Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]#[N:5].Cl[CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>C1C=CC=CC=1.CN(C)C=O>[C:28]([O:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19][CH2:18][N:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]#[N:5])(=[O:30])[CH3:29]
Reactant: CCOC(=O)CCCCCCNC#N
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC(CCCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (57%, in mineral oil) (0.48 g., 0.01 mole) is washed twice with benzene then suspended in benzene (50 ml.) and dimethylformamide (50 ml.). Ethyl 7-cyanamidoheptanoate (1.98 g. 0.01 mole) (Example N, Step 2) is added and the suspension heated on the steam bath for 15 minutes. The reaction mixture is cooled to room temperature, 1-chloro-4-acetoxynonane (2.6 g., 0.01 mole) (Example A, Step 3) is added and then the reaction is heated on the steam bath for 2 hours then stirred 18 hours at room temperature. The reaction is poured into water (300 ml.) and extracted with benzene (3 × 100 ml.). The benzene is washed with brine then dried over sodium sulfate. Removal of the solvent yields an oil which is purified by silica gel chromatography, elution solvent 3% methanol in chloroform, evaporation of the appropriate fraction affords ethyl 7-[N-(4-acetoxynonyl) cyanamido]-heptanoate. The yield is 3.2 g. (83 %).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([N:20]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.O.NN>C(O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH2:20])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N4C(=O)c5ccccc5C4=O)on3)s2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)cc1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
To a solution of Example 48E (1.06 g, 2.4 mmol) in ethanol (15 mL) was added hydrazine monohydrate (0.698 mL, 144 mmol). The reaction was heated at 60° C. for 45 minutes and then filtered. The filtrate was concentrated and purified by flash chromatography on silica gel eluting with 90:8:2 dichloromethane/methanol/concentrated ammonium hydroxide to provide 746 mg of title compound (98%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34 (d, J=6.62 Hz, 3H) 3.80 (s, 3H) 3.99-4.16 (m, 1H) 6.66-6.74 (m, 2H) 6.81-6.85 (m, 1H) 6.99-7.11 (m, 2H) 7.33-7.41 (m, 2H) 7.92 (s, 1H); MS (ESI) m/z 318.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2](=[C:6]([Cl:8])[Cl:7])[C:3](Cl)=[O:4].Cl.[NH2:10][CH2:11][C:12]#[N:13].C(Cl)(Cl)Cl>CCCCCC>[C:11]([CH2:12][NH:13][C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:8])[Cl:7])#[N:10]
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Reactant: N#CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: N#CCNC(=O)C(Cl)=C(Cl)Cl
Yield: 84.6 %

Procedure:
A stirred mixture of 38.8 g (0.2 moles) trichloroacryloyl chloride, 18.5 g. (0.2 moles) aminoacetonitrile hydrochloride and.150 ml chloroform was refluxed for thirty hours, with evolution of gas and dissolution of most of the aminoacetonitrile hydrochloride. The mixture was filtered hot to remove unreacted aminoacetonitrile hydrochloride. The filtrate was stripped to give an oil. The oil was rubbed with hexane and soon solidified to give 36.1 g of the above-identified product as an off-white solid, which liquified at about 56°-59° C. A small portion of product was recrystallized from a benzene-hexane mixture to give a white solid, melting point 58°-60° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]2=[CH:10][C:9]=1[CH2:17][C:18]([O:20]C)=O)=O.O.[NH2:23][NH2:24].C(O)(=O)C>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:8]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:9]=2[CH2:17][C:18](=[O:20])[NH:24][N:23]=1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccco1)OCO2
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc3c(cc2C(c2ccco2)=NN1)OCO3

Procedure:
The title compound was prepared from methyl 2-(2-furoyl)-4,5-methylenedioxyphenylacetate (120 mg, 0.42 mmol), hydrazine hydrate (70 μL, 1.2 mmol), and acetic acid (50 μL) in ethanol (20 mL) as a light yellow solid (37 mg, 33%), mp: 234°-236° C. 1H NMR (CDCl3) 8.50 (s, 1H), 7.60 (m, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 6.71 (m, 1H), 6.54 (m, 1H), 6.06 (s, 2H), 3.44 (s, 2H). Anal. Calcd. for C14H10N2O4 : C, 62.22; H, 3.73; N, 10.37. Found: C, 62.07; H, 3.63; N,10.11.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].[BH4-].[Na+].CCOC(C)=O>CO>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: CCCCN
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCNCc1cncn1Cc1ccc(C#N)c(F)c1
Reaction time: 18 h

Procedure:
To a solution of the product from Step G (114 mg, 0.498 mmol) in 1 mL of methanol was added n-butylamine (0.059 mL, 0.60 mmol). After 18 hours, sodium borohydride was added (25 mg, 0.66 mmol) and the reaction was stirred for one hour. The solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as a yellow oil.
Reaction SMILES: [K:1].CCO.[CH3:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)C.C1(C)C=CC=CC=1>[K:1].[CH3:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH2:16][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1
Reactant: COCCOc1cc(C)c([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1cc(OCCOC)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1.86 g of potassium are initially charged in 120 ml of dry diethyl ether, and 15 ml of EtOH are added slowly. The mixture is cooled to 0° C. 5 g of 2-(2-methoxyethoxy)-4-methyl-5-nitropyridine are dissolved in 15 ml of dry ether and 3 ml of EtOH and added. 27.5 g of diethyl oxalate were dissolved in 100 ml of toluene and, at 0° C., added dropwise over a period of 45 min. The mixture is stirred at room temperature for 24 h. The precipitate is allowed to settle, the mixture is filtered and the precipitate is washed with ether/n-heptane 1:1. The precipitate is dried under high vacuum. This gives ethyl 3-[2-(2-methoxyethoxy)-5-nitropyridin-4-yl]-2-oxopropionate potassium salt as a red solid. (LC-MS protonate form) C13H16N2O7 (312.28), MS (ESI): 313 (M+H+).
Reaction SMILES: [B-](F)(F)(F)F.[N:6]#[O+:7].[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11].N1C=CC=CC=1>C(#N)C>[N:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: N#[O+]
Reactant: O=C(O)[C@@H]1CCCN1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: O=NN1CCC[C@H]1C(=O)O

Procedure:
To a cooled suspension of 28.2 g. of nitrosyl tetrafluoroborate in 300 ml. of dry acetonitrile there is added, with vigorous stirring, over the course of 10 minutes, 18.4 g. of L-proline, followed by a solution of 19 g. of pyridine in 50 ml. of acetonitrile during 15 minutes. The stirring is continued for an hour and the reaction mixture is then concentrated to dryness under reduced pressure. The residue is extracted with 3×200 ml. of ethyl acetate, the ethyl acetate extracts are combined, washed twice with saturated sodium chloride solution that has been made slightly acidic with concentrated hydrochloric acid. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and concentrated to dryness at room temperature under reduced pressure. The product, N-nitroso-L-proline metls at 108°-109° (dec.) after crystallization from a mixture of ether and petroleum ether (30°-60°).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C1C=CC=CC=1.[CH2:16]=[N:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>C(O)(=O)C.O>[S:1]1[CH:5]=[C:4]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: C=NC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)NCc1csc2ccccc12
Reaction time: 48 h
Yield: 59.9 %

Procedure:
In 150 ml of glacial acetic acid was dissolved 33.6 g of benzo[b]thiophene, and 50 ml of a benzene solution of 19.6 g of methylideneisopropylamine was added dropwise to the solution under ice-cooling. After allowing the temperature to rise to room temperature and stirring the mixture for 2 days, the reaction mixture was poured in 500 ml of water and washed thrice with 100 ml of ether. The aqueous layer thus formed was adjusted to pH 10.0 with an aqueous 5N sodium hydroxide solution and extracted 4 times with 100 ml ethyl acetate. The ethyl acetate layer was collected, washed with an aqueous saturated sodium chloride solution, dried by sodium sulfate, dried, then dried under reduced pressure, and the product was subjected to silica gel column chromatography to provide 30.8 g (yield of 60%) of (benzo[b]thiophen-3-ylmethyl)isopropylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:36]([C:30]2[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:29]=2[O:28][CH3:27])(=[O:38])=[O:37])=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c3c(c(OC)cc21)OCCN(C(=O)OC(C)(C)C)C3C
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-methoxy-5-methylbenzenesulfonyl chloride (24.0 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 6-methoxy-8-[(2-methoxy-5-methylphenyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (4.4 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (4.6 mg). MS m/z 417 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]\[C:10]1[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cc(/C=C\C(=O)OC(C)(C)C)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)OC(C)(C)C)cc1CC(=O)O

Procedure:
Methyl (Z)-5-t-butoxycarbonylvinyl-2-methoxyphenylacetate (250 mg, from above) in ethyl acetate (5 mL) in the presence of Pd/C (10% Pd content, 44 mg) was subjected to a Parr apparatus under 50 PSI of hydrogen gas for 1 hour. The mixture was filtered through celite and the filter cake washed with ethyl acetate. The filtrate and washing solution were combined and concentrated to give the desired product. 1H NMR (400 MHz, acetone-d6): δ 7.10 (d, 1H), 7.04 (s, 1H), 6.88 (d, 1H), 3.76 (s, 3H), 3.57 (s, 3H), 3.55 (s, 2H), 2.78 (t, 2H), 2.48 (t, 2H), 1.40 (s, 9H). This compound (100 mg) was then treated with LiOH monohydrate (27 mg) in ethanol/H2O (3:1, 4 mL) for 5 hours. The ethanol was evaporated on vacuo and the residual acidified to pH-1 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Concentration in vacuo afforded acid 10 (80 mg) as a white solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:12])([F:11])[C:8]([NH2:10])=[O:9].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)=[O:21])=[CH:16][CH:15]=1>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:10][C:8](=[O:9])[C:7]([F:12])([F:11])[F:6])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(Cl)c1ccc(Br)cc1
Reactant: NC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NS(=O)c1ccc(Br)cc1)C(F)(F)F
Reaction time: 0.17 h

Procedure:
Thionyl chloride (0.53 mL) is added to an ice-cooled solution of 4-bromobenzenesulfinic acid (400 mg) in dichloromethane (15 mL) under an argon atmosphere. The reaction mixture is stirred for 2 h at 0° C., warmed to room temperature, and stirred for an additional 30 min. The mixture is concentrated and the residue is co-evaporated twice with toluene to give crude 4-bromobenzenesulfinic chloride, which is dissolved in tetrahydrofuran (3 mL) and cooled to −78° C. n-Butyllithium (1.6 M in hexane; 2.26 mL) is added to 2,2,2-trifluoroacetamide (205 mg) in tetrahydrofuran (3 mL) at −78° C. and the reaction mixture is stirred for 10 min. The mixture is added to the 4-bromobenzenesulfinic chloride solution at −78° C. and the reaction mixture is stirred for 1 h. The cooling bath is removed and the reaction is quenched by addition of water and brine. The aqueous layer is extracted with ethyl acetate and the combined extracts are washed with brine and concentrated in vacuo to give the title compound which is used for the next step without further purification. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=314 [M−H]−.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:3])[CH3:2].[C:18](OC(N1C2CCC1CNC2)=O)(C)(C)C>>[CH:1]([N:4]1[CH:5]2[CH2:10][CH2:18][CH:9]1[CH2:8][N:7]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:6]2)([CH3:2])[CH3:3]
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CC(C)N1C2CCC1CN(c1ccc(N)cc1)C2

Procedure:
This compound is prepared according to the same procedure as described for Intermediate 7 using 8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane (J. Med.Chem., 1998, 41, 674-681).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[Br:21]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([Br:21])[C:10]([C:14]#[N:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C#N)nn1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1c(Br)c(C#N)nn1Cc1ccccc1
Yield: 95.1 %

Procedure:
1-Benzyl-5-methyl-1H-pyrazole-3-carbonitrile (3.38 g, 17.1 mmol) was treated with potassium acetate (2.35 g, 24.0 mmol) and bromine (3.01 g, 18.9 mmol) in glacial acetic acid (48 mL) according to the method described in Part F of Examples 1-4. After the 2 M aqueous sodium carbonate was added in the work-up, a white solid was isolated by filtration and washed with water to yield 4.49 g of 1-benzyl-4-bromo-5-methyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:18]=1)[C:7]([NH:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([NH2:17])=[O:16])=O>[OH-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:7]2[NH:17][C:15](=[O:16])[C:11]3=[CH:12][CH:13]=[CH:14][N:10]3[N:9]=2)[CH:18]=1
Reactant: NC(=O)c1cccn1NC(=O)c1cc(Cl)ccc1F
Agent: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c(-c2cc(Cl)ccc2F)nn2cccc12
Temperature: 80 °C
Yield: 48.1 %

Procedure:
1-(5-Chloro-2-fluoro-benzoylamino)-1H-pyrrole-2-carboxylic acid amide (200 mg, 0.71 mmole) was dissolved in 5 ml 28% ammonium hydroxide in a sealed tube and heated to 80° C. overnight. Purged solution with nitrogen to remove excess ammonia and acidified with 1M hydrochloric acid to pH 2. Product was isolated by filtration, washed with water and vacuum dried to give 90 mg product (yield: 48%)
Reaction SMILES: C(C1C=CC=CC=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=[CH:12]2)#N.C(#N)C.O>C(O)(=O)C>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([CH:18]([N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=1
Reactant: CCCCC(c1ccc(C(F)(F)F)cc1)n1ccc2cc(-c3ccccc3C#N)ccc21
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(c1ccc(C(F)(F)F)cc1)n1ccc2ccccc21
Temperature: 95 °C

Procedure:
5-(2-Cyanophenyl)-1-[1-(4-trifluoromethylphenyl)-1pentyl]indole (1.9 moles, 800 mg) was dissolved in 2.0 g of tributyltinazide and heated at 95° C. for 24 hours. The solution was cooled. Acetonitrile, water, and acetic acid (50 ml of 8:1:1) were added. The acetonitrile solution was washed with hexane, concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The product was chromatographed on silica gel eluted with ethyl acetate to yield 120 mg of 5-[2-tetrazol-5-yl)phenyl]-1-[1-(4- trifluoromethylphenyl)-1-pentyl]indole.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:38][C:39]1[C:44]([CH3:45])=[CH:43][C:42]([C:46](=[O:48])[NH2:47])=[CH:41][C:40]=1[CH3:49])[C:10]([N:12]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33])[CH:13]([C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[CH3:14])=[O:11])=O)(C)(C)C.CC(C)=O.Cl.[OH-].[Na+]>O>[NH2:8][CH:9]([CH2:38][C:39]1[C:44]([CH3:45])=[CH:43][C:42]([C:46](=[O:48])[NH2:47])=[CH:41][C:40]=1[CH3:49])[C:10]([N:12]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33])[CH:13]([C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[CH3:14])=[O:11]
Reactant: COc1ccc(CN(C(=O)C(Cc2c(C)cc(C(N)=O)cc2C)NC(=O)OC(C)(C)C)C(C)c2nc(-c3ccccc3)c[nH]2)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CN(C(=O)C(N)Cc2c(C)cc(C(N)=O)cc2C)C(C)c2nc(-c3ccccc3)c[nH]2)cc1C(=O)O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A 1 L three-necked round-bottomed flask equipped with a mechanical stirrer, addition funnel and a thermocouple was charged without agitation. 34.2 g of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid (see Example 9 of US 2005/0203143), 340 ml of acetone, and 17 ml of 204 mmolar concentrated HCl were combined in the flask. The stirring was started and the resulting slurry formed a clear solution. This solution was heated to 45° C. under vigorous stirring and aged at this temperature for a period of two hours. After the completion, the reaction mass was cooled to ambient temperature and the supernatant was removed by suction. The vessel along with the residue was rinsed with 20 ml of acetone and then removed as previously. 170 ml of water was added and the reaction mass and was aged under stirring until a homogeneus solution resulted. This solution was then added over a period of ˜½ hr to a solution of 90 ml of 1N NaOH and water. The pH was adjusted to 6.5-7.0 accordingly. The resulting slurry was aged for about 2 hrs at ambient temperature, cooled to 10-15° C., aged at that temperature for about 1 hr, and then filtered. The solid was washed with 10 ml water, air-dried for a period of 4 to 5 hrs, and then placed in a vacuum oven at 50-55° C. until the water content was less than 3%.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:24])[CH3:23])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[OH:8].Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[O:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:23])[CH3:24])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[O:8][CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[O:33][CH:34]=1
Reactant: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Reactant: Cc1nc(CCl)co1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)co1
Temperature: 60 °C
Yield: 25 %

Procedure:
To a solution of Intermediate 1 (509 mg, 1.32 mmol) in N,N-dimethylformamide (5 mL) was added 4-chloromethyl-2-methyl-oxazole from Step A (173 mg, 1.32 mmol), potassium carbonate (273 mg, 1.98 mmol) and 18-crown-6 (40 mg). The slurry was heated at 60° C. for eighteen hours. The reaction was allowed to cool to room temperature and then partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a colorless oil. (160 mg, 25% yield). MS (M+H): 482; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.17 (s, 3H), 2.20 (s, 3H), 2.50 (s, 3H), 5.40-5.48 (m, 2H), 7.54-7.58 (m, 2H), 7.66 (s, 1H), 7.93 (s, 1H), 8.13 (d, J=8.21 Hz, 1H), 8.77 (d, J=5.08, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[CH3:20][C:21]([CH2:23]Br)=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:22][C:21]([CH3:23])=[CH2:20])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: C=C(C)CBr
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
A mixture of the product from Example 232b (56 mg, 0.17 mmol), 2-methyl-3-bromo propene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (55 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1>S(Cl)(Cl)=O.C(OCC)C>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([NH:10][C:4](=[O:5])[C:3]([C:2]([F:9])([F:8])[F:1])=[CH2:7])=[CH:12][C:13]=1[C:19]([F:20])([F:21])[F:22])#[N:16]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: C=C(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
2-Trifluoromethyl-acrylic acid (36.0 mmoL) in thionyl chloride (2.86 mL) was refluxed for 30 min. Excess thionyl chloride was removed in vacuo to yield a residue. 4-Amino-2-trifluoromethyl-benzonitrile (36.0 mmoL) in diethyl ether (50 mL) was added dropwise to the residue at −40C. The reaction mixture was slowly warmed to room temperature. The reaction mixture was then partitioned between diethyl ether and water. The diethyl ether layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the brown oil) was then purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compound as yellow solid.