Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].F[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([O:30][C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:10]([NH2:23])[N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OC1CCCCC1
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Nc1nc(OC2CCCCC2)nc2c1ncn2C1CCCCO1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sodium tert-butoxide (3.29 g, 34.2 mmol) was added portionwise to cyclohexanol (15 ml) at room temperature. The mixture became very thick and more cyclohexanol (10 ml) was added and the mixture heated to 50° C. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added and the mixture heated at 50° C. for 1 hour and then warmed to 60° C. and heated for a further 2 hours at which point LCMS showed complete reaction. The mixture was cooled to room temperature and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated on a water bath at 60° C. The residue was dissolved in dichloromethane and purified on a 70 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 30 mins. Some product-containing fractions were contaminated with cyclohexanol and these were re-purified on a 70 g silica cartridge using a 0-100% ethyl acetate-cyclohexane gradient over 40 mins. Product-containing fractions from the two purifications were combined and evaporated in vacuo to give the title compound as a pale yellow foam (1.59 g).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>CCO.CN(C=O)C.[Pd]>[NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(CO)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cccc(CO)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 2-amino-3-nitrobenzyl alcohol (1.4 g) and 10% Pd/C (140 mg) in EtOH (40 ml) and DMF (10 ml) was stirred under an atmosphere of hydrogen at ambient temperature for 18 h. The catalyst was removed by filtration through Celite, the filtrate reduced in vacuo and azeotroped with toluene (2×50 ml) to give 2,3-diaminobenzyl alcohol (1.15 g) as a dark brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:15][CH:16]=1.Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:15][CH:16]=2)=[N:6][CH:7]=1
Reactant: Oc1nc(Cl)ncc1Br
Reactant: Nc1ccc(S(N)(=O)=O)nc1
Agent: Cl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(O)n2)cn1
Temperature: 100 °C
Reaction time: 30 h

Procedure:
2.0 g (9.62 mmol) of 5-bromo-2-chloro-4-hydroxypyrimidine and 1.686 g (9.62 mmol) of 5-amino-pyridine-2-sulfonic acid amide are mixed in 50 ml of DMF (p.a.) with 2.88 ml of hydrochloric acid (4 molar in dioxane). It is stirred for 30 hours at 100° C., cooled and concentrated by evaporation. After being taken up in methanol, 1.505 g (45% of theory) of 5-(5-bromo-4-hydroxy-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide is crystallized out, which is dried at 50° C. in a vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=O)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][NH2:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][NH:37][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:11]=1[CH:22]([CH3:23])[CH3:24])=[O:27]
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3cccnc3)c2c1
Reactant: NCc1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3cccnc3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxylic acid (Compound 41, 365 mg, 0.997 mmol) in CH2Cl2 (12 ml) was added EDC (288 mg, 2.00 mmol) and DMAP (146 mg, 1.50 mmol), followed by 3,4-difluorobenzyl amine (171 mg, 1.50 mmol). The crude material was purified by chromatography on silica gel (0→70% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][C:16]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:23][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:26]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: COc1ccccc1C(N)=NO
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3ccccc3OC)c(C)c2)n1

Procedure:
Oxalyl chloride (126 μL; 1.5 mmol; 3 eq.), Intermediate 26 (120 mg; 0.5 mmol; 1 eq.), Intermediate 1 (82 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 90/10) followed by precipitation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([F:30])[F:29])=[CH:24][CH:23]=2)[C:17]1=[O:31])(C(C)(C)C)(C)C>ClCCl>[F:30][CH:28]([F:29])[C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([OH:15])[C:17]2=[O:31])=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1[C@@H](O)CCN1Cc1ccc(C(F)F)cc1
Reaction time: 2 h
Yield: 123 %

Procedure:
A solution of 4 M HCl in dioxane (0.62 mL, 2.5 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one (440 mg, 1.24 mmol) in dichloromethane (1.24 mL) at RT. The reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to afford (S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg, quantitative yield): LC-MS (M+H)+242.1.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:9]([NH:17]C(=O)OC(C)(C)C)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[OH:29][C:27]([C:26]([F:31])([F:30])[F:25])=[O:28].[C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:9]([NH2:17])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccccc2N(c2ccccc2)C1

Procedure:
A solution of tert-butyl 1-phenyl-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (375 mg, 1.16 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2 mL) at ambient temperature for 3 hours. The solvent was removed under reduced pressure and diethylether added. The solid that formed was filtered and dried to give 1-phenyl-1,2,3,4-tetrahydroquinolin-3-amine TFA salt as a yellow solid (350 mg). M.p.=201-203° C. 1H NMR (DMSO) 400 MHz δ 8.13 (s, br, 2H), 7.46 (m, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.15 (m, 1H), 6.99 (m, 1H), 6.77 (dt, J=1.2 and 7.6 Hz, 1H), 6.59 (m, 1H), 3.86 (m, br, 2H), 3.56 (m, 1H), 3.27 (m, 1H), 2.90 (dd, J=5.2 and 12 Hz, 1H). LCMS m/e 225 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH:15][CH2:16][CH:17]([CH2:19]O)[OH:18]>>[OH:18][CH:17]1[CH2:16][O:15][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][CH2:19]1
Reactant: OCC(O)CO
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: OC1COC(c2ccc(Cl)cc2)OC1

Procedure:
Using the method of Example 21, 42 g 4-chlorobenzaldehyde, 27.6 g glycerol and 4 ml 40 percent sulfuric acid were reacted to form 5-hydroxy-2-(4-chlorophenyl)-1,3-dioxane. The reaction mixture was dissolved in benzene and washed successively with two 50 ml volumes of 5 percent aqueous sodium bicarbonate, two 50 ml volumes aqueous sodium bisulfite and two 100 ml volumes of water. The benzene solution was dried with magnesium sulfate, filtered and evaporated under reduced pressure to form an oil which crystallized, m.p. 95°-100° C (recrystallized from benzene-ligroin).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:8]([C:7]2[C:6]([CH3:5])=[C:14]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:20][CH:19]=1
Reactant: COc1ccccc1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2C)cc1
Yield: 68.8 %

Procedure:
To a suspension of 95.6 g (0.716 mole) of aluminum chloride in 500 ml of methylene dichloride was added, rapidly and with stirring, a solution of 110.1 g (0.551 mole) of 2-methyl-3-nitrobenzoyl chloride in 400 ml of methylene dichloride. The mixture was then transferred to an addition funnel, added with stirring to a solution of 59.8 g (0.551 mole) of anisole over a thirty minute period, and the reaction mixture then heated under reflux for two hours. The mixture was decomposed by the careful addition, with stirring, of 1 liter of water and then filtered. The organic layer was separated from the aqueous layer, dried and taken to dryness, and the residue recrystallized from ethyl acetate to give 102.9 g of 3-(4-methoxybenzoyl)-2-methylnitrobenzene, m.p. 110°-113° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[CH2:12]([O:14][CH:15](OCC)[O:16][CH2:17][CH3:18])[CH3:13]>>[CH2:12]([O:14][CH:15]([O:16][CH2:17][CH3:18])[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1)[CH3:13]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)n1cc(C#N)c2ccccc21
Yield: 86 %

Procedure:
1H-Indole-3-carbonitrile (5.07 g, 35.7 mmol) was heated with triethylorthoformate (60 mL) in a pressure vessel at 160° C. for 3 d. Upon cooling, the solvent was evaporated and the residue was submitted to chromatography (20% ether in hexanes) to afford the title compound (7.46 g, 86%). NMR (300 MHz, CDCl3, δ): 7.92 (s, 1H), 7.76 (m, 1H), 7.62 (m, 1H), 7.32 (m, 2H), 6.23 (s, 1H), 3.63 (m, 4H), 1.23 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[C:22]3[C:21]([CH3:23])=[C:20]([CH3:24])[S:19][C:18]=3[C:17]([Br:25])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[CH:6][C:5]=1[OH:26])([CH3:3])[CH3:2].C([O-])(=O)C.[K+].[Br:32]Br>C(O)(=O)C>[Br:32][C:6]1[CH:7]=[C:8]([C:10]2[C:22]3[C:21]([CH3:23])=[C:20]([CH3:24])[S:19][C:18]=3[C:17]([Br:25])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:26]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C(C)C)c3)c2c1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(C(C)C)c3)c2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a suspension of 2-isopropyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.35 g, 0.81 mmol) and potassium acetate (0.80 g, 8.11 mmol) in glacial acetic acid (11 mL) was added a solution of bromine (0.05 mL, 0.97 mmol) in glacial acetic acid (1.5 mL) dropwise at room temperature. An additional 1 mL of acetic acid was used to rinse the pipette and flask. After stirring at room temperature for 4 h the reaction was quenched with a small amount of dilute sodium bisulfite and diluted with water (100 mL). The white solid was collected on a sintered glass funnel, washed well with water and dried (Na2SO4) to give the title compound as a white solid (0.40 g, 98%): mp 157-162° C.; (DMSO-d6): δ9.20 (s, 1H), 8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.49-7.48 (m, 2H), 7.35 (d, 1H), 7.13 (d,1H), 3.40 (septet, 1H), 2.42 (s, 3H), 1.60 (s, 3H), 1.16 (d, 6H); MS(+FAB): [M+H], 2 bromine isotope pattern, 502 (12%), 504 (30%), 506 (18%); Anal. Calc. for C23H20Br2OS: C, 54.78; H, 4.00; N, 0.00. Found: C, 53.67; H, 3.84; N, 0.03.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]1([C:17]([N:19]=[C:20]=[O:21])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([C:17]([NH:19][C:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C:2]2=[O:10])=[O:21])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NC(=O)C1CCCCC1
Reactant: O=C1Cc2ccccc2N1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N1C(=O)Cc2ccccc21)C1CCCCC1
Temperature: 25 °C

Procedure:
To a stirred slurry of 20.0 g (0.15 mole) of 2-oxindole in 150 ml of toluene was added 29.6 g (0.19 mole) of cyclohexylcarbonyl isocyanate. The mixture was heated under reflux for ca. 30 minutes and then it was cooled to room temperature. The solid was recovered by filtration and then it was recrystallized from ethanol. This afforded 26.5 g of the title compound as fluffy, colorless crystals, m.p. 144.5°-145.5° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4](Br)[C:3]=1[OH:16].[K+].[Br-]>>[C:2]1([C:2]2[C:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[O:7][C:6]=3[CH:5]=[C:4]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:9]=3)[C:3]=2[OH:16])[CH:10]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(Br)cc2oc3ccccc3c2c1Br
Agent: [Br-]
Agent: [K+]
Product: Oc1c(-c2ccccc2)cc2oc3ccccc3c2c1-c1ccccc1

Procedure:
The title compound was prepared as a light yellow-orange solid (0.058 g, 59%) from 1,3-dibromodibenzofuran-2-ol using a procedure similar to step 2 of Example 39, mp>46° C. (decomp.); 1H NMR (CDCl3) δ5.14 (s, 1H), 6.99-7.08 (m, 2H), 7.35-7.44 (m, 2H), 7.48-7.68 (m, 1H); IR (KBr) 3530, 3060, 1600, 1500, 1460, 1450, 1420, 1320, 1260, 1220, 1160, 1130, 1070, 890, 800, 750, and 700 cm−1; mass spectrum [EI], m/z 336 (M)+; Anal. Calcd. for C24H16O2.10H2O: C, 81.34; H, 5.12; N, 0.00, Found: C, 81.12; H, 4.79; N, −0.03.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1>CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)=[S:29])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: COc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccc(Cl)c2)cc1NC(=S)Nc1ccc(F)cc1
Yield: 89.7 %

Procedure:
Prepared according to the procedure described for Example 100 using 3-amino-N-(3-chlorophenyl)-4-methoxy-benzamide from Example 16 (0.5545 g, 2.01 mmol) and 4-fluorophenyl isothiocyanate (0.3073 g, 2.01 mmol), and omitting the trituration in methanol to afford the product (0.775 g); m.p. 184-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13]=1[O:14][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1c(OCc2ccccc2)c2cc(OC)ccc2n1-c1ccccc1

Procedure:
A mixture of 155 g (0.52 mole) of 3-hydroxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1984)], 83.0 g (0.60 mole) of anhydrous potassium carbonate, and 68 ml (97.8 g; 0.57 mole) of benzyl bromide in 2250 ml of acetone was stirred at reflux for 20 hours. The mixture was cooled, filtered, and the filter cake was washed several times with fresh acetone. The combined filtrates were evaporated (vacuum) to yield a crude residue of 5-methoxy-1-phenyl-3-(phenylmethoxy)-1H-indole-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:38])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:72]([O:74][C:75]([N:77]1[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]1)=[O:76])[CH3:73]>CN(C=O)C>[CH2:72]([O:74][C:75]([N:77]1[CH2:78][CH2:79][N:80]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:38])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:81][CH2:82]1)=[O:76])[CH3:73]
Reactant: CC(C)C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a mixture of 116 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-methyl-pentanoic acid in 2.5 ml DMF were added 84 mg HATU, 116 l DIPEA and 32 l 1-ethoxycarbonylpiperazine. After stirring for 12 h it was concentrated and the crude product thus obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 70 mg MS (ES+): m/e=666.
Reaction SMILES: [CH3:1][Si:2](Cl)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16][Si:17]([Li])([C:24]1C=CC=CC=1)[C:18]1C=CC=CC=1.[Si](Cl)(C)(C)C>O1CCCC1>[CH3:1][Si:2]([Si:17]([CH3:24])([CH3:18])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: [Li][Si](C)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)[Si](C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A slurry 89.3 g of Li metal cut into small pieces in 1500 ml dry tetrahydrofuran (THF) under an Ar atmosphere was treated dropwise with neat Ph2MeSiCl (1302.2g, 5.59 moles). During the addition, agitation was provided via a mechanical stirrer and an ice bath was employed as necessary to hold the reaction temperature under 40° C. The mixture was then allowed to stir overnight (16 hr.) at room temperature. The dark red solution of Ph2MeSiLi was then treated with 607.7g (5.59 moles) of Me3SiCl dissolved in 700 ml dry THF. Again an ice bath was utilized to maintain the reaction mixture temperature under 40° C. Near the end of the Me3SiCl addition, the red color of Ph2MeSiLi was completely discharged. Upon completion of the addition, the now essentially colorless mixture was filtered to remove precipitated LiCl and unreacted Li metal. Solvent was removed from the resulting clear solution at reduced pressure and the residual oil fractionally distilled at 0.3 mm Hg to afford 1074.1 g of title compound (71%), bp 108°-110° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1>CCOCC>[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: c1ccsc1
Reactant: Cc1ccnc(Cl)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(-c2cccs2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.8 %

Procedure:
Part B: To thiophene (0.66 g) in dry ether (25 mL) at 0° C. was added n-butyl lithium in hexanes (1.6 M, 2.7 mL) and the reaction was stirred at 0° C. for 15 minutes. After cooling to −30° C., a solution of 2-chloro-4-methylpyrimidine (1.0 g) in ether (10 mL) was slowly added and the reaction was stirred at −30° C. for 30 minutes and at 0° C. an additional 30 minutes before quenching with a mixture of acetic acid (glacial, 0.45 mL), water (0.5 mL) and tetrahydrofuran (1.0 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.77 g) in tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0° C. before aq. sodium hydroxide solution (3 M, 50 mL) was added. The organic layer was separated, washed with water, and dried with magnesium sulfate. The solvent was evaporated and the resultant crude oil was chromatographed on silica gel (30% ethyl acetate in hexanes; Rf 0.55) to yield 2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g). Anal. Calcd: % C, 51.46; % H, 3.33; % N, 13.33. Found: % C, 51.77; % H, 3.35; % N, 12.97.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:5]([O:7]C(C)C)=[O:6]>C(O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:5]([OH:7])=[O:6]
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(C(=O)O)cc1Br
Yield: 90.1 %

Procedure:
A solution of 1-methylethyl 3-bromo-4-[(1-methylethyl)oxy]benzoate (D20) (2.36 g, 7.84 mmol) in ethanol (100 mL) and aqueous sodium hydroxide (2M, 39 mL) was heated to reflux for 5 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (125 mL) and water (125 mL), the latter acidified with 2M HCl (40 mL). The aqueous layer was extracted with further ethyl acetate (70 mL) and the combined organic extracts dried (phase separator) and concentrated in vacuo to give the title compound as an off-white solid (1.83 g, 7.06 mmol). δH (methanol-d4, 400 MHz): 8.05 (1H, d), 7.89 (1H, dd), 7.23 (1H, d), 4.79 (1H, septet), 1.32 (6H, d). MS (ES): C10H11BrO3 requires 258, 260; found 257, 259 (M−H+).
Reaction SMILES: Cl.N[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.N([O-])=[O:26].[Na+]>Cl.O1CCOCC1.O>[CH2:12]([O:11][C:9]([C:8]1[C:3](=[O:26])[NH:4][C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][C:7]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc(N)c1C(=O)OCC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a mixture of 90 ml of 2% hydrochloric acid and 60 ml of dioxane was dissolved 3.50 g (10 mmol) of 2-amino-3,4-diethoxycarbonyl-6-phenylpyridine hydrochloride. A solution of 0.83 g (1.2 eq.) of sodium nitrite dissolved in 3 ml of water was added dropwise thereto. The mixture was stirred at room temperature for 4 hours and left standing overnight. The solvent was distilled off. The resulting crystals were collected by filtration with water. The crystals were recrystallized from ethanol, to give pale yellow prisms.