and the volatiles removed from the filtrate in vacuo. The yellow solid obtained was recrystallized from methylene chloride, giving 3.45 g of the desired compound as yellow crystals, mp 223°-225° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].I[CH2:15][C:16]#[N:17].Cl>C1COCC1.O>[CH2:11]([O:10][C:8]([CH:7]([CH2:15][C:16]#[N:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: N#CCI
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC#N)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
In this example 10 g of ethyl phenylacetate in 10 ml of THF was added dropwise to 61 ml of a 1 molar solution lithium bis[trimethylsilvllamide in tetrahydrofuran, under nitrogen, at -78° C. The mixture was stirred for one hour at -78° C. A solution containing 10.2 g of iodoacetonitrile in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78° C. for about one-half hour and then stirred for two hours and allowed to warm toward room temperature during this period. The reaction mixture was then added to water and the pH adjusted to pH 1 by the addition of aqueous 10% hydrochloric acid. The mixture was washed with saturated aqueous sodium chloride solution and extracted three times with ethyl ether. The extracts were combined, washed twice with aqueous saturated sodium bicarbonate, dried over magnesium sulfate and evaporated affording 10.7 g of the title compound is an oil. The oil was further purified by chromatography over silica gel eluting with 20% vol. ethyl acetate petroleum ether.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CN(C)[CH:21]=[O:22]>>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[CH:21]=[O:22])=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2ccnn2C)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2c(C=O)cnn2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide (300 mL) was cooled to 0° C. and treated with phosphorus oxychloride (80 g, 0.52 mol). After completion of the addition, the resulting mixture was warmed to room temperature and stirred for 1 hour. 5-(4-Methylphenyl)-1-methyl-1H-pyrazole (C2) (30.0 g, 174 mmol) was added and the reaction mixture was heated to 120° C. and stirred overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into ice-water (700 mL), then adjusted to a pH of approximately 8 with saturated aqueous sodium carbonate solution. The resulting mixture was extracted with dichloromethane (4×300 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient: 1:100 to 1:30 ethyl acetate in petroleum ether) afforded the product as a yellow solid. Yield: 28.2 g, 141 mmol, 81%. 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 3.81 (s, 3H), 7.33 (br AB quartet, JAB=8 Hz, ΔνAB=17 Hz, 4H), 8.04 (s, 1H), 9.60 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CS(O[CH2:11][CH2:12][C@H:13]([NH:21]C(OC(C)(C)C)=O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=O)=O>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:13]([NH2:21])[CH2:12][CH2:11][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:19][CH:18]=1
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCN(CC)CC[C@H](N)c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
Diethylamine (0.426 mL, 4.12 mmol) and (S)-3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (Intermediate 59) (500 mg, 1.37 mmol) were dissolved in THF (10 mL) and sealed into a microwave tube. The reaction was heated to 120° C. for 50 minutes in the microwave reactor and cooled to room temperature. The reaction mixture was concentrated and diluted with DCM (5 mL). TFA (1 mL) was added and the reaction was stirred at 20° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford (S)-1-(4-chlorophenyl)-N3,N3-diethylpropane-1,3-diamine (119 mg, 36.0%) as a yellow oil.
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](CBr)=[CH:9][CH:8]=1.O>CS(C)=O>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:1]=[O:4])=[CH:9][CH:8]=1
Reactant: BrCc1ccc(Br)c2ccccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Br)c2ccccc12
Temperature: 95 °C
Reaction time: 3 h

Procedure:
Sodium bicarbonate (1.4 g) is added to a solution of crude 1-bromo-4-bromomethyl-naphthalene (2.5 g) in DMSO (25 ml). The reaction is stirred for 3 h at 95° C. and cooled down to room temperature. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 4-bromo-naphthalene-1-carbaldehyde as colorless crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][C@H:30]1[C@@H:34]([CH3:35])[CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:29][C@H:30]1[C@@H:34]([CH3:35])[CH2:33][N:32]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:31]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2C[C@@H](N)[C@@H](C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (150 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 5 hours. After cooling, the resulting precipitate was collected by filtration. This precipitate was added to the mixture of concentrated hydrochloric acid-methanol (1:1, 6 ml) and stirred for 1.5 hours at room temperature. The reaction mixture was neutralized by concentrated aqueous ammonia and allowed to stand in the refrigerator. The resulting crystals were collected by filtration and washed with cold water to give the title compound (90 mg) as colorless prisms, mp 185°-188° C. (decompd.).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH:14][C:15](OC)=[O:16])[C:11]([F:13])=[CH:12][C:7]=2[S:6][C:5]1=[O:19])([CH3:3])[CH3:2].[H-].[Na+].[NH2:22]/[C:23](/[C:30]([F:33])([F:32])[F:31])=[CH:24]\[C:25]([O:27]CC)=O.O>CN(C)C=O>[CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([N:14]3[C:25](=[O:27])[CH:24]=[C:23]([C:30]([F:31])([F:32])[F:33])[NH:22][C:15]3=[O:16])[C:11]([F:13])=[CH:12][C:7]=2[S:6][C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: COC(=O)Nc1cc2c(cc1F)sc(=O)n2C(C)C
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Yield: 41.8 %

Procedure:
To a solution of 3-isopropyl-6-fluoro-5-methoxycarbonylamino -2(3H)-benzothiazolone (2.8 g) in N,N-dimethylformamide (10 g), sodium hydride (0.4 g) and ethyl 3-amino-4,4,4-trifluorocrotonate (0.9 g) were added, and the resultant mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography to give 1-[3-isopropyl-6-fluoro-2(3H) -benzothiazolon -5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine -2,6-dione (0.8 g).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1ccc(C(C)(C)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(C)(C)OC)cc1
Yield: 153.1 %

Procedure:
To a solution of methyl 4-(1-hydroxy-1-methylethyl)benzoate (340 mg, 1.75 mmol) in methanol (20 mL) was added p-toluenesulfonic acid (70 mg, 0.37 mmol). The mixture was refluxed for 48 h, concentrated in vacuo, and the residue chromatographed (silica gel, 10% ethyl acetate/90%hexanes to 30% ethyl acetate/70% hexanes) to give 118 mg (32%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([O:13]C(C2CC2)=O)[C:9]2[C:4](=[CH:5][C:6]([Cl:20])=[C:7]([F:19])[CH:8]=2)[N:3]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]2[C:4](=[CH:5][C:6]([Cl:20])=[C:7]([F:19])[CH:8]=2)[N:3]=1
Reactant: Cc1nc2cc(Cl)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2cc(Cl)c(F)cc2c(O)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
2,3-Dimethyl-4-cyclopropanecarbonyloxy-6-fluoro-7-chloroquinoline (590 mg) prepared as described in Example 9 was dissolved in 5 ml of methanol, and 5 ml of a 10% aqueous sodium hydroxide solution was added to this solution. The mixture was stirred at 50° C. for 3 hr. The reaction mixture was allowed to stand for cooling, was then poured into 50 ml of water, and was neutralized with 1 N hydrochloric acid, and the precipitate was then collected by filtration to give 400 mg of 2,3-dimethyl-4-hydroxy-6-fluoro-7-chloroquinoline. In 3 ml of tetrahydrofuran was suspended 26.4 mg of 60% sodium hydride. Separately, 100 mg of 2,3-dimethyl-4-hydroxy-6-fluoro-7-chloroquinoline (starting material 1) prepared above was suspended in 2 ml of tetrahydrofuran, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 0.1 ml of methyl chloroformate (starting material 2) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 48 mg of 2,3-dimethyl-4-methoxycarbonyloxy-6-fluoro-7-chloroquinoline (compound 28). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9](=[NH:14])[O:10][CH2:11][CH2:12][CH3:13])[CH:6]=[N:7][CH:8]=1)[CH3:2].[N:15]#[C:16]N>C(#N)C>[C:16]([N:14]=[C:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[O:10][CH2:11][CH2:12][CH3:13])#[N:15]
Reactant: N#CN
Reactant: CCCOC(=N)c1cncc(CC)c1
Solvent: CC#N
Product: CCCOC(=NC#N)c1cncc(CC)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 44 %

Procedure:
The propyl 5-ethyl-3-pyridinecarboximidate were then dissolved in acetonitrile (5 ml), and an aqueous solution (30 ml) of cyanamide (1.13 g, 26.9 mmol), Na2HPO4 (1.29 g, 9.1 mmol) and NaH2PO4 ·2H2O (8.45 g, 54.2 mmol) was added to the solution. The mixture was stirred at room temperature for 19 hours. After reaction, the mixture was extracted with chloroform (50 ml×2). The chloroform layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to silica gel column chromatography (Wako Gel C-200, 50 g; eluted with hexane:ethyl acetate=5:1) to give 1.51 g (7.0 mmol) of propyl N-cyano-5-ethyl-3-pyridinecarboximidate (yield, 44%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[OH-].[K+]>O.C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:13][CH:12]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 11.72 g (0.1 mole) of indole, 17.71 g (0.11 mole) of 4-chlorobenzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O, 2.5 g (2.5 mmoles) of PEG-1000 and 100 mL of toluene was stirred and heated at 55°-65° for 22 hours. After cooling to room temperature, 50 mL of H2O was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined organic phases were washed with 2N HCl (2×50 mL), H2O (2×50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 29 g of orange-brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 1:1 CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 12-19 were combined giving 23.11 g of crude product as a pink oil The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed as before. Fractions 20-30 were combined giving 20.33 g (84%) of 1-(4-chlorobenzyl)indole as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and hexanoic acid to yield (3aR,4S,7aR)-4-hexanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.53 min; UPLC Method I
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH2:7][C:6]1=O)(OC)=[O:2].C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].[O-]CC.[Na+]>CCO>[N:16]1[C:6]2[CH2:7][S:8][CH2:9][C:5]=2[C:1](=[O:2])[NH:17][CH:15]=1
Reactant: N=CN
Reactant: COC(=O)C1CSCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1CSC2
Temperature: 90 °C

Procedure:
Commercially available 4-carbomethoxytetrahydro-3-thiophenone (5 g, 31.2 mmol) is dissolved in EtOH (284 mL). Formamidine acetate (22 g, 211 mmol) is then added followed by sodium ethoxide (45 mL, 121 mmol, 21% w/w) and the mixture is heated at 90° C. for 14 hours. Reaction is cooled to room temperature and concentrated to a residue which is absorbed onto silica and separated via FCC (0-10% Methanol:CH2Cl2) to give the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:18]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:10]([O:12][CH3:18])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: C=C(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enoic acid (550 mg, 2.399 mmol) in tetrahydrofuran (11 mL) at 0° C., was added TMS-diazomethane (4.80 mL, 4.80 mmol) dropwise over 5 min. The reaction mixture was then stirred at 0° C. for 15 min. After gradually warmed to room temperature, the mixture was stirred for 16 h. The reaction mixture was evaporated to dryness to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enoate (580 mg, 2.386 mmol, 99% crude yield) as a dark yellow oil which was taken to the next step without purification. 1H NMR (400 MHz, CDCl3): δ ppm 4.91 (s, 1H), 4.85 (s, 1H), 4.75 (s, 1H), 4.38 (q, J=16.00 Hz, 1H), 3.73 (s, 3H), 2.33-2.53 (m, 2H), 1.71 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:38])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([C:34]([F:37])([F:36])[F:35])[CH:27]=1)[C:11]([NH:13][NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:38])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([C:34]([F:36])([F:35])[F:37])[CH:27]=1)[C:11]1[O:24][C:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:13]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyl-oxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (944 mg, 1.73 mmol) in CH2Cl2 (30 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (907 mg, 3.46 mmol), iodine (878 mg, 3.46 mmol) and Et3N (0.96 mL, 6.92 mmol). The reaction mixture was warmed to room temperature, stirred for 30 min and quenched with sat. aq. sodium thiosulfate (200 mL). The solution was extracted with CH2Cl2 (200 mL). The organic extract was washed with sat. aq. sodium thiosulfate (150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-30% EtOAc in hexanes) to provide the title compound as a light yellow oil (790 mg, 87%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.19 (dd, J=2.5, 8.8 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 5.19 (dd, J=7.2, 9.0 Hz, 1H), 4.55 (dq, J=6.1, 7.2 Hz, 1H), 1.47 (d, J=6.1 Hz, 3H), 0.74 (s, 9H), 0.09 (s, 3H), −0.07 (s, 3H).