Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7].[N:20]1([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])[CH2:22][CH2:21]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CCOC(=O)C1=C(NC(=O)CCCCBr)CCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)CCCCN2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Yield: 85.8 %

Procedure:
In 350 ml of toluene, 66.5 g of ethyl 2-(5-bromopentanoylamino)cyclohex-1-enecarboxylate as synthesized in above Step 4-1-B, 46.9 g of 2-piperazin-1-ylquinoline and 22.3 g of triethylamine were dissolved and heated under reflux for an overnight. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, followed by washing with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off under reduced pressure. Purifying the residue on silica gel column chromatography (n-hexane:ethyl acetate:methanol=1:6:0.2) to provide 79.8 g (86%) of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylate.
Reaction SMILES: C(OC([NH:8][CH:9]([C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[CH:16][F:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.Cl>CCOCC>[NH2:8][CH:9]([C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[CH:16][F:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=CF)c1cccc(OC)c1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(N)C(=CF)c1cccc(OC)c1
Yield: 96 %

Procedure:
A solution of ethyl 2-tert-butoxycarbonylamino-3-(3'methoxyphenyl)-4-fluoro-3-butenoate (218 mg) in ether (10 ml) saturated with dry HCl is left overnight by which time colorless needles crystallize. These are collected and dried to afford pure recemic ethyl 2-amino-3-(3'-methoxyphenyl)-4-fluoro-3-butenoate (150 mg): colorless needles, m.p. 141°-142°:
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([NH2:12])=[O:11])[C:6]=1[N+:13]([O-])=O)[CH:2]([CH3:4])[CH3:3]>[Pd].C(O)C>[NH2:13][C:6]1[C:7]([C:10]([NH2:12])=[O:11])=[N:8][NH:9][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cc1[nH]nc(C(N)=O)c1N
Reaction time: 64 h
Yield: 94.8 %

Procedure:
5-Isobutyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (4.7 g, 22 mmol) and 10% palladium on carbon (300 mg) in ethanol (80 ml) was stirred under hydrogen (60 psi) at room temperature for 4 hours, and held under nitrogen for 64 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure of dichloromethane:methanol (100:0 changing to 95:5 then 90:10, by volume) to give 4-amino-5-isobutyl-1H-pyrazol-3-carboxylic acid amide (3.8 g) as an off-white solid, which was a mixture of rotamers. 1H NMR (400 MHz, DMSO-D6): δ=12.20-12.28 (1H, brs), 7.00-7.10 (1.34H, brs), 6.80-6.85 (0.66H, brs), 4.27-4.40 (2H, brs), 2.27-2.36 (2H, d), 1.78-1.88 (1H, m), 0.77-0.84 (6H, d) ppm. LRMS (electrospray): m/z [M+H]+ 183, [M+Na]+ 205. Anal. Found C, 52.27; H, 7.78; N, 30.59. C8H14N4O requires C, 52.73; H, 7.76; N, 30.75%.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:14]1([CH:20]=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2]=1[N:17]1[CH2:18][CH2:19][N:14]([CH:20]=[O:21])[CH2:15][CH2:16]1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Reactant: O=CN1CCNCC1
Solvent: CCO
Product: O=CN1CCN(C2=C(O)C(=O)c3ccccc3C2=O)CC1
Reaction time: 20 h

Procedure:
A mixture of 3.48 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone, 2.28 of 1-piperazinecarboxaldehyde and 200 ml of absolute ethanol was stirred for 20 hours, then concentrated to one-half its original volume and refrigerated overnight. The solid was collected and recrystallized from dichloromethane/ethanol, giving 2.65 g of the desired product, mp 200°-203° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][C:17]2([C:20]([O:22]C(C)(C)C)=[O:21])[CH2:19][CH2:18]2)=[O:11])=[CH:5][CH:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH:30]([CH3:35])[C:31]([F:32])([F:33])[F:34])[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][C:17]2([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]2)=[O:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(C(=O)Nc2cccc(CC3(C(=O)OC(C)(C)C)CC3)c2)C(C)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(C(C(=O)Nc2cccc(CC3(C(=O)O)CC3)c2)C(C)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.52 g (3.11 mmol) of (+/−)-tert-butyl 1-(3-{[2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}benzyl)cyclopropanecarboxylate were dissolved in 3 ml of dichloromethane, and 12 ml of TFA were added at RT. The reaction mixture was stirred at RT for 2 h and then concentrated under reduced pressure, and the residue was dried under high vacuum overnight. This residue was triturated with acetonitrile, and the resulting solid was filtered off with suction, washed with a little acetonitrile and dried under high vacuum. This gave 1.16 g (86.2% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29]2)[N:23]=1.C(OC(N1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH:7]4[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]4)=[CH:20][CH:21]=3)=[O:34])[CH2:29]2)[N:23]=1
Reactant: O=C(O)[C@H]1CCN(c2cccnn2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)[C@H]3CCN(c4cccnn4)C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 1A, substituting tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and (S)-1-(pyridazin-3-yl)pyrrolidine-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:28])=[C:4]([CH3:27])[C:5]2[O:10][C:9]([C:12]3[O:13][C:14]4[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH:23]=[O:24])=[CH:17][C:15]=4[CH:16]=3)([CH3:11])[CH2:8][CH2:7][C:6]=2[C:25]=1[CH3:26].[Na]>C(O)C>[OH:1][C:2]1[C:3]([CH3:28])=[C:4]([CH3:27])[C:5]2[O:10][C:9]([C:12]3[O:13][C:14]4[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][OH:24])=[CH:17][C:15]=4[CH:16]=3)([CH3:11])[CH2:8][CH2:7][C:6]=2[C:25]=1[CH3:26]
Reactant: COc1cc(C=O)cc2cc(C3(C)CCc4c(C)c(O)c(C)c(C)c4O3)oc12
Agent: [Na]
Solvent: CCO
Product: COc1cc(CO)cc2cc(C3(C)CCc4c(C)c(O)c(C)c(C)c4O3)oc12
Reaction time: 0.5 h

Procedure:
A mixture of 0.2 g of rac-2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-7-methoxy-5-benzofurancarboxaldehyde and 20 mg of sodium borohyride in 5 ml of ethanol was stirred under nitrogen for 30 minutes. It was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated. Crystallization from ether/hexane yielded colorless crystals with m.p. 122°-125°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[C:13]2[C:19]#[N:20])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[BH4-].[Na+]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[C:13]2[C:19]#[N:20])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C=O)cc2C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(-n2cc(CO)cc2C#N)cc1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 1-(4-ethoxycarbonylphenyl)-4-formylpyrrole-2-carbonitrile (2.0 g) in 1,2-dichloroethane (10 ml) was added sodium borohydride (296 mg) in one portion under nitrogen at ambient temperature. The mixture was stirred for one hour at the same temperature and then quenched with aqueous saturated ammonium chloride solution at 5° C. The organic layer was washed with water and brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted by a mixture of ethyl acetate and n-hexane (2:1) to give 1-(4-ethoxycarbonylphenyl)-4-hydroxymethylpyrrole-2-carbonitrile (1.3 g) as a white solid.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH:21]([F:23])[F:22])=[C:14]([CH:20]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])(C)(C)C.CCN(C(C)C)[CH:27]([CH3:29])[CH3:28].C(Cl)(=O)C(C)C>Cl.CCO.CCOC(C)=O>[F:23][CH:21]([F:22])[C:13]1[N:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH:27]([CH3:29])[CH3:28])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)cnc1C(F)F
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A solution of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-2-(difluoromethyl)nicotinate (500 mg, 1.51 mmol) in HCl in EtOH (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the concentrate was dissolved in DMF (2 mL). The solution was treated with DIPEA (464 mg, 3.60 mmol) and isobutyryl chloride (115 mg, 1.08 mmol) at rt. The reaction mixture was stirred for 2 h before it was diluted with EtOAc and was washed with H2O and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.75 (s, 1H), 8.48 (t, 1H), 8.14 (s, 1H), 7.59-7.24 (t, J=54 Hz, 1H), 4.39-4.32 (m, 4H), 2.44 (m, 1H), 1.35-1.29 (t, J=6.9 Hz, 3H), 1.04-1.02 (d, J=6.9 Hz, 6H); MS [M+H]+: 301.36.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([N:8]([S:19]([CH3:18])(=[O:21])=[O:20])[C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.3 %

Procedure:
To a solution of 4-nitroaniline (5.04 g, 36.5 mmol) in CH2Cl2 (100 ml) cooled to 0° C. were added Et3N (6.61 mL, 47.4 mmol) and MsCl (3.39 mL, 43.8 mmol) and the mixture was stirred at room temperature overnight to give dimethanesulfonyl-(4-nitro-phenyl)-amine as a yellow solid (10.46 g, 98%) following work-up.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:10]=[CH:11][CH:12]=[CH2:13].[P]>[Rh]>[CH2:8]=[C:7]([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH2:1][OH:9]
Reactant: C=CC=C
Reactant: C=CCCCC=CCO
Agent: [Rh]
Agent: [P]
Product: C=C(CC=CC)CCCC=CCO

Procedure:
7-methylene-2,9-undecadiene-1-ol was prepared from 2,7-octadiene-1-ol and butadiene by employing a catalyst which had an atomic ratio of trivalent phosphorus to rhodium of 3.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:27]>CS(C)=O>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[O:27])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: O
Reactant: COc1ccc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)c(OC)c1
Solvent: CS(C)=O
Product: COc1ccc(C(=O)/C(=N\C2CCCC2)n2ncc(C#N)c2N)c(OC)c1
Reaction time: 24 h
Yield: 19.7 %

Procedure:
A light brown solution of 3-(cyclopentylamino)-2-(2,4-dimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (1.09 g, 3.1 mmol) in DMSO (200 mL) was stored for 35 days at RT. Within 24 h, it became a dark brown solution. After 35 days, LC/MS analysis indicated the absence of starting material and the presence of a strong desired peak. Then, it was poured into water (1 L) and the resulting cloudy brown solution was extracted with ethyl acetate (2×200 mL). Then, the combined extracts were washed with water and brine solution (2 L) to remove the DMSO. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the red brown paste (1.25 g) which was purified using an ISCO (150 g) column chromatography eluting with 0-40% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 224 mg (19.7% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(2,4-dimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.85 (br m, 8H), 3.66 (m, 1H), 3.66 (s, 3H), 3.87 (s, 3H), 6.62 (d, J=2.4 Hz, 1H), 6.71 (dd, J=2.4 and 9.0 Hz, 1H), 7.63 (s, 1H), 7.86 (d, J=9.0 Hz, 1H), 8.05 (brs, 2H). LC/MS calcd. for C19H21N5O3 (m/e) 367.4, obsd. 368.0 (M+H, ES+).
Reaction SMILES: [CH2:1]([S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][CH2:40][NH2:41])=[CH:37][CH:36]=1>CN(C=O)C.C(OCC)(=O)C.Cl>[F:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][CH2:40][NH:41][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH2:10][S:9][CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:12]=2)=[CH:37][CH:36]=1
Reactant: O=C(O)c1cccc(CSCCc2ccccc2)c1
Reactant: NCCc1ccc(F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(F)cc1)c1cccc(CSCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 3-(phenethylthiomethyl)benzoic acid (0.5 g, 1.84 mmol) in DMF (8 mL) were added EDC (0.49 g, 2.57 mmol), HOBT (0.28 g, 1.84 mmol) and 4-fluorophenethylamine (0.24 mL, 1.84 mmol). The clear reaction mixture was stirred at rt for 2 h and diluted with ethyl acetate and 1 N aqueous HCl solution. The organic layer was separated, washed with brine and dried over MgSO4. The filtrate was concentrated in vacuo. The residue was dissolved in DCM and purified by flash chromatography on silica gel eluting with 20% ethyl acetate in dichloromethane to give the desired product (0.34 g, 47%) as a white solid. 1H NMR (CDCl3) δ 7.61 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.20-7.11 (m, 5H), 6.97 (t, J=8.0 Hz, 2H), 6.11 (s, 1H), 3.69 (s, 2H), 3.67-3.63 (m, 2H), 2.94-2.79 (m, 4H), 2.63-2.61 (m, 2H). MS (ESI): 394.1 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@H:20]4[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]4)[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:31]([O:35][P:36](N(CC)CC)(=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:34])([CH3:33])[CH3:32].N1C=NN=N1.C1C=C(Cl)C=C(C(OO)=O)C=1>C1COCC1.C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@@H:20]4[O:21][C@H:22]([CH2:29][O:30][P:36](=[O:42])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[O:35][C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:23]([OH:28])[C@H:24]([OH:27])[C@H:25]4[OH:26])[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Reactant: CCN(CC)P(=O)(OC(C)(C)C)OC(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccc([C@@H]2O[C@H](COP(=O)(OC(C)(C)C)OC(C)(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 47.9 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 1.0 g, 2.4 mmol) in THF (15 ml) was added a solution of Diethyl-phosphoramidic acid di-tert-butyl ester (780 mg, 3.12 mmol) in THF (5 ml) at 0° C. followed by a solution of tetrazole (435 mg, 6.2 mmol) in DCM (12.5 ml). After stirring for 5 min at same temperature, it was stirred at room temperature for 20 min. Reaction mixture was cooled to −40° C. and added a solution of m-CPBA (830 mg, 4.8 mmol) in DCM (5 ml). The reaction mixture was stirred at same temperature for 5 min and then at room temperature for 2 h. Reaction mixture was cooled to 0° C. and quenched by the addition of 10% sodium bisulfite solution (5 ml). This was extracted with ether (3×10 ml). Combined organic layer was washed with brine (5 ml), dried over sodium sulfate and concentrated to give 700 mg of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH2:24]([C:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH3:27])[CH3:25]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (LC/MS): 360.2 (M+H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:33](=[O:35])[NH2:34])=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl>[CH:36]1([NH:39][CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:33]([NH2:34])=[O:35])=[C:19]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]([F:30])([F:31])[F:32])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:38][CH2:37]1
Reactant: CS(=O)(=O)OCc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Reactant: NC1CC1
Solvent: ClCCl
Product: NC(=O)c1sc(-n2cnc3cnc(CNC4CC4)cc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 6, 58 mg of [1-(5-carbamoyl-4-{[2-(trifluoromethyl)benzyl]oxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (compound A1) and 228 mg of cyclopropylamine in 5 ml dichloromethane yield the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([NH:29][N:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH2:39][CH3:40])C)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[CH2:39]([O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27])[CH3:40]
Reactant: CCOc1ccccc1N(C)NC(=O)OC(C)(C)C
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1-n1c(=O)c2c(n1C)[C@]1(C)CC[C@H]2C1(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
Triethylamine (944 μL, 6.7 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 693 mg, 3.23 mmol) in 1,2-dichloroethane (3 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2-ethoxy-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (544 mg, 2.04 mmol) in 1,2-dichloroethane (6 mL) was added over 2 min. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min, and then in an oil bath at 50° C. for 2 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 20-50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with ether and then petroleum ether. The residue was triturated with hexanes, and the solid was dried overnight under high vacuum at 70° C. and then at 85° C. for 1 h to give (4S,7R)-2-(2-ethoxy-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (200 mg, 30%) as an off-white solid. ES(+)-MS (M+H) 327.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCC(C)C)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CON=C(C(=O)O)c1csc(N)n1
Yield: 91.6 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetate (syn isomer, 19.6 g.), 2N aqueous solution of sodium hydroxide (72.2 ml.), methanol (72.2 ml.) and tetrahydrofuran (72.2 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetic acid (syn isomer, 16.1 g.), mp 180° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH:30]1([CH:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:5]3[CH2:4][C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])[C:6]3=[O:11])=[CH:17][CH:18]=2)[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C1NCc2c(F)cccc21
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
At 0° C., 280 mg (1.85 mmol) of 4-fluoro-2,3-dihydro-1H-isoindol-1-one were added to a suspension of 96.3 mg (2.41 mmol, 60% pure) of sodium hydride in 1 ml of DMF. The mixture was stirred for 30 min, and 654.5 mg (1.85 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were then added at 0° C. Stirring was continued for a further 2 h, and water and ethyl acetate were then added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1 to 5:1). This gave 394 mg (50.2% of theory) of the target compound.