Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:4][Si:5]1([CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])[C:9]2[CH:10]=[C:11]([Si](C)(C)C)[S:12][C:8]=2[C:7]2[S:17][C:18]([Si](C)(C)C)=[CH:19][C:6]1=2)[CH3:2].FC(F)(F)C(O)=O.O>C(Cl)(Cl)Cl>[CH2:30]([CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][Si:5]1([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:32][CH2:33][CH2:34][CH3:35])[C:9]2[CH:10]=[CH:11][S:12][C:8]=2[C:7]2[S:17][CH:18]=[CH:19][C:6]1=2)[CH3:31]
Reactant: CCCCC(CC)C[Si]1(CC(CC)CCCC)c2cc([Si](C)(C)C)sc2-c2sc([Si](C)(C)C)cc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCC(CC)C[Si]1(CC(CC)CCCC)c2ccsc2-c2sccc21
Reaction time: 3.5 h
Yield: 94 %

Procedure:
4,4-bis(2-ethylhexyl)-2,6-bis(trimethylsilyl)-dithieno[3,2-b:2′,3′-d]silole (Compound G1, synthesized in accordance with Non-patent Document J. Am. Chem. Soc. 2008, 130, 16144-16145, 1.03 g, 1.786 mmol) was placed in a 200 mL four-necked recovery flask in a nitrogen atmosphere, and dissolved in chloroform (50 mL). Trifluoroacetic acid (0.265 mL, 3.573 mmol) was added dropwise, and the mixture was agitated for about 3.5 hours. Water was added to the reaction solution, and the lower layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. This was dissolved in hexane and subjected to silica gel column chromatography (solvent: hexane) to obtain 4,4-bis(2-ethylhexyl)-dithieno[3,2-b:2′,3′-d]silole (Compound G2) as a light yellow oily substance (702 mg, yield 94%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:36])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:15]=[N:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:8][C:7]=1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C=O.O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][C:5](=[O:36])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:40])[CH2:23][CH2:24]3)[N:15]=[N:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:8][C:7]=1[O:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester dihydrochloride in DCM (6 mL) was added formaldehyde solution in water (37%, 2.26 mmol, 0.168 mL) and 2 drops of acetic acid. Sodium triacetoxyborohydride (3.02 mmol, 674 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1 h and partitioned between ethyl acetate (40 mL) and saturated aq. sodium bicarbonate solution (40 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on basic alumina using 0-4.5% MeOH in DCM to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester. This was converted to the title compound using 4 N HCl in dioxane (296 mg). LCMS: m/z 483 [M+1] 1H NMR (400 MHz, CD3OD) δ 7.86-7.93 (2H, m), 7.65-7.71 (1H, m), 7.34-7.38 (1H, m), 5.38-5.55 (1H, m), 4.61-4.65 (1H, m), 3.89 and 3.89 (3H, s), 3.11-3.65 (6H, m), 2.94 (3H, s), 1.16-2.57 (18H, m), 0.83 (3H, dt).
Reaction SMILES: [CH3:1][O:2]C(OC)CNC1C=CC(F)=CC=1.[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][NH:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:18][CH:17]=1.[NH2:30][C:31]1[S:32][C:33]([C:37]([NH:39][CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:38])=[C:34]([CH3:36])[N:35]=1>>[CH3:27][O:26][CH:23]([O:24][CH3:25])[CH2:22][N:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:29][CH:28]=1)[C:1](=[O:2])[NH:30][C:31]1[S:32][C:33]([C:37]([NH:39][CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:38])=[C:34]([CH3:36])[N:35]=1
Reactant: COC(CNc1ccc(F)cc1)OC
Reactant: COC(CNCc1ccc(F)cc1)OC
Reactant: Cc1nc(N)sc1C(=O)NCc1cccnc1
Product: COC(CN(Cc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2cccnc2)s1)OC
Yield: 69 %

Procedure:
Following the procedure as described in step B of Preparation 2, making variations as required to replace N-(2,2-dimethoxyethyl)-4-fluoroaniline with N-(4-fluorobenzyl)-2,2-dimethoxyethanamine to react with 2-amino-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, 2-(3-(2,2-dimethoxyethyl)-3-(4-fluorobenzyl)ureido)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide was obtained in 69% yield: MS (ES+) m/z 488.4 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[O:12][CH2:11][CH2:10][N:9]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and pentanoyl chloride (301 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(2-phenylmorpholin-4-yl)pentan-1-one are collected and the solvent is removed in vacuo to give 412 mg of colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:13][N:12]=[C:11]([C:14]([O:16]CC)=[O:15])[C:10]=2C)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Li+].[OH-].O.Cl.[CH2:24]1COCC1>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[N:12]([CH3:24])[N:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1n[nH]c(-c2cccc(C#N)c2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(-c2cccc(C#N)c2)cc1C(=O)O
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of ethyl 5-(3-cyanophenyl)-4-methyl-1H-pyrazole-3-carboxylate (100 mg, 392 μmol, Eq: 1.00) in THF (5 ml) in MeOH (1.00 ml) was added LiOH 1M (2.35 ml, 2.35 mmol, Eq: 6). The mixture was stirred overnight. To the residue was added water and HCl 1N (pH:1), this aqueous phase was extracted two times with ethyl acetate, the resulting organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the desired compound (52 mg, 52.6%) as a yellow solid. MS (ISP): 228.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.CCCCCC>CCO>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:10]2[CH2:9][CH2:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:13]#[N:14])[CH2:12][CH2:11]2)=[N:29][CH:30]=1
Reactant: Clc1ncc(Br)cn1
Reactant: N#CC1(c2ccccc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCCCCC
Product: N#CC1(c2ccccc2)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of 4-phenylpiperidine-4-carbonitrile (0.35 g, 1.55 mmol) in EtOH (5 mL) was added DIPEA (0.8 mL, 4.55 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.15 g, 1.3 mmol). The mixture was heated up to 70° C. for 1 h. After reaction completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the product as a yellow solid (0.31 g, 70% yield). MS: 343.09 [M+H]+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[OH:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:37]4[CH2:38][CH2:39][C@@H:35]([OH:34])[CH2:36]4)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: O[C@@H]1CCNC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC[C@@H](O)C3)oc21
Temperature: 90 °C

Procedure:
N,N-Diisopropylethylamine (0.48 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.500 g) were added to a solution of (R)-3-hydroxypyrrolidine (0.22 mL) in DMF (30 mL). The reaction mixture was heated to 90° C. for 2 h. The mixture was allowed to cool to room temperature, poured into water (60 mL), and extracted with ethyl acetate (4×50 mL) then CH2Cl2 (2×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 98/2, 97/3, 95/5) followed by recrystallization from ethyl acetate to yield 0.360 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 189-190° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.64, 8.54, 7.41-7.32, 6.85, 4.73, 4.55, 4.22-4.16, 3.93, 3.68, 2.78-2.74, 2.68-2.62, 2.52-2.47, 2.41-2.37, 2.02-1:94, 1.58-1.50; MS (ESI+) m/z 416 (M+H)+; [α]25D=−3 (CH2Cl2).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21](=[O:23])[CH3:22]>C1COCC1>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21]1([CH3:8])[CH2:22][O:23]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1c(F)cc(F)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2c(F)cc(F)cc2F)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(2,4,6-trifluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After completion of this addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted with diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:24])([F:23])/[C:17](/[CH3:22])=[CH:18]\[C:19](Cl)=[O:20].C(Cl)(=O)C(Cl)=O.FC(F)(F)/C(/C)=C\C(O)=O>C1(C)C=CC=CC=1>[C:1]([N:5]([C:19](=[O:20])/[CH:18]=[C:17](\[C:16]([F:24])([F:23])[F:15])/[CH3:22])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: C/C(=C/C(=O)Cl)C(F)(F)F
Agent: C/C(=C/C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: C/C(=C/C(=O)N(NC(=O)c1ccccc1)C(C)(C)C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g,) in 2 ml toluene was added dropwise to a solution of beta-trifluoromethylcrotonyl chloride (prepared by addition of oxalyl chloride (1.3 g) to a solution of 1.5 g beta-trifluoromethylcrotonic acid in 5 ml toluene at 23° C.). After 30 min. at 23° C., the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (20 ml) and ether (20 ml). The ether layer was evaporated under reduced pressure to about 10 ml and the excess hydrazine was removed by filtration. The filtrate was evaporated to give N'-t-butyl-N-benzoyl-N'-(beta-trifluoromethylcrotonyl)hydrazine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:15][C:3]=1[C:4]([O:6]CC1C=CC=C(Cl)C=1)=[O:5].[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:15][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(OCc1cccc(Cl)c1)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A solution of (3-chlorophenyl)methyl 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoate (970 mg, 2.3 mmol) in dioxane (30 ml) and water (15 ml) was treated with lithium hydroxide (monohydrate) (145 mg, 3.5 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then evaporated in vacuo, the residue take up into water (50 ml) and washed with ether (100 ml). The aqueous layer was then acidified with 2M HCl the extracted with ether (2×150 ml). Organic layers combined, washed with brine, dried and evaporated in vacuo to afford the title product as a white solid (600 mg). MS (ES−) m/z 295 [M−H]− (C14H1035Cl2O3). 1H-NMR (400 MHz, d6-DMSO) δ 5.17 (2H,s), 7.17-7.20 (1H, m), 7.38-7.53 (6H,m), 13.4 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[I:30][C:31]1[CH:32]=[C:33]([OH:41])[CH:34]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:41][C:33]2[CH:34]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:36]=[C:31]([I:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CS(=O)(=O)c1cc(O)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a mixture of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.17 g, 2.49 mmol), 3-iodo-5-methanesulfonyl-phenol (620 mg, 2.08 mmol), and potassium carbonate (575 mg, 4.16 mmol) were added dimethylformamide (13.4 mL) and acetone (26.8 mL) at room temperature. The resulting suspension was heated to reflux for 2 days. Then, the reaction mixture was cooled to room temperature and diluted with water (100 mL). The organic compound was extracted into ethyl acetate (3×50 mL) and the combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layers were dried over anhydrous magnesium sulfate and filtration of the drying agent and concentration of the solvent gave the crude product which was purified by using an ISCO 40 g column, eluting with 2-20% ethyl acetate in hexanes to afford 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (1.3 g, 91%) as a colorless oil: ES(+)-HRMS m/e calcd for C30H41IO8S (M+Na)+ 711.1459, found 711.1460.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:21])[CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])[CH3:4].[CH3:22]I>CN(C)C=O>[CH2:3]([O:5][C:6]([CH:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:21])[CH:16]=3)[N:11]([CH3:22])[C:10]=2[CH2:9]1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2c(n(C)c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1.3 g. of 55 percent sodium hydride in mineral oil, 8 g. of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester and 50 ml. of dimethylformamide was stirred at room temperature. After 1.5 hours all the sodium hydride had reacted and a solution of 4.5 g. of methyl iodide in 15 ml. of dimethylformamide was added. The mixture was stirred for 6 hours between 60°-65° C. Upon cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was partitioned between ether (200 ml.) and water (200 ml.). The ether phase was separated and washed by extraction with water (2 × 100 ml.). After the ether solution had dried over sodium sulfate, the desiccant was removed by filtration and the ether evaporated, yielding 7.2 g. of product. Following crystallization from methanol, 4.6 g. of 6-chloro-9-methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester was obtained, m.p. 126°-127°.
Reaction SMILES: C(OCC)C.[CH2:6]([Li:10])[CH2:7][CH2:8][CH3:9].[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15]C>>[CH-:6]1[C:15]2[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=[CH:7]1.[Li+:10]
Reactant: [Li]CCCC
Reactant: CCCCCC
Solvent: CCOCC
Product: [Li+]
Product: c1ccc2[cH-]ccc2c1
Temperature: 25 °C

Procedure:
A 100 mL Schlenk flask is charged with diethyl ether, 50 mL, and n-butyllithium, 5.22 mL (14.67 mmole) of a 2.81M solution in hexane, at -78° C. To the magnetically stirred, chilled solution is added nitrogen degassed indene, 1.70 g (14.6 mmole). The mixture is stirred and warmed to room temperature over 1 to 2 hours. The solution is stirred at least an additional 4 hours at room temperature to insure complete reaction prior to further use.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH:36]([C:44]([OH:46])=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[C@H:9]([C:16]([NH:35][CH:36]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]([OH:46])=[O:45])=[O:18])[CH2:10]1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC(Cc1ccccc1)C(=O)O
Product: CON=C1C[C@@H](C(=O)NC(Cc2ccccc2)C(=O)O)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and DL-phenylalanine, the title compound was obtained in 62% purity by HPLC. MS(ESI+): m/z=500.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(F)c1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1cccc(N=C=S)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
Into a solution of 2-chloro-3-fluoroaniline (2.61 g, 17.94 mmol) in 50 mL of toluene at room temperature, thiophosgene (2.1 mL, 26.91 mmol) and triethylamine (3.02 mL, 26.91 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (2.99 g, 89%). 1H NMR (CDCl3) δ 7.10 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)N5CCCC5)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1)N1CCCC1
Reaction time: 0.03 h

Procedure:
A solution of N-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide, 67f, (11.5 g, 19.3 mmol) in THF (150 mL) was added sodium methoxide (4.173 g, 19.31 mmol). After stirring the reaction mixture for 2 minutes, the mixture was poured into an aqueous saturated solution of NaHCO3. The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (10% MeOH/CH2Cl2) to afford 6.5 g of the desired product. The product was converted to an HCl salt by dissolving in MeOH (100 mL) and adding 2.4 mL of 12M HCl solution at room temperature. The solution was stirred at for 1 hour and the HCl salt precipitated out and filtered to provide 7.05 g of the HCl salt.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([O:26][C:27]([C@:29]1([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34][C@H:33](O)[C@@H:32]2[C@H:30]1[C@H:31]2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[C:22]([O:26][C:27]([C@:29]1([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34][C@@H:33]([Br:20])[C@@H:32]2[C@H:30]1[C@H:31]2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Br)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 25 °C
Yield: 78.2 %

Procedure:
Dissolve triphenylphosphine (41.97 g, 158.4 mmol) in fresh toluene (660 mL) and add bromine (8.14 mL, 158.4 mmol) until a yellow color persists. Add dropwise a solution of ditert-butyl(1S,2S,4S,5R,6R)-2-(tert-butoxycarbonylamino)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (32.75 g, 79.2 mmol) in toluene (176 mL) and anhydrous pyridine (528 mL) during 45 min. Stir the reaction at 75° C. overnight. Cool to room temperature, dilute with ethyl acetate, filter and concentrate to dryness. Slurry the crude in methyl tert-butyl ether, filter to remove the solids and concentrate the filtrate to dryness. Purify the crude by silica gel chromatography (750 g) eluting with hexane:ethyl acetate (0:100 to 80:20) to obtain the title compound as a white solid (29.52 g, 78%). MS (m/z): 498, 500 (M+23).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.O>[NH:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[CH:16]=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1n[nH]c2c1CNCC2
Reaction time: 1 h

Procedure:
1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.70 g, 3.1 mmol) was dissolved in trifluoroacetic acid (10 mL) at 0° C., stirred for 1 h, and was concentrated. The residue was dissolved in ethanol and treated with concentrated hydrochloric acid (1 mL). The bis-hydrochloride salt precipitated out as a white solid which was filtered to give 510 mg (83%). The free base was prepared as needed by dissolving the salt in water, loading it onto an SCX column, flushing with methanol, and then eluting with 2 M ammonia in methanol.