Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12.[H-].[Na+].[CH3:39]N(C)C=O.CI>C(OCC)(=O)C>[CH3:39][O:1][CH:2]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(C)(C)C)c2nc(C)nn12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(OC)C(C)(C)C)c2nc(C)nn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A mixture of 4′-{[4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g), sodium hydride (0.03 g) and N,N-dimethylformamide (5 mL) was stirred at 0° C. for 10 min, methyl iodide (0.046 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.22 g, 72%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].CN(C)C=O.[CH3:16][O:17][CH2:18]Cl>C(OCC)(=O)C.O>[CH3:16][O:17][CH2:18][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[I:3]
Reactant: Oc1ccccc1I
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
216 mg of 60% oily sodium hydride was added to a mixture of 1.65 of 2-iodophenol and 20 ml of N,N-dimethylformamide under ice-cooling followed by stirring at room temperature for 30 minutes. Under ice-cooling, 570 μl of chloromethyl methyl ether was added thereto, followed by stirring for 30 minutes at room temperature. Water and ethyl acetate were added thereto. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed, to give 2.12 g of the target compound.
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].S(=O)(=O)([OH:16])N>O.CC(C)=O>[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]([OH:16])=[O:9]
Reactant: O=Cc1ccccc1F
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Sodium chlorite (1.45 g, 16.11 mmol) in 2 mL water was added at 0° C. to 2-fluoro-benzaldehyde (0.5 g, 4.03 mmol) in 5 mL acetone. After 5 minutes, sulphamic acid (1.17 gm, 12.086 mmol) was added and the resulting mixture was stirred at 0° C. for 20 minutes. Water was then added, and the resulting precipitate was filtered under reduced pressure. The aqueous layer was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 2-fluorobenzoic acid in 86% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[CH:18]=[CH:19][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCc1ccccc1
Product: CCc1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and ethylbenzene.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[S:24])[NH2:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].N1(C(OC(C)(C)C)=O)CCNCC1.C(N1C=CN=C1)(N1C=CN=C1)=S.N>>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22](=[S:24])[N:23]=[CH:3][N:4]([CH3:6])[CH3:5])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: N
Agent: S=C(n1ccnc1)n1ccnc1
Product: CN(C)C=NC(=S)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 95 %

Procedure:
A mixture of 122 mmol N,N-dimethylformamide dimethyl acetal and 6.11 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, 1,1′-thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037–5054) was heated at 110° C. for 3 h. The reaction mixture was then concentrated in vacuo and the residue was resuspended in ethyl acetate/tetrahydrofuran (1:1) and washed with brine. The organic phase was dried over sodium sulphate and concentrated in vacuo to afford the title compound as a light yellow crystalline solid (yield 95%). MS (m/e): 301.4 (M+H+, 100%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[N:8][C:9]=1[Cl:10]>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:13])[CH3:12])[CH:7]=[N:8][C:9]=1[Cl:10]
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cnc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
To a well stirred suspension of sodium borohydride (66.21 g, 1.75 mole) in methanol (3.5 L) cooled to 0° C. with a dry ice/acetone bath was added 1-(5,6-dichloro-pyridin-3-yl)-ethanone 8 (665 g, 3.5 mole) at a rate such that the temperature remained at 0° C. After solid addition was complete, the reaction mixture was stirred an additional 1 h, after which time LC/MS analysis of an aliquot showed that the reaction was complete.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[N:16]1[C:25]2[C:20](=[CH:21][C:22]([NH:26]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc2ncccc2c1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc2ncccc2c1
Temperature: 110 °C
Yield: 82.5 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), quinolin-6-ylamine (72.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 130 mg (82%) of greenish yellow solid mp 277-278° C.; MS (ESI) m/z 316.10 (M+1); Analysis for C19H13N3O2: Calcd: C, 72.37; H, 4.16; N, 13.33. Found: C, 71.86; H, 4.02; N, 13.25.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]2([CH3:23])[CH3:22])[CH:7]=[N:8][CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]2([CH3:23])[CH3:22])[CH:7]=[N:8][CH:9]=1
Reactant: COC(=O)c1cncn1C1c2ccccc2C(=O)N(C)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)c2ccccc2C(n2cncc2CO)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2,3,3-trimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (190 mg, 0.367 mmol) in THF (5.5 mL) at −25° C. is added lithium aluminum hydride (18 mg, 0.48 mmol). The reaction is permitted to warm to 0° C. over 2 h and the reaction is stirred for an additional 30 min at 0° C. After a total of 2.5 h the reaction is quenched at 0° C. by the consecutive addition of 9:1 THF/H2O (0.225 mL), 2M aqueous NaOH (0.090 mL), and H2O (0.170 mL). The reaction is warmed to room temperature and diluted with THF (2.0 mL). After addition of MgSO4 (250 mg), the heterogeneous mixture is stirred for 15 min and then filtered through a pad of Celite. The pad of Celite is washed with ethyl acetate and the combined filtrate is concentrated in vacuo. The resulting residue is purified by silica gel flash chromatography (dichloromethane-methanol, 49:1 to 9:1) to afford 4-(5-hydroxymethyl-imidazol-1-yl)-2,3,3-trimethyl-3,4-dihydro-2H-isoquinolin-1-one as a colorless foam. High resolution mass spectrum (ES+) m/z 286.1547 [(M+H)+; calculated for C16H20N3O2: 286.1556]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (s, 3 H), 1.36 (s, 3 H), 2.12 (br. s, 1 H), 3.11 (s, 3 H), 4.65-4.95 (m, 2 H), 5.33 (s, 1 H), 6.95 (s, 1 H), 7.31-7.36 (m, 1 H), 7.37 (s, 1 H), 7.43-7.54 (m, 2 H), 8.18-8.25 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:11](=[O:12])[C:5]2=[CH:4][N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:11](=[O:12])[C:5]2=[CH:4][N:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1ccccc1-c1nc2nc(N)ncc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2nc(NC(C)=O)ncc2c(=O)[nH]1

Procedure:
A stirred mixture of 7-amino-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.59 g) and acetic anhydride (5 ml) was heated under reflux for 1.5 hours. Excess acetic anhydride was removed under reduced pressure. The solid residue was washed with water and triturated with hot methanol to yield the title compound, 0.57 g, m.p. 273-4° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([OH:14])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3].[Na+].[CH3:16][CH:17]([CH3:24])[CH2:18][C:19](=O)[C:20]([O-:22])=[O:21].C([BH3-])#N.[Na+]>O>[C:20]([CH:19]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([OH:14])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3])[CH2:18][CH:17]([CH3:24])[CH3:16])([OH:22])=[O:21]
Reactant: CC(C)CC(=O)C(=O)[O-]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(CC(C)C)C(=O)O)C(=O)O
Yield: 85.2 %

Procedure:
A solution of L-alanyl-L-isoleucine (150 mg) and 4-methyl-2-oxopentanoic acid sodium salt (564 mg) in water was adjusted to pH 7 and treated with 140 mg of sodium cyanoborohydride at room temperature for several days. The reaction was quenched with strong acid ion-exchange resin, added to a column of the same resin, and eluted with 2% pyridine in water. Freeze drying afforded 200 mg (84.9%) of white fluffy solid, N-(1-carboxy-3-methylbutyl)-L-alanyl-L-isoleucine. Mass spectrum showed peaks at 460 for the disilylated derivative, and 445 for disilyl molecular ion minus methyl (460-15). The nmr spectrum showed a broad doublet centered at 0.95 ppm, complex absorption in the 1.2-1.8 ppm range, and a broad weak singlet at 3.7 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1.O.C1(C)C=C[C:21]([S:24](O)(=O)=O)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:21]2=[S:24])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(Cl)cc1NCCCNC(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Cl)cc1N1CCCN(C(C)C)C1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a suspension of the diamine of Step C (6.47 g) in dioxane (100 mL) was added N,N′-thiocarbonyl-di-1,2,4-triazole (4.85 g) and the mixture was stirred at room temperature for 2 hours. Para-toluenesulfonic acid monohydrate (7.07 g) was added and the reaction mixture was heated at reflux under nitrogen until the reaction was complete by TLC (31 hours). Upon cooling the mixture was evaporated to dryness. The solid residue was redissolved in ethyl acetate, the solution was washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel packed in hexane. Elution with a gradient of 20-25% ethyl acetate in hexane provided the title compound (5.81 g, 76.4%) as a white solid which was further triturated in hexane, m.p. 176-178° C.
Reaction SMILES: F[C:2]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:16])[CH:3]=1.[F:17][S:18]([F:29])([F:28])([F:27])([F:26])[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[CH3:15][S:12]([C:11]1[C:2]([O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:18]([F:29])([F:17])([F:26])([F:27])[F:28])[CH:20]=2)=[CH:3][C:4]([CH3:16])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:14])=[O:13]
Reactant: Oc1cccc(S(F)(F)(F)(F)F)c1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 25 °C
Yield: 27.6 %

Procedure:
600 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate, 700 mg of 3-pentafluorosulfanylphenol and 1.6 g of Cs2CO3 were stirred in 4 ml of anhydrous DMF at 100° C. for 3 h. The mixture was then cooled to RT, diluted with 100 ml of EA and washed 3 times with 20 ml of water each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with DIP. 300 mg of a colorless oil were obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-4-fluorobiphenyl-2-carbonitrile (2 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.4 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.3 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.4 g, 87%).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[C:41]([S:53]([CH3:56])(=[O:55])=[O:54])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[C:41]([S:53]([CH3:56])(=[O:54])=[O:55])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(-c2ccc(Br)cc2S(C)(=O)=O)cc1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: COc1ccc(-c2ccc(C#Cc3cc(Cl)ccc3OCC(=O)OC(C)(C)C)cc2S(C)(=O)=O)cc1
Yield: 72 %

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-4′-methoxy-2-(methylsulfonyl)biphenyl (Intermediate 205), the title compound was obtained as a brown sticky solid in 72% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[OH:1][C@H:2]1[CH2:3][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH3:7])[CH2:5]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (50 mg, 0.09 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and extracted with 5% MeOH/CH2Cl2 (2×). The combined organics were concentrated and triturated with EtOAc to afford 19 mg (50%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-hydroxy-cyclobutyl)-ethyl]-amide as a light yellow solid. MS: (M+H)+=409; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.09 (s, 1H), 8.42 (s, 1H), 8.39 (dd, J=8.7, 5.3 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.71 (dd, J=9.6, 2.1 Hz, 1H), 7.26 (td, J=9.1, 1.9 Hz, 1H), 4.96 (br. s., 1H), 4.14 (s, 3H), 4.07-4.26 (m, 2H), 2.23-2.41 (m, 1H), 1.98-2.19 (m, 3H), 1.84-1.98 (m, 1H), 1.20 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH2:39][CH:40]([OH:44])[CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:44][CH:40]([CH2:41][CH2:42][CH3:43])[CH2:39][CH2:38][CH3:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CCCC(O)CCC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(CCC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 61.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-heptanol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (44 mg, yield 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]3[CH2:14][CH2:13]3)[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>[Cu]I.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.C(N(CC)CC)C>[CH:12]1([C:10]2[CH:11]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]3([CH3:18])[CH3:17])[CH2:14][CH2:13]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C3CC3)c2O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C3CC3)c2O1

Procedure:
Following general procedure D and using 6-bromo-8-cyclopropyl-2,2,4,4-tetramethyl chroman (Intermediate 32, 0.376 g, 1.22 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (3 mL), anhydrous tetrahydrofuiran (5 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), the title compound was obtained as an oil (0.173 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]([O:10]C)=O)=[CH:5][S:6][CH:7]=1.O.[NH2:13][NH2:14]>CO>[CH3:1][O:2][C:3]1[C:4]([C:8]([NH:13][NH2:14])=[O:10])=[CH:5][S:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1cscc1OC
Solvent: O
Solvent: CO
Product: COc1cscc1C(=O)NN

Procedure:
Methyl 4-methoxy-3-thiophenecarboxylate (50.8 g, 0.295 mol) was refluxed with hydrazine hydrate (30 ml) in methanol (250 ml) overnight. The solvent was evaporated and the residue was diluted with water (300 ml) and extracted with dichloromethane (5×100 ml). The dichloromethane extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to give the title compound as an off white solid, 49.5 g, m.p. 91°-92°.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]([S:58]([CH3:61])(=[O:60])=[O:59])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:57])[C@H:28]([NH:37][C:38]([C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][N:41]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:39])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:23][CH2:22]1.CCO.ClCCCl.NN>CCOC(C)=O>[NH2:3][CH2:12][CH2:13][N:14]([S:58]([CH3:61])(=[O:59])=[O:60])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:57])[C@H:28]([NH:37][C:38]([C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][N:41]2[C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])=[O:39])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN2C(=O)c3ccccc3C2=O)S(C)(=O)=O)CC1
Agent: NN
Solvent: ClCCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN)S(C)(=O)=O)CC1
Yield: 94.5 %

Procedure:
To a 50 mL round-bottomed flask equipped with stirring was added a solution of tert-butyl 3-(N-((1R)-2-[4-(2-{[2-(1,3-dioxoisoindolin-2-yl)ethyl](methylsulfonyl)-amino}phenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step e) (433.5 mg, 0.5 mmol) in 3:1 EtOH:1,2-dichloroethane (15 mL) followed by hydrazine (Aldrich) (49 mg, 1.5 mmol). The reaction mixture was stirred at 60° C. for 12 h. The organic solvents were removed in vacuo to provide a white solid which was dissolved in EtOAc (20 mL) and washed with satd NaHCO3 (20 mL) and satd NaCl (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (349 mg). MS (ESI, pos. ion) m/z: 738 (M+1); MS (ESI, neg. ion) m/z: 736 (M−1). Calc'd for C38H48ClN5O6S: 737.30.