Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:20]([NH:22][C@H:23]([C:27]([OH:29])=O)[CH:24]([CH3:26])[CH3:25])=[O:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:44][C@H:45]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:1]([O:18][CH:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:20]([NH:22][C@H:23]([C:27]([NH:44][C@H:45]([C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:59])[CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:29])[CH:24]([CH3:25])[CH3:26])=[O:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)N[C@H](C(=O)O)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Yield: 90.4 %

Procedure:
Starting from N-(2-hexadecanoyloxyhexadecanoyl)-L-valine (2.4 g) prepared by the method of Preparation B-2 and dibenzyl L-glutamate (1.26 g), dibenzyl N-[N-(2-hexadecanoyloxyhexadecanoyl)-L-valyl]-L-glutamate (3.2 g) was obtained as crystals according to a similar manner to that of Example 2. M.p. 65° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 28.1 %

Procedure:
The title compound (0.09 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2-bromoacetic acid methyl ester (1.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C16H18ClN3O2, 319.11. found, m/z 320.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.31 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 4.93 (s, 2H), 3.56 (s, 3H), 3.27-3.25 (br m, 2H), 3.19-3.17 (br m, 2H), 3.04-3.03 (br m, 2H), 2.90-2.88 (br m, 2H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][C:26]=1[F:27]>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[C:26]([F:27])[CH:25]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (6.0 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.3 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCO)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCNC(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.6 ml of methanesulfonyl chloride in 3 ml of methylene chloride is added dropwise at 0° to a solution of 1.5 g (0.0075 mol) of N-(2-hydroxyethyl)-4-chlorobenzamide and 1 ml of triethylamine in 15 ml of methylene chloride. After 15 minutes, the mixture is poured on to ice/water and extracted. There are obtained 2.1 g of N-(2-methylsulfonyloxyethyl)-4-chlorobenzamide in crystalline form which is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[O:25])=[CH:16][N:15]=1>CN(C=O)C>[CH:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[N:15][CH:16]=1)=[O:25]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: O=Cc1cnc(Cl)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ncc(C=O)c3ccccc23)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxybenzamide (0.96 g, 7.0 mmol) in DMF (15 mL) at rt was added sodium hydride (0.28 g, 7.0 mmol). After 1 h, 1-chloro-isoquinoline-4-carbaldehyde (WO01/53274, 1.34 g, 7.0 mmol) was added and the reaction heated at 120° C. for 16 h. The solvent was removed in vacuo and the residue washed with water (100 mL), ether (50 mL) and MeCN (50 mL) to give the title compound: RT=3.13 min; m/z (ES+)=292.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 136.3 %

Procedure:
To a suspension of 3-hydroxy-2-nitrobenzoic acid (500 mg) and potassium carbonate (1.13 g) in dimethylformamide (5 ml) was added benzyl bromide (1.12 g) at ambient temperature, and the mixture was stirred overnight. To the reaction mixture-was added water, and extracted with ethyl acetate twice. The organic layers were combined, wished with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (hexane—ethyl acetate) and crystallized with diisopropyl ether to give benzyl 3-benzyloxy-2-nitrobenzoate (676 mg).
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](Cl)(=[O:15])[O:11][CH:12]([Cl:14])[CH3:13]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:10](=[O:15])([O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:11][CH:12]([Cl:14])[CH3:13]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC1CCCCCCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OC1CCCCCCC1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a solution of cyclooctanol (1.79 g) in chloroform (40 mL), pyridine (1.13 mL) was added, and then the reaction solution was cooled to −60° C. To the reaction solution, 1-chloroethyl carbonochloridate (1.53 mL) was added at the same temperature over 10 minutes. The reaction solution was thereafter heated to room temperature and stirred at the same temperature for 3 hours. Chloroform was added to the reaction solution and the organic layer was washed three times with brine and then dried over magnesium sulfate. The insoluble was filtered and the filtrate was concentrated under reduced pressure to give 1-chloroethyl cyclooctyl carbonate (A-11-1, 3.70 g) as a colorless oil.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([CH:18]=O)=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[OH-].[Na+].Cl.[CH3:32][O:33][NH2:34]>CO.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([CH:18]=[N:34][O:33][CH3:32])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C=O)cc23)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2ccccn2)C[C@@H](NC(=O)OC(C)C)C1
Yield: 27.2 %

Procedure:
Dissolve (S)-(7-formyl-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (181 mg, 0.48 mmol) in methanol (10 mL) and 1.0 N sodium hydroxide (2.4 ml, 2.4 mmol). Add methoxyamine hydrochloride (120 mg, 1.44 mmol) and stir at room temperature overnight. Dilute with ethyl acetate, wash with 10% potassium carbonate, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product on a 12 g silica gel column eluting with 30% ethyl acetate/dichloromethane to obtain the pure title compound (53 mg, 27%). LCMS 407.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[F:31][C:32]1[CH:37]=[C:36]([CH:38]=[O:39])[CH:35]=[CH:34][C:33]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:33]2[CH:34]=[CH:35][C:36]([CH:38]=[O:39])=[CH:37][C:32]=2[F:31])[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=Cc1ccc(B(O)O)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C=O)cc2F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.62 mmol) and (2-fluoro-4-formylphenyl)boronic acid (158 mg, 0.94 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.26 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (300 mg, 91%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=1)#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1ccc(OCC(=O)OC)cc1
Product: COC(=O)COc1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1f with 2j produced 3ak. MS found M+H=483. The oxalate salt of 3ak was recrystallized from ethyl acetate.
Reaction SMILES: C[C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[C:5]2[S:4][CH:3]=[CH:2][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cc1csc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncnc2ccsc12
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3H-thieno[3,2-d]pyrimid-4-one (3, 2.7 g, 18 mmol) in phosphorus oxychloride (18 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with diethyl ether. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 4-chlorothieno[3,2-d]pyrimidine (2.9 g, 97% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[CH:10]=2)[CH:7]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:11]1([C:9]2[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([C:22]#[C:21][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:7][N:6]3[N:8]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: C#Cc1ccccc1
Reactant: Brc1cnc2cc(C3CCC3)nn2c1
Product: C(#Cc1cnc2cc(C3CCC3)nn2c1)c1ccccc1

Procedure:
The title compound, light brown solid, MS: m/e=274.3 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-cyclobutyl-pyrazolo[1,5-a]pyrimidine (example 18, step 1) and phenylacetylene.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[CH2:6])([CH3:4])[CH3:3].[CH3:7][SiH:8]([Cl:10])[Cl:9]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.CCCCCC>[CH3:1][Si:2]([CH3:4])([CH3:3])[CH2:5][CH2:6][Si:8]([CH3:7])([Cl:10])[Cl:9]
Reactant: C[SiH](Cl)Cl
Reactant: C=C[Si](C)(C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CCCCCC
Product: C[Si](C)(C)CC[Si](C)(Cl)Cl
Reaction time: 4 h
Yield: 67357.8 %

Procedure:
There was allowed 100 g (1.0 mmol) of trimethylsilyl ethene to react with 127 g (1.1 mol) of methyldichlorosilane in a 500-ml flask equipped with a dropping funnel, reflux condenser, stirrer and nitrogen gas introducing tube, by steps of placing 20 ml of a mixture of trimethylsilyl ethene and methyldichlorosilane and 0.0051 g (0.01 mmol) of chloroplatinic acid in the flask, adding dropwise the remaining mixture of trimethylsilyl ethene and methyldichlorosilane thereto over a period of 4 hours while stirring the reaction mixture, and continuing the stirring for another 1 hour to complete the reaction. Subsequently, 200 ml of hexane was added to the reaction mixture, and the catalyst precipitated was filtered off. The filtrate was condensed and vaccum-distlled. 145 g (yield: 75%) of (2-trimethylsilylethyl)methyldichlorosilane was obtained.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[C:23]([C:29]([OH:31])=[O:30])[NH:24]3)[CH2:16][CH2:15]1.[F:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[C:23]([C:29]([O:31][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:30])[NH:24]3)[CH2:16][CH2:15]1
Reactant: Oc1ccc(F)cc1
Reactant: CN1CCN(c2cccc3[nH]c(C(=O)O)cc23)CC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc3[nH]c(C(=O)Oc4ccc(F)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.8 %

Procedure:
A solution of carbonyl diimidazole (0.95 g, 5.86 mmol, 2.1 equivalents) and 4-(4-Methylpiperazin-1 yl)indole-2-carboxylic acid (0.710 g, 2.74 mmol) in anhydrous tetrahydrofuran (5 mL) was heated at 50° C. under nitrogen for 5 hours. The reaction was cooled to room temperature, and a preformed solution of 4-fluorophenol (2.90 g, 25.9 mmol, 9.4 equivalents) and sodium hydride (60% in oil, 1.17 g, 29.2 mmol, 10,7 equivalents) in anhydrous tetrahydrofuran (15 mL) was added rapidly. The resulting reaction solution was stirred at room temperature under nitrogen for 12 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the resulting solution was extracted with a saturated solution of sodium hydrogen carbonate (2×25 mL). The organic layer was dried (magnesium sulfate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 100 g) and elution with 20% methanol in ethyl acetate to afford crude 4-methyl-1-(2-(4-fluorophenoxycarbonyl)-1H-indol-4-yl)piperazine (0.225 g, 0.68 mmol crude, 25% crude).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][N:20]([CH3:32])[C:21](=[O:31])[C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:27][CH2:26][N:25]([C:22]([CH3:24])([CH3:23])[C:21]([N:20]([CH3:32])[CH3:19])=[O:31])[CH2:30][CH2:29]3)=[CH:4][C:5]=2[N:6]=1
Reactant: CN(C)C(=O)C(C)(C)N1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.8 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (146 mg, 0.42 mmol) in DMF (5 mL) were added N,N-dimethyl-2-piperazin-1-yl-isobutyramide (100 mg, 0.50 mmol), cesium carbonate (273 mg, 0.837 mmol) and water (23 μL, 1.26 mmol). The resulting mixture was stirred at RT for 17 h. The reaction mixture was loaded directly onto an Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography to give the title compound as an off-white solid (131 mg, 67%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[N:19](S(C5C=CC(C)=CC=5)(=O)=O)[N:20]=[CH:21][CH:22]=4)=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)O1.Br[C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50]([NH2:52])=[O:51].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[N:20]1[NH:19][C:18]([C:17]2[C:11]3[C:12](=[N:13][CH:14]=[C:9]([C:45]4[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=4)[C:50]([NH2:52])=[O:51])[CH:10]=3)[NH:15][CH:16]=2)=[CH:22][CH:21]=1
Reactant: NC(=O)c1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2nccc2-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)c1cncc(-c2cnc3[nH]cc(-c4ccn[nH]4)c3c2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-3-[2-(toluene-4-sulfonyl)-2H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (56 mg, 0.09 mmol) in a 1:1 acetonitrile/saturated aqueous NaHCO3 solution (2 mL total) in a microwave vial was added 5-bromonicotinamide (20 mg, 0.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (3.7 mg, 0.004 mmol). The vial was capped, flushed with N2, evacuated under vacuum, and heated in a microwave at 90° C. for 1800 seconds. The product was extracted into ethyl acetate and the organic layer was dried, over Na2SO4. The solution was filtered and concentrated under vacuum. The residue was redissolved in a 1:1 MeOH/acetone solution (2 mL, total) and treated with 200 uL of 50% KOH (aq) solution and stirred at ambient temperature for 1 hour. Citric acid (1M) was added dropwise until pH=7 and the product was extracted into ethyl acetate. The organic layer was dried over Na2SO4, filtered, and adsorbed onto silica gel. The material was purified by flash chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexane then concentrated under vacuum. The residue was titrated with diethyl ether to afford the title compound as a beige solid (0.8 mg, 3% yield). 1H NMR (500 MHz, d6-DMSO) δ 12.6 (s, 1H), 11.8 (s, 1H), 8.95 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.25 (s; 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.41 (d. J=7.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H). MS: m/z 305.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:22]#[N:23]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:22]#[N:23])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Temperature: 140 °C
Yield: 16 %

Procedure:
A mixture of 4-(4-chloro-phenyl)-4-(4-iodo-phenyl)-piperidine and copper (I) cyanide in DMF was heated at 140° C. under nitrogen for 6 hours then allowed to cool. The mixture was diluted with ethyl acetate, washed with a mixture of conc. ammonia and brine (×5), dried (MgSO4), filtered and concentrated to give a residue which was partially purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 10%) and dichloromethane to afford the title compound (46 mg, <16%). This was taken on to the next reaction without further purification. LCMS (PS-A2) Rt 2.39 min [M+H]+297.
Reaction SMILES: C(O[C@H](CCCCCCCCCC(C)C)CC(O)=O)C1C=CC=CC=1.[CH2:26]([O:33][C@H:34]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])[CH2:35][C:36]([O:38]CC(C1C=CC(Br)=CC=1)=O)=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Zn]>[CH2:26]([O:33][C@H:34]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])[CH2:35][C:36]([OH:38])=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)CCCCCCCCCCC[C@H](CC(=O)OCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Agent: CC(C)CCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Agent: [Zn]
Product: CC(C)CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Yield: 90 %

Procedure:
In a manner similar to the synthesis of 107, compound 119 (350 mg, 0.611 mmol) was treated with zinc (<10 micron, 397 mg, 6.11 mmol) to afford 108 as an amorphous solid (207 mg, 97%). Rf=0.45 (toluene/ethyl acetate, 3/1, v/v); [α]25D=−2.5° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.34-7.26 (m, 5H, aromatic), 4.57 (s, 2H, CH2Ph), 3.87 (m, 1H, H-3), 2.64 (dd, 1H, J2a,2b=15.6 Hz, J2a,3=6.9 Hz, H-2a), 2.55 (dd, 1H, J2a,2b=15.6 Hz, J2b,3=5.1 Hz, H-2b), 1.68-1.38 (m, 3H, H-4, H-15), 1.26-1.14 [m, 20H, H-(5-14)], 0.86 (d, 6H, J15,16=6.9 Hz, H-16); 13C NMR (75 MHz, CDCl3): δ 176.95 (C═O), 138.08-127.71 (aromatic), 75.71 (C-3), 71.53 (CH2Ph), 39.47 (C-2), 39.05 (C-12), 34.12 (C-4), 22.65 (C-14). HR MS (m/z) calculated for C24H40O3 [M+Na]+, 399.2870; found, 399.2552.