Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1SC2C=CC=CC=2C=1C(OCC)=O.ClC1C(Cl)=C(Cl)C=CC=1[N+]([O-])=O.[Cl:28][C:29]1[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([N+:51]([O-])=O)[C:30]=1[NH:31][C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[C:33]=1[C:41]([O:43][CH2:44][CH3:45])=[O:42].Cl.[Sn+2]>C(O)C.CS(C)=O>[NH2:51][C:46]1[C:30]([NH:31][C:32]2[S:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[C:33]=2[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:29]([Cl:28])[C:49]([Cl:50])=[CH:48][CH:47]=1
Reactant: CCOC(=O)c1c(Nc2c([N+](=O)[O-])ccc(Cl)c2Cl)sc2ccccc12
Agent: CCOC(=O)c1c(N)sc2ccccc12
Agent: Cl
Agent: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(N)ccc(Cl)c2Cl)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (6.6 g), 2,3,4-trichloronitrobenzene (7.0 g) and dimethyl sulfoxide (70 ml), crude crystals (12 g) of ethyl 2-(2,3-dichloro-6-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (40 ml), 18% hydrochloric acid (60 ml) and tin(II) chlorihe.dihydrate (24.6 g), ethyl 2-(6-amino-2,3-dichloroanilino)benzo[b]thiophene-3-carboxylate (4.2 g) was obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To trichloroacetyl chloride (48 mL; 0.43 mol) taken in anhydrous ether (150 mL) under nitrogen was added pyrrole (25 g, 0.37 mol) dissolved in anhydrous ether (500 mL) through a dropping funnel over a 2-hour period. The violet ether solution began to reflux during addition. Refluxing was continued for 1 h before the reaction was quenched with a solution of sodium carbonate (33 g, 0.31 mol) in water (200 mL). The layers were separated and the red organic layer was washed four times with water (4×50 mL) and once with brine (1×50 mL) and finally dried over anhydrous sodium sulphate. The red ether solution was then filtered through CELITE® and washed with ether. The solvent was removed under vacuum to afford 2-trichloroacetylpyrrole (Example 1A, 72 g, 91% yield).) as an ash colored solid (72 g, 91% yield). LC-MS, [M−H]+=212. 1H NMR (DMSO-d6, 300 MHz): δ 9.63 (brs, 1H), 7.39 (m, 1H), 7.19 (m, 1H), 6.40 (m, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:9]=1[C:10](=O)[O:11][C:12]2=[O:18].C(OCC)C.CC(=O)OCC>C1COCC1.O>[F:7][C:8]1[C:9]([CH2:10][OH:11])=[C:13]([CH2:12][OH:18])[C:14]([F:17])=[CH:15][CH:16]=1
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(F)ccc(F)c1CO
Yield: 52.1 %

Procedure:
Lithium aluminium hydride (792 mg, 19.8 mmol) was suspended in THF (6 ml) and cooled in an ice bath. A solution of 4,7-difluoro-isobenzofuran-1,3-dione (730 mg, 3.97 mmol) in THF (6 ml) was added during 5 min. After completion of the reaction (5 min), diethyl ether (30 ml) was added. Subsequently, 2 ml of EA were added in order to decompose excess of lithium aluminium hydride, and thereafter water was slowly added until the alumina salts precipitated. The supernatant was decanted and the precipitate washed twice with EA. The combined extracts were dried over sodium sulfate, filtered and evaporated to dryness to yield 360 mg of the title compound.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]([N:15]1[CH2:21][CH:20]2[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)=[O:14].O.NN>CCO>[NH2:3][CH2:12][C:13]([N:15]1[CH2:16][CH:17]2[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH2:19][CH2:18]2)[CH2:21]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)CN1C(=O)c3ccccc3C1=O)C2
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)CN)C2
Yield: 42.5 %

Procedure:
To a stirred solution of tert-Butyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 0.187 mmol) in EtOH (1.9 mL) was added hydrazine monohydrate (19.0 mg, 0.375 mmol) at room temperature and the mixture was refluxed for 1 h. After cooling, the precipitates formed were filtered off. The filtrate was evaporated in vacuo and the residue was purified by preparative TLC (SiO2, 20×20 cm, 1 mm, CH2Cl2/MeOH/aqueous NH3=92/6/2) to afford a product (21.4 mg, 42%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Product: CCCC(=O)OCCCCc1ccccc1
Reaction time: 36 h
Yield: 98.9 %

Procedure:
To 4-phenyl-1-butanol (7.0 g, 0.047 mol) was added anhydrous dichloromethane (20 mL). A solution of butyryl chloride (4.79 g, 0.045 mol) in anhydrous dichloromethane (20 mL) was added dropwise. The solution was stirred for 36 hours. At this point the reaction was concentrated under reduced pressure to give a crude oil. Column chromatography [silica gel; eluent hexanes-ethyl acetate (3:1)] provided the desired product (9.8 g, 94%) as a clear viscous liquid. 1H(CDCl3) δ(ppm): 0.94 (t, 3H); 1.61-1.71 (m, 6H); 2.27 (t, 2H); 2.64 (t, 2H); 4.08 (t, 2H); 7.16-7.19 (m, 3H); 7.25-7.29 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[I-].[Na+]>O.CC(C)=O>[CH2:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)c1ccc(O)c(CS(C)(=O)=O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(CS(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
A mixture of 14.0 g. of 4'-hydroxy-3'-methylsulfonylmethylacetophenone, 9.3 g. of potassium carbonate, 7.8 ml. of benzyl chloride and a catalytic amount of sodium iodide in 250 ml. of acetone and 250 ml. of water is refluxed with stirring for 16 hours. The acetone is removed and the aqueous phase is extracted with chloroform, washed with water, dried and evaporated to yield an oil which is recrystallized in 2-propanol to give crystalline 4'-benzyloxy-3'methylsulfonylmethylacetophenone, m.p. 94°-97° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:4]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
2-Chloronicotinoyl chloride (4.0 g, 23 mmol) was added to a solution of 4-chloroaniline (3.2 g, 25 mmol) and N,N-diisopropylethylamine (7.7 mL, 46 mmol) in tetrahydrofuran (40 mL), and then the mixture was stirred at room temperature for 3 hours. Ethyl acetate (150 mL) was added to the reaction mixture, and the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (100 mL) twice and brine (100 mL) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the precipitated solid was filtered off. The solid was washed with diethyl ether:ethyl acetate (3:1), and then dried under reduced pressure to give 4.2 g of the title reference compound as a white solid. (Yield 82%)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH2:16])[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH:6]3[CH3:17].Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH:16][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][NH:23]4)[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH:6]3[CH3:17]
Reactant: CC1CCc2c(F)ccc3nc([C@H](C)N)n1c23
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC1CCc2c(F)ccc3nc([C@H](C)Nc4ncnc5[nH]cnc45)n1c23
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A mixture of (S)-1-(7-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethylamine (15.8 mg, 0.0677 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (17.8 mg, 0.0745 mmol), and DIPEA (0.0346 mL, 0.20 mmol) in n-butanol (0.5 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (1.5 mL) and cooled in an ice bath. HCl in isopropanol (1.25 M, 1 mL) was added and the mixture stirred at 0° C. for 90 min and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) afforded 407 as a white solid (8 mg, 34%). Analytical data shows the product to be a mixture of diastereomers (ratio ˜1:1) which could be separated. LCMS (Method K): RT 2.59 & 2.62 min [M+H]+ 352. 1H NMR (CD3OD, 400 MHz): 8.25 & 8.24 (1H, 2 s), 8.10 & 8.08 (1H, 2 s), 7.39-7.35 (1H, m), 6.96-6.91 (1H, m), 5.93 & 5.82 (1H, 2 bs), 5.26-5.21 & 4.93-4.87 (1H, 2 m), 3.09-3.03 (1H, m), 2.97-2.88 (1H, m), 2.27-2.21 (1H, m), 2.15-2.03 (1H, m), 1.83 & 1.78 (3H, 2 d, J=6.9 Hz), 1.45 & 1.41 (3H, 2 d, J=6.7 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5]C(=O)[C@@H]1CCCN1S(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-prolyl-O-[(1-tert-butoxycarbonyl)-piperidin-3-yl)methyl]-L-tyrosine methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with N-Boc-3-piperidinemethyl tosylate in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide to provide a solid, mp=60-62° C.
Reaction SMILES: [Cl:1]C1C2C(=CC=CC=2)N=CC=1C(OCC)=O.[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[F:28])[N:24]=[CH:23][C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:21]2O>>[Cl:1][C:21]1[C:20]2[C:25](=[CH:26][C:27]([F:28])=[C:18]([F:17])[CH:19]=2)[N:24]=[CH:23][C:22]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1O
Product: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl

Procedure:
The title compound was prepared following the procedure described in Step 2 for the synthesis of 3a using 2c instead of 2a. 1H NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.08 Hz), 4.56 (2H, q, J=7.08 Hz), 7.72 (1H, d, J=8.79 Hz), 8.39 (1H, d, J=8.78 Hz), 9.23 (1H, s). m/z 271.6/273.6 (M+/M+2). m/z 272.6 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([NH2:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:24]1[C:25]2[C:32]([CH3:33])=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:1][N:2]([CH3:22])[C:3](=[O:21])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([NH2:20])[CH2:19][CH2:18][N:17]([C:24]3[C:25]4[C:32]([CH3:33])=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(N)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(N)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 120 °C
Yield: 54 %

Procedure:
3-(4-aminopiperidine-4-carboxamido)phenyl dimethylcarbamate from step B (0.109 g, 0.36 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.060 g, 0.36 mmol), and N,N-diisopropylethylamine (0.277 g, 2.14 mmol) were combined in isopropanol (5 mL) and heated in a sealed tube at 120° C. for 18 hours. The mixture was concentrated, and the residue was purification by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford the title compound (0.085 g, 55%) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][S:12]([CH:15]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:16]([NH:18][CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:17])(=[O:14])=[O:13].[C:43]([O-])([O-])=O.[K+].[K+].IC.O>CN(C)C=O.C(Cl)Cl>[CH3:43][N:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[S:12]([CH:15]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:16]([NH:18][CH:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=1)[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:17])(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(CC(NC(=O)C(Cc2ccccc2)S(=O)(=O)Nc2ccc3ccccc3c2)C(=O)N2CCCC2)cc1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CI
Product: CN(c1ccc2ccccc2c1)S(=O)(=O)C(Cc1ccccc1)C(=O)NC(Cc1ccc(C#N)cc1)C(=O)N1CCCC1
Reaction time: 24 h
Yield: 86.1 %

Procedure:
2 g of compound 4 are dissolved in 20 ml of dimethylformamide at 0° C. and 0.475 g of K2CO3 and 0.214 ml of ICH3 are added. After 24 hours at 5° C., 20 ml of H2O and 40 ml of CH2Cl2 are added. The organic phase decanted is washed, dried and concentrated to dryness. The residue is recrystallized from (CH3)2CHOH to give 1.76 g of final product which melts at 186° C.
Reaction SMILES: C([O:4][CH:5]([CH2:19][CH2:20][S:21]([CH3:23])=[O:22])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])(=O)C.[OH-].[Na+]>CO.ClCCl>[CH2:9]([NH:8][C:6](=[O:7])[CH:5]([OH:4])[CH2:19][CH2:20][S:21]([CH3:23])=[O:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCNC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
To a solution of 1-(decylamino)-4-(methylsulfinyl)-1-oxobutan-2-yl acetate (22.4 g, 63.4 mmol) in methanol (300 mL) was added 2.5 N NaOH (39 mL, 97.5 mmol) and the resulting solution was stirred at room temperature for 5 hrs. The reaction was quenched with concentrated HCl (12.5 mL) and then evaporated to a small volume. The resulting mixture was treated with EtOAc (200 mL) and then washed with 1N HCl (150 mL), saturated sodium bicarbonate (50 mL), dried over magnesium sulfate, filtered and evaporated to give a solid. The solid was dissolved in dichloromethane and purified by silica gel chromatography with 0-10% methanol/dichloromethane. The desired fractions were collected and evaporated to give a white solid (13.6 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.83 Hz, 3 H) 1.15-1.32 (m, 14 H) 1.32-1.46 (m, 2 H) 1.75-1.87 (m, 1 H) 1.94-2.06 (m, 1 H) 2.51 (d, J=1.27 Hz, 3 H) 2.58-2.88 (m, 2 H) 3.00-3.12 (m, 2 H) 3.89-4.02 (m, 1 H) 5.69 (d, J=5.40 Hz, 1 H) 7.76 (t, J=5.56 Hz, 1 H). m/z 306 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7]([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.CC1(C)N([O-])C(C)(C)CC(OC)C1.[Br-].[K+].Cl[O-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:12])([F:11])[F:13])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c(C(O)C(F)(F)F)nc2cc1Cl
Agent: COC1CC(C)(C)N([O-])C(C)(C)C1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2[nH]c(C(=O)C(F)(F)F)nc2cc1Cl
Temperature: 25 °C

Procedure:
1-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanol (0.33 g; 1.2 mmole), 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy free radical (4-methoxy-TEMPO free radical; 5.6 mg; 0.03 mmoles) and potassium bromide (KBr; 22 mg, 0.18 mmoles) were dissolved in THF (3.5 mL). The reaction mixture was stirred while cooled to −10° C., after 10 min. a sodium hypochlorite solution (bleach; 10-13% aqueous; 3.0 mL; 5.0 mmoles) was added and the reaction mixture was allowed to stir for 15 min., then warmed to room temperature and stirred for 15 min. The reaction mixture was diluted with water (20 mL) and ethyl acetate (30 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The extracts were combined and washed with water (30 mL) and brine (40 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo and then purified by column chromatography (SiO2; 100% diethyl ether) to yield the title compound as a white solid.
Reaction SMILES: CN[C:3](=[O:10])[C@H:4]([C:6]([CH3:9])([CH3:8])[CH3:7])[NH2:5].Cl.CC(O)=[O:14]>>[NH2:5][C@H:4]([C:3]([OH:10])=[O:14])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(=O)O
Agent: Cl
Product: CC(C)(C)[C@H](N)C(=O)O
Yield: 41 %

Procedure:
A solution of (S)-N-methyl-tert-leucinamide in 100 ml of a 6N solution of HCl/CH3COOH (1:1) was heated under reflux for 14 days. Then, the mixture was evaporated, the residue was chromatographic over AMBERLITE. Evaporation and drying gave 750 mg (41%) of (S)-tert-leucine, [α]=+6.2 (c=1.62, 5N HCl), 97% e.e.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH2:15][CH2:14][CH2:13]3)[CH:4]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].CCCCCC.CCOC(C)=O.CCOC(C)=O>C1COCC1.CCOCC>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([O:9][C:5]4[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[CH:7][N:6]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:32])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CNc1cc(Oc2ccc3c(c2)CCCN3)ncn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNc1cc(Oc2ccc3c(c2)CCCN3C(=O)Nc2ccc(C(C)(C)C)cc2)ncn1
Reaction time: 0.5 h

Procedure:
A solution of 90 mg (0.35 mMol) of 6-methylamino-4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrimidine (Step 3.2) in 2 ml of THF and a solution of 63.3 mg (97%; 0-35 mMol) of 4-tert.butyl-phenyl-isocyanate in 4 ml ether are mixed and stirred for 30 min. After concentration of the reaction mixture, a chromatography (Combi Flash; hexane/EtOAc 1:2→EtOAc) gives the title compound: m.p.: 175-176° C.; MS: [M+1]+=432; Anal.: C,H,N.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[N:3]1[C:10]([OH:12])=[O:11].[Li+].[B-](CC)(CC)CC.C(N(C(C)C)C(C)C)C.CN(C1C=CC=CN=1)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1.O>[N:3]1([C:10]([OH:12])=[O:11])[CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH:6]=[CH:2]1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)O
Agent: CC[B-](CC)CC
Agent: CN(C)c1ccccn1
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C1CC=CN1C(=O)O
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The (5S)-2-oxopyrrolidine-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl),5-ethyl ester (Formula G)(4.80 kg) was dissolved in toluene (30.97 liters; Kf max 0.01% water) and cooled to −50° C. This solution was charged with SuperHydride (LiEt3BH 1 M in THF; 19.96 liters) in a manner so that the reaction temperature did not exceed −45° C. After complete addition, the mixture was stirred at −45 to −50° C. for 30 minutes. N-ethyldiisopropylamine (DIPEA; 14.47 liters) was then added to the reaction mixture in a manner so that the temperature did not exceed −45° C. Dimethyaminopyridine (0.030 kg) was added as a solid to the mixture. The reaction mixture was then charged with trifluoroacetic anhydride (TFAA) (4.70 kg) in a manner so that the reaction temperature did not exceed −45° C. After complete addition, the reaction mixture was warmed to 20 to 25° C. within one hour and kept for an additional 2 hours at this temperature. The reaction mixture was then cooled to 0° C. and slowly charged with water (48.00 liters) so that the reaction temperature did not exceed 5° C. Aqueous and organic phases were then separated and the organic phase was again washed with 48 liters of water (0 to 5° C. ). The organic later was then evaporated and degassed at 40° C. A yellowish oil was obtained with a yield of 4.5 kg (18.66 mol, 100%) of the 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1-dimethylethyl), 5-ethyl ester (BOC-DHPEE)(Formula III).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>C(Cl)Cl>[CH3:31][C@H:11]1[C:12]2[C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:15]=[N:14][C:13]=2[C@H:9]([OH:8])[CH2:10]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(C3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (77 μL, 1.0 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylate (13 mg, 0.04 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour and concentrated to give (5R,7R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol as an oil, which was used further without purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1)(=[S:16])[NH2:15]>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)[S:16][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: CCOC(=O)C1CCN(C(N)=S)CC1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)C1CCN(c2nc(-c3cccc([N+](=O)[O-])c3)cs2)CC1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A solution of 2-bromo-1-(3-nitrophenyl)ethanone (621 mg, 2.54 mmol) and ethyl 1-carbamothioylpiperidine-4-carboxylate (500 mg, 2.31 mmol) in ethanol (7.7 mL) was heated to reflux for 16 hours, and then cooled to room temperature. The mixture was concentrated under reduced pressure and the resulting residue purified directly by CombiFlash (0-70% ethyl acetate/hexanes) to provide 457 mg (1.26 mmol, 49% yield) of ethyl 1-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate as a yellow solid.