Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10]([O:14][C:15](ON=C(C1C=CC=CC=1)C#N)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:14][C:15]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCN1CCNCC1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCN1CCNCC1

Procedure:
1-(2-aminoethyl)piperazine (1.29 g, 10 mmol) is dissolved in 20 mL of dioxane: water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain 1-[2-tert-butoxycarbonylaminoethyl]piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-[2-tert-butoxycarbonylaminoethyl]piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-[2-tert-butoxycarbonylaminoethyl]piperazine (1.396 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifluoroacetic acid to obtain the pure title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[C:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[CH:24]=[C:19]([C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13])[CH:20]=[CH:21][C:22]=2[OH:25])([CH3:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc(F)cc1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(F)cc2)c1
Yield: 76 %

Procedure:
4-Fluoro-α-methylstyrene (18 g) as prepared in Example 2 and 20.6 g of 4-tert-octyl-phenol are reacted according to the procedure of Example 3 to yield 26 g of the title compound as a reddish, viscous oil whose structure is consistent with 1Hnmr and mass spectroscopy.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[CH:9][O:10]2)=[CH:5][CH:4]=1)#[CH:2].Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:33]([O:32][C:28]1[CH:27]=[C:26]([C:2]#[C:1][C:3]2[CH:12]=[C:11]3[C:6]([C:7](=[O:24])[C:8]([C:13]4[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=4)=[CH:9][O:10]3)=[CH:5][CH:4]=2)[CH:31]=[CH:30][N:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Reactant: CC(C)(C)Oc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)Oc1cc(C#Cc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)ccn1
Temperature: 85 °C

Procedure:
N-(4-(7-ethynyl-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide (100 mg, 0.29 mmol) was combined with 4-bromo-2-tert-butoxypyridine (0.074 mg, 1.1 eq), PdCl2(PPh3)2 (10 mg, 0.05 eq), copper iodide (4 mg 0.002 eq), triphenylphosphine (6 mg 0.03 eq) and triethylamine (0.12 ml, 4.0 eq) in dry tetrahydrofuran (10 ml) and heated in microwave for 30 minutes at 85° C. Solvent was removed from the product under reduced pressure, and the residue was extracted with ethyl acetate in the presence of water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-(4-(7-((2-tert-butoxypyridin-4-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide. This crude product was dissolved in dichloromethane/trifluoroacetic acid 1:1 (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate in the presence of water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was heated in acetonitrile, cooled, and the solids were filtered out. This procedure was repeated twice in order to afford N-(4-(4-oxo-7-((2-oxo-1,2-dihydropyridin-4-yl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[N:11][N:10]=[N:9]1)C.Cl.O>C(O)(=O)C>[N:8]1([CH2:7][CH2:6][CH2:5][C:4]([OH:13])=[O:3])[CH:12]=[N:11][N:10]=[N:9]1
Reactant: CCOC(=O)CCCn1cnnn1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCn1cnnn1

Procedure:
6.65 g of 4-(tetrazol-1-yl)-butyric acid ethyl ester are stirred in 42.7 ml of acetic acid, 8.1 ml of concentrated HCl and 17.2 ml of water for 3 hours at 100°. After cooling, the reaction mixture is concentrated three times each with toluene and ether under reduced pressure in a rotary evaporator. After drying under a high vacuum, the title compound is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[Li+].CC([N-]C(C)C)C.F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCCCl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
In a round bottom flask under nitrogen, 2-chloro-ethanol (8.3 mL, 120 mmoles) in THF (40 mL) was cooled to 0° C. LDA (60 mL, 120 mmoles) was added dropwise, while maintaining the temperature constant at 0° C. The mixture was stirred at this temperature for 15 minutes, followed by the addition of 2,4-difluoronitrobenzene (11 mL, 100 mmoles). The mixture was stirred at room temperature overnight. Reaction mixture was diluted with water, extracted with EtOAc, washed with brine (1×), dried over Na2SO4, and concentrated under vacuum, to afford the title compound as an off-white solid (20.0 g, 91 mmoles).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1>C(O)(=O)C.O>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][CH:2]=[O:1])=[CH:13][CH:12]=1)=[O:29]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCC2OCCO2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCC=O)cc1
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A mixture of 4-[3-[4-[2-(1,3-dioxolan- 2-yl)ethyl]phenyl]-3-oxopropyl]-5-methyl-2-phenyloxazole (2.17 g) and 50% acetic acid-water (60 ml) was stirred at 75°-80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, neutralized with an aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure; the residue was subjected to silica gel column chromatography. From the fraction eluted with ether-hexane (1:1), 3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]propionaldehyde (1.5 g, 78%) was obtained, which was then recrystallized from ether-isopropyl ether to yield colorless needles having a melting point of 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21](=[S:23])[NH2:22])[NH:8]2)=[CH:4][CH:3]=1.Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]3[S:23][C:25]([CH2:26][OH:27])=[CH:28][N:22]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=CC(Br)C=O
Reactant: CN(c1c(Cl)ccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1c(Cl)ccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A mixture of 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.60 g), bromomalonaldehyde (0.38 g) and N,N-dimethylacetamide (10 ml) was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 ml) and methanol (5 ml) was added sodium borohydride (70 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.38 g, yield 54%) as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 214-215° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:22]([F:30])[CH:23]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: COc1cc(Br)cc2[nH]ncc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Br)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 65.4 %

Procedure:
To a solution of 6-bromo-4-(methyloxy)-1H-indazole (1.0 g, 4.40 mmol) in dichloromethane (50 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.16 g, 8.80 mmol), pyridine (0.71 mL, 8.79 mmol), copper acetate (1.2 g, 6.62 mmol) and powdered 4A molecular sieves (2 g). The reaction mixture was stirred at room temperature in the presence of air for 5 days. Celite was added to the mixture and stirred for 10 mins then the mixture was filtered through a pad of celite and then the filtrate was washed with dichloromethane, then washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-30% ethyl acetate in hexane to yield the title compound (D9) (1.23 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:35]([CH3:49])[CH2:36][CH2:37][N:38]1C(=O)C2C(=CC=CC=2)C1=O>>[CH3:24][O:23][C:21](=[O:22])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH:35]([CH3:49])[CH2:36][CH2:37][NH2:38])[CH2:9][CH2:10]2)[CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[F:33])[CH:16]=1
Reactant: COC(=O)c1cccc(N(Cc2cc(Cl)ccc2F)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: COC(=O)c1cccc(N(Cc2cc(Cl)ccc2F)C2CCN(C(C)CCN)CC2)c1

Procedure:
Using general procedure C with the carbamate (910 mg, 1.91 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (565 mg, 2.60 mmol) and then using general procedure D gave 3-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-benzoic acid methyl ester as a white foam (473 mg, 56% over 3 steps).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.N([O-])=[O:14].[Na+].S(=O)(=O)(O)O>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([OH:14])=[CH:3][CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(-c2ncco2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(-c2ncco2)cc1
Yield: 47.9 %

Procedure:
2-(4-Aminophenyl)oxazole [m.p. 121°-123° C.; Rosenbaum et al., J. Am. Chem. Soc. 64, 2444 (1942)] (10.3 g) was diazotized with 4.93 g of sodium nitrite and 215 ml of 2N sulfuric acid. The resulting diazonium salt was heated until no more nitrogen was evolved, and the product was isolated and recrystallized from ethylene dichloride to give 4.96 g of 4-(2-oxazolyl)phenol, yellow crystals, m.p. 167°-168° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]2[S:17][CH2:16][NH:15][C:14]2=[O:18])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])[CH3:3].[Mg].C(OCC)(=O)C>CO>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]2[S:17][CH2:16][NH:15][C:14]2=[O:18])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)ccc1O
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1cc(CC2SCNC2=O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A portion of the title compound from Example 78 (395.1 mg; 1.5 mmol) was dissolved in 9 ml of methanol. Magnesium (72.9 mg; 3.0 mmol) was then added to the solution and the resulting reaction mixture was stirred at room temperature for 3 hours. After 3 hours, most of the magnesium which had been added originally appeared to be gone so an additional 182.3 mg (7.5 mmol) of magnesium were added. Stirring of the reaction solution at room temperature continued overnight. By the next morning a yellow precipitate had formed. This precipitate was dissolved by adding the methanolic reaction solution to an ethyl acetate/1N hydrochloric acid mixture. The organic layer from the resulting two-phase mixture was isolated and then dried over sodium sulfate. The volatile components of the organic layer were removed and the resulting residue was chased with methylene chloride. The residue was then dissolved in 25 ml of methylene chloride and the resulting solution was chromatographed on a silica gel chromatography column using a 5-20% isopropyl alcohol in hexanes gradient. Those fractions identified as containing essentially pure product were evaporated to provide 0.29 g of title compound. m.p. 65-70° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][CH2:41][CH:42]([F:44])[F:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][CH:42]([F:43])[CH2:41][NH:40][C:19]1[N:18]=[C:17]2[CH2:16][NH:15][CH2:24][CH2:23][C:22]2=[N:21][C:20]=1[N:25]1[CH2:26][CH2:27][CH:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH2:29][CH2:30]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 6-benzyl-N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (132.5 mg, 0.210 mmol) in THF (2.1 mL) was treated with Pd(OH)2 (20 wt %, 29.6 mg, 0.042 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction was stirred under hydrogen atmosphere for 1 h. The reaction mixture was opened to air and was filtered through a pad of Celite™, eluting with EtOAc and MeOH. The filtrate was concentrated under reduced pressure to give the title compound as a TFA salt (114 mg), which was used without further purification. ESI-MS m/z [M+H]+ 426.5.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[OH-].[Na+]>C(O)(C)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: OCCCCCCBr
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCCCCCCSc1nc2ccccc2[nH]1
Reaction time: 5 h
Yield: 100 %

Procedure:
3.0 g of 2-mercaptobenzimidazole and 3.8 g of 6-bromohexanol was added to 20 ml of isopropanol and refluxed with stirring for 5 hours. After cooling, the reaction mixture was neutralized with 2 N NaOH aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (20% ethyl acetate:methylene chloride) to obtain 5.0 g of the title compound (yield: 100%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].N1C=CN=C1.CN(C)C=O>O>[Si:1]([O:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCO)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyldimethylsilyl chloride (150 g) was added to a mixture of 3-hydroxypropiophenone (125 g), imidazole (142 g) and dimethylformamide (330 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water (600 ml) and extracted with diethyl ether (600 ml). The organic layer was separated, washed with water (4×30 ml), dried (Na2SO4) and evaporated to give 3-(tert-butyldimethylsilyloxy)propiophenone as an oil (186 g, b.p. 114°-118° C. at 0.01 mm Hg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].[NH3:11]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10]
Reactant: N
Reactant: Fc1ccccc1N=C=S
Solvent: CCOCC
Product: NC(=S)Nc1ccccc1F

Procedure:
To a stirred solution of 7.0 g (0.045 mol) of 2-fluorophenyl isothiocyanate in 100 ml of ether, was added ammonia gas over a three minute period. A white solid crystallized and was collected by filtration to yield 5.3 g of N-(2- fluorophenyl)thiourea. melting point 147-148° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.N1CCCCC1>C(OCC)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(C)=CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1ccc(SC(C)(C)CC(=O)O)cc1
Temperature: 105 °C

Procedure:
A heavy-walled screw cap tube was charged with 3-methyl-2-butenoic acid (13.86 g, 138.4 mmol), 4-methoxy thiophenol (20.0 g, 138.4 mmol), and piperidine (3.45 g, 41.6 mmol). This mixture was heated to 105° C. for 32 hours, cooled to room temperature and dissolved in ethyl acetate (EtOAc) (700mL). The resulting solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried over Na2SO4. Concentration of the dry solution under reduced pressure afforded an oil which, upon standing in the freezer, provided a crystalline solid. 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid was isolated as pale-yellow crystals by washing the crystalline solid with pentane. (27.33 g, 82%). 1H NMR (300 MHz, CDCl3) δ: 7.48 (2H, d, J=9.0 Hz), 6.89 (2H, d, J=8.9 Hz), 3.83 (3H, s), 2.54 (2H, s), 1.40 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:11]OC(=O)OC.CCN(CC)CC>C(OCC)(=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: COC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1ccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
A solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (54 kg from multiple batches based on wt % assay, 274 mol) in ethyl acetate from the previous step was distilled under vacuum at 45±5° C. to a volume of about 110 L (2 L/kg) and then cooled to 25±5° C. Dimethylcarbonate (33.0 kg, 367 mol) and Et3N (22.0 kg, 217 mol) were added and the mixture was distilled under vacuum at 50±5° C. to a volume of about 85 L. N,N-dimethylformamide (82.5 kg, 1.6 L/kg) was added and the mixture was distilled under vacuum at 50±5° C. until no distillate was observed. The mixture was cooled to 25±5° C., and dimethylcarbonate (165 kg, 1833 mol), Et3N (60.5 kg, 598 mol), and tetrabutylammonium bromide (11.0 kg) were added. The reaction mixture was heated to 88±5° C. After 12 hours at 105-110° C. (jacket temperature), which corresponded to 83-85° C. reaction mixture temperature, HPLC analysis indicated 59.6% of the starting material remained. The jacket temperature was increased to 115-120° C. (corresponding to 84-87° C. reaction mixture temperature). After 18 hours at 115-120° C. (jacket temperature) HPLC analysis indicated 0.2% of the starting material remained. The mixture was cooled to 25° C. and then concentrated under vacuum at 55±5° C. to remove most of the dimethylcarbonate and Et3N. Next, the mixture was cooled to 25° C. and MTBE (340 kg) was added, followed by water (440 kg). The mixture was stirred for 30 minutes. Stirring was stopped and the mixture was left for 30 minutes for phase separation to occur. The aqueous phase was extracted with MTBE (2×209 kg). The MTBE phases were combined and washed with brine solution (286 kg). Activated charcoal (2.7 kg) was added to the organic phase, which was stirred for 1 hour and then filtered through a pad of Celite. The filter cake was washed with MTBE (55 kg). The organic layers were combined (750 kg, 6.45% by HPLC-assay) and distilled to dryness to obtain the title compound as yellow oil (48.4 kg). The product was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]([C:13]([OH:15])=O)[CH2:11][CH2:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][CH:2]=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:27][CH2:28][N:29]([C:13]([CH:10]4[C:8]5[C:9]6[CH:1]=[CH:2][NH:3][C:4]=6[CH:5]=[CH:6][C:7]=5[CH2:12][CH2:11]4)=[O:15])[CH2:30][CH:31]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: O=C(O)C1CCc2ccc3[nH]ccc3c21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(C1CCc2ccc3[nH]ccc3c21)N1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1
Yield: 38.5 %

Procedure:
A solution of 14a (1.4 g), 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1-H-indole (1.6 g), dicyclohexylcarbodiimid (1.9 g), and 4-dimethylaminopyridine (0.1 g) in THF (100 ml) was stirred for 24 hours at room temperature. The mixture was filtered and evaporated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (3:2) giving 1.1 g of the title product as an amorpheous powder.