Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:29](O)[CH2:30][OH:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:17])[O:31][CH2:30][CH2:29][O:18]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)c1cc2cc(CC(C)=O)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 1-(4-nitro-benzyl)-5-(2-oxo-propyl)-1H-indole-2-carboxylic acid ethyl ester (1.91 g, 5.03 mmol), ethylene glycol (406 mg, 0.365 ml, 6.54 mmol), and p-toluenesulfonic acid monohydrate (110 mg, 0.58 mmol) in toluene (50 ml) was heated to about 150° C. under a Dean-Stark trap under nitrogen for two hours. The solution was cooled, diluted with ethyl acetate, washed with dilute sodium bicarbonate and brine, dried over sodium sulfate, filtered, and dried under reduced pressure to give the title compound in crude form (2.4 g), which was reacted without further purification.
Reaction SMILES: CC(=[O:7])C(C)(C)C.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>[Cl-].C[N+](CCCC)(CCCC)CCCC.O>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([OH:7])=[O:14])=[CH:11][CH:10]=1.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: CC(=O)C(C)(C)C
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: O=Cc1ccc(Cl)cc1
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In a 100 gallon stainless steel reactor was charged pinacolone (154.5 kg, 94% pure, 1453 moles), methyltributylammonium chloride (1.09 kg, 75% aqueous solution, 3.47 moles) and water (2.23 kg) and the reactor contents were heated to 40° C. Melted p-chlorobenzaldehyde (109.1 kg, 97.5% pure, 757.1 moles) addition was then started at a rate of 1.82 kg/min (the complete addition therefore took 60 minutes). Ten minutes after the start of the addition of the aldehyde, NaOH (12.36 kg, 50 wt % aqueous solution, 154.5 moles) addition was started at a rate of 0.41 kg/min (the complete addition therefore took 30 minutes). After the addition of the aldehyde was complete, the reactor temperature was increased to 60° C. and heated at that temperature for 3 hours. At that point analysis of the reaction mixture by LC (after negecting the pinacolone and a small amount of p-chlorobenzoic acid formed by air oxidation of the p-chlorobenzaldehyde) indicated that the organic phase contained 96.3% Phenyl aldol and 0.3% unreacted p-chlorobenzaldehyde. The reaction mixture was neutralized with 36% aqueous hydrochloric acid till pH 8.0 and the phases were allowed to settle. The aqueous (lower) phase was discarded and the organic phase was subjected to distillation under reduced pressure to recover all the excess pinacolone. The residue (166.1 kg) was the product Phenyl aldol and was found to be 96.8% pure which translates to a yield of 95.4% based on p-chlorobenzaldehyde.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C)C=O.ClCCl.[CH3:15][NH:16][C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18]>O>[CH:2]([C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]=1[C:17]([NH:16][CH3:15])=[O:18])=[O:3]
Reactant: CNC(=O)c1cc2ccccc2[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1[nH]c2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Oxalyl chloride (2.6 mL, 30 mmol) was added drop-wise to an ice-cooled solution of dimethylformamide (34 mL) and dichloromethane (90 mL), then N-methyl-1H-indole-2-carboxamide (3.51 g, 20 mmol) was added and the mixture stirred at rt for 1 h. Water was added and the resulting precipitate filtered, washed with water and diethyl ether. The product was dried to afford the title compound (2.03 g, 50%). 1H NMR (300 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.2 (s, 1H), 9.51 (s, 1H), 8.26 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.47-7.10 (m, 2H), 2.73 (d, J=4.6 Hz, 3H).
Reaction SMILES: C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.CC(C)([O-])C.[Na+].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]2[S:37][C:38]([CH2:40][CH2:41][CH3:42])=[N:39][C:32]=12.[NH2:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=1[S:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:50][C:48]1[CH:47]=[CH:46][C:45]([S:51][C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=2)=[C:44]([NH:43][C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[S:37][C:38]([CH2:40][CH2:41][CH3:42])=[N:39][C:32]=23)[CH:49]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CCCc1nc2c(Cl)ccnc2s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: Cc1ccccc1
Product: CCCc1nc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2s1
Temperature: 25 °C
Yield: 8.3 %

Procedure:
A dry nitrogen-purged flask was charged with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (40.4 mg, 0.118 mmol), tris(dibenzylideneacetone)-dipalladium (27 mg, 0.0295 mmol), and sodium tert-butoxide (87.7 mg, 0.885 mmol). A solution of the product of Example 5G (125.5 mg, 0.590 mmol) in anhydrous toluene (5 mL) was added via syringe, followed by the product from Example 6c (136 mg, 0.590 mmol). The reaction was heated at reflux in a preheated 110° oil bath for 14 hours, cooled to room temperature, treated with additional 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (40.4 mg) and tris(dibenzylideneacetone)dipalladium (27 mg), and heated at reflux for an additional 7 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. Purification by silica gel flash chromatography with a gradient of 15% to 30% ethyl acetate/methylene chloride gave impure material. Purification by silica gel flash chromatography with a gradient of 1% to 2% methanol/methylene chloride afforded the desired title compound as a light yellow solid (20 mg, 0.049 mmol, 8%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.03 (t, J=7.35 Hz, 3H) 1.76-1.94 (m, 2H) 2.31 (s, 3H) 3.10 (t, J=7.35 Hz, 2H) 5.76 (s, 1H) 6.67-6.73 (m, 2H) 6.96-7.04 (m, 1H) 7.08-7.14 (m, 1H) 7.20 (d, J=8.46 Hz, 2H) 7.29 (s, 1H) 8.14 (d, J=5.52 Hz, 1H) 8.55 (s, 1H) 9.73 (s, 1H); MS (DCI/NH3) m/z 408 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:45][O:46][CH2:47][C:48]([O:50]C(C)(C)C)=[O:49])[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:45][O:46][CH2:47][C:48]([OH:50])=[O:49])[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nsc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
Trifluoroacetic acid (13.6 ml) was added to a solution of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.4 g) in methylene chloride (7.0 ml) and anisole (3.4 ml) under ice-cooling, followed by stirring at ambient temperature for 1.5 hours. The reaction mixture was added dropwise to diisopropyl ether (150 ml), and the precipitates were collected by filtration and then added to a mixture of water and ethyl acetate. After adjusting to pH 7.5 with a saturated aqueous sodium bicarbonate, the aqueous layer was separated and then adjusted to pH 2.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with cold water and then dried to obtain 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.39 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[CH:33]=O)([CH3:27])[C:23]([F:26])([F:25])[F:24].C(OC(N1CCC[C@H](NCC2C=C(C(F)(F)C)C=CC=2OC(F)(F)F)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:32]2[CH:35]=[C:28]([C:22]([CH3:27])([CH3:21])[C:23]([F:26])([F:24])[F:25])[CH:29]=[CH:30][C:31]=2[O:36][CH3:37])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(C)(C)C(F)(F)F)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 12 and Compound 71 in the same manner of Compound 26.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].I[CH:10]([CH3:12])[CH3:11].[OH-].[K+]>C(O)C.O>[CH:10]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)I
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(O)cc1
Yield: 45.8 %

Procedure:
To a solution of hydroquinone (55.7 g, 0.5 mol) and 2-iodopropane (57.5 g, 0.33 mol) in ethanol was added a solution of potassium hydroxide (78.5 g, 0.5 mol) in water (100 mL). The dark brown solution was then refluxed for 16 hours. Ethanol was removed and the aqueous phase was acidified with 2N HCl and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give over 70 g of crude material, which was triturated with dichloromethane and filtered. The filtrate was concentrated and purified on silica gel (5˜35% ethyl acetate/hexane) to give 23.0 g of product as a brown oil (46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.30 (d, J=5.88 Hz, 6H) 4.30-4.50 (m, 1H) 4.78 (s, 1H) 6.66-6.86 (m, 4H). MS (ESI): m/z 151 (M−H). 1H NMR (300 MHz, CDCl3) δ ppm 8.31 (d, J=1.84 Hz, 1H) 7.99 (dd, J=8.46, 1.84 Hz, 1H) 7.77 (d, J=9.19 Hz, 1H) 7.20-7.34 (m, 2H) 6.89-7.01 (m, 2H) 4.48-4.62 (m, 1H) 2.65 (s, 3H) 1.37 (d, J=5.88 Hz, 6H). MS m/z (DCI) 405.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)=[N:8]1)=[O:4].[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(Cl)Cl.N#N.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.CCO>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1)=[O:4]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)C(=O)OCn1cnc(-c2cccc(Br)c2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cnc(-c2cccc(-c3ccc(C=O)cc3)c2)n1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A vial equipped with magnetic spin vane was charged with [[3-(3-Bromophenyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate (0.203 g; 0.60 mmol; Ex IV-24), 4-formylphenyl boronic acid (0.099 g; 0.66 mmol), and PdCl2(dppf).CH2Cl2 (0.012 g; 0.015 mmol), was sealed with a septum and evacuated/backfilled with N2 (×3). PhMe/EtOH (4:1, 3 mL) and 2M Na2CO3 (0.72 mL; 1.44 mmol) were added through the septum via syringe and the mixture was stirred at 80° C. for 2.5 h. Upon cooling, the mixture was partitioned between EtOAc/water and the layers were separated. The aqueous layer was extracted with EtOAc (×2), combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum/film. LC/MS (method A) 2.60 min; m/z 364 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 5-methoxy-2-methylaniline (20 mg, 0.144 mmol) similar to Example 92 and isolated as a yellow solid (18 mg, 52%). 1H NMR (CDCl3): 8.85-8.82 (m, 1H), 8.59-8.56 (m, 1H), 7.90-7.84 (m, 1H), 7.45-7.40 (m, 2H), 7.24 (d, J=8.1 Hz, 1H), 6.87 (s, 1H), 6.83 (dd, J=2.6, 8.3 Hz, 1H), 6.69 (s, 1H), 3.81 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: NC1N=C2C(N=CN2)=C(OCC2C=CC(C[NH:18][C:19](=[O:34])[C:20]3[CH:25]=[CH:24][C:23](CNC(=O)C(F)(F)F)=[CH:22][CH:21]=3)=CC=2)N=1.CO.C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)C(O)=O.[C:52](#[N:54])C>O>[NH2:54][CH2:52][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:19]([NH2:18])=[O:34]
Reactant: Nc1nc(OCc2ccc(CNC(=O)c3ccc(CNC(=O)C(F)(F)F)cc3)cc2)c2nc[nH]c2n1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Weighed into a 50 ml round-bottomed flask were 25 mg (50 μmol) of N-(4-((2-amino-9H-purin-6-yloxy)methyl)benzyl)-4-((2,2,2-trifluoroacetamido)methyl)benzamide. 10 ml of methanol, 2 ml of an aqueous solution saturated with Na2CO3 and 4 ml of water were added. It was left stirring overnight at ambient temperature. The deprotection was monitored by HPLC on a Merck Lichrospher RP °18, 5 μm, 125×4.6 column with a gradient of acetonitrile in water containing 0.2% of trifluoroacetic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([C:21](=[O:30])[N:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=1[F:31])[C:10](=[O:32])[NH:9]2)=[O:4].O.[OH-].[Li+].CO.Cl>O1CCCC1.O>[C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([C:21](=[O:30])[N:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=1[F:31])[C:10](=[O:32])[NH:9]2)([OH:4])=[O:2]
Reactant: COC(=O)c1scc2[nH]c(=O)n(-c3cc(C(=O)N(C)c4ccccc4)ccc3F)c(=O)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(F)c(-n2c(=O)[nH]c3csc(C(=O)O)c3c2=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 5-methoxycarbonyl-3-[2-fluoro-5-(N -methyl-N-phenylcarbamoyl) phenyl]thieno[3,4-d]pyrimidine -2,4(1H,3H)-dione (0.18 g) and lithium hydroxide-monohydrate (0.17 g) in tetrahydrofuran (6 mL)-methanol (3 mL)-water (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: methylene chloride/methanol=8/1) to give the title compound (0.12 g).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:31])[C@@H:8]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([O:36][CH:37]([O:39][NH:40][C:41]([C:43]1[S:47][C:46]2[CH:48]=[C:49]([CH:52]=O)[CH:50]=[CH:51][C:45]=2[CH:44]=1)=[O:42])[CH3:38])[CH:33]([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>ClCCCl.C(O)(=O)C>[CH:1]1([O:6][C:7](=[O:31])[C@@H:8]([N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:52][C:49]3[CH:50]=[CH:51][C:45]4[CH:44]=[C:43]([C:41](=[O:42])[NH:40][O:39][CH:37]([O:36][CH2:32][CH:33]([CH3:34])[CH3:35])[CH3:38])[S:47][C:46]=4[CH:48]=3)[CH:25]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNc3cccc(CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC4CCCC4)c4ccccc4)c3)cc2s1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To (S)-[(3-Amino-benzyl)-tert-butoxycarbonyl-amino]-phenyl-acetic acid cyclopentyl ester (0.317 g, 0.75 mmol) was added 6-Formyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy)-amide (Scheme 7) (0.210 g, 0.65 mmol) in DCE (8 ml). 2 drops of glacial acetic acid were added, and then sodium triacetoxyborohydride (0.170 g, 0.8 mmol). The mixture was stirred for 2 h and then poured into DCM (150 ml). The solution was washed with saturated sodium bicarbonate (50 ml), then dried (MgSO4), concentrated and purified by flash column chromatography to yield the desired product as a pale yellow foam (0.346 g, 73% yield). 1H NMR (300 MHz, CDCl3), δ: 8.35-8.43 (1H, m), 7.56-8.05 (2H, m), 7.01-7.41 (8H, m), 6.90-7.01 (1H, m), 6.42 (1H, dd, J=2.6, 7.9 Hz), 5.25-5.31 (1H, m), 5.12 (1H, q, J=5.2 Hz), 4.40 (1H, d, J 5.4 Hz), 4.00 (1H, dd, J=3.1, 15.8 Hz), 3.60-3.70 (1H, m), 3.35-3.40 (1H, m), 1.33-1.94 (21H, m), 0.98 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz)
Reaction SMILES: [CH3:1][C@:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:6]3=[C:7]([C@:15]([CH3:24])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][CH2:17][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>ClCCl>[CH3:1][C@:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:6]3=[C:7]([C@:15]([CH3:24])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][CH2:17][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([NH:12][C:39](=[O:40])[O:41][CH3:42])[CH:10]=2
Reactant: C[C@@]1(c2ccccc2)CCN2CC[C@@](C)(c3ccccc3)c3cc([N+](=O)[O-])cc1c32
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1cc2c3c(c1)[C@](C)(c1ccccc1)CCN3CC[C@@]2(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (1S,7S)-1,7-dimethyl-9-nitro-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline (7), (115 mg, 0.31 mmol), in dichloromethane (15 mL) was added three equivalent of triethyl amine (0.129 mL, 0.93 mmol), followed by methyl chloroformate (0.031 mL, 0.406 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl (1S,7S)-1,7-dimethyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-ylcarbamate (829), (69 mg 52%). 1H NMR (300 MHz, Acetone-d6) ppm 1.72 (s, 6H) 1.89-2.03 (m, 2H) 2.17-2.30 (m, 2H) 2.73-2.88 (m, 2H) 2.92-3.03 (m, 2H) 3.56 (s, 3H) 7.05-7.33 (m, 12H) 8.02 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[O:12])[NH:8]2)=[CH:4][C:3]=1[C:29]([NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1)=[O:30].[CH:37]1(B(O)O)[CH2:39][CH2:38]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1.Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:15]([F:16])([F:18])[F:17])=[O:12])[N:8]2[CH:37]2[CH2:39][CH2:38]2)=[CH:4][C:3]=1[C:29]([NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1)=[O:30]
Reactant: OB(O)C1CC1
Reactant: N#CC1(NC(=O)c2cc3cc(C(=O)NC(c4cccc(C(F)(F)F)c4)C(F)(F)F)[nH]c3cc2Cl)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)c2cc3cc(C(=O)NC(c4cccc(C(F)(F)F)c4)C(F)(F)F)n(C4CC4)c3cc2Cl)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 6.7 %

Procedure:
6-Chloro-N5-(1-cyanocyclopropyl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide (0.20 g, 0.34 mmol), cyclopropylboronic acid (0.063 g, 0.69 mmol) and sodium carbonate (0.074 g, 0.69 mmol) were initially charged as a suspension in N,N-dimethylformamide (1 ml), and a hot solution of copper(II) acetate (0.064 g, 0.34 mmol) and 2,2′-bipyridyl (0.054 g, 0.34 mmol) was added. The reaction mixture was stirred at 70° C. over 16 h. After cooling, hydrochloric acid (10 ml, 1 mol/l) was added and the organic phase was removed. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue is purified by means of preparative HPLC (Kromasil100, C18 250×20; eluent: acetonitrile in water, gradient: 10-100%) to obtain 0.013 g (6% of theory) of 6-chloro-N5-(1-cyanocyclopropyl)-1-cyclopropyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[CH:11]=[CH:10][CH:9]=[CH:8]3.C1C[O:17][CH2:16]C1.C([Li])CCC.CN(C)C=O>O.C(OCC)C>[S:1]1[C:5]([CH:16]=[O:17])=[CH:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[CH:11]=[CH:10][CH:9]=[CH:8]3
Reactant: c1ccc2cc3sccc3cc2c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=Cc1cc2cc3ccccc3cc2s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Naptho[2,3-b]thiophene (4, 4.00 g, 21.7 mmol., 1.00 equiv.) and THF (360 mL) were added to a 500 mL Schlenk flask. The mixture was cooled to −78° C. and n-butyllithium was added (2.5 M in hexanes, 9.6 mL, 24 mmol., 1.1 equiv.). The mixture was stirred at −78° C. for 15 minutes before removing the dry ice/acetone bath and stirring at ambient for 2 hours. The mixture was cooled back to −78° C. and N,N-dimethylformamide (2.0 mL, 26 mmol., 1.2 equiv.) was added. The mixture was left to warm slowly to room temperature while stirring for 16 hours. The solution was diluted with water (500 mL) and diethyl ether (500 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (250 mL). The combined organic layers were washed with brine (300 mL), dried with MgSO4 and concentrated. The crude material was purified by silica gel column chromatography (solid loading, dichloromethane) to give a yellow solid (3.69 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ ppm 10.18 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.16 (s, 1H), 8.07-7.88 (m, 2H), 7.54 (dddd, J=21.45, 8.05, 6.69, 1.28 Hz, 2H).