Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([CH:6]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:7]([CH:9]2[CH2:11][CH2:10]2)=O)=O)[CH2:3][CH2:2]1.O.[NH2:22][NH2:23]>C(O)(=O)C.C(O)C>[CH:1]1([C:4]2[C:6]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[C:7]([CH:9]3[CH2:11][CH2:10]3)[NH:23][N:22]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(OC(C(=O)C2CC2)C(=O)C2CC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccc(Oc2c(C3CC3)n[nH]c2C2CC2)cc1
Temperature: 90 °C
Yield: 91.9 %

Procedure:
The 4-(1-cyclopropanecarbonyl-2-cyclopropyl-2-oxo-ethoxy)-benzonitrile (44 g, 162 mmol) was dissolved in acetic acid (500 ml). A solution of hydrazine hydrate (8.7 ml, 179 mmol) in ethanol (50 ml) was then added at room temperature and the reaction mixture was heated to 90° C. for approximately 3 hours. The solvents were then evaporated under reduced pressure and the residues were partitioned between diethyl ether (600 ml) and dilute aqueous ammonium hydroxide (25 ml concentrated ammonium hydroxide in 500 ml water), and the layers were separated. The aqueous layer was further extracted with diethyl ether (3×200 ml) and the combined organic layers were washed with water (2×50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The solid was slurried in diisopropyl ether (50 ml), filtered and rinsed with diisopropyl ether (2×30 ml) and pentane (2×100 ml) to provide the title compound (39.5 g, 58%) as a colourless solid. 1H-NMR (400 MHz, CDCl3): δ=0.76-0.81 (m, 8H), 1.59-1.65 (m, 2H), 7.01 (d, 2H), 7.60 (d, 2H); LRMS: APCl+: m/z 266 [MH+]; APCl−: m/z 264 [M−H]−.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][O:14][C:15](=[O:21])[C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.Cl.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:13][O:14][C:15](=[O:21])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-BOC-glycine (150 mmol) in DMF (250 mL) at 0° C., is added proline methyl ester.HCl (150 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0,164 mmol), ethyl-3-(3-dimethylamino)propyl carbodiimide.HCl (31.4 g, 0,164 mmol) and 4-methylmorpholine (22.6 g, 0.224 mmol). The reaction mixture is stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture is poured in water (750 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts are washed as follows: KHSO4 (0.25 M, 2×50 mL), water (1×50 mL), saturated aqueous NaHCO3 (2×50 mL) and saturated NaCl (1×50 mL). The organic layer is dried over MgSO4, filtered and the solvent removed in vacuo to give title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: O=C(CCl)N1CCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCC3)c(F)c2)C(C)C)c1
Yield: 76.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (19 mg) was obtained.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[N:31]=[C:32]=[S:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[NH:31][C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:33]
Reactant: S=C=Nc1cc(Cl)ccc1Cl
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cc(Cl)ccc4Cl)CC3)nc21

Procedure:
Pipemidic acid (51 mg, 0.168 mmol) and 2,5-dichlorophenyl isothiocyanate (20 μL, 0.140 mmol) were used. Purification on silica yielded compound 20 in Table 1, below (42.7 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 9.39 (s, 1H), 9.06 (s, 1H), 7.57 (d, J=2.39 Hz, 1H), 7.42-7.36 (m, 1H), 7.20 (d, J=7.35 Hz, 1H), 4.55-4.39 (m, 2H), 4.31-4.02 (m, 8H), 1.52 (t, J=6.88 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][C@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][C@@H:41]([OH:53])[CH2:40][NH:39][C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)=[O:14]
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccc2n1
Temperature: 15 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of 2-methylquinoline-6-carboxylic acid (1 g, 5.35 mmol) in DCM (100 mL), was added HATU (2.44 g, 6.42 mmol) and TEA (1620 mg, 16.043 mmol). The solution was stirred at 15° C. for 30 minutes before (S)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (1.76 g, 8.55 mmol) was added. The resulting solution was stirred for 16 h at 15° C. until LCMS analysis showed the reaction to be complete. The mixture was then concentrated under vacuum and the residue purified by Preparative HPLC to give the desired title compound (502.1 mg, 25%). 1H NMR (400 MHz, METHANOL-d4) δ 8.31 (br. s., 1H), 8.08 (d, J=8.8 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.17-7.03 (m, 4H), 4.23-4.11 (m, 1H), 3.78 (br. s., 2H), 3.59 (d, J=5.5 Hz, 2H), 2.91 (br. s., 4H), 2.78-2.69 (m, 5H). LCMS (m/z): 376.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[Cl:32])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[O:40](C(C)=O)[C:41]([CH3:43])=O>>[C:41]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[Cl:32])[CH:5]=[CH:4][N:3]=1)(=[O:40])[CH3:43]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-3-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (120 mg, 0.27 mmol) in (Ac)2O (5 mL) was added Et3N (0.4 mL, 1.12 mmol). The reaction mixture was stirred at rt for 8 hours and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a white solid (65 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[C:9]2[CH3:24])=[CH:4][CH:3]=1.[CH2:27]([NH2:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][C:10]([C:21]([NH:37][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])=[C:9]2[CH3:24])=[CH:25][CH:26]=1
Reactant: CCCCCCCCCCN
Reactant: COc1ccc(-c2cc(C(=O)O)c(C)n2CCc2ccc(Br)cc2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCNC(=O)c1cc(-c2ccc(OC)cc2)n(CCc2ccc(Br)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromophenethyl)-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylic acid (2.00 g, 4.83 mmol) in DMF (10 ml) were added n-decylamine (838 mg, 5.33 mmol), diethyl cyanophosphate (946 mg, 5.80 mmol) and triethylamine (0.673 ml, 4.83 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction solution were added n-decylamine (838 mg, 5.33 mmol), diethyl cyanophosphate (946 mg, 5.80 mmol) and triethylamine (0.673 ml, 4.83 mmol) and the mixture was stirred room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate anhydride, and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the object compound as a solid. 2.16 g (80.9%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:21])[N:13]=[C:14](S(C)(=O)=O)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:21])[N:13]=[C:14]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(-c3ccc(F)cc3)nc12
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 60 °C
Yield: 66.4 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-methylsulfonyl-thiazolo[5,4-d]pyrimidin-5-amine (0.40 g, 1.23 mmol) and triethylamine (0.26 ml, 1.85 mmol) in dioxane (6 ml) was added piperazine (0.16 g, 1.85 mmol). The reaction mixture was heated at 60° C. for 5 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 15:1), furnishing the title compound as a light yellow solid (0.27 g, 67%).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:4][C:3]=1S(O)(=O)=O.N1C(Cl)=NC(Cl)=NC=1Cl>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1Sc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Clc1nc(Cl)nc(Cl)n1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 23 was repeated, except that the compounds shown in 1st, 2nd and 3rd columns of the following table were used in place of the 1-amino-4-(3'-amino-2',4',6'-trimethyl-5'-sulfophenylthio)anthraquinone-2-sulfonic acid, cyanuric chloride and 1-aminobenzene-3-β-sulfatoethylsulfone, respectively thereby obtaining a corresponding anthraquinone compound. The color shade on cotton of the compound is as shown in a 4th column of the table.
Reaction SMILES: [CH2:1]([C@@H:4]1[C@H:9]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:7]2([CH3:8])[C:6](=[O:30])[CH2:5]1)[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH:2]=[CH2:3].[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.O>[CH2:1]([C@@H:4]1[C@H:9]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:7]2([CH3:8])[C@@H:6]([OH:30])[CH2:5]1)[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:14][C:13]=1[CH2:12][CH2:11]3)[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@H]1C[C@H](O)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Yield: 90.9 %

Procedure:
A solution of 341 mg (0.850 mmol) of 71, 129 mg (3.40 mmol) of NaBH4 in THF (9 mL) with 37 drops of H2O was stirred at rt for 3 h, poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×, 50 mL). Combined organic extracts were washed with 10% Na2S2O5 (30 mL), H2O (30 mL), dried over Na2SO4 and concentrated in vacuo giving a yellow oil. Purification by flash chromatography on a 3×21 cm column of silica gel using 2:1 hexanes/EtOAc as eluent gave 311 mg (91%) of 72. Data for 72: TLC, T-1, Rf 0.37; 1H NMR (500 MHz, CDCl3) δ 0.83 (s, 3H, H-18), 1.02 (t, 1H, J=10.3 Hz, H-14), 3.70 (t, 1H, J=9.2 Hz, H-17α), 5.01–5.06 (m, 2H, ═CH2), 5.04 (s, 2H, benzylic-H), 5.78–5.86 (m, 1H, —CH═), 6.72 (d, 1H, J=2.7 Hz, H-4), 6.79 (dd, 1H, J=8.6, 2.7 Hz, H-2), 7.22 (d, 1H, J=8.6 Hz, H-1), 7.31–7.44 (m, 5H, Ar—H).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[S:8]1[CH:9]=[CH:10][C:6]([C:3](=[O:5])[CH2:4][C:15]([O:16][CH3:17])=[O:18])=[CH:7]1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)c1ccsc1
Yield: 46 %

Procedure:
24 g (0.6 mmol) of sodium hydride (60%) are added in portions at 0° C., over a period of 10 minutes, to 25.2 g (0.2 mmol) of 3-acetylthiophene in 600 ml of dimethyl carbonate, and then the whole is heated at reflux for 30 minutes, allowed to cool and poured into 1 liter of a water/ice mixture containing 53 ml of acetic acid. Extraction is carried out 3 times with 250 ml of ether each time. The combined organic phases are dried over magnesium sulphate. After evaporation, the residue is chromatographed on silica (eluant: dichloromethane) to yield 17 g of the desired compound (yield: 46%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.Cl[C:13]1[CH:22]=[C:21]([Cl:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.ClC1C=C(Cl)C2C(=CC=C(Cl)C=2)N=1>>[Cl:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH:22]=1
Reactant: c1ccc2c(c1)CCCNC2
Reactant: Clc1cc(Cl)c2ccccc2n1
Agent: Clc1ccc2nc(Cl)cc(Cl)c2c1
Product: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12

Procedure:
The title compound was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and 2,4-dichloroquinoline (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinoline respectively. MS obsd. (ESI+) [(M+H)+] 309. 1H NMR (400 MHz, CDCl3) δ ppm 7.92-7.88 (dd, J=1.2, 8.0 Hz, 1 H), 7.65 (d, J=8 Hz, 1 H), 7.53-7.45 (m, 2 H), 7.24-7.10 (m, 5 H), 4.81 (s, 2 H), 4.09 (brs, 2 H), 3.02-2.97 (m, 2 H), 1.94-1.88 (m, 2 H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@@:9]1(C)[C:28]([O-])=[O:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[BH4-]>C1COCC1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:10][C@H:9]1[CH2:28][OH:29])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@@H]2CN(C(=O)OC(C)(C)C)[C@](C)(C(=O)[O-])C2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of 1-BOC-2-methyl-(2S,4S)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate (1.18 g, 2.71 mmol) prepared in Step B of Example A1 in THF (10 ml) was added LiBH4 (177 mg, 8.13 mmol). The solution was stirred at 70° C. for 2 h, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with a saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated in vacuo to give the title compound (0.88 g, 81%).
Reaction SMILES: [O:1]1[C:3]2[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1=2.[H][H]>[Pd]>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C1=CC2=C(CCCCCCCC1)O2
Agent: [Pd]
Product: OC1CCCCCCCCCCC1
Yield: 20 %

Procedure:
In a reaction example shown in this report, when epoxycyclododecadiene is subjected to a reduction reaction with a hydrogen gas in the presence of a palladium catalyst carried on γ-alumina under a reduced pressure of 1.3 MPa at a reaction temperature of 90° C., cyclododecanol is obtained at a yield of 20%. In the report, a palladium catalyst carried on titania and a palladium catalyst carried on silica were employed. In each case, the yield of the cyclododecanol was less than 20%.
Reaction SMILES: Cl.S[CH:3](O)C.[O:6]=[CH:7][C@H:8]([C@@H:10]([C@@H:12]([C@H:14]([CH3:16])[OH:15])[OH:13])[OH:11])[OH:9].CO>C(O)C(N)(CO)CO>[CH3:3][CH2:16][C@H:14]([OH:15])[C@@H:12]([OH:13])[C@@H:10]([OH:11])[C@H:8]([OH:9])[CH:7]=[O:6]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Reactant: CC(O)S
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CO
Product: CC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
The product from the previous step (89.6 mg; 0.546 mmol) was dissolved in Tris.HCl buffer (50 mM, pH 7.5; 2 mL) containing mercaptoethanol (2 mM) and MnCl2 (2 mM). An aliquot of the L-fucose isomerase crude extract (preparation described infra), (1 mL, 820 units) was added and the mixture was stirred overnight at room temperature. Methanol (2 vol) was added and the mixture was filtered through Celite. The solvent was distilled under reduced pressure and the residue chromatographed on Dowex 50W-X8 resin (Barium form, 400 mesh, 2.5×9.5 cm) with water/ethanol (1:1). Compound 8c (75.2 mg, 84%) was obtained as a yellowish oil: (89 mg, 0.50 mmol, 25%). [α]D=−47.6 (c=0.5, MeOH, 30 min), [Lit. [α]Deg=−26.2° (c=1, pyridine), Lit [α]Deg=−33° (c=1.2, water)]. 1H-NMR (400 MHZ, D2O) δ (ppm): 5.03 (H1α, d, JH1α,H2α=3.7 Hz), 4.39 (H1β, d, JH1β,H 2β=8 Hz), 3.73 (H5α, m), 3.69 (H4α, H4β, d, J=3 Hz), 3.66 (H3α, d, JH2α,H3α=3.5 Hz), 3.62 (H2α, d, JH2α,H3α=3.5 Hz), 3.45 (H3β, dd, JH2β,H3β=10 Hz, JH3β,H4β=3-5 Hz), 3.35 (H5β, t, JH5β,CH2=3 Hz), 3.29 (H2β, dd, JH1β,H2β=8 Hz, JH2β,H3β=10 Hz), 1.4-1.51 (CH2, α and β), 0.77 (CH3, α and β). 13C-NMR (100 MHZ, D2O) δ (ppm): 96.42 (C1β), 92.23 (C1α), 76.43, 73.15, 72.04, 69.72 (β anomer), 71.81, 70.22, 69.51, 68.45 (α anomer), 23.01 (CH2, α and β), 9.41 (CH3, α and β). HRMS Calcd for C7H14O5+H+ 179.0919, found 179.0914.
Reaction SMILES: Cl.[P:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=1)([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:3].C(=O)(O)[O-].[Na+]>C(O)C>[P:2]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=1)([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOP(=O)(OCC)Oc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)(OCC)Oc1ccc(CO)cc1
Yield: 98 %

Procedure:
The solution of HCl (8 ml) in ethanol (100 ml) was added to diethyl 4-(TBDMS-oxymethyl)phenyl phosphate. The resultant solution was stirred for 20 minutes and neutralized with sodium bicarbonate. The mixture was extracted three times with ether and the combined organic layer was dried over magnesium sulfate. After removal of solvent, the compound was obtained in a yield of 98%. Without further purification, it was directly used in next step.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[CH3:9][N:10]1[CH:14]=[C:13]([NH2:15])[C:12]([CH3:16])=[N:11]1.C([O-])(=O)C.[K+]>CCOC(C)=O>[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:5](=[O:7])[CH3:6])[C:12]([CH3:16])=[N:11]1
Reactant: Cc1nn(C)cc1N
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cn(C)nc1C
Reaction time: 1 h

Procedure:
Acetic anhydride (27.2 mL, 243.89 mmol) was dropwise added to a stirred suspension of 1,3-dimethyl-pyrazol-4-amine hydrochloride (12 g, 81.30 mmol) and potassium acetate (7.98 g, 81.30 mmol) in EtOAc (250 mL) at 25° C. The suspension was stirred for 1 hour and the insoluble was removed by filtration. After evaporation of the solvent, the resulting crude material was purified by chromatography on silica gel eluting with 0% to 10% of MeOH in DCM. After evaporation of the solvent, the residue was triturated in Et2O. The resulting precipitate was collected by filtration, washed with Et2O and dried to a constant weight to afford N-(1,3-dimethylpyrazol-4-yl)acetamide. The filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford more N-(1,3-dimethylpyrazol-4-yl)acetamide. The two batches were combined to give N-(1,3-dimethylpyrazol-4-yl)acetamide (6.40 g, 51.4%) as a off-white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COCCOc1ccc2ncnc(Cl)c2c1
Product: COCCOc1ccc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1
Yield: 64 %

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (146 mg, 0.5 mmol) and 4-chloro-6-(2-methoxyethoxy)quinazoline from Example 40A (119 mg, 0.5 mmol) using the procedure described in Example 46 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea (160 mg, 0.32 mmol, 64%). 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.03 (s, 1H), 8.76 (s, 1H), 7.96-7.85 (m, 2H), 7.70 (dd, 1H), 7.58-7.42 (m, 3H), 7.30 (d, 1H), 6.50 (s, 1H), 4.37-4.30 (m, 2H), 3.79-3.74 (m, 2H), 3.38 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:9]2[N:10]=[CH:11][CH:12]=[N:13][C:8]=2[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)C>[N:10]1[C:9]2[CH2:14][CH:6]([CH2:4][OH:3])[CH2:7][C:8]=2[N:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C1Cc2nccnc2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1Cc2nccnc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 4.5 g (23.4 mmol) of 6,7-dihydro-5H-cyclopentapyrazine-6 carboxylic acid ethyl ester (prepared by analogy to the method described in WO99/02517) in 90 ml of anhydrous tetrahydrofuran under argon was added 1.33 g (35.1 mmol) of lithium aluminum hydride. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 100 ml of diethyl ether at 0° C. and treated with excess of a saturated aqueous solution of sodium sulfate. Further solid sodium sulfate was added and the organic phase was filtered to remove salts. The solvent was evaporated to dryness to give 3.3 g (94%) of product as an oil.