Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][O:8][CH2:7][C:6]2([CH3:14])[CH3:13].BrB(Br)Br.O>C(Cl)Cl>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[CH2:9][O:8][CH2:7]1
Reactant: COc1ccc2c(c1)C(C)(C)COC2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)COCc2ccc(O)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.9 %

Procedure:
6-methoxy-4,4-dimethyl-3,4-dihydro-1H-isochromene (Intermediate 41, 350 mg, 1.8205 mmol) was dissolved in DCM (10 mL) and the solution was cooled to 0° C. Tribromoborane (228.04 mg, 0.9102 mmol) was added and the resulting mixture was stirred at 0° C. for 2 hours. Water (10 mL) was added and the two phases were separated. Organics were dried over Na2SO4, filtered and dried in vacuo. The crude was purified by flash chromatography (Biotage system) on silica gel using a SNAP 25 g as column and cyclohexane/ethyl acetate from 100:0 to 70:30 as eluent affording the title compound (42 mg).
Reaction SMILES: [Cl:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][CH:21]([OH:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[F:27][C:28]1[CH:29]=[N:30][NH:31][C:32]=1[Sn](CCCC)(CCCC)CCCC>>[Cl:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([C:32]3[NH:31][N:30]=[CH:29][C:28]=3[F:27])[C:15]([N:19]3[CH2:22][CH:21]([OH:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(O)C2)c(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(O)C2)c(-c2[nH]ncc2F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 92 using N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-5-iodonicotinamide (Stage 88.1) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole. After purification by flash chromatography on silica gel, the residue was dissolved in MeCN (2 mL), sonicated and then stirred at RT for 90 min. The resulting suspension was filtered, washed with MeCN (3 mL) and dried to afford the title product as a white solid. HPLC (Condition 7) tR=5.72 min, UPLC-MS (Condition 8) tR=0.93 min, m/z=454.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.53-3.61 (m, 2H) 3.91-4.01 (m, 2H) 4.37-4.47 (m, 1H) 5.57 (br. s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.83-7.97 (m, 3H) 8.04 (d, J=1.96 Hz, 1H) 8.78 (d, J=1.96 Hz, 1H) 10.23 (br. s, 1H) 13.03 (br. s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[N:9][O:10][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(CBr)=NOC(=O)c1ccc(Cl)cc1
Yield: 100.3 %

Procedure:
To the mixture of ethyl 3-bromo-2-(hydorxyimino)propanoate (3 g, 14.3 mmole) and 4-chlorobenzoyl chloride (2.75 g, 15.71 mmole) in dry methylene chloride (100 ml) at 0° to 5° C. with stirring, was slowly added dry pyridine (1.2 g, 15.18 mmole). After addition, the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with 50 ml of methylene chloride and washed with water and brine. The organic layer was dried with magnesium sulfate and the solvent evaporated to afford 5.0 g (99% yield) of ethyl 3-bromo-2-(4-chlorobenzoyloximino)propanoate as a white solid, m.p. 82°-84.5° C.
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2ccccc2)CCN(C)C1
Temperature: 95 °C

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg, 0.111 mmol), phenylboronic acid (20 mg, 0.166 mmol) and K3PO4 (58.8 mg, 0.217 mmol) in DMF-water (4.5:0.5 mL) was added PdCl2(PPh3)2 (3.8 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-phenyl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (4 mg). 1H NMR (TFA salt, CD3OD) δ (ppm): 7.79-7.65 (m, 2H), 7.3 (s, 1H), 7.2-7.1 (m, 4H), 7.1-7.0 (m, 2H), 6.9 (d, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.61-3.60 (m, 1H), 3.25-3.2 (m, 1H), 3.05-3.00 (m, 1H), 2.9 (s, 3H), 2.4 (s, 3H), 2.4-2.39 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Yield: 95.6 %

Procedure:
By the method of Example 3, Step A, 23.15 g (0.147 mole) of 3-fluoro-4-nitrophenol and 29.92 g (0.175 mole) of 2-iodopropane were reacted in the presence of 20.73 g (0.150 mole) of anhydrous potassium carbonate in 450 mL of acetone, yielding 28.0 g of 4-isopropoxy-2-fluoronitrobenzene as an oil. The NMR was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12](C#C)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].O=C(C1C=CC([Br:30])=CC=1)CCC(C)C.C[Al](C)C>CCCCCC>[CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([Br:30])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: C#Cc1ccc(C(C)(C)CCC(C)C)cc1
Reactant: CC(C)CCC(=O)c1ccc(Br)cc1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)CCC(C)(C)c1ccc(Br)cc1

Procedure:
Reaction Scheme 6 discloses specific synthetic steps leading to 4-(1,1,4-trimethylpentyl)phenylethyne (Compound 32). In this synthetic route 4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 29, obtained as shown in Reaction Scheme 5) is reacted under a nitrogen atmosphere with trimethylaluminum in hexane to yield 4-(1,1,4-trimethylpentyl)bromobenzene (Compound 33). The bromobenzene derivative 33 is converted through the corresponding trimethylsilylethyne derivative 34 into the target intermediate 32 by treatment with trimethylsilyl ethyne and subsequently with KOH in isopropanol, as described above. ##STR10##
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.C(Cl)Cl>[C:1]1([N:7]2[C:11]([NH:12][C:20](=[O:21])[O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccnn1-c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1ccnn1-c1ccccc1)Oc1ccccc1
Reaction time: 1 h

Procedure:
1-Phenyl-1H-pyrazol-5-amine (1 eq) was dissolved in DCE (0.1M), phenylchloroformate (1.1 eq) was added. The reaction was stirred 1 h, then diluted with DCM and washed with water and brine, dried and concentrated under reduced pressure to afford the product in quantitave yield.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]([CH2:8][CH3:9])[CH2:4][C:5]([OH:7])=[O:6].[CH3:12][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:12][O:6][C:5](=[O:7])[CH2:4][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:8][CH3:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCC(CC(=O)O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCC(CC(=O)OC)C(F)(F)F
Yield: 92.3 %

Procedure:
To a stirred solution of Example 1D (250 mg, 1.47 mmol) in dichloromethane (10 mL) and methanol (0.25 mL), under nitrogen atmosphere, trimethylsilyldiazomethane (2.0 M solution in diethyl ether) (2.1 mL, 4.19 mmol) was added drop wise at 0° C. The reaction mixture was stirred keeping the temperature below 5° C. for 1 h. The solvent was removed (40° C., 25 bar) yielding 250 mg (75.4%) of a yellow oil that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][OH:57])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][O:57][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[C:28]([N:32]6[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)[CH:29]=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Reactant: OCC1CCCCC1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCC5CCCCC5)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using cyclohexanemethanol (31 μL, 0.25 mmol) to give 5-{3-[2-[4-(6-cyclohexylmethoxy-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([N+:11]([O-:13])=[O:12])[CH3:10])(=O)=O.[I-:15].[Na+].O>CC(C)=O>[CH3:10][C:9]([N+:11]([O-:13])=[O:12])([CH3:14])[CH2:8][CH2:7][CH2:6][I:15]
Reactant: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(CCCI)[N+](=O)[O-]
Reaction time: 8 h
Yield: 99.6 %

Procedure:
4-Methyl-4-nitropentanol methanesulfonate (3.38 g, 15 mmol) was dissolved in acetone (50 ml) and sodium iodide (8.7 g, 58 mmol) was added. The mixture was stirred overnight. Water (20 ml) was added and acetone was evaporated by concentration under reduced pressure. The residue was extracted with ethyl acetate (50 ml). The extract was washed with 5% aqueous sodium thiosulfate solution (20 ml) and saturated brine (20 ml), and ethyl acetate was evaporated by concentration under reduced pressure to give the objective compound (3.84 g, yield 99.6%).
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:32](=[O:33])[N:17]3[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]4[S:25][CH:26]=[N:27][N:28]=4)[CH2:20][S:21][C@H:16]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)C1=CSCCO1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1=CSCCO1

Procedure:
2-(2,3-Dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 1 g.) was allowed to react with 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) in a similar manner to that of Example 1 to give the captioned compound (2.3 g.), pale yellow powder, mp. 160° to 165° C. (dec.).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@H:8]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=1)(=O)=O.[C-:27]#[N:28].[Na+].[Na+].[I-]>CS(C)=O.O>[C:27]([CH2:6][CH2:7][C@@H:8]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(OC(F)F)cc1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCC#N)c1ccc(OC(F)F)cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a stirred solution of 388 in DMSO (5 mL) was added NaCN (92.0 mg, 1.88 mmol) and NaI (25.6 mg, 0.171 mmol) and the mixture heated at 85° C. overnight. After cooling to RT, the mixture was diluted with H2O (100 mL), stirred for 30 min and filtered to afford a tan solid. The solid was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 25% EtOAc) to afford 261 mg (47%) of (R)-tert-butyl 3-cyano-1-(4-(difluoromethoxy)phenyl)propylcarbamate (390) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=O)=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH3:28]>CO>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH2:28])=[O:24])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: N
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Solvent: CO
Product: NC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 48 h

Procedure:
A solution of the product of Example 1 (200 mg) in methanol (10 ml), prepared under argon, was cooled to 4° C.and saturated with dry ammonia gas, then sealed in a pressure bottle and kept for 2 days. The orange crystals which formed, after filtration and washing with a little methanol, gave the title compound, 140 mg: m.p. 247° to 248° C.; NMR (d6DMSO) δ 8.16 (2H, d), 7.99 (2H, d), 7.55 (1H, bs), 7.37 (1H, bs), 7.02 (2H, d), 6.81 (2H, d), 4.54 (2H, s), 3.85 (2H, s), 3.33 (4H, t), 2.60 (4H, t); m/e 355 (M+H)+ ; calculated for C19 H22N4O3 : C, 64.4; H, 6.3; N, 15.8. found: C, 64.4; H, 6.4; N, 15.6%.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH:9][NH2:10])=[N:7][CH:6]=[CH:5][N:4]=1.[C:11]([N:16]=[C:17]=[S:18])(=[O:15])[O:12][CH2:13][CH3:14].CO>C(Cl)(Cl)Cl>[Cl:2][C:3]1[C:8]([NH:9][NH:10][C:17]([NH:16][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[S:18])=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: NNc1nccnc1Cl
Reactant: CCOC(=O)N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)NC(=S)NNc1nccnc1Cl
Yield: 120.9 %

Procedure:
A solution of 2-chloro-3-hydrazinylpyrazine hydrochloride (3.32 g, 18.34 mmol) in anhydrous chloroform was treated with O-ethyl carbonisothiocyanatidate (1.9 mL, 16.11 mmol) at room temperature. Anhydrous methanol (10 mL) was added to the reaction mixture which was then concentrated under reduced pressure to yield ethyl 2-(3-chloropyrazin-2-yl)hydrazinecarbonothioylcarbamate (5.37 g) as an orange solid.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25]O>>[CH2:1]([CH:8]([CH2:12][C:13]([N:15]1[CH2:16][C@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:23]1)=[O:14])[C:9]([O:11][CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (100 mg) was added a 3% solution of hydrogen chloride in methanol (2 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed successively with saturated sodium bicarbonate solution and brine, treated with activated charcoal, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 91 mg of methyl 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate as a colorless viscous oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:19][C:16]([CH3:17])([CH3:18])[CH2:15][C@H:2]([OH:1])[CH2:3][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC(C)(C)C)cc1
Product: CC(C)(C)C[C@H](O)CN1CCOCC1
Temperature: 160 °C
Yield: 67 %

Procedure:
(S)-toluene-4-sulfonic acid 2-hydroxy-4,4-dimethyl-pentyl ester obtained from Example 4, step A (700 mg, 2.4 mmol) was charged to a large microwave reactor vial and treated with morpholine (3 mL). The vial was crimped shut and heated to 160° C. for 6 minutes. The solvent was then removed. The resulting oil was dissolved in ethyl acetate and extracted 3 time with aqueous 1 M HCl. The organics were discarded and the aqueous layer was made basic with solid NaOH and extracted 3 times with ethyl acetate. The organic extracts were combined, dried over MgSO4 and the solvent was removed to afford 330 mg (67%) of material which was used without further purification: HPLC-MS calcd. for C11H23NO2 (M+H+) 202.2, found 202.5.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].[C:9]1(=O)[CH2:12][CH2:11][CH2:10]1>CO.[Pd]>[CH:9]1([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[C:6]([OH:8])=[O:7])[CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C1CCC1
Reaction time: 20 h

Procedure:
A mixture of (S)-pyrrolidine-2-carboxylic acid (1.0 g, 8.69 mmol), cyclobutanone (671 mg, 9.56 mmol) and 10% Pd/C (44 mg) in MeOH (10 mL) was stirred under an atmosphere of hydrogen for 20 hours. The reaction mixture was filtered through Celite® and the filtrate concentrated under vacuum. The resulting residue was triturated with diethyl ether to afford (S)-1-cyclobutyl-pyrrolidine-2-carboxylic acid. 1H NMR (300 MHz, CDCl3) δ: 4.41 (s, 1H), 3.86 (dt, 1H), 3.78-3.63 (m, 2H), 2.78 (m, 1H), 2.55 (m, 1H), 2.57-2.09 (m, 4H), 1.91 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[CH3:14][N:15]1[CH:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[NH:17][C:16]1=[O:23]>>[CH3:14][N:15]1[CH:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=2)[C:16]1=[O:23]
Reactant: CN1C(=O)NC2CCCC21
Reactant: C[Si](C)(C)C#Cc1ccc(Br)nc1
Product: CN1C(=O)N(c2ccc(C#C[Si](C)(C)C)cn2)C2CCCC21

Procedure:
The title compound, an off-white solid, MS: m/e=314.1 (M+H+), was prepared in accordance with the general method of example 106, step 4 starting from 2-bromo-5-((trimethylsilyl)ethynyl)-pyridine (Example 37, step 1) and (3aRS,6aSR)-1-methylhexahydrocyclopenta[d]imidazol-2(1H)-one (Example 106, step 3).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH:12]=[CH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:30]([O:33][CH2:34][CH3:35])(=[O:32])C.C(Cl)(Cl)Cl>O1CCOC1>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH2:12][C@@H:11]1[CH:30]1[O:33][CH2:34][CH2:35][O:32]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C=CC(=O)O1
Reactant: CCOC(C)=O
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1COCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Yield: 94 %

Procedure:
A solution containing 228 mg (0.998 mmol) compound (2a) and 18.0 mg (0.998 mmol) benzophenone in 200 mL [1,3]-dioxolane was irradiated at 20° C. for 5 hours according to the general procedure. Column chromatography (silica gel 35 g, ethyl acetate in hexanes 30%) gave compound (3a) (285 mg, 94%) as a colorless solid, Rf=0.35, [α]25D 18.3°, c 1.3, CHCl3, IR (neat) 2953, 2857, 1778, 1125 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 0.05 (s, 6H), 0.87 (s, 9H), 2.45 (dd, 1H, J=4.2 Hz, J=17.7 Hz), 2.68 (d, 1H, J=17.7 Hz), 2.72-2.79 (m, 1H), 3.65 (dd, 1H, J=2.7 Hz, J=11.4 Hz), 3.86-3.91 (m, 3H), 3.97-4.01 (m, 2H), 4.50 (mc, 1H), 4.88 (d, 1H, J=3.6 Hz). 13C-NMR (75.4 MHz, CDCl3, Dept) δ: 5.52 (+), 18.18 (quat), 25.77 (+), 30.12 (−), 39.67 (+), 64.71 (−), 65.36 (−), 65.47 (−), 80.24 (+), 103.94 (+), 176.55 (quat). C14H26O5Si; Exact Mass: 302.15; Mol. Wt.: 302.44; C, 55.60, H, 8.67, O, 26.45, Si, 9.29.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c12
Reaction time: 2 h

Procedure:
To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (52 mg, 0.16 mmol) in 1 mL of dichloromethane at 0° C. was added triethylamine (0.067 mL, 0.91 mmol) and acetic anhydride (0.058 mL, 0.52 mmol). After two hours, the mixture was partitioned between ethyl acetate and 3N HCl solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled compound. HRMS (ES) exact mass calculated for C15H18N4O5SNa (M+Na+): 389.0890. Found 389.0889.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=O>ClCCl>[CH2:12]([O:11][C:7](=[O:10])[CH:8]=[N:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])[CH3:13]
Reactant: CCOC(=O)C=O
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CCOC(=O)C=NC(C)(C)CO
Reaction time: 16 h
Yield: 98.1 %

Procedure:
2-Amino-2-methyl-1-propanol (9.54 ml, 0.10 mol) was added to a stirred solution of ethyl glyoxylate (50% soln. in toluene, 21 ml, 0.10 mol) in dichloromethane (100 ml) in the presence of 4 Å molecular sieves. The reaction was stirred under nitrogen for 16 h whereupon the system was filtered through Dicalite® and washed with more dichloromethane. Evaporation of the solvent in vacuo gave (1,1-dimethyl-2-hydroxy-ethylimino)-acetic acid ethyl ester (17.0 g) as an oil (EIMS: m/z=174 [M+H]+). 2-Fluorobenzoyl chloride (0.60 ml, 5.00 mmol) and then pyridine (0.96 ml, 12.0 mmol) were added to a stirred solution of the above described ethyl ester (0.87 g, 5.00 mmol) in dichloromethane (8 ml) cooled to ˜5° C. and under nitrogen. After 1.5 h water (20 ml) was added, the layers separated and the aqueous phase washed with more dichloromethane (30 ml). The combined organic phase was then washed with 1N hydrochloric acid (25 ml) before being dried (MgSO4), filtered and solvent removed in vacuo. The crude residue was purified by chromatography on silica using dichloromethane as eluant, to give 3-(2-fluorobenzoyl)-4,4-dimethyl-oxazolidine-2-carboxylic acid ethyl ester (0.64 g) as an oil, EIMS: m/z=296 [M+H]+