Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCCC[C@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 31.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 126 mg, 0.283 mmol), (1R,2S)-2-phenylcyclohexanol (50.0 mg, 0.284 mmol), sodium hydride (63%; 21.6 mg, 0.567 mol) and DMSO (2.0 mL), to yield the title compound (53.6 mg, 31%) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[O:30][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:34])(=[O:4])=[O:3].CO.[Cl:37]CCl>Cl.C(O)(=O)C>[ClH:37].[ClH:37].[NH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][C:11]2([CH2:10][C:9](=[O:34])[C:8]3[C:31](=[CH:32][CH:33]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=3)[O:30]2)[CH2:16][CH2:15]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCOCCN1CCC2(CC1)CC(=O)c1cc(NS(C)(=O)=O)ccc1O2
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCOCCN)CC1)O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ten drops of concentrated hydrochloric acid was added to a solution of tert-butyl 2-(2-(6-(methylsulfonamido)-4-oxospiro[chroman-2,4′-piperidine]-1′-yl)ethoxy)ethylcarbamate (12, 0.51 g, 1.02 mmol) in 5 mL of glacial acetic acid and the resulting solution was stirred at room temperature. After ˜1.5 hours, TLC (silica gel, 10% methanol in dichloromethane, UV visualization) shows complete disappearance of starting compound 12 (Rf=0.2−0.3) and a new spot at the origin. Volatile components were removed under reduced pressure on the rotary evaporator. Toluene (˜10 mL) was added and evaporated under reduced pressure on the rotary evaporator. The toluene addition and evaporation was repeated two more times and the residue was dried under high vacuum. The resulting residue was triturated with 3 mL of diethyl ether, resulting in formation of a tan solid. The diethyl ether was removed under reduced pressure on the rotary evaporator followed by high vacuum to give a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CCN(CC)CC>C(Cl)Cl>[CH:26]1([NH:31][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([OH:16])([CH3:15])[CH3:14])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NC1CCCC1)C(C)(C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a mixture of (R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (0.5 g, 2.144 mmol), HATU (0.978 g, 2.57 mmol) and cyclopentanamine (0.423 mL, 4.29 mmol) in DCM (10 mL) was added Et3N (0.598 mL, 4.29 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, concentrated, and purified by silica column chromatography (MeOH/DCM, 0-10%) to afford the title compound (0.6 g, 93%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][C@H:14]2[O:19][C:18]3[CH:20]=[C:21]([NH2:25])[C:22]([F:24])=[CH:23][C:17]=3[O:16][CH2:15]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[C:27]1(Cl)[C:33](=O)C(Cl)=C(Cl)C(=O)[C:28]=1Cl.C(C=C)=O.[OH-].[Na+]>C(O)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH:14]2[O:19][C:18]3=[C:20]4[C:21](=[C:22]([F:24])[CH:23]=[C:17]3[O:16][CH2:15]2)[N:25]=[CH:33][CH:27]=[CH:28]4)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3cc(F)c(N)cc3O2)cc1
Agent: C=CC=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC2COc3cc(F)c4ncccc4c3O2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1.06 g (2.72 mmole) of [(2S)-7-amino-6-fluoro-2,3-dihydro-1,4-benzodioxin-2y]methyl 4-methylbenzenesulfonate hydrochloride was added 100 mL of concentrated hydrochloric acid. Then 0.66 g (2.68 mmole) of p-chloranil was added with sufficient ethanol to wash down the solid. The heterogeneous mixture was heated to reflux and a solution of 0.25 g (4.45 mmole) of acrolein in 10 mL of ethanol was added dropwise. Reflux was continued for an additional 1 hour. The mixture was then allowed to come to room temperature and added to ice water. The solution was made basic with 1 N NaOH and extracted with methylene chloride. The extract was dried over magnesium sulfate, filtered and concentrated to a crude brown oil in vacuum. This was column chromatographed on silica gel with 1:1 hexane/ethyl acetate and the product-containing fractions concentrated in vacuum to give 0.60 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 8.6 δ (1 H); doublet 8.2 δ (1 H); doublet 7.75 δ (2 H); multiplet 7.4 δ (1 H); doublet 7.25 δ (2 H); doublet 7.0 δ (1 H); multiplet 4.58 δ (1 H); multiplet 4.2-4.4 δ (3 H); multiplet 4.2 δ (1 H); singlet 2.4 δ (1 H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:26])=[O:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:26])=[O:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1nc(-c2ccc(S(C)=O)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(S(C)=O)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 61.8 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 61.8%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[O:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:17](O)=[C:14](OC)[CH:13]=1>>[N:4]1([CH2:3][CH2:2][O:1][C:17]2[CH:19]=[CH:20][C:12]([CH:11]=[O:10])=[CH:13][CH:14]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc(C=O)ccc1O
Product: O=Cc1ccc(OCCN2CCOCC2)cc1

Procedure:
4-[2-(4-Morpholinyl)-ethoxy]-benzaldehyde was prepared from N-(2-hydroxyethyl)morpholine (Aldrich) and vanillin (Aldrich) by method H above.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1F)([O-:5])=[O:4].[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:19][C:20]1[CH:16]=[CH:17][C:18]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
This compound was made by the procedure of Example 2 from Compound A (46.5 g, 0.010 mole), NaH (4 g as 60% oil suspension, 0.10 mole) and 2,4-dinitrofluorobenzene (27.9 g, 0.15 mole) in THF (150 ml). The final product was purified by distillation to give a liquid product, yield 45.0 g (71.3%). Bp. 150°-160° C./0.5 mm. H1NMR (CDCl3): δ8.80 (d, J=2.5 Hz, 1H), 8.70 (dd, J=2.5, 10 Hz, 1H), 7.24 (d, J=10 Hz, 1H), 4.68 (t, J=12 Hz, 2H); F19NMR (CDCl3): -71.3 (d, J=10.1 Hz, 2F), -77.4 (m, 1F), -80.2 (q, J=7.6 Hz, 3F), -82.5 to -86.0 (m, F), -122.9 (t, J=11.6 Hz, 2F), -145.9 (q, J=19.4 Hz, 1F).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][CH2:21][CH2:22][Cl:23])[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1c2ccc(Br)cc2ccn1CCCCl
Temperature: 70 °C
Reaction time: 10 h

Procedure:
A solution of 6-bromoisoquinolin-1(2H)-one (Example 1b) (2 g) dissolved in NMP (20 mL) was treated with potassium carbonate (1.974 g) and 1-bromo-3-chloropropane (8.83 ml) under nitrogen. The resulting mixture was stirred at 70° C. for 10 h. The cooled reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was dried (MgSO4), and evaporated. The residue was purified (SiO2 chromatography, elution with a mixture of DCM and isohexane) to give the subtitle compound (1.70 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9].[NH:24]1[CH2:29][CH2:28][CH2:27][N:26]=[CH:25]1>>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:26]2[CH2:27][CH2:28][CH2:29][N:24]=[CH:25]2)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2)=[O:9]
Reactant: C1=NCCCN1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2C=NCCC2)ccc1Cl

Procedure:
Prepared according to the method described in Example 8 from 5-bromomethyl-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 8b,) and 1,4,5,6-tetrahydro-pyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[N:7]=1.[OH-].[Na+]>CO.O>[C:14]([NH:13][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:17])=[O:2])[CH:11]=[C:10]([CH3:12])[CH:9]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)CCc1cc(C)cc(NC(C)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cc(C)cc(CCC(=O)O)n1
Reaction time: 18 h

Procedure:
6.15 g of 3-(6-acetylamino-4-methylpyridin-2-yl)-propionic acid methyl ester (compound C5) is dissolved in 100 ml methanol and 70 ml water. Subsequently, 30.44 ml of a 1.0 M solution of NaOH is added while stirring is continued for 18 h at r.t. 2.0 g of amberlite IR-120 [H+]is added and the suspension is stirred for 10 min to neutralize the reaction mixture. The ion exchange resin is removed by filtration and 7.1 g of the crude product is isolated as a colourless solid after evaporation of solvent. Purification by chromatography on silica gel (eluent: dichloromethane/ethanol 10:1) affords 5.32 g of the the title compound. M.p. 202° C. ESI-MS: 223.1 (MH+). TLC: Rf=0.13 (cyclohexane/ethyl acetate 1:1+1.0 vol % acetic acid).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.O>C(#N)C>[Br:20][C:3]1[CH:4]=[CH:5][C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1ccc(CNc2cccc(Cl)n2)cn1
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1ccc(CNc2ccc(Br)c(Cl)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (567, 4.50 g, 0.0156 mol) in acetonitrile (120.0 mL) under an atmosphere of nitrogen, N-bromosuccinimide (3.03 g, 0.0170 mol) in acetonitrile (50 mL) was added slowly. The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give a white solid (568, 6.20 g, 80.2%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1.O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(N)ccc1-n1cnc(Br)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
700 mg (2.35 mmol) 4-bromo-1-(2-methoxy-4-nitro-phenyl)-1H-imidazole and 2.755 g (12.2 mmol) stannous chloride dihydrate were suspended in a mixture of 40 ml ethyl acetate and 10 ml ethanol and stirred for 1 h at 70° C. The resulting mixture was poured into cold water and neutralized by addition of a saturated solution of sodium hydrogen carbonate. The product was extracted with ethyl acetate, dried and evaporated to give 627 mg (100%) of 4-(4-bromo-imidazol-1-yl)-3-methoxy-phenylamine as a yellowish solid. MS ISP (m/e): 268.0/270.1 (100/82) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.49 (s, 1H), 7.77 (s, 1 H), 7.05 (s, 1H), 6.99 (d, 2H), 6.35-6.25 (m, 2H), 3.86 (s broad, 2H), 3.77 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:5][CH:4]=1.N([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>C(O)(=O)C.O>[N:2]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:7][CH:8]=1)=[N+:27]=[N-:28]
Reactant: CC(C)C(C(=O)OCc1ccccc1)c1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(C(=O)OCc1ccccc1)c1ccc(N=[N+]=[N-])cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 20 ml of water and 11 ml of concentrated hydrochloric acid at <10° was added a solution of 14.17 g of 2-(4-aminophenyl)-3-methylbutanoic acid, benzyl ester in 50 ml of acetic acid. At 0° to 5° was added a solution of 3.62 g of sodium nitrite in 12.5 ml of water. The mixture was stirred at 0° to 5° for an additional 45 minutes, then poured into a stirred solution of 3.25 g of sodium azide in 12.5 ml of water in an ice-cooled beaker. Gas evolved immediately along with formation of orange oil. After 3-4 minutes, the mixture was diluted with water to 400 ml, then extracted with butyl chloride. The butyl chloride solution was washed with water (3 times) and saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to 13.5 g of oil, 2-(4-azidophenyl)-3-methylbutanoic acid, benzyl ester, which began to solidify. The infrared spectrum of the oil shows absorption peaks at 2130 cm-1 (azide) and 1740 cm-1 (ester carbonyl). Thin-layer chromatography on silica gel-coated plates in chloroform or butyl chloride showed only one spot.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:29]C(C)(C)[O:31][C@H:14]2[C@H:13]1[OH:34])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@H:13]([OH:34])[C@H:14]([OH:31])[C@@H:15]([OH:29])[CH2:16][N:17]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@H]3[C@@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
The above compound (5) (1.1 g) was dissolved in methanol (25 mL) and a cation exchange resin (Muromac, 3.0 g) was added, and then the mixture was stirred overnight at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1) to obtain the titled compound (974 mg) as a syrup.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:30])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)=[O:12])[NH:8][N:7]=1)(=[O:5])[CH3:4].Cl.O>CCO.[BH4-].[Na+]>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]3[CH:10]=[C:6]([CH:3]([OH:5])[CH3:4])[NH:7][N:8]=3)=[O:12])[CH3:30])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Sodium borohydride (0.930 g, 24.57 mmol) and EtOH (105 ml) were placed in to the reaction flask under nitrogen atmosphere. (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (15 g, 37.8 mmol) was added in small portions to keep temperature below 25° C. After 3.5 h sodium borohydride (0.07 g, 1.85 mmol) was added and the mixture was stirred for additional 60 min to complete the reaction. 16 ml of ˜10% HCl in EtOH was added carefully to set pH to 3.5 and the mixture was stirred overnight at RT. Water (30 ml) was added and the stirring was continued for 3 h. The precipitate was filtered, washed with 2×10 ml of cold water:EtOH (1:1) and dried under vacuum to obtain 12.2 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (, 3H), 1.39 (d, 3H), 4.24-4.52 (m, 3H), 4.76-4.86 (m, 1H), 5.42 (d, 1H), 6.42 (bs., 1H), 6.94 (d, 1H), 7.82 (d, 1H), 8.00 (bs, 2H), 8.09 (bs, 1H), 8.20 (d, 1H), 13.05 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:11][C:12]1([CH3:33])[CH:20]2[CH:16]([CH2:17][N:18]([C:21](=[O:31])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19]2)[C:15](=[O:32])[CH:14]=[CH:13]1.[Cl-].[Ce+3].[Cl-].[Cl-].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1([CH3:33])[CH:20]2[CH:16]([CH2:17][N:18]([C:21](=[O:31])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19]2)[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:32])[CH:14]=[CH:13]1
Reactant: COc1ccccc1[Mg]Br
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)C=CC(C)(C)C2C1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)C=CC2(C)C
Temperature: 15 °C
Yield: 54.7 %

Procedure:
To a suspension of 22.73 g of 2-methoxyphenylmagnesium bromide in 70 cm3 of tetrahydrofuran, cooled to 15° C., are added, dropwise and with stirring, a solution of 6.77 g of (3aRS,7aRS)7, 7-dimethyl-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,7,7a -hexahydro-1H-4-isoindolone in 10 cm3 of tetrahydrofuran, followed by 5.3 g of anhydrous cerium chloride. The reaction mixture is stirred at room temperature for 18 hours, treated with 80 cm3 of saturated aqueous ammonium chloride solution, taken up in 100 cm3 of ethyl acetate and washed with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 5.5 cm, height 30 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 75 cm3 fractions. Fractions 17 to 40 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 4.98 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]2,3,3a,4,7,7a-hexahydro-1H-4-isoindolol are obtained in the form of a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[CH2:14]1[O:32][C:31]2[CH:30]=[CH:29][C:18]([CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23](SC)=[N:24][CH:25]=3)=[CH:17][C:16]=2[O:15]1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:23]2[NH:22][C:21](=[O:28])[C:20]([CH2:19][C:18]3[CH:29]=[CH:30][C:31]4[O:32][CH2:14][O:15][C:16]=4[CH:17]=3)=[CH:25][N:24]=2)=[N:6][CH:7]=1
Reactant: CSc1ncc(Cc2ccc3c(c2)OCO3)c(=O)[nH]1
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccc3c(c2)OCO3)c(=O)[nH]1
Yield: 77.7 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.88 g) and 5-(3,4-methylenedioxybenzyl)-2-methylthio-4-pyrimidone (0.83 g) were refluxed in pyridine (3 ml) for 24 hours. The pyridine was removed in vacuo and the resulting brown oil triturated with ethanol giving a cream solid which was recrystallised from dimethylformamide/ethanol giving 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(3,4-methylenedioxybenzyl)-4-pyrimidone (1.1 g) as a colourless solid m.p. 145°-6° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:47])[CH2:19][N:20]1[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[N:22]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[CH:31][CH:30]=2)[C:21]1=[O:46])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](O)(=O)[CH2:49][CH3:50]>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:47])[CH2:19][N:20]1[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[N:22]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[CH:33][CH:34]=2)[C:21]1=[O:46])[C:13]([O:15][CH:49]([CH3:50])[CH3:48])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CN2C(=O)N(CC(=O)NC[C@H](NC(=O)OCc3ccccc3)C(=O)O)C(=O)C2(C)C)cc1
Reactant: CCC(=O)O
Solvent: CC(C)O
Product: Cc1ccccc1NC(=O)Nc1ccc(CN2C(=O)N(CC(=O)NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)C)C(=O)C2(C)C)cc1

Procedure:
The compound was prepared from (S)-2-benzyloxycarbonylamino-3-((4,4-dimethyl-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)acetylamino)propionic acid and isopropanol as described in Examples 95, 96, 98-102 and 104-116. Batch size: 0.465 mmol of the starting propionic acid. Yield: 233 mg.