Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O:5][C:6]1[C:7]([O:9][C@H:10]([C@H:13]([CH2:15][OH:16])[OH:14])[C:11]=1[O-:12])=[O:8])([O-])([O-])=O.[Mg+2].[K+].CO.C(O)C>CC(C)=O>[OH:12][C:11]1[C@@H:10]([C@@H:13]([OH:14])[CH2:15][OH:16])[O:9][C:7](=[O:8])[C:6]=1[OH:5]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1OP(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CO
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
the resulting potassium magnesium L-ascorbate 2-phosphate is isolated from the resulting aqueous solution by concentration and/or treatment with methanol, ethanol or acetone.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([O:19][C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:29][CH:28]=2)=[O:25])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)(=O)C>[CH2:13]([O:19][C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][N:36]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:34])=[CH:31][CH:32]=2)=[O:25])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Solvent: CC(=O)O
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 90 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(hexyloxy)-N-[4-(hydrazinocarbonyl)phenyl]-benzamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 110 mg of the title compound (90%) as a yellow powder in 91.1% purity by HPLC (Rt: 5.86, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][C:16]=2[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O-:36][C:37]#[N:38].[Na+].C(OCC)(=O)C.O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:14]2[C:15]3[C:16](=[CH:17][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:19][CH:20]=3)[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)=[N:38][C:37]2=[O:36])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCOc1ccc(NCCCc2ccc(OC)c(OC)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CCCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 338 mg (0.72 mmol) of the product prepared in step C in 6 ml AcOH is treated with 70 mg (1.1 mmol) sodium cyanate. The mixture is stirred for 1.5 h at rt. A yellow product results after work-up with ethyl acetate/water, which is purified by chromatography (CH2Cl2/MeOH) to afford a yellow foam.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)=[CH:48][C:49]4[N:54]5[C:55](=[O:58])[NH:56][N:57]=[C:53]5[CH2:52][O:51][C:50]=4[N:59]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:47]([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)=[CH:48][C:49]4[N:54]5[C:55](=[O:58])[NH:56][N:57]=[C:53]5[CH2:52][O:51][C:50]=4[N:59]=3)=[CH:44][CH:45]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Yield: 170.1 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (7 mg, 0.01 mmol) was reacted to afford the title compound (7 mg, quantitative). LCMS (Method A): RT=3.54 min, M+2H+=413. 1H NMR (500 MHz, MeOD): 8.56 (1H, s), 7.44 (2H, d), 7.38 (2H, d), 7.30-7.29 (3H, m), 7.23-7.21 (m, 2H), 5.41 (2H, s), 2.78-2.72 (m, 2H), 2.59-2.53 (m, 2H), 2.25-2.18 (m, 1H), 1.99-1.91 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:13]1([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH2:24])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C.C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]3[N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NC1CCCCC1N1CCCC1
Solvent: CC#N
Solvent: CCO
Product: Clc1ccc2c(NC3CCCCC3N3CCCC3)ccnc2c1

Procedure:
3.87 g from 3.6 g of 4,7-dichloroquinoline and 3.06 g of (2-pyrrolidin-1-yl-cyclohexyl)-amine (reaction duration 24 hours at 120° C.); colourless crystals from acetonitrile/ethanol, m.p.: 228°-231° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.Cl>O.ClC1C=CC=CC=1Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:10])[CH2:8][C:6](=[CH2:7])[C:5]([OH:11])=[O:12])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: C=C1CC(=O)OC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 20 °C
Yield: 70 %

Procedure:
212 g (1.59 mol) of anhydrous aluminum chloride are introduced into 1800 g of o-dichlorobenzene and the mixture is brought to 45° C. with stirring. A solid mixture of 78.5 g (0.7 mol) of itaconic anhydride and 132 g (0.7 mol) of 4-chlorobiphenyl is added in the course of one hour. The reaction mixture is stirred at 45° C. for two hours and then added to an ice-cold mixture of 900 g of water and 100 g of hydrochloric acid (37%). The aqueous phase is separated off. The organic phase is washed three times with a mixture of 1000 g of water and 25 g of hydrochloric acid (37%) in each case. After washing three times, it is allowed to cool to approximately 20° C. and the colorless product is then filtered off with suction. This is then washed twice with 150 g of ethanol/water 90:10 in each case. The product is dried at 80° C. and about 110 mbar until free of solvent and water. 148 g (0.49 mol) of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid (70%) are obtained as a colorless, finely crystalline powder. By working up the mother liquor, as described in Example 1, the yield is increased to 87%. (HPLC purity 99.3-99.5%).
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][NH:16][C:17]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([C@@H:26]3[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]3[C:32](=[O:53])[CH2:33][C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:25])=[O:18])[CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C>ClCCl.CS(C)=O.C(Cl)(Cl)Cl>[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][NH:16][C:17]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([C@@H:26]3[CH2:30][C:29](=[O:31])[CH2:28][N:27]3[C:32](=[O:53])[CH2:33][C:34]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:25])=[O:18])[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(NC[C@H]1CCCN(CC2CCCCC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 72.2 %

Procedure:
To a solution of 0.0037 ml of oxaryl chloride in 0.3 ml of dichloromethane, 0.0065 ml of dimethyl sulfoxide was added at −78° C., followed by 20 minutes' stirring at the same temperature. Then a solution of 25 mg of (2R)-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 0.9 ml of dichloromethane was added at the same temperature, followed by 30 minutes' stirring, addition of 0.0024 ml of triethylamine at the same temperature, and 20 minutes' stirring at room temperature. The reaction liquid was diluted with chloroform, washed with saturated brine and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified with a preparative thin-layer chromatography (Kieselgel™ 60F254, Art5744 (Merck); chloroform/methanol=9/1), to provide 18 mg of the title compound as a pale pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:17][C:18]1[C:19]([OH:31])=[C:20]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:21]=[CH:22][C:23]=1[OH:24]>ClCCCl.ClCCl>[Cl:1][C:2]1[C:3]([C:8]([OH:7])=[O:9])=[C:4]([C:5]([C:22]2[CH:21]=[C:20]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:19]([OH:31])=[C:18]([Cl:17])[C:23]=2[OH:24])=[O:6])[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)CCc1ccc(O)c(Cl)c1O
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(=O)c2cccc(Cl)c2C(=O)O)c(O)c(Cl)c1O
Yield: 48.5 %

Procedure:
To a solution of 3-chlorophthalic anhydride (3.7 g, 20 mmol) ((J. Org. Chem., 1987, 52, 129-134) in 60 mL of anhydrous 1,2-dichloroethane was added 6.6 g (50 mmol) of AlCl3 followed by 4.6 g (20 mmol) of methyl 3-(3-chloro-2,4-dihydroxyphenyl)propanoate (WO 03/023357). The reaction was heated at reflux for 30 min, cooled and concentrated. The resultant gelatinous material was partitioned between cold 2 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to afford an oily material (mixture of 6- and 2-chloroisomers). The oil was dissolved in dichloromethane (˜40 mL) and briefly sonicated (ultrasound bath) to initiate crystallization. The mixture was cooled (ice/water bath) and allowed to crystallize for 30 min (extended crystallization time will result in co-crystallization of undesired 2-chloro isomer). The crystals were collected by filtration washed with cold dichloromethane. Drying under vacuum afforded 4.01 g of desired 6-chloro isomer (32). 1H NMR (DMSO-d6) δ 12.47 (br s, 1H), 10.78 (br s, 1H), 8.06 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 6.76 (s, 1H), 3.46 (s, 3H), 2.27 (m, 2H), 2.41 (t, J=6.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N+:10]2[O-:29])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc2ccc[n+]([O-])c2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
7-(methyloxy)-8-[(phenylmethyl)oxy]quinoline (0.30 g; 1.13 mmol) and 77% by weight m-chloroperbenzoic acid (0.38 g; 1.69 mmol) are added in succession to dry CH2Cl2 (11 ml) at 4° C. under argon. The mixture is stirred for 48 hours at ambient temperature, then CH2Cl2 (40 ml) is added. The reaction medium is washed with a saturated aqueous solution of NaHCO3 (2×50 ml) and the solvent is evaporated under reduced pressure. The resulting oil is purified by silica gel chromatography, eluted with a CH2Cl2/CH3OH (95/5, v/v) mixture to yield 7-(methyloxy)-8-[(phenylmethyl)oxy]quinoline-N-oxide in the form of a yellow oil (0.18 g; 0.64 mmol, yield=58%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.43 (dd, 3J (H, H)=6.0 Hz, 4J ((H, H)=1.0 Hz, 1H); 7.68-7.58 (m, 4H); 7.41-7.30 (m, 4H); 7.10 (dd, 3J (H, H)=8.5 Hz, 3J (H, H)=6.0 Hz, 1H); 5.23 (s, 2H); 3.96 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 138.4; 128.9; 128.7; 128.2; 127.8; 127.6; 125.7; 124.9; 123.4; 119.5; 118.8; 116.8; 107.7; 75.2; 57.1. MS (CID, NH3): m/z=282 (MH+). Analysis (%) for C17H15NO3: calculated C, 72.58; H, 5.37; N, 4.98. found C, 72.74; H, 4.91; N, 4.87.
Reaction SMILES: N1CCCCC1.[C:7]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]=O)#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O)(=O)[CH2:29][C:30]([OH:32])=[O:31].N1C=CC=CC=1>O>[C:7]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]=[CH:29][C:30]([OH:32])=[O:31])#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCCCCCCC#Cc1cnccc1C=O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC#Cc1cnccc1C=CC(=O)O
Temperature: 80 °C
Yield: 57.3 %

Procedure:
Piperidine (0.1 ml) was added to a stirred, homogeneous mixture of 3-(1-tridecynyl)pyridine-4-carboxaldehyde (0.73 g, 2.56 mmole, from Example 1), malonic acid (523 mg, 5.12 mmole) and pyridine (5 ml) under nitrogen and the mixture was heated to 80° C. for 1 hour. After then refluxing for an additional 3 hours the mixture was cooled, added to water (40 ml) and acidified to pH 1. The resulting precipitate was washed with water, dried and recrystallised from methanol to give 0.48 g (57%) of the title compound, mp 177°-178° C., νmax (mull) 2450 (broad), 1870 (broad), 1690, 1625, 1595 cm-1 ; δ(DMSO) 0.84 (3H, distorted t, terminal CH3), 1.23 (14H, m, alkylene chain), 1.45 (2H, m, CH2 (CH2)2C≡C), 1.59 (2H, m, CH2CH2C≡C), 2.54 (2H, t, J 6.6 Hz, CH2C≡C), 6.88 (1H, d, J 16 Hz, C=CHCO), 7.82 (1H, d, J 5 Hz, C-5H), 7.83 (1H, d, J 16 Hz, Ar CH=C), 8.52 (1H, d, J 5 Hz, C-6H), 8.64 (1H, s, C-2H), 12.81 (1H, s, OH).
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH2:16]1[S:18][CH2:17]1.[Cl-].[NH4+]>N>[N:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH2:16][CH2:17][SH:18])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCc1ccncc1
Reactant: C1CS1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CCN(CC)CCC(CCS)c1ccncc1
Reaction time: 0.5 h

Procedure:
To stirred liquid ammonia (2 liters) was added ferric nitrate (0.1 gm) followed by sodium metal (2.3 gms) in small pieces. The mixture was allowed to stand for 30 minutes and 3-(4-pyridyl)-1-diethylamino propane (19.2 gms) was then added. A deep yellow colour was allowed to develop over a period of 2 hours, after which time ethylene sulphide (6.0 gms) was added quickly. A vigorous reaction occurred and the mixture was stirred for a further 5 hours. Ammonium chloride (7 gms) was added, and the solvent was allowed to evaporate overnight. The residual tacky solid was extracted into pyridine and the extract was filtered and the solvent evaporated. Distillation of the residual oil-yielded 3-(4-pyridyl)-5-diethylamino-pentane-1-thiol, (18 gms, 72% conversion) b.p. 140°-143° C/0.2 mm Hg, characterised by the following spectra:
Reaction SMILES: [CH3:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6]([C@@H:8]1[C:12]([CH3:14])([CH3:13])[S:11][CH2:10][N:9]1[C:15](=[O:29])[C@@H:16]([OH:28])[C@@H:17]([NH2:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:7].C([O:37][C:38]1[C:39]([CH3:48])=[C:40]([CH:44]=[CH:45][C:46]=1[F:47])[C:41](O)=[O:42])(=O)C>>[CH3:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6]([C@@H:8]1[C:12]([CH3:14])([CH3:13])[S:11][CH2:10][N:9]1[C:15](=[O:29])[C@@H:16]([OH:28])[C@@H:17]([NH:27][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([F:47])=[C:38]([OH:37])[C:39]=1[CH3:48])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:7]
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reactant: CC(=O)Oc1c(F)ccc(C(=O)O)c1C
Product: COc1ccc(C[C@H](NC(=O)c2ccc(F)c(O)c2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Yield: 67.6 %

Procedure:
The reaction was carried out in the same manner as in Step 3 of Example 1 using the compound obtained in Step 2 of Example 1 (94 mg) and 3-acetoxy-4-fluoro-2-methylbenzoic acid (45 mg). The resulting crude product was purified by recryatallization from a mixture of EtOAc and n-hexane to obtain the target compound (84 mg, 67%).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][C:19]([CH3:24])=[C:20]([CH2:22]O)[N:21]=3)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:22][C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:12][CH:13]=2)[O:18][C:19]=1[CH3:24]
Reactant: Cc1oc(-c2ccc(Cn3cnc4ccccc43)cc2)nc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Cn3cnc4ccccc43)cc2)nc1CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {2-{4-[(1H-benzimidazol-1-yl)methyl]phenyl}-5-methyl-1,3-oxazole-4-yl}methanol (0.045 g, 0.14 mmol) in CH2Cl2 was treated with a solution of thionyl chloride (0.10 mL, 1.4 mmol) in CH2Cl2 (2 mL), heated to reflux temperature, stirred for 30 min, cooled to room temperature and concentrated in vacuo. The resultant residue was partitioned between CH2Cl2 and water. The organic phase was separated, washed with water, brine, dried over Na2SO4, and evaporated to dryness under reduced pressure to give the title product, LCMS (ESI+) 337 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C=O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][C:17]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a mixture of 2-benzyloxy-5-bromophenylacetic acid (3.2 g) in toluene (100 ml) was added thionyl chloride (1.0 ml) and DMF (3 drops ). The reaction was stirred at 80° C. for 1 hour and cooled to ambient temperature. ethyl 4-aminobenzoate (2.0 g) and triethylamine (2 ml) were added to the reaction mixture with stirring. After standing for 18 hours, the mixture was diluted with dichloromethane and washed with water, 1N HCl solution, water and saturated aqueous NaHCO3 solution. The organic extract was dried (MgSO4), filtered and evaporated and the residue purified by trituration with diethyl ether to give ethyl 4-[2-benzyloxy-5-bromophenylacetamido]benzoate (2.0 g) mpt. 174-176° C.
Reaction SMILES: C=O.[OH-].[Na+].[C:5]([Si:9]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:10][CH:11]1[CH:15]([CH:16]=[O:17])[O:14][CH:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH:12]1[O:26]C(=O)C)([CH3:8])([CH3:7])[CH3:6].[C:42](O)(=[O:44])C>O1CCOCC1>[C:5]([Si:9]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:10][CH:11]1[C:15]([CH2:42][OH:44])([CH2:16][OH:17])[O:14][CH:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH:12]1[OH:26])([CH3:7])([CH3:6])[CH3:8]
Reactant: CC(=O)O
Reactant: CC(=O)OC1C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(C=O)OC1n1ccc(=O)[nH]c1=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OC1C(O)C(n2ccc(=O)[nH]c2=O)OC1(CO)CO)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Hydroxymethylation of the 5′-aldehyde is performed as per the method of Cannizzaro which is well documented in the literature (Jones, G. H., et. al., J. Org. Chem. 1979, 44, 1309-1317). These conditions are expected to additionally remove the 2′-O-acetyl group. Generally, Briefly, formaldehyde (2.0 eq., 37% aq.) and NaOH (1.2 eq., 2 M) is added to a solution of Compound 10 in 1,4-dioxane. After stirring at room temperature for several hours, this mixture is neutralized with acetic acid, evaporated to dryness, suspended in methanol, and evaporated onto silica gel. The resulting mixture is added to the top of a silica gel column and eluted using an appropriate solvent system to give Compound 11.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[CH:23]=[CH:24][CH2:25]Br>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:25][CH:24]=[CH:23][C:22]3[CH:27]=[CH:28][CH:29]=[C:20]([C:19]([F:18])([F:30])[F:31])[CH:21]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: FC(F)(F)c1cccc(C=CCBr)c1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(C(F)(F)F)c1)CC2
Yield: 41 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 3-trifluoromethyl-cinnamyl bromide in anhydrous dimethylformamide for one hour at 20° C. Yield: 41% of theory, Melting point: 102°-105° C. (petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13]
Reactant: OB(O)c1ccncc1
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Yield: 31.1 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]piperidine (0.150 g, 0.350 mmol) was dissolved in methylene chloride (3.5 ml) and after adding thereto in sequence copper acetate (0.064 g, 0.350 mmol), 4-pyridylboronic acid (0.086 g, 0.700 mmol), Molecular Sieves 4A (0.150 g), triethylamine (0.088 g, 0.874 mmol) and pyridine (0.069 g, 0.874 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.055 g, 0.109 mmol, 31%).