Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][CH:9](OC)OC)=[CH:4][C:3]=2[O:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.[ClH:32].[NH4+].[OH-]>FC(F)(F)C(O)=O.CO.O.CC(C)=O.CCOCC>[ClH:32].[CH3:18][O:19][C:20]1[C:21]2[C:8]3[N:7]=[CH:6][C:5]4[C:14]([C:9]=3[CH2:23][C:22]=2[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])=[CH:15][C:16]1[O:17][CH2:1][O:2][C:3]=1[CH:4]=4
Reactant: COC(CNCc1ccc2c(c1)OCO2)OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: O
Product: COc1cc2c(c(OC)c1OC)-c1ncc3cc4c(cc3c1C2)OCO4
Temperature: 100 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Amine 12b (2.28 g, 9.52 mmol) and 3,4,5-trimethoxybenzaldehyde (10c, 3.77 g, 19.2 mmol) were reacted in trifluoracetic acid (25 mL) with stirring at 100° C. for 3 h. The reaction mixture was cooled and hydrochloric acid (2 M in ether, 10 mL) and ether (200 mL) were added. The precipitate was isolated and dissolved in methanol-water-acetone 1:1:1 (250 mL) and NH4OH was used to bring the mixture to a basic pH. The mixture was extracted with chloroform (350 mL). The organic layer was washed with brine (200 mL), dried (Na2SO4) and concentrated. The residue was dissolved in chloroform (60 mL) and hydrochloric acid (2 M in dry ether, 10 mL) was added. The precipitate was collected and washed with hot methanol (10 mL) and ether 20 (mL) to provide a yellow hygroscopic solid (1.65 g, 45%), mp 257-259° C. 1H NMR (300 MHz, CD3OD) δ 9.04 (s, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.18 (s, 1H), 6.32 (s, 2H), 4.28 (3H), 4.25 (2H), 3.98 (3H), 3.90 (s, 3H); low resolution ESIMS m/z (rel intensity) 352 (MH+, 100). Anal. Calcd for C20H18NO5Cl(H2O)1.9: C, 56.92; H, 5.21; N, 3.32. Found: C, 56.92; H, 5.02; N, 3.29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:16]([CH3:15])[NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: CN(N)c1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A 10.0 g. portion of 6-(p-chlorophenyl)-3-chloropyridazine and 6.1 g. of methyl hydrazine in 125 ml. of butanol is mixed and heated at reflux overnight. The reaction mixture is cooled, filtered, the precipitate is washed with butanol and water and dried. Recrystallization from ethanol gives 6-(p-chlorophenyl)-3-(1-methylhydrazino)pyridazine.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]([C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>CO>[C:21]([C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[O:31][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: COC(=O)C(Oc1cccc(C(C)(C)C)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
In an identical manner as in Example 39, 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate is reacted with 3.75 g of 3-tert-butylphenol in methanol to give a yellow oil. Fractional bulb-to-bulb distillation gives the product as a viscous yellow oil (182° C. @ 0.05 mm).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CCCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCCC2)C1=O
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that [5-cyclohexyl-1-(2-cyclohexyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 79, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.44 (1H, s), 7.45 (3H, m), 7.38 (1H, d), 7.24 (2H, m), 7.11 (1H, d), 7.05 (1H, d), 6.70 (1H, br s), 4.70 (1H, d), 4.44 (1H, d), 4.21 (2H, m), 3.66 (2H, s), 2.80 (1H, m), 2.47 (1H, m), 2.18-1.66 (11H, m), 1.44-1.22 (9H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 56.91; H, 6.96; N, 8.36%; C32H38N4O5S.C7H17NO5.2.0H2O requires: C, 56.99; H, 7.24; N, 8.52%.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH:11]([CH2:15][CH2:16][C:17](OCC)=[O:18])[CH2:10]1)=O.C(N(CC)CC)C.C1(C)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>O>[ClH:1].[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:7][N:9]1[CH2:14][CH2:13][NH:12][CH:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10]1
Reactant: CCOC(=O)CCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CN2CCNC(CCCO)C2)cc(OC)c1OC
Reaction time: 3 h

Procedure:
To a mixture of ethyl 4-(3,4,5-trimethoxybenzoyl)2-piperazine propionate hydrochloride obtained in Reference Example 31 (1.3 g), triethylamine (315 mg) and toluene (10 ml) is added dropwise, while stirring, at room temperature a 3.4M toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al®) (9 g). To the reaction mixture, after stirring for 3 hours, is added water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is led to its hydrochloride, which is recrystallized from ethanol to give 4-(3,4,5-trimethoxybenzyl)-2piperazine propanol dihydrochloride as colorless crystals (1 0 g) m.p. 212-215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[Na+].[OH-].[Na+].Cl>O.C(O)(=O)C>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:14][C:13](=[O:12])[NH:1]2
Reactant: N#C[O-]
Reactant: Nc1cccc(Br)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2c(Br)cccc2[nH]1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
2-Amino-6-bromobenzoic acid (2.97 g, 13.7 mmol) was suspended in a mixture of water (100 mL) and acetic acid (1.5 mL) at 35° C. then a suspension of sodium cyanate (2.23 g, 34.4 mmol) in 10 mL of water was added slowly to the mixture. Upon completion of addition, the resulting mixture was stirred at 35° C. for 30 minutes and then sodium hydroxide (24.7 g, 619 mmol) pellets were slowly added to the mixture to yield a thick precipitate. The mixture was cooled to 5° C. in an ice bath and the pH of the suspension was adjusted to 4 using concentrated HCl. Once at the prescribed pH, the suspension was filtered and the solid was washed with water and dried under vacuum while heating at 100° C. to give 5-bromo-1H-quinazoline-2,4-dione (1.91 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.30 (1 H, br. s.), 11.26 (1H, br. s.), 7.43-7.48 (1H, m), 7.40 (1H, dd, J=7.78, 1.25 Hz), 7.16 (1H, dd, J=7.91, 1.13 Hz).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH:24]([CH3:29])[C:25]([O:27]C)=[O:26])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH:24]([CH3:29])[C:25]([OH:27])=[O:26])[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)NCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(NCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)C(=O)O
Temperature: 0 °C

Procedure:
To a solution of methyl 2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoate (100 mg, 0.25 mmol) in ethanol (10 mL) was added aqueous NaOH (3 mL, 20%, 5.0 eq.) and refluxed for 1 hr. Then the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 with 1 M HCl, concentrated and the residue was dissolved in dichloromethane, washed with water, dried and concentrated to give 2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid as a white solid (70 mg, yield: 75%). ESI-MS: 384.1 (M+H)+. HPLC: 97.18%. 1H NMR (400 MHz, CD3OD) δ: 7.88 (s, 1H), 7.83 (d, 1H), 7.73 (d, 1H), 7.49 (dd, 1H), 7.26 (d, 1H), 7.15 (dd, 1H), 4.29-4.38 (m, 3H), 4.04 (q, 1H), 2.25 (d, 2H), 1.90 (d, 2H), 1.60 (d, 3H), 1.36-1.44 (m, 2H), 1.21-1.31 (m, 2H), 1.09-1.15 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: [C:1]([C:6]1[S:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)(OCC)=[O:2].C(O)C.[BH4-].[Na+]>O>[CH3:12][CH:11]([C:9]1[N:10]=[C:6]([CH2:1][OH:2])[S:7][CH:8]=1)[CH3:13]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)c1csc(CO)n1
Yield: 112.7 %

Procedure:
A solution of 4.5 g of 2-carboethoxy-4-(1-methylethyl)thiazole, 100 ml of ethyl alcohol and 1.1 g of sodium borohydride was heated to reflux for 4 hr. The reaction mixture was then condensed to one half of the original volume in vacuo, diluted with 150 ml of water and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4) and condensed in vacuo to give 4.0 g of 4-(1-methylethyl)-2-thiazole methanol; m.p. 80°-82° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(N)cc1
Yield: 65 %

Procedure:
A solution of 1-methanesulfonyl-4-nitro-benzene (500 mg, 2.48 mmol) in methanol (20 ml) was hydrogenated over 10% Pd—C (100 mg) at atmospheric pressure until no further gas uptake was observed. The reaction mixture was then filtered over celite and concentrated to give a residue, which was recrystallized from ethanol to yield 4-methanesulphonyl-phenylamine (276 mg, 65%) as solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[O:24]1[C:29]2[CH:30]=[CH:31][C:32](B(O)O)=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1>>[O:24]1[C:29]2[CH:30]=[CH:31][C:32]([C:6]3[N:7]=[C:8]([N:10]4[C:14]5[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=5[N:12]=[CH:11]4)[S:9][C:5]=3[C:3]([OH:2])=[O:4])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1ccc2c(c1)OCCO2
Product: COc1cc2ncn(-c3nc(-c4ccc5c(c4)OCCO5)c(C(=O)O)s3)c2cc1OC
Yield: 21.6 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 1,4-benzodioxane-6-boronic acid (27 mg, 0.15 mmol) gave 4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (9.5 mg, 22%) as a white solid. MS 440 m/z (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:37]=[C:36]([F:38])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31][CH2:32][CH2:33][S:34][CH3:35])=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:39])[CH:5]=1)[CH3:2].ClC1C=CC=CC=1C(OO)=[O:48].ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:39])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[C:21]([O:31][CH2:32][CH2:33][S:34]([CH3:35])=[O:48])=[CH:20][N:19]=3)=[N:10]2)=[C:36]([F:38])[CH:37]=1)[CH3:2]
Reactant: O=C(OO)c1ccccc1Cl
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCSC)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1.24 g 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-[2-(methylsulfanyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (4-16, 2.26 mmol, 1. eq.) in 2.15 ml of dry chloroform, was added slowly at 0° C. a solution of 557 mg 2-chlorobenzenecarboperoxoic acid (77%, 2.49 mmol, 1.1 eq.) in 2.15 ml chloroform. After 30 min dichloromethane and sodium thiosulfate-solution (10%) were added. The slurry was stirred for 5 min. After separating the solid (product) the aqueous layer was washed with dichloromethane twice. The organic layers were dried with sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography and combined the former isolated solid to yield 1.22 g (2.05 mmol, 91%) of the analytically pure target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.C1C(=O)N([Cl:49])C(=O)C1>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][C:7]=1[Cl:49]
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Temperature: 60 °C

Procedure:
A solution of 49A (300 mg, 0.49 mmol) in 5 mL of acetonitrile was cooled to 0° C. and treated with NCS (0.49 mmol). The reaction was heated to 60° C. overnight. The reaction mixture was partitioned with EtOAc and aqueous saturated NaHCO3, then washed with brine. The organic layer were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography to provide the title compound. MS (m/z) 641 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:52]=[O:53].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:52][OH:53])[CH:50]=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 51 (4.19 g, 5.9 mmol) was dissolved in 45 mL 1,4-dioxane, followed by addition of 9.6 mL 37% formaldehyde solution and dropwise addition of 17.82 mL 1 M sodium hydroxide solution. The reaction mixture was stirred for 16 hours at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 100 mL ethyl acetate and 50 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (100 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 5j (4.36 g, pale yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[C:11]([CH3:13])[S:10][C:6]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Product: CCN1Cc2cc(C)sc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21]C)=[O:20].[OH-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:18]([C:19]([OH:21])=[O:20])[O:10][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1O
Reactant: COC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccc(Br)cc2o1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
8.0 g (39.8 mmol) of 4-bromo-2-hydroxybenzaldehyde and 1.47 g (3.98 mmol) of tetra-n-butylammonium iodide are mixed with 22 g (159.19 mmol) of anhydrous potassium carbonate. 9.07 g (83.57 mmol) of methyl chloroacetate are added. The reaction mixture is heated at 130° C. for 4 h and then cooled to 0° C. in an ice bath. 100 ml of THF and a solution of 13.4 g (238.8 mmol) of potassium hydroxide in 50 ml of water are added, and the mixture is then stirred at RT overnight. The THF is removed under reduced pressure. The remaining aqueous phase is diluted with water and acidified with conc. hydrochloric acid. The precipitated product is filtered off and dried under high vacuum. Silica gel 60 (Merck, Darmstadt; eluent: toluene, toluene/acetic acid 50:1, toluene/acetic acid/methyl acetate 35:1:5) is used for final purification. The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 3.8 g (40% of theory) of the title compound are isolated.
Reaction SMILES: CCCCCCCCCCC.[CH:12]12[NH:22][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:16][CH2:15][CH2:14]C2>>[CH:15]12[CH2:14][CH2:18][CH:19]3[CH:17]([NH:22][CH2:12][CH:21]1[CH2:20]3)[CH2:16]2
Reactant: C1CCC2CCCCC(C1)N2
Solvent: CCCCCCCCCCC
Product: C1CC2CC3CNC2CC13

Procedure:
4.3.1.13,8 ]undecane; 11-azabicyclo[4.4.1]undecane;
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(Sc2cnc(NC(C)=O)s2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(Sc2cnc(N)s2)cc1
Yield: 86.5 %

Procedure:
A mixture of 2-acetylamino-5-(4-methoxyphenylthio)thiazole (1.7 g) in a mixture of ethanol (40 ml) and aqueous 6N hydrochloric acid (6 ml) was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 10 using aqueous sodium hydroxide under cooling. The precipitates were collected by filtration, washed with water and recrystallized from ethanol to give 2-amino-5-(4-methoxyphenylthio)thiazole (1.25 g, yield: 86.8%). mp: 119°-120° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=[O:19])[CH2:13][CH2:14][C:15]=3[C:16](I)=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CC3
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(=O)CC3
Yield: 81 %

Procedure:
Into a 500 ml Parr bottle, Intermediate 1 (11 g, 27.56 mmol) was added, followed by 5% Pd—C (700 mg) in EtOH (200 ml). The mixture was shaken over 50 psi hydrogen for 16 hours. The contents were filtered through celite and solvent evaporated in vacuo. The remaining residue was purified by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexane) to give the title product as a white solid (6.1 g). 1H NMR (300 MHz, CDCl3) δ 7.31 (d, J=7.8 Hz, 1H); 7.22 (d, J=7.8 Hz, 1H); 4.16 (q, J=6.9 Hz, 2H); 3.62-3.60 (m, 6 μl); 3.05-2.96 (m, 4 μl); 2.70-2.66 (m, 2H); 1.27 (t, J=6.9 Hz, 3H; MS: ESI (positive): 274 (M+H).
Reaction SMILES: [BH4-].[Na+].Cl[C:4]1([F:14])[CH2:6][CH:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CN(C)C(=O)C.[Co](Cl)Cl>[F:14][CH:4]1[CH2:6][CH:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)C1CC1(F)Cl
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C1CC1F
Yield: 84 %

Procedure:
Sodium borohydride (243 mg, 6.43 mmol) was added to and dissolved in N,N-dimethylacetamide (1.5 mL) at room temperature, followed by addition of an N,N-dimethylacetamide solution (1.0 mL) of tert-butyl 2-chloro-2-fluoro-cyclopropane-1-carboxylate (cis/trans=57/43) (hereinafter the compound will be referred to as “compound (1d)”) (500 mg, 2.57 mmol). Cobalt chloride (33.4 mg, 1.54 mmol) was added to the resultant solution. After completion of addition, the resultant mixture was stirred at 50° C. for 14 hours. After completion of reaction, the whole reaction mixture was diluted with an HPLC mobile phase to 50 mL, to thereby yield a solution containing 344.6 mg (yield: 84%) of the title compound. Yield was determined by means of high performance liquid chromatography (HPLC) (the same shall apply hereinafter).