Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:27]([O:29][CH3:30])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].Cl.[CH3:32][C@@H:33]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C@H:34]([NH:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C:35](ON1C(=O)CCC1=O)=[O:36].C(N(CC)CC)C>CN(C)C=O>[NH:45]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C@H:34]([C:35]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:27]([O:29][CH3:30])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:36])[C@@H:33]([CH3:32])[O:56][C:57]([CH3:59])([CH3:60])[CH3:58]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(N)=O
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
9.3 g of H-Gln-Asn-Phe-OCH3 hydrochloride and 11.9 g of Z-Thr(tBu)-OSU are dissolved in 150 ml of dimethylformamide to form a clear solution. 2.85 ml of triethylamine in 10 ml of dimethylformamide are added and the batch is stirred for 21 hours at room temperature. The batch is then concentrated under reduced pressure and taken up in much ethylacetate+chloroform (9:1), and extracted with 2 × 200 ml of 5% citric acid and 1 × 100 ml of water. The insoluble precipitate is then filtered off, the filtrate extracted with 2 × 200 ml of 2N-sodium carbonate solution and 3 × 100 ml of water, dried over sodium sulfate, and evaporated. The residue is recrystallized, together with the filter residue mentioned above, from dimethylformamide+ether (1:1). Melting point, 237°- 241°C (decomp.); [α]20D = + 8° (c = 1% in dimethylformamide).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1>>[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:38][CH:37]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: COc1ccc(C=CCc2ccccc2)cc1
Yield: 85.9 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.16 g, 7.06 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.4 mL, 7.06 mmol, 1.0 equiv.) and 4-methoxybenzaldehyde (1.44 g, 10.6 mmol, 1.5 equiv.), 1.36 g (86%) of the title compound as a light yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 99:1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>[OH-].[Na+]>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3.2 g (12.2 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 6.7 ml (60.3 mmol) 1-methylpiperazine was stirred at 100° C. for 2.5 h. The reaction mixture was cooled to r.t., treated with 10 ml 0.1N NaOH and extracted. The aqueous phase was separated and extracted twice with THF and the organic phases were washed twice with brine. The combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2: MeOH=99:1) to yield 3.3 g (83.7%) product as beige foam.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:18][C:19]([O:21]C(C)(C)C)=O)=[C:5]([NH:10][C:11](OC(C)(C)C)=[O:12])[S:6][C:7]=1[S:8][CH3:9])#[N:2].C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[C:1]([C:3]1[C:4]2[NH:18][C:19](=[O:21])[C:11](=[O:12])[NH:10][C:5]=2[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: CSc1sc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)c1C#N
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Product: CSc1sc2[nH]c(=O)c(=O)[nH]c2c1C#N
Yield: 72.3 %

Procedure:
Reaction of di-t-butyl 4-cyano-5-(methylthio)thiophene-2,3-dicarbamate (1.0 g, 2.6 mmol) and diethyl oxalate (12 ml, 88 mmol) in acetic acid (15 ml) was performed following the procedure outlined in example 1 (Method D). Yield 0.45 g (72%) of the title compound. M.p. >225° C. MS (70 eV): m/z 239 (694, M), 224 (8), 211 (4), 196 (100), 162 (3), 136 (10), 109 (50), 94 (20), 82 (27), 70 (27).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][C:13]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[N:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I:25]I.[OH-].[K+].S(=O)(O)[O-].[Na+]>CN(C=O)C>[I:25][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[O:14][C:13]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[N:12][N:11]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4[nH]ccc4c3)o2)cc1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(I)c4c3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution of 5-(1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (28.0 g, 87.5 mmol) in DMF (270 mL) was added I2 (24.42 g, 96.25 mmol) followed by KOH (12.27 g, 218.75 mmol). The mixture was stirred at RT for 1 h, then poured into ice with 5% sodium bisulfite. The aqueous layer was extracted with DCM and the combined organic layers were washed with water, dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 2-3% MeOH in DCM) to give 5-(3-iodo-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (23.2 g, 52.0 mmol, 59.44%). MS (ESI, pos. ion) m/z: 447.0 (M+1); 1H-NMR (DMSO-d6) δ 11.87 (s, 1H), 8.22 (t, 1H), 7.69-7.65 (m, 2H), 7.44 (d, J=9 Hz, 2H), 7.34 (s, 1H), 6.92 (d, J=9 Hz, 2H), 5.76 (s, 1H), 4.38 (d, 2H), 3.73 (s, 3H).
Reaction SMILES: CI.[CH:3]([C:5]1[S:13][C:12]2[C:11](=[O:14])[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][NH:8][C:7]=2[CH:6]=1)=[O:4].[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:3]([C:5]1[S:13][C:12]2[C:11](=[O:14])[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]([CH3:20])[C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cc(C=O)sc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C=O)sc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Methyl iodide (1.2 mL, 19.3 mmol) was added to a mixture of ethyl 2-formyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (3.0 g, 11.9 mmol), potassium carbonate (2.5 g, 18.1 mmol) in DMF (30 mL) at 0° C. After the addition of methyl iodide, the mixture was stirred at room temperature for 1 hr. The mixture was diluted with water (40 mL), stirred at room temperature for 15 minutes, and then filtered. The collected solid was washed with water and dried in vacuo, leaving a solid (1.3 g, 41%). The aqueous phase was extracted with methylene chloride (2×50 mL). The organic layers were combined, washed with water (50 mL) and brine (50 mL), and dried over magnesium sulfate. Removal of the solvent gave a second crop of product (0.34 g).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1>[C:21]([O:20][C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([S:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][C:6]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 26 h
Yield: 96.9 %

Procedure:
To a solution of 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid methyl ester (3.25 g, 6.0 mmol) in THF (32.5 mL) was added aqueous LiOH [prepared from LiOH monohydrate (1.02 g, 24 mmol) and H2O (10 mL)] dropwise at room temperature. The mixture was stirred at room temperature for 26 hours, and then evaporated. The aqueous mixture was diluted with 100 mL of H2O, washed with AcOEt (50 mL), and then carefully acidified to pH 4-5 with 10% HCl at 5° C. under stirring. The resulting solid was collected by filtration, washed with H2O, and dried at 60° C. overnight under reduced pressure to give the title compound as pale yellow crystal (3.09 g, 98%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 1.48 (s, 9H), 3.22 (septet, J=7.0 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.5, 1.8 Hz, 1H), 7.89 (d,J=1.8 Hz, 1H), 8.58 (s, 1H), 8.84 (d,J=8.5 Hz, 1H), 9.61 (s, 1H), 10.16 (s, 1H), 12.98 (br-s, 1H)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][P:17]([O-:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[P:17]([Cl:1])([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:26]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Product: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Temperature: 40 °C

Procedure:
Dibenzyl chlorophosphate was prepared by adding N-chlorosuccinimide (2.2 g) to a solution of dibenzylphosphite (4.4 g) in dry toluene (70 ml) at room temperature with stirring. The resulting solid was filtered off and the filtrate concentrated to ca. 10 ml. and added to a solution of 4′-methoxyphenyl 2,3,4-tri-O-acetylmannoside (3.86 g) in pyridine (30 ml) at 0° C. and the mixture allowed to stand over night. The mixture was warmed to 40° C. for 1 h and the solvent evaporated under reduced pressure. The residue was chromatographed on a silica gel 60 chromatography column (2.5×55 cm). The column was first eluted with CHCl3 and this fraction discarded. Subsequent elution with 20% acetone/CHCl3 gave 4′-methoxyphenyl 2,3,4-tri-O-acetylmannoside dibenzylphosphate (2.9 g). (1Hnmr, CDCl3: 2.06, s, 3H; 2.09, s, 3H; 2.13, s, 3H; 3.53, t, 1H; 3.6, s, 3H; 3.88, t, 1H; 3.97, m, 1H; 4.8, d, 1H; 5.12, m, 1H; 5.3, m, 2H; 6.81, d, 2H; 6.97, d, 2H; 7.3, m, 10H.) Starting material (1.46 g) was recovered from the column by elution with 10% EtOH/CHCl3.
Reaction SMILES: [O:1]1[CH2:3][CH2:2]1.[F:4][C:5]([F:16])([F:15])[C:6]1[CH:7]=[C:8]([CH2:12][CH2:13]Br)[CH:9]=[CH:10][CH:11]=1.[Mg].S(=O)(=O)(O)O>C(OCC)C>[F:4][C:5]([F:15])([F:16])[C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:3][CH2:2][OH:1])[CH:9]=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1cccc(CCBr)c1
Reactant: C1CO1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: OCCCCc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 75.3 %

Procedure:
5.5 g of oxirane in 20 ml of diethyl ether are added dropwise, at about 0° C., to a Grignard solution prepared from 28.5 g of 2-(3-trifluoromethylphenyl)-ethyl bromide and 2.9 g of magnesium in 200 ml of diethyl ether. After stirring the mixture for 1 hour and adding 100 ml of 10% strength sulphuric acid, it is extracted with diethyl ether and the residue is distilled. About 18.5 g of 4-(3-trifluoromethylphenyl)-butan-1-ol are obtained and are dissolved in 70 ml of toluene, 16 g of p-toluenesulphonyl chloride and 25 ml of pyridine are added and the mixture is stirred. After 2 days, the precipitate is filtered off and worked up by extraction. After concentrating the organic phase, 25.7 g of the tosylate of the substituted butanol remain and are taken up in 250 ml of ethanol and the mixture is added dropwise to a solution prepared from 11.5 g of diethyl malonate and 1.6 g of sodium in 220 ml of absolute ethanol. The mixture is heated under reflux for 24 hours and then concentrated and the residue is partitioned between water and methylene chloride. After several extractions, the organic phases collected are dried and concentrated. The residue is purified by chromatography over a 500 g silica gel column and gives 24.9 g of 4-(3-trifluoromethylphenyl)-butylmalonic acid diethyl ester, which is used in (d).
Reaction SMILES: [CH:1]([Si:4]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH3:3])[CH3:2].C([Li])CCC.[CH2:29]=[O:30]>CCOCC.CCCCCC>[CH:21]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:18]([CH3:20])[CH3:19])[C:5]1([CH2:29][OH:30])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:23])[CH3:22]
Reactant: C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)C1c2ccccc2-c2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)C1(CO)c2ccccc2-c2ccccc21
Yield: 57.7 %

Procedure:
To a solution of 1.0 g of 9-triisopropylsilylfluorene in 10 mL of dry ether and 30 mL of dry hexane was added dropwise 2.5 mL of 1.5M n-butyllithium. The mixture was refluxed for 15 hours and cooled in an ice bath. Gaseous formaldehyde, generated by heating dried paraformaldehyde at 170° C., was passed through a 8-mm tube into the reaction mixture with the aid of a slow stream of nitrogen until the deep red color had faded to pale yellow (ca. 5 min). The mixture was quenched immediately with 40 mL of half sat'd NH4Cl and washed with brine (10 mL) and water (20 mL). The pooled aqueous layer was extracted with ether (2×20 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated in vacuo to give an oil which was chromatographed on silica gel (230-400 mesh, 2×40-cm packed column) with an eluant consisting of Skelly B--ether (3:1), to afford 0.63 g (57.7%) of the alcohol as a white solid. Recrystallization from Skelly F gave 0.38 g (34.8%) of the pure 9-triisopropylsilyl-9-fluorenemethanol as colorless crystals m.p. 106°-107.5° C.; IR (KBr): 3505, 3405 cm-1 (OH); 1H NMR (CDCl3): δ 0.83 (d, 18H, Si-C-Me2), 1.20-1.42 (hept, 3H, C--S--CH), 4.71 (s, 2H, CH2), 7.20-7.95 (m, 8H, aryl).
Reaction SMILES: [Br:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[Cl:13].C(ON=O)(C)(C)C.NC1C(Cl)=CC(C(OC)=O)=CC=1Cl.N>CC#N>[Br:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)c1cc(Cl)c(Br)c(Cl)c1
Agent: CC(C)(C)ON=O
Agent: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: N
Solvent: CC#N
Product: O=Cc1cc(Cl)c(Br)c(Cl)c1
Reaction time: 0.17 h

Procedure:
Methyl 4-bromo-3,5-dichlorobenzoate: CuBr2 (7.5 g, 34.08 mmol) in MeCN (50 mL) was stirred at 80° C. for 30 min. To this solution tert-butylnitrite (6.5 mL, 54.55 mmol) was added dropwise at the same temperature and the mixture was stirred for another 10 min. Methyl 4-amino-3,5-dichlorobenzoate in MeCN (30 mL) was added dropwise to the reaction mixture which was then stirred at 80° C. for 30 min. The reaction mixture was brought to ambient temperature. Aqueous ammonia solution (20 mL) was added and extracted with petroleum ether. The organic layer was washed with brine followed by water. The organic solution was dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (7.5 g, 77%): 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 2H), 3.94 (s, 3H); ESIMS m/z 282 ([M]+); IR (thin film) 1733, 762, 514 cm−1.
Reaction SMILES: C(OC([NH:11][C:12]1([CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1)=O)C1C=CC=CC=1.Cl>[C].[Pd].O1CCOCC1>[NH2:11][C:12]1([CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)CCC1(NC(=O)OCc2ccccc2)CCCC1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCC1(N)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a mixture of tert-butyl 3-(1-{[(benzyloxy)carbonyl]amino}cyclopentyl)propanoate (0.58 g), dioxane (17 ml), and palladium-carbon (0.12 g) was added 1 M hydrochloric acid (1.7 ml) under ice-cooling, followed by stirring at room temperature for 1 hour under a hydrogen atmosphere. The insolubles in the reaction mixture were separated by filtration through Celite and the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether to obtain tert-butyl 3-(1-aminocyclopentyl)propanoate (0.11 g).
Reaction SMILES: Cl.[CH:2]1([O:6][C:7]2[C:16]([C:17]3[N:18](COCC[Si](C)(C)C)[C:19]([CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:20][N:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:48])[N:12]3[C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])[CH2:5][CH2:4][CH2:3]1>ClCCl.O1CCCC1>[CH:2]1([O:6][C:7]2[C:16]([C:17]3[NH:18][C:19]([CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:20][N:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:48])[N:12]3[C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])[CH2:5][CH2:4][CH2:3]1
Reactant: C[C@H]1CCc2c(ccc(-c3ncc(C4CCN(C(=O)OC(C)(C)C)CC4)n3COCC[Si](C)(C)C)c2OC2CCC2)N1C(=O)C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H]1CCc2c(ccc(-c3ncc(C4CCNCC4)[nH]3)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Hydrogen chloride (gas) was bubbled into a solution of tert-butyl 4-(2-((S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)piperidine-1-carboxylate (0.094 g, 0.14 mmol) in dichloromethane (4 mL) and tetrahydrofuran (1 mL), and the resulting solution stirred for 1.5 h at room temperature. The reaction mixture was concentrated under vacuum, and the residue was dissolved in methanol (5 mL). The pH of the solution was adjusted to 8 with saturated aqueous sodium carbonate solution, and the resulting solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-(5-cyclobutoxy-2-methyl-6-(5-(piperidin-4-yl)-1H-imidazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.0018 g, 3%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.71-0.78 (m, 1H), 0.82-0.99 (m, 2H), 1.13-1.18 (m, 4H), 1.21-1.41 (m, 5H), 1.55-1.65 (m, 1H), 1.75-2.21 (m, 9H), 2.32-2.48 (m, 2H), 2.89-3.11 (m, 4H), 3.31-3.34 (m, 1H), 4.16-4.21 (m, 1H), 4.70-4.81 (m, 1H), 6.97 (s, 1H), 7.26 (d, J=8.40 Hz, 1H), 7.65 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z 435 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>C(O)C.O>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCC2(C)c3cc(C(=O)C(=O)O)ccc3N(C)C12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (0.25 g) in 95% ethanol (1.0 ml) was added a solution of 0.14 g of KOH in water (1.0 ml). The mixture was stirred at 0° C. for 30 minutes and then refluxed for 4 hours. The solution was cooled, the ethanol was removed under reduced pressure and the remaining aqueous residue was diluted with water (3.0 ml), cooled to 0° C. and neutralized with a 1.0N aqueous HCl solution. The water was then removed and the residue was taken up in dichloromethane and washed with water to remove any unreacted starting material. The aqueous washes were then concentrated to afford 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][CH:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1.[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=O.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][C:13]([CH:11]=[N:1][CH:2]2[CH2:10][CH:9]3[N:5]([CH2:6][CH2:7][CH2:8]3)[CH2:4][CH2:3]2)=[CH:14][CH:15]=1
Reactant: NC1CCN2CCCC2C1
Reactant: O=Cc1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: C(=NC1CCN2CCCC2C1)c1ccncc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
(±)-7-Amino-1,2,3,5,6,7,8,8a-octahydroindolizine (4.91 g (35.0 mmol), prepared as described in 1)) was dissolved in toluene (95 ml). To the solution were added 4-formylpyridine (3.34 ml, 35.0 mmol) and anhydrous magnesium sulfate (3.75 g, 31.2 mmol), and the resulting mixture was stirred at 70° C. for 3 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure, to give the title compound (8.08 g) as a pale yellow oil (yield quantitative).
Reaction SMILES: C(O)C.Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Cl:23])=[CH:13][C:12]=1[F:24].[S-:25][C:26]#[N:27].[K+].CCCCCC>C(OCC)(=O)C>[S:25]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Cl:23])=[CH:13][C:12]=1[F:24])[C:26]#[N:27]
Reactant: Fc1cc(Cl)c(SCC(F)(F)F)cc1OCCCCCBr
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#CSCCCCCOc1cc(SCC(F)(F)F)c(Cl)cc1F
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To 60 ml of ethanol were added 4.2 g (10.3 mmol) of 5-bromopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether and 5.0 g (51.5 mmol) of potassium thiocyanate. The mixture was refluxed for 4 hours under heating. The mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. Then extraction was conducted by adding water and ethyl acetate. The organic phase obtained was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 3.9 g (yield: 98%) of an intended product.