Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.C1COCC1.[N:7]([CH2:10][C:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)=[O:12])=[N+:8]=[N-:9].Cl>C1(C)C=CC=CC=1.C1COCC1>[N:7]([CH2:10][C@@H:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)[OH:12])=[N+:8]=[N-:9]
Reactant: CC1(C)OCc2cc(C(=O)CN=[N+]=[N-])ccc2O1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)OCc2cc([C@@H](O)CN=[N+]=[N-])ccc2O1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
R-(+)-2-Methyl-CBS-oxazaborolidine solution in toluene (1M, 7.5 ml) was added to THF (75 ml) and the solution was diluted to 0° C. Borane-THF complex (1M solution in THF, 125 ml) was added and the mixture was stirred under nitrogen for 15 min. A solution of 2-azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (24.7 g) in THF (250 ml) was added dropwise over 1.5 h at 5° C. The mixture was stirred for a further 1 h and then cautiously treated with 2M HCl (100 ml). The reaction mixture was extracted with ether and the organic layer was washed with 2M HCl, NaHCO3, brine, dried (MgSO4). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with diethyl ether-petrol (40–60° C.) (1:9; 1:1) to give the title compound (16.99 g). ES+ve 250 (MH)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:53][N:54]([CH3:58])[C:55](Cl)=[O:56]>C(Cl)Cl>[CH3:53][N:54]([CH3:58])[C:55]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1)=[O:56]
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 5C (41.5 mg, 0.051 mmol) and DIEA (0.045 mL, 0.256 mmol) in CH2Cl2 (1 mL) at room temperature was added dimethylcarbamic chloride (4.94 μL, 0.054 mmol), slowly, via syringe. The reaction was stirred overnight at room temperature. Volatiles were removed via a stream of nitrogen and TFA (0.5 mL) was added. The mixture was then heated at 60° C. in an oil bath for 4 h. The reaction was then cooled to room temperature and the TFA was removed under reduced pressure. The resulting crude material was diluted with 1 mL of THF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=56.165 min. 6-((trans-4-((dimethylcarbamoyl)amino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide, 2TFA (18 mg, 45.2% yield) was obtained as a white foam. LC/MS, m/z 533.1 (M+1). HPLC Rt=4.200 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.31 (1H, s), 9.82 (1 H, s), 8.73 (1H, d, J=2.47 Hz), 8.51 (1H, t, J=6.05 Hz), 8.44 (1H, d, J=5.22 Hz), 8.34 (1H, d, J=3.85 Hz), 8.12 (1H, s), 7.97 (1H, s), 7.68-7.80 (1H, m), 7.50 (1H, d, J=8.52 Hz), 7.17-7.26 (1H, m), 7.02 (1H, dd, J=6.74, 5.36 Hz), 5.84-5.93 (1H, m), 3.77-3.87 (1H, m), 3.40 (1H, d, J=6.05 Hz), 2.78 (6H, s), 2.06 (2H, s), 1.80 (2H, s), 1.34 (4H, d, J=12.10 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O[C:33]1[CH:42]=[C:41]2[C:36]([C:37]([C:54]3[CH:59]=[C:58]([O:60][CH3:61])[C:57]([O:62][CH3:63])=[C:56]([O:64][CH3:65])[CH:55]=3)=[C:38]([C:50]([O:52][CH3:53])=[O:51])[N:39]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]2=[O:43])=[CH:35][C:34]=1[O:66][CH3:67].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C=O.C(OCC)(=O)C.O>[CH3:67][O:66][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:33]=1[O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:40](=[O:43])[N:39]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]([C:50]([O:52][CH3:53])=[O:51])=[C:37]2[C:54]1[CH:55]=[C:56]([O:64][CH3:65])[C:57]([O:62][CH3:63])=[C:58]([O:60][CH3:61])[CH:59]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC(=O)c3ccc[nH]3)cc2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Pyrrol-2-carboxylic acid (38.4 mg) and 1-hydroxybenzotriazole monohydrate (53 mg) are dissolved in acetonitrile (10 ml), and thereto is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66.3 mg), and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is added to a solution of the compound obtained in Example 214 (162 mg) and potassium carbonate (48 mg) in dimethylformamide (10 ml), and the mixture is stirred at room temperature for 30 minutes. Water and ethyl acetate are added to the reaction mixture. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 6-methoxy-3-methoxycarbonyl-2-phenyl-7-(2-pyrrolylcarbonyloxy)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (145 mg) as listed in Table 18.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Yield: 54 %

Procedure:
A mixture of 4-nitrophenol (3.5 g, 25 mmol), N-(2-chloroethyl)morpholine hydrochloride (4.7 g, 25 mmol), and potassium carbonate (13.2 g, 125 mmol) in acetone (100 mL) was heated to reflux for 18 hours. The solvent was removed under vacuum. The residue was partitioned between water (150 mL) and ethyl acetate (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×100 mL) and extracted with dilute aqueous HCl (2×125 mL). These extracts were washed with CH2Cl2 (2×125 mL), made basic (NaOH), and extracted into ethyl acetate (3×75 mL). These organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 3.4 g as a pale yellow solid, in 54% yield; 1H NMR (CDCl3) δ 2.59 (t, J=4.7 Hz, 4H), 2.84 (t, J=5.7 Hz, 2H), 3.74 (t, J=4.7 Hz, 4H), 4.20 (t, J=5.7 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 8.20 (d, J=9.0 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)[N:5]=[C:4]([N+:24]([O-:26])=[O:25])[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[N+:24]([C:4]1[N:3]=[C:2]2[O:10][CH2:9][CH2:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:6]2[N:5]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)[Si](C)(C)OCCC(c1ccccc1)n1nc([N+](=O)[O-])nc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1nc2n(n1)C(c1ccccc1)CCO2
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-1-(3-(tert-butyldimethylsilyloxy)-1-phenylpropyl)-3-nitro-1H-1,2,4-triazole (510 mg, 1.16 mmol) in tetrahydrofurane (11.6 mL) was added under an atmosphere of nitrogen at room temperature 1 M tetrabutyl ammonium fluoride solution in tetrahydrofurane (3.47 mL, 3.47 mmol). The yellow solution was stirred at room temperature over night. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a light yellow solid (174 mg, 61%) after column chromatography on silica gel using a gradient from heptane/ethyl acetate 4:1 to 1:1 (v/v) as eluent. MS ISP (m/e): 247.2 (100) [(M+H)+], 264.1 (36). 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.42-7.38 (m, 3H), 7.09 (d, 2H), 5.61 (t, 1H), 4.56 (m, 2H), 2.77 (m, 1H), 2.42 (m, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[N:10]=[N:9][C:8]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12](=[O:19])[N:13]([CH2:16][CH2:17][CH3:18])[C:14](=[O:15])[C:7]=2S1)(=[O:3])[CH3:2]>O1CCOCC1>[C:1]([NH:4][C:5]1[C:7]2[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[C:12](=[O:19])[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=2[NH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CCCn1c(=O)c2c(n(Cc3ccccc3)c1=O)N=NC(NC(C)=O)S2
Solvent: C1COCCO1
Product: CCCn1c(=O)c2c(NC(C)=O)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 93 %

Procedure:
A solution of 3-acetylamino-8-benzyl-6-propylpyrimido[4,5-e][1,3,4]thiadiazine-5,7(6H,8H)dione (4.0 g) in dioxane (50 ml) was refluxed for one hour. The reaction mixture was concentrated to dryness, and the concentrate was dissolved in methanol. Insoluble sulfur was filtered off. To the filtrate was added a small volume of water, which was left standing for cooling, then colorless crystals (3.4 g), m.p. 108°-110° C., were obtained.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[N:31]=[N:30][CH:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:17][C:16]=3[F:33])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]4[N:31]=[N:30][CH:29]=[N:28]4)[O:23][C:22]3=[O:32])=[CH:17][C:16]=2[F:33])=[CH:11][CH2:10]1)=[O:8]
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3ccc(N4C[C@H](Cn5ncnn5)OC4=O)cc3F)CC2)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C([C@@H](O)CO)N1CC=C(c2ccc(N3C[C@H](Cn4ncnn4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.4 %

Procedure:
(5R)-3-(4-(1-((4S)-2,2-Dimethyl-1,3-dioxolane-4-carbonyl)-1,2,5,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(tetrazol-2-ylmethyl)oxazolidin-2-one (550 mg, 1.17 mM) in a mixture of tetrahydrofuran (25 ml) and aqueous hydrochloric acid (1M, 10 ml) was stirred at room temperature for 24 hours, then concentrated by evaporation to a solid. The solid was filtered, washed with water, followed by a small volume of ethanol, then triturated with diethyl ether to give the title compound as a colourless solid (450 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[N:3]=1.[C:16]([OH:21])(=O)[CH2:17][CH2:18][CH3:19]>>[CH3:15][C:4]1[N:3]=[C:2]2[N:1]=[C:15]([CH2:4][CH2:5][CH3:6])[NH:8][C:7]2=[C:6]([CH3:11])[C:5]=1[NH:12][C:16](=[O:21])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)O
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Product: CCCC(=O)Nc1c(C)nc2nc(CCC)[nH]c2c1C

Procedure:
The title compound is prepared using the method outlined in Example 5 step 2 starting with 2-amino-4,6-dimethyl-3,5-dinitropyridine in the place of 2-amino-6-methylpyridine and butyric acid in the place of valeric acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:5]=[C:6]([O:19][CH:20]([CH3:22])[CH3:21])[C:7]=1[O:8]CC1C=CC([N+]([O-])=O)=CC=1.C(O)(=O)C>C1COCC1.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:5]=[C:6]([O:19][CH:20]([CH3:22])[CH3:21])[C:7]=1[OH:8]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2ccc([N+](=O)[O-])cc2)c(OC(C)C)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c(OC(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of the product isolated in step c (750 mg) and acetic acid (1.5 ml) in THF (50 ml) was added zinc dust (1.5 g) under vigorous stirring. The mixture was stirred for 2 h and then filtered. The mixture was diluted with EtOAc and washed with sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClC1C(CO)=CC(F)=C(Cl)N=1>>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: OCc1cc(F)c(Cl)nc1Cl
Product: OCc1ccc(Cl)nc1Cl
Yield: 88.6 %

Procedure:
Compound 13A (0.82 g, 89%) was prepared from 2,6-dichloro-nicotinic acid (1.0 g, 5.2 mmol) using a procedure similar to the synthesis of 1A. HPLC Rt=1.39 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][C:9]=2[CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:28]([O:37]C(OC(C)(C)C)=O)[C:27]([C:45]([F:48])([F:47])[F:46])=[CH:26][CH:25]=1>>[C:33]([O:32][C:30]([C:29]1[C:28]([OH:37])=[C:27]([C:45]([F:48])([F:47])[F:46])[CH:26]=[CH:25][C:24]=1[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH2:19][CH2:20][CH3:21])=[CH:6][CH:7]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCc1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CCCc1cc(CC(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from methyl (4′-hydroxy-2-propyl-1,1′-biphenyl-4-yl)acetate (140 mg, 0.493 mmol) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (228 mg, 0.542 mmol) obtained in Example (28-5), the title compound was obtained as a yellow amorphous compound (128 mg, yield: 48%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CO.C(O)C.C([O:15][C@@H:16]1[C@@H:20]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:31])[C:28]([Cl:30])=[CH:29][C:24]=3[N:23]=[C:22]2[I:32])[CH2:19][C@@H:18]([CH2:33][O:34]C(=O)C)[C@@H:17]1[O:38]C(=O)C)(=O)C>O.C(O)(=O)C>[Cl:30][C:28]1[C:27]([Cl:31])=[CH:26][C:25]2[N:21]([C@@H:20]3[C@@H:16]([OH:15])[C@@H:17]([OH:38])[C@H:18]([CH2:33][OH:34])[CH2:19]3)[C:22]([I:32])=[N:23][C:24]=2[CH:29]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(I)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: OC[C@@H]1C[C@H](n2c(I)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Sodium carbonate (40 mg, 0.37 mmol) was dissolved in water (0.7 mL) and methanol (3 mL) and ethanol (3 mL) were added. To this stirred mixture was added (±)(1R*,2S*,3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (215 mg, 0.37 mmol). After 2 hours at ambient temperature, acetic acid was added to adjust the pH to 7 and volatiles were evaporated in vacuo. Resolidification of the residual solid from 3:1 ethanol-water gave (±)-(1R*,2S*,3S*,5S*)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as a white powder (153 mg, 94%), m.p. 209°-210° C. dec.; 1H-NMR(DMSO-d6) δ: 8.22 and 7.91 (both s, 2,2 aromatic CH), 5.12 (t, J=4.5 Hz, 1, OH), 4.95 (d, J=6.2 Hz, 1, OH), 4.9-4.8 (m, 1, NCH), 4.70 (t, J=3.5 Hz, 1, OH), 4.6-4.5 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.7-3.6 and 3.55-3.45 (both m, 1 each, OCH2), 2.2-2.0 (m, 3, CH2 and CH); mass spectrum(CI): 443 (M+1).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[CH:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11](O)/[CH:12]=[CH:13]/[CH3:14].[C:17]([O:23]C)([O:21][CH3:22])(OC)[CH3:18]>C(CC(O)=O)(C)(C)C>[CH3:1][CH:2](/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH:13]([CH3:14])[CH2:18][C:17]([O:21][CH3:22])=[O:23])[CH2:18][C:17]([O:21][CH3:22])=[O:23]
Reactant: C/C=C/C(O)CCCCCCC(O)/C=C/C
Reactant: COC(C)(OC)OC
Agent: CC(C)(C)CC(=O)O
Product: COC(=O)CC(C)/C=C/CCCCCC/C=C/C(C)CC(=O)OC
Temperature: 80 °C
Yield: 75.1 %

Procedure:
A mixture of tetradeca-2E,12E-diene-4,11-diol (5.0 g, 22.0 mmole), trimethyl orthoacetate (20 ml, 165 mmole), and t-butylacetic acid (0.1 g, 0.86 mmole) was heated to 120-140° C. for 3.0 hours with the slow distillation of the methanol formed during the reaction. The solution was cooled to 80° C. and the lower boiling materials were removed by vacuum distillation to afford dimethyl 3,14-dimethylhexadeca-4E,12E-diene-1,16-dioate (5.59 g, 75% yield) as an oil which was suitable for use in the subsequent reaction. C20H34O4 (338.49 g/mole). 1HNMR (500 MHz, CDCl3): 1.001 (d, 6H), 1.33-1.18 (m, 8H), 1.929 (dd, 4H), 2.257 (dt, 4H), 2.599 (dt, 2H), 3.634 (s, 6H), 5.32-5.27 (m, 2H), 5.43-5.36 (m, 2H) ppm. 13CNMR (125 MHz, CDCl3): 20.54, 28.99, 29.51, 32.52, 33.76, 41.89, 51.49, 129.74, 134.10, 173.22 ppm. IR (νmax(cm−1)): 2926(s), 2912(s), 2852(m), 1742(s), 1458(m), 1437(m), 1358(m), 1284(m), 1246(m), 1192(m), 1168(m), 1072(w), 1008(m), 970(m), 879(w), 839(w), 725(w). MS (m/z): 338(M+), 306, 275, 264, 257, 246, 233, 223, 215, 204, 191, 177, 163, 149, 135, 121, 108, 95, 81, 67, 55, 41.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][NH:11][CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C)C=O>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:11]1[CH2:12][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])[C@:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[C@@H:10]1[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N(CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 66 h
Yield: 66.2 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (2.5 g, 5.9 mmol) in N,N-dimethylformamide (50 mL) was added tert-butyl bromoacetate (2.5 g, 12.8 mmol) and Cs2CO3 (5 g, 15.4 mmol). The reaction mixture was stirred at room temperature for 66 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10) to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester as a white foam (2.1 g, 66%).
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][NH2+:9][CH2:10][CH2:11]Cl)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]=[S:25]>>[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]1[N:9]([CH2:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:10][CH2:11][S:25]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]CC1CCCCC1
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]2[CH3:16])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][CH:12]1[N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH:9]2[CH:13]1[CH2:14][CH2:15][NH:8]2
Reactant: CCOC(=O)N1CC2C(CCN2Cc2ccccc2)C1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2NCCC2C1C

Procedure:
13 g (44.9 mmol) of ethyl 2-benzyl-6-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 150 ml of ethanol are hydrogenated ar 100° C. and 100 bar on 2 g of palladium-active carbon (10% Pd). The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(O)(=O)C>CO.[Pd]>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:2][CH2:3]2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Reaction time: 96 h
Yield: 29.6 %

Procedure:
Benzyl 1-piperazinecarboxylate (5.00 g) and tert-butyl 4-oxopiperidine-1-carboxylate (4.52 g) were dissolved in methanol (100 ml), and acetic acid (2.34 ml) and 10% palladium on carbon (1.55 g) were added thereto, followed by stirring under a hydrogen atmosphere for 4 days. The catalyst was removed by filtration, and the filtrate was concentrated. To the residue were added acetone (50 ml) and water (50 ml) to dissolve, and sodium hydrogencarbonate (6.67 g) was added and stirred while cooling in an ice bath. Benzyl chloroformate (3.89 ml) was added thereto, followed by stirring in an ice bath for 3.5 hr. Part of the reaction mixture was concentrated, and ethyl acetate:tetrahydrofuran=1:1 (200 ml) and water (100 ml) were added thereto, followed by stirring at room temperature for 10 min. The organic layer was separated. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=50:1). Fractions containing the target compound were concentrated to provide the titled compound as a pale yellow oil (2.71 g, 29.6%).