Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][NH:8]1.C(N(CC)CC)C>C(#N)C>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc2ncnc(Cl)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
6 ml phosphorus oxychloride are added dropwise to 12.1 g of 3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline in 120 ml acetonitrile and the mixture is heated to an internal temperature of 40° C. Then 9.3 ml triethylamine are added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is cooled to ambient temperature and left to stand overnight. The solution of the product is reacted further without purification (see Example III).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>ClCCl>[F:24][C:21]([F:22])([F:23])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:40])[CH2:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:31][CH:30]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)([OH:29])[C:25]([F:28])([F:26])[F:27]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
2-(4-((4-(4-Aminobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.336 mmol, 150 mg) and 2-phenylacetyl chloride (0.504 mmol, 0.067 mL, 78 mg) were combined in dichloromethane (3 mL) and cooled to 0° C. Triethylamine (0.672 mmol, 0.093 mL, 68.0 mg) was added and the mixture allowed to stir at 0° C. for 2 hours before allowing to warm to room temperature and stirring overnight. The reaction was diluted with dichloromethane and washed with water. The mixture was filtered through a hydrophobic frit and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: dichloromethane-10% methanol/dichloromethane gradient) to afford the title compound (124.4 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH:9]=[N:10][C:11]([CH3:14])([CH3:13])C)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:15]([Si:19]([CH3:25])([CH3:24])[O:20]CC#C)([CH3:18])([CH3:17])[CH3:16]>C(#N)C.C(Cl)Cl.[Zn]>[Si:19]([O:20][CH2:14][C:11]1[N:10]=[CH:9][C:3]2[C:2]([CH:13]=1)=[CH:7][N:6]=[C:5]([Cl:8])[CH:4]=2)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:25])[CH3:24]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)N=Cc1cc(Cl)ncc1Br
Agent: [Zn]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCc1cc2cnc(Cl)cc2cn1
Temperature: 70 °C

Procedure:
A mixture of N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine (530 mg, 1.9 mmol), tert-butyldimethyl(2-propynyloxy)silane (0.59 mL, 2.9 mmol), NiCl2(DPPP) (52 mg, 0.1 mmol), and zinc (252 mg, 3.9 mmol) in acetonitrile (5 mL) was heated at 70° C. under an atmosphere of nitrogen. The cooled reaction mixture was diluted with methylene chloride (50 mL), filtered over Celite, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as an orange waxy solid (340 mg, 57%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[C:15](O)=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)Cl.C(Cl)(=O)[C:22](Cl)=[O:23].Cl>Cl[Ti](Cl)(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:22](=[O:23])[CH2:15][CH:10]1[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(C2CCCCC2C(=O)O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C1CCCCC1CC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
Combine 2-(3-methoxy-phenyl)-cyclohexane carboxylic acid (11.50 g, 46.3 mmol), methylene chloride (200 mL), catalytic DMF (4.0 mL) and slowly add oxalyl chloride (4.8 mL, 55.6 mmol), stir at room temperature. After 1.5 hours, at 0° C. add TiCl4 (12.7 mL, 115.78 mmol) and let reaction warm to room temperature. After 3.5 hours, quench reaction with ice water and add 5N HCl. Allow reaction mixture to stir for 30 minutes then extract with ethyl acetate and wash with sodium bicarbonate solution (aq), then Brine. Dry the organic phase with anhydrous sodium sulfate then concentrate and flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (9.91 g, 93%) as a yellow oil. TLC Rf=0.26 in 5:1 hexanes:ethyl acetate 1H NMR (CDCl3): 8.01 (d, 1H, J=8.8 Hz), 6.83 (m, 1H), 6.72 (m, 1H), 3.86 (s, 3H), 2.89 (m, 2H), 2.45 (m, 2H), 1.60 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]([O:13][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2,4-Dihydroxy-butyl)-carbamic acid tert-butyl ester in dichloromethane (15 ml) was added triethylamine (1.96 ml). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (0.82 ml) was added drop wise. The mixture was stirred at 0° C. for 2 hours. The mixture was filtered and dichloromethane was added (200 ml). The mixture was washed with 0.2M hydrochloric acid (50 ml), water (30 ml) and 0.2M sodium carbonate (50 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give crude methanesulfonic acid 1-(tert-butoxycarbonylamino-methyl)-3-methanesulfonyloxy-propyl ester (1.24 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].C(OC(=O)C)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>C(O)(=O)C>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[C:5]([N+:28]([O-:30])=[O:29])[CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c2ccccc12
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(C#N)c2ccccc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 4.2 g (15.7 mmol) 4-cyano-1-ethoxalylaminonaphthalene in 125 ml glacial acetic acid was added 125 ml acetic anhydride. At 15° C. a solution of 12 ml 100% nitric acid in 60 ml glacial acetic acid was added dropwise. Stirring was continued at 25° C. for 24 h and then at 50° C. for 1.5 h. The reaction mixture was poured into 500 ml ice-water to give 3.5 g (72%). M.p. 178.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:25]=[CH:24][C:18]3[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=4[CH:16]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:30][C:29]=1[F:28])=[O:36]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)oc(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 133, step 3) by Suzuki coupling with 3-fluoro-4-methoxycarbonylphenylboronic acid [CAS Reg. No. 505083-04-5]. MS (neg. ion, m/e)=536.3 [(M−H)−].
Reaction SMILES: Cl.[NH2:2][N:3]1[C:7]([CH3:8])=[N:6][N:5]=[C:4]1[NH:9][NH2:10].[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=O.Cl>C(O)C>[ClH:11].[NH2:2][N:3]1[C:7]([CH3:8])=[N:6][N:5]=[C:4]1[NH:9][N:10]=[CH:14][C:13]1[C:12]([Cl:11])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20]
Reactant: Cc1nnc(NN)n1N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Product: Cc1nnc(NN=Cc2c(Cl)cccc2Cl)n1N

Procedure:
To a solution of 5.25 g (0.032 mole) of 4-amino-3-hydrazino-5-methyl-1,2,4-triazole hydrochloride in 100 ml of 75 percent ethanol was added 5.6 g (0.032 mole) of 2,6-dichlorobenzaldehyde and 0.5 ml of concentrated hydrochloric acid. The mixture was stirred and heated at reflux for 16 hours. After cooling, the precipitate was collected and washed with chilled ethanol and ether. Yield: 7.0 g, m.p. 244°-245° (D).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8](C)(C)[C:9](OCC)=[O:10])=O)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH2:8][C:9](=[O:10])[NH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccc(Cl)cc2)=NN1
Yield: 82.2 %

Procedure:
A mixture of 26 g (0.10 mol) of ethyl α-(4-chlorobenzoyl)isobutyrate, 10 g (0.20 mol) of hydrazine monohydrate and 200 ml of ethanol was heated under reflux for 18 hours. The reaction solution was concentrated under reduced pressure. The obtained crude product was washed successively with water, methanol-water and diethyl ether-n-hexane and then air dried, to give 16 g of the object compound as white crystals (yield 84%).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[N+]([NH:20][C:21](N)=[O:22])([O-])=O>CC(C)=O.O>[CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[CH2:4][N:3]1[C:21]([NH2:20])=[O:22]
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H]1[C@H](Oc2cccc(C(F)(F)F)c2)CN1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine (purity 56.6% contains diphenylmethane) and 2.4 g (0.0225 mole) of nitrourea in 40 ml of acetone was treated with 4 ml of water, then heated until a clear homogenous solution was obtained. The reaction mixture was stirred overnight as it cooled to ambient temperature and diluted with water until an oil separated. The oil solidified and was recrystallized from ethanol/water, yielding 4.3 g of white plate-like crystals; m.p. 117°-118° C. The product was recrystallized from benzene, yielding 3.35 g (96.8%) of crystals, m.p. 118°-119° C.
Reaction SMILES: [Cl:1]Cl.[C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([C:3](=[O:5])[CH3:4])[CH2:7][CH2:8]2
Reactant: CC(=O)N1CCc2ccccc21
Reactant: ClCl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(Cl)ccc21

Procedure:
74.5 g (1.05 moles) of chlorine were added with stirring at 20° to 30° C. to a mixture of 161 g (1 mole) of 1-acetyl-indoline in 1,050 ml of glacial acetic acid and the mixture was stirred for 15 minutes after which 8500 ml of water were added thereto with stirring. The mixture was stirred for 30 minutes and sodium bisulfite was added to destroy excess chlorine and was then vacuum filtered. The recovered product was dissolved in 250 ml of hot isopropanol and the mixture was cooled with stirring and then vacuum filtered. The product was rinsed with 250 ml of isopropanol to obtain 5-chloro-1-acetyl-indoline which was saponified as in Example 1 to obtain 70 g (45% yield) of 5-chloro-indoline.
Reaction SMILES: [CH3:1][S:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](O)=[O:23])=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5]>C(O)(=O)C>[CH3:1][S:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:15](=[O:25])[C:16]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:17]3[C:22]2=[O:23])=[CH:12][CH:13]=1)([CH3:7])[C:4]([OH:6])=[O:5]
Reactant: CSC(C)(C(=O)O)c1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Solvent: CC(=O)O
Product: CSC(C)(C(=O)O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Yield: 96.6 %

Procedure:
α-Methylthio-α-[p-(o-carboxybenzoylamino)phenyl]propionic acid (146 mg) was dissolved in 1 ml of acetic acid, and the solution was heated under reflux for 3 hours. Acetic acid was removed under reduced pressure to afford 134 mg of α-methylthio-α-(p-phthalimidophenyl)propionic acid as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[NH:24][C:23]5C=[CH:26][CH:27]=[C:28](CO)[C:22]=5[N:21]=4)=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:3][N:2]=1.[CH3:31][CH2:32][N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])C.CS(Cl)(=O)=O.N1CCCC1>C1COCC1>[N:33]1([CH2:32][C:31]2[C:23]3[N:24]=[C:20]([C:19]4[C:13]5[C:14](=[N:15][CH:16]=[C:11]([C:4]6[C:5]7[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=7)[CH:1]=[N:2][CH:3]=6)[CH:12]=5)[NH:17][N:18]=4)[NH:21][C:22]=3[CH:28]=[CH:27][CH:26]=2)[CH2:34][CH2:36][CH2:39][CH2:37]1
Reactant: CCN(C(C)C)C(C)C
Reactant: OCc1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: c1ccc2c(-c3cnc4[nH]nc(-c5nc6c(CN7CCCC7)cccc6[nH]5)c4c3)cncc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A suspension of Compound 3 (30 mg, 0.08 mmol) and DIPEA (28 μl, 0.36 mmol) in dry THF (1 mL) was cooled to 0° C. Methanesulfonyl chloride (18 μl, 0.23 mmol) was added dropwise and the mixture was stirred at 0° C. for 3 hours. Pyrrolidine (32 μl 0.39 mmol) was added and the suspension was gradually warmed to room temperature and stirred for 2 hours. The reaction was quenched with water (0.1 mL) and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography to give Compound 7 (13 mg, 38%) as a yellow powder. 1H NMR (300 MHz MeOD) δ 9.36 (s, 1H), 9.10 (d, 1H, J=2.1 Hz), 8.78 (d, 1H, J=2.1 Hz), 8.55 (s, 1H), 8.27 (d, 1H, J=7.8 Hz), 7.95 (m, 1H), 7.83 (m, 2H), 7.72 (dd, 1H, J=1.8, 7.2 Hz), 7.39 (m, 2H), 4.75 (s, 2H), 3.38 (b, 4H), 2.01 (b, 4H); MS (ESI) m/z: 446 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][C@@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: [H][H]
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Yield: 69.5 %

Procedure:
To a solution of (R)-tert-butyl 4-benzyl-2-methylpiperazine-1-carboxylate (10 g, 34.5 mmol) in methanol (100 mL) was added Pd/C (1.0 g) and the reaction mixture was subjected to hydrogenolysis under balloon pressure of hydrogen, at room temperature for 8 h. The reaction mixture was filtered through celite bed and the bed was washed with methanol. The filtrate was concentrated under reduced pressure to afford the crude product which was purified by silica gel (100-200 mesh) column chromatography eluting with 5% methanol in chloroform to afford 4.8 g of (R)-tert-butyl 2-methylpiperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1([C:15](=[O:17])[NH2:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:18][CH2:19][C:20](OC)(OC)OC.C(O)(=O)C>>[Cl:18][CH2:19][C:20]1[NH:16][C:15](=[O:17])[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]2)[N:1]=1
Reactant: COC(CCl)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(CCl)NC2=O
Temperature: 118 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
1C (0.3M) was added 2-chloro-1,1,1-trimethoxyethane (4.0 equivalents) and acetic acid (2.0 equivalents). The mixture was stirred for 12 hr at 118° C. Solvent was removed under reduced pressure and the residue was purified by crystallization from cold diethyl ether to afford tert-butyl 2-(chloromethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1D, 67%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([CH:11]=[CH:12][CH:13]=1)N.N([O-])=[O:16].[Na+]>O>[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1c(O)cccc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution of concentrated sulphuric acid (7.3 mL) in water (97 mL) was added to 3-chloro-2-methylaniline (0.84 mL, 7.06 mmol) and the mixture heated at 90° C. until solution was achieved. The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (510 mg, 12.75 mmol) in water (5 mL) was added dropwise. The reaction mixture was allowed to warm to ambient temperature over 2 h. Excess sodium nitrite was destroyed by the addition of urea. The resultant mixture was added to a solution of concentrated sulphuric acid (5.0 mL) in water (55 mL), heated to 90° C. and stirred at this temperature for a further 1 h. The resultant product mixture was filtered through dicalite and extracted with dichloromethane (2×200 mL). The organic phase was washed with NaHCO3 (aq.), dried (MgSO4) and evaporated under reduced pressure to afford the desired product (830 mg, 83%) as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:25])[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[N:24])[CH:22]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)(C)C.[Pd]>[NH2:10][C:11]1([CH3:25])[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[N:24])[CH:22]=2)[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2cncc(C#N)c2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC1(N)CCN(c2cncc(C#N)c2)CC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (5′-cyano-4-methyl-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-4-yl)-carbamic acid benzyl ester (0.051 g, 0.15 mmol) in isopropanol, (3.0 mL) at room temperature was added ammonium formate (0.050 g, 0.8 mmol) and 10% Pd/C (15 mg) under nitrogen. The reaction mixture was stirred at 90° C. for 18 hours, cooled, filtered through Celite and concentrated under reduced pressure to provide the titled compound. MS (CT) m/z 292 (M+1)+; 1H NMR (300 MHz, methanol-d4) δ ppm 8.48 (d, 1H), 8.18 (d, 1H), 7.65 (m, 1H), 3.49-3.36 (m, 2H), 3.32-3.36 (m, 2H), 1.73-1.61 (m, 4H), 1.20 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][N:5]([C:21](=[O:40])[C@H:22]([CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1)[NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.O[Li].O>C1COCC1.O>[C:28]1([CH2:27][O:26][C:24]([NH:23][C@H:22]([C:21]([N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:12]=2)[CH2:4][C:3]([OH:41])=[O:2])=[O:40])[CH2:34][C:35]2[N:39]=[CH:38][NH:37][CH:36]=2)=[O:25])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 110.6 %

Procedure:
To a solution of the ester from Step 2 (1.53 g, 2.75 mmol) in THF (15 mL) and H2O (5 mL) at 0° C. was added LiOH hydrate (0.14 g, 3.30 mmol) and the solution was stirred 5 hours at 0° C. The solution was concentrated, the residue taken up in H2O, and the pH was adjusted to 4-5 with 1N HCl. The resulting mixture was concentrated and dried in vacuo to afford 1.65 g of the title compound as a white solid;
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)([F:4])[F:3].Br[CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:16]>>[F:1][C:2]([F:4])([F:3])[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C@H:14]([C:15]([OH:17])=[O:16])[CH:32]([CH3:34])[CH3:33])=[CH:8][CH:7]=1
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Product: CC(C)[C@H](Nc1ccc(SC(F)(F)F)cc1)C(=O)O

Procedure:
Following the procedure of Example 43, p-aminophenyl trifluoromethyl sulfide is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylthiophenyl)valine, MS m/e 475 (M+).
Reaction SMILES: NC1CC2[C:5](=CC=CC=2)[N:4](CC2CO2)[C:3]1=O.[Cl:17][C:18]1[S:44][C:21]2[NH:22][C:23]([C:25]([NH:27][CH:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:38][CH:39]([OH:42])[CH2:40]O)[C:29]3=[O:43])=[O:26])=[CH:24][C:20]=2[CH:19]=1>>[Cl:17][C:18]1[S:44][C:21]2[NH:22][C:23]([C:25]([NH:27][CH:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:38][CH:39]([OH:42])[CH2:40][N:4]([CH3:5])[CH3:3])[C:29]3=[O:43])=[O:26])=[CH:24][C:20]=2[CH:19]=1
Reactant: NC1Cc2ccccc2N(CC2CO2)C1=O
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Product: CN(C)CC(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21

Procedure:
The title compound was prepared by a two-step coupling-epoxide opening sequence. Standard amide bond formation analogous to Method 3 except using 3-amino-1-(oxiran-2-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (Method 19) as amine and 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9) as the acid component formed the title compound as a white solid which was used without further purification. The crude amide product (150 mg) was dissolved in EtOH (5 mL) followed by addition of dimethylamine in EtOH (5.0–6.0 M in EtOH, 0.5 mL) and the reaction was stirred overnight under argon. The reaction was diluted with EtOAc (40 mL) and sat. aqueous NaHCO3 (20 mL) and the separated organic layer was dried (MgSO4), filtered and evaporated to dryness. Purification by column chromatography (MeOH:DCM 2:9) afforded the title compound (41 mg) as a yellow solid.
Reaction SMILES: C(OC([C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])=O)C.O.S(=O)(=O)(O)O>C(O)(=O)C>[C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C1(CCCCCOC(C)=O)CCCC1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCCCCC1CCCC1=O

Procedure:
300 g of 1-(5-acetoxypentyl)-2-oxo-cyclopentane-carboxylic acid ethyl ester were refluxed for 5 hours in 1.5 l of acetic acid, 600 ml of water and 300 g of sulfuric acid. Subsequently, the solution was concentrated under reduced pressure, 1liter of semi-saturated sodium chloride solution was added, and the solution was extracted with acetic acid ethyl ester. The organic phase was washed with 500 ml of saturated sodium chloride solution and dried over sodium sulfate. 50 ml of acetic anhydride were added, and the whole was refluxed for 4 hours. The solvent was distilled off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure in a column having a height of 30 cm.