Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[CH:8](=[C:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[CH2:9][CH3:10]>C(Cl)Cl>[CH2:8]([CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[CH2:9][CH3:10]
Reactant: CCC=C1CCCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CCCC1=O
Temperature: 50 °C
Reaction time: 28 h
Yield: 95.1 %

Procedure:
In a 100 ml-volume three-way-cocked eggplant type flask whose atmosphere had been displaced with nitrogen was charged 845 mg (0.5 mmole) of Ru2Cl4 ((+)-BINAP)2 (NEt3), and 12.4 g (100 mmole) of 2-propylidenecyclopentanone and 50 ml of methylene chloride were added thereto to form a solution. The solution was put in a 100 ml autoclave having been displaced with nitrogen and stirred at 50° C. under a hydrogen pressure of 90 kg/cm2 for 28 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography using a mixed solvent of diethyl ether and hexane (1:4 by volume) as an eluent to obtain 12 g (percent yield: 97%) of 2-propylcyclopentanone as a clear yellow liquid. 1H-NMR (CDCl3)δ(ppm): 1.50 (t, 3H, J=7 Hz), 1.42 (m, 4H), 1.50-2.80 (m, 7H)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:18]=1)[CH3:12]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (250 mg, 1.24 mmol) was coupled to aniline (64) (241 mg, 1.24 mmol) using Method C to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14]O)=[CH:12][N:11]=[C:10]1[S:16][CH2:17][CH2:18][CH3:19].S(Cl)([Cl:22])=O>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][Cl:22])=[CH:12][N:11]=[C:10]1[S:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: CCCSc1ncc(CCl)n1Cc1ccccc1Cl
Product: Cl
Yield: 94 %

Procedure:
A mixture of 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole (0.117 g, 0.393 mmol) in thionyl chloride (1 mL) was refluxed for 2 hours, evaporated in vacuo to an amorphous solid and triturated with ether to provide 1-(2-chlorophenyl)methyl-5-chloromethyl-2-propylthio-1H-imidazole hydrochloride (0.13 g, 94%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][C@H:36]1[OH:48]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][C@@H:36]4[OH:48])=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]C)=[CH:20][CH:19]=2)=[CH:5][CH:4]=1.[Cl:26]C1C=CC=C(C(OO)=O)C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[ClH:26].[ClH:26].[ClH:26].[SH:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:19]=[CH:20][C:21]([SH:24])=[CH:22][CH:23]=2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(NCCCNCCCNc2ccc(SC)cc2)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cl
Product: Sc1ccc(NCCCNCCCNc2ccc(S)cc2)cc1

Procedure:
Dissolve 1,9-bis[4-methylmercaptophenyl]-1,5,9-triazanonane (1.88 g, 5 mmol) in chloroform (20 mL) and treat with metachloroperbenzoic acid (863 mg, 5 mmol). Add calcium hydroxide (556 mg, 7.5 mmol) and stir for 15 minutes. Filter and evaporate the solvent in vacuo. Dissolve the residue in trifluoroacetic anhydride (10 mL) and heat at reflux for 30 minutes. Evaporate the volatiles in vacuo and dissolve the residue in a mixture of methanol-triethylamine (1:1, 100 mL) and evaporate the solvent in vacuo. Dissolve the resdiue in chloroform, wash with saturated ammonium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give the crude 1,9-bis[(4-mercaptophenyl)]-1,5,9 triazanonane.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[C:11]([CH2:13][N:14]3[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]3)[CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:24][CH:23]=1>>[C:2]([C:7]1[N:12]=[C:11]([CH2:13][N:14]2[CH:18]=[CH:17][C:16]([NH:19][C:30](=[O:31])/[CH:29]=[CH:28]/[C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:33])([F:34])[F:20])=[CH:27][CH:26]=3)=[N:15]2)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2cccc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1cccc(Cn2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=414.93.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9](OC)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[C:1]1([CH:7]2[NH:8][C:9](=[NH:17])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(C2=CCCCC2)CCCC1
Solvent: CO
Product: Cl
Product: N=C1CCCCC(C2=CCCCC2)N1

Procedure:
The product of EXAMPLE 253 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)=[CH:8][C:4]=2[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[OH:40]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:40][C:4]1[CH:5]=[CH:6][N:7]=[C:2]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3ccnc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5 mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190° C. in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluents hexane and acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61% yield) as a yellow solid MS (m/z) 487.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][C:12]([CH3:17])([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][C:12]([CH3:17])([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1Cc2c([nH]c3ccc(Cl)cc23)CC1(C)C
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1Cc2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)CC1(C)C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2,3,3-trimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=1>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][N:35]2[CH2:34][CH2:33][N:32]([CH2:31][C:30]3[CH:38]=[CH:39][C:27]([F:26])=[CH:28][CH:29]=3)[CH2:37][CH2:36]2)[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCC1CO1
Solvent: CCO
Product: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCC(O)CN1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A mixture comprising 2.4 g of N-benzyloxycarbonyl-3-(2,3-epoxypropyloxy)-4-methoxybenzylamine, 30 ml of ethanol and 1.4 g of 4-fluorobenzyl-piperazine, was refluxed under heating with stirring overnight. The mixture was cooled to room temperature, and then the reaction solution was concentrated under reduced pressure and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=19:1) to obtain 2.6 g of the above-identified compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:30]2>COC(O)CC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:30]5)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Reactant: NC(=O)CN1Cc2ccc(N)cc2C1
Agent: CCC(O)OC
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5c(c4)CN(CC(N)=O)C5)nn23)cn1

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.112 g, 0.298 mmol) and 2-(5-Amino-1,3-dihydro-isoindol-2-yl)-acetamide (0.077 g, 0.40 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h in methoxypropanol. Yellow solid precipitated out which was filtered off and washed with water (47 mg, 38%). Found to be pure desired product. LCMS=415.9 (M+H), HPLC rt=2.039 min, purity=96%. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.51 (s, 1H), 9.02 (s, 1H), 8.98 (s, 1H), 8.42 (dd, J=8.7 Hz, 2.3 Hz, 1H), 7.89 (s, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.34 (s, 1H), 7.18-7.10 (m, 3H), 6.99-6.95 (m, 2H), 4.01 (s, 2H), 3.94 (s, 5H), 3.29 (s, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH2:30][CH:29]=[CH:28][CH2:27][CH2:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:26][CH:27]=[CH:28][CH2:29][CH2:30]1
Reactant: C1=CCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CC=CCC4)cc3c2)cc1

Procedure:
The product from Example 1C and 1,2,3,6-tetrahydropyridine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 329 (M+H)+;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:34][CH3:35])=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:7]=2)[C:17]=1[O:34][CH3:35])(=[O:25])=[O:24]
Reactant: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Reactant: CC(C)CN
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(C(C)C)sc1-c1ccnc(NCC(C)C)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzenesulfonamide (150 mg, 0.279 mmol) and isobutylamine (0.140 mL, 1.397 mmol) the title compound was obtained as an off-white foam (86.3 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 7.94 (d, J=4.9 Hz, 1H), 7.54-7.73 (m, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.15-7.32 (m, 3H), 6.99-7.17 (m, 2H), 5.74 (dd, J=2.2, 1.1 Hz, 1H), 3.24-3.28 (m, 1H), 3.12 (s, 3H), 3.01 (br. s., 2H), 1.81 (dt, J=13.3, 6.6 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H), 0.85 (d, J=6.6 Hz, 6H). MS (ESI): 574.2 [M+H]+.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:20][CH:19]=2>C(#N)C>[N+:25]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:24]=[C:16]([CH3:15])[N:17]2[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-:27])=[O:26]
Reactant: Cc1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cn1c(C)cc2c([N+](=O)[O-])cccc21
Temperature: 60 °C

Procedure:
Water (4.5 ml), potassium carbonate (25.9 g, 187 mmol) and ethyl bromoacetate (20.8 ml, 188 mmol) were added sequentially to a suspension of 2-methyl-4-nitro-1H-indole (30 g, 170 mmol) in acetonitrile (225 ml) and the mixture heated at 60° C. for 16 hours. After allowing to cool to ambient temperature, water (225 ml) was added and the resulting mixture was broken up and then filtered. The solid was washed with water (2×75 ml), followed by IMS (2×75 ml) then dried in a vacuum oven to give (4-nitro-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester, 32.15 g (72%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([C:25](=[O:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1.O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:22]2[CH2:23][CH2:24][N:19]([C:25](=[O:27])[CH3:26])[CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Yield: 68.8 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (100 mg, 0.32 mmol) and 1-(piperazin-1-yl)ethanone (83 mg, 0.65 mmol) in NMP (1 mL) was heated to 110° C. for 16 h, cooled then diluted with H2O (15 mL) and extracted with ethyl acetate (2×15 mL). The organics were washed with brine (8 mL), dried (Na2SO4) then filtered and concentrated in vacuo. The residue was subjected flash silica column chromatography (100% ethyl acetate) to furnish 1-(4-(3-(benzylamino)-4-nitrophenyl)piperazin-1-yl)ethanone (mg, 0.22 mmol) as a yellow solid (71 mg, 0.19 mmol) 61% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.83 (m, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.39 (m, 4H), 7.28 (m, 1H), 6.40 (dd, J=2.5 Hz, 10 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 4.58 (d, J=6 Hz, 2H) 3.50-3.29 (m, 8H), 2.34 (s, 3H).+ESI HRMS (calcd for C19H22N4NaO3, M+Na) 377.1590, found 377.1584
Reaction SMILES: [C-:1]1([C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17].P(Cl)(Cl)[Cl:19]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([C:6]([CH3:11])([CH3:10])[C:7]([Cl:19])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17]
Reactant: CC(C)(C(=O)O)[c-]1cccc1
Reactant: ClP(Cl)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C(=O)Cl)[c-]1cccc1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 2-ferrocenyl-2-methylpropionic acid (7.55 g) and pyridine (15 drops) in 500 cm3 of dry benzene was slowly added 25 cm3 of phosphorous trichloride. The resulting mixture was stirred for 3 h at 60° to 70° C. After this time the solution was decanted off and the solvent removed under vacuum. The red-brown viscous residue obtained was twice more evaporated from dry benzene to give 6.91 g (85%) of 2-ferrocenyl-2-methylpropanoyl chloride, a red brown solid, which was recrystallised from light petroleum (40° to 60° C.). The ferrocenyl acid chloride (6.91 g) was dissolved in 10 cm3 of dichloromethane and added to a mixture of 6-aminopencillanic acid (5.18 g) and triethylamine (4.85 g) in 100 cm3 of dichloroethane at 2° C. The resulting mixture was stirred for 1 hour at 15° C., filtered and filtrate evaporated cold `in vacuo`. The residue was dissolved in a mixture of water and ethyl acetate and the aqueous phase adjusted to pH 2.5 with 2M HCl. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts of ethyl acetate were washed several times with water, dried and filtered. To the dry ethyl acetate solution was added 10 cm3 of a 40% solution of sodium 2-ethylhexanoate in 4-methylpentan-2-one. The mixture was concentrated under vacuum and then poured into 600 cm3 of dry ether. The product, which separated as a pale yellow solid, was collected by filtration and dried to yield 8.43 g (72%) of the penicillin. The i.r. spectrum showed a strong β-lactam carbonyl absorption at 1760 cm-1. A thin layer silica gel chromatogram (chloroform/acetone/acetic acid) showed a single substance.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:22][C:23](OC(C)=O)=[O:24]>C(Cl)Cl>[C:23]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)(=[O:24])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (200 g, 1 mol) and Et3N (150 g, 1.5 mol) in DCM (3000 mL) was added Ac2O (102 g, 1 mol) dropwise over 1 h, while maintained the temperature at 0° C. After addition, the mixture was stirred 0° C. for another 2 h, at which time TLC showed the reaction was completed. The solution was quenched by addition of water (1 L). The organic phase was collected and washed with saturated aqueous NaHCO3 (1 L), dried (Na2SO4) and concentrated to give crude product. Four batches were run in parallel and produced a combined crude product weight of 670 g. This crude was used directly in the step. LCMS (m/z): 243.1 (M+1).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CCCC(OC)=O)(OC)=O.[OH2:19]>>[CH3:1][C@H:5]([OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)CCCCCCCCCCC(=O)OC
Reactant: O
Product: CCCCCC[C@H](C)O

Procedure:
Interesterification was carried out in the same manner as in Example 9, except for replacing dimethyl tetradecadicarboxylate with 140 g of dimethyl decamethylenedicarboxylate at 80° C. for 25 hours. The water content of the reaction system was 0.04% by weight, and 95% of the lipase particles had a particle size of 20 to 60 μm. Gas chromatography of the reaction mixture revealed that 58 mol % of (R,S)-2-octanol had been converted to its decamethylenedicarboxylic acid ester. The reaction mixture was treated in the same manner as in Example 9 to remove lipase, and the filtrate was subjected to simple distillation at 95° C. and 3 mmHg. However, it was impossible to isolate (S)-(-)-2-octanol with high purity due to co-distillation of other components.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[NH:18][C:19](=[O:35])[CH2:20][NH:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:8].CCN(CC)CC>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[N:21]([CH2:20][C:19]([NH:18][C:10]1[C:9]([CH:7]([CH3:6])[CH3:8])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:15]([CH3:17])[CH3:16])=[O:35])[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)N(CC(=O)Nc1c(C(C)C)cccc1C(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 120 h

Procedure:
Several milliliters of methylchloroformate was added to the product from Example 4 (0.60 g) in a mixture of excess NEt3 and EtOAc at room temperature. Vigorous outgassing occurred with the formation of a precipitate. The solution was stripped to dryness and the residue taken up in a mixture of 50 mL THF and 50 mL saturated NaHCO3 solution. Excess methyl chloroformate was added at room temperature. This solution was allowed to sit 5 days at room temperature. The reaction mixture was diluted with EtOAc and washed with aqueous K2CO3 solution and aqueous NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated to a white solid. The solid was slurried in hexane/EtOAc 9/1 and collected by filtration. 0.55 g (80%). NMR (CDCl3) δ 1.06 (12H, d), δ 2.56 (2H, m), δ 3.84 (3H, s), δ 4.20 (2H, s), δ 6.80 (1H, bs), δ 7.0-7.5 (13H, m). IR (KBr) 3443, 2963, 1705, 1685, 699 cm-1.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25]>>[C:28]([O:27][C:23]([NH:24][NH:25][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:14])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1

Procedure:
The product was synthesized as described in Example 109 A using 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (500 mg, 1.58 mmol) and tert-butyl carbazate (230 mg, 1.74 mmol). 1H NMR (DMSO-d6) δ 10.35 (s, 1H), 8.95 (s, 1H), 8.4 (s, 1H), 8.1 (m, 2H), 7.9 (d, 1H), 7.65 (d, 1H), 7.4 (t, 2H), 1.3-1.5 (m, 9H), ES-MS m/z 371 [M+1]+.