Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH2:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[NH2:30][CH:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH2:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Temperature: 65 °C

Procedure:
A mixture of 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide (25 mg, 0.074 mmol), ammonium acetate (57 mg, 0.74 mmol) and sodium cyanoborohydride (9 mg, 0.15 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (20 mg, 80%). LCMS calculated for C17H16ClFNO2 (M−NH2)+: m/z=320.1. found: 320.1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34]>ClCCl>[CH3:36][O:35][C:33]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1)=[O:34]
Reactant: N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reaction time: 3 h
Yield: 67.7 %

Procedure:
(5R)-3-(4-((3R)-3-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (200 mg, 0.5 mM) in dichloromethane (20 ml) was cooled to 0° and treated with 5% sodium bicarbonate solution (5 ml). The resulting suspension was stirred vigorously, methyl chloroformate (245 mg, 2.6 mM) added, and stirring continued for 3 hours at ambient temperature. The organic layer was separated, washed with 2% sodium dihydrogen phosphate (2×10 ml), brine (10 ml), and dried (magnesium sulfate), to give the desired product (143 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:7]=1[CH:8]=O)(=[O:4])=[O:3].Cl.[NH2:19][OH:20]>C(O)C>[OH:20][N:19]=[CH:8][C:7]1[CH:10]=[C:11]([CH:12]=[CH:13][C:6]=1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C=O)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(C=NO)c1
Yield: 88.9 %

Procedure:
A mixture of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde (2.56 g, 0.01 mol) and hydroxylamine hydrochloride (0.87 g, 0.0125 mol) in ethanol (40 mL) was heated at reflux for 2 h. The mixture was filtered hot, and the filtrate was concentrated to dryness. The residue was suspended in water. The solid was collected by filtration and recrystallized from ethyl acetate-hexane to give 2.42 g (89%) of methyl 3-[(N-hydroxyimino)methyl]-4-[(methylsulfonyl)amino]benzoate as an off-white powder, mp 160° C.
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)C.[S:10](Cl)(Cl)(=[O:12])=[O:11].[Cl:15][C:16]1[C:17]([F:45])=[C:18]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:43][CH3:44])=[C:30]([CH2:33][N:34]([CH3:42])[C:35]4([C:39]([NH2:41])=[O:40])[CH2:38][NH:37][CH2:36]4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:19]=[CH:20][CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([F:45])=[C:18]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:43][CH3:44])=[C:30]([CH2:33][N:34]([CH3:42])[C:35]4([C:39]([NH2:41])=[O:40])[CH2:38][N:37]([S:10]([CH3:1])(=[O:12])=[O:11])[CH2:36]4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(S(C)(=O)=O)C1
Reaction time: 1 h
Yield: 31.9 %

Procedure:
Diisopropylethylamine (72 μl, 0.41 mmol) then sulfonyl chloride (11 μl, 0.14 mmol) were added to a solution of the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide (Example 74) (60 mg, 0.12 mmol) in CH2Cl2 (1 ml) at 0° C. After 1 hour, the reaction mixture was diluted in 50 ml CH2Cl2 and washed with water. The organic layer was dried on MgSO4, then concentrated under reduced pressure. The crude product was purified on preparative HPLC (standard basic condition) to give the title product (20 mg, 33%) as a white powder; 1H NMR Spectrum: (CDCl3) 2.17 (s, 3H), 3.05 (s, 3H), 3.61 (s, 2H), 3.97 (s, 3H), 4.03 (d, 2H), 4.11 (s, 2H), 7.21 (s, 1H), 7.30 (m, 1H), 7.48 (m, 2H), 7.60 (brs, 2H), 8.38 (s, 1H), 8.44 (s, 1H), 9.75 (s, 1H); Mass Spectrum: (M+H)+ 523.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[C:22]([C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1)(=[O:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([C:22](=[O:24])[NH2:23])=[CH:26][CH:27]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: NC(=O)c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation 8), 4-carbamoylphenethyl bromide (0.25 g--see Preparation 13), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. On cooling to room temperature, water (40 ml) was added and the resulting mixture extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a yellow foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.13 g.
Reaction SMILES: [H-].[Na+].Cl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[CH3:16].I[CH2:25][CH3:26]>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:25][CH3:26])[CH:18]=1)[CH3:16]
Reactant: CCI
Reactant: C[C@@H](NCCCc1ccccc1Cl)c1cccc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1cccc([C@@H](C)NCCCc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NPS R-568 (30.3 g 100 mmol) in dichloromethane at −78° C. was treated dropwise with borontribromide (50 g, 200 mmol). The reaction 40 was stirred 1 hr at rt and poured over ice. The hydrobromide was extracted from the aqueous phase with chloroform. The chloroform solubles were then washed (4×100 ml) with 50% HCl. The chloroform wash was dried over anhydrous magnesium sulfate and concentrated to afford (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride as a solid. A solution of sodium hydride (0.48 g, 20 mmol) in dimethylformamide was treated with (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride (3.25 g, 10 mmol) and the reaction stirred 1 hr at rt. The reaction was treated with iodoethane (1.71 g, 11 mmol) and stirred 16 hr at rt. Work-up and chromatography through silica using 3% methanol in chloroform afforded (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-ethoxyphenyl)ethylamine, 6T, as an oil; m/z (rel. int.) 316 (M+, 1), 302 (100), 282 (11), 196 (5), 178 (7), 149 (74), 121 (34), 103 (25), 91 (28), 77 (29).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][CH2:5][CH3:6].C1C=CC2N(O)N=[N:23]C=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:42][CH2:43][C@@:44]1([OH:97])[CH2:55][N:53]2[CH2:54][C@@H:46]([CH2:47][C@:48]([C:93]([O:95][CH3:96])=[O:94])([C:63]3[CH:68]=[C:67]4[C:69]56[C@@H:80]([N:81]([CH3:82])[C:66]4=[CH:65][C:64]=3[O:91][CH3:92])[C@@:79]([OH:87])([C:83]([O:85][CH3:86])=[O:84])[C@H:78]([OH:88])[C@:74]3([CH2:89][CH3:90])[CH:75]=[CH:76][CH2:77][N:72]([C@H:73]53)[CH2:71][CH2:70]6)[C:49]3[NH:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:50]=3[CH2:51][CH2:52]2)[CH2:45]1.[NH2:98][CH2:99][CH2:100][CH2:101][NH-:102].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:42][CH2:43][C@@:44]1([OH:97])[CH2:55][N:53]2[CH2:54][C@@H:46]([CH2:47][C@:48]([C:93]([O:95][CH3:96])=[O:94])([C:63]3[CH:68]=[C:67]4[C:69]56[C@@H:80]([N:81]([CH3:82])[C:66]4=[CH:65][C:64]=3[O:91][CH3:92])[C@@:79]([OH:87])([C:83]([O:85][CH3:86])=[O:84])[C@H:78]([OH:88])[C@:74]3([CH2:89][CH3:90])[CH:75]=[CH:76][CH2:77][N:72]([C@H:73]53)[CH2:71][CH2:70]6)[C:49]3[NH:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:50]=3[CH2:51][CH2:52]2)[CH2:45]1.[NH2:98][CH2:99][CH2:100][CH2:101][NH-:102].[NH2:1][C@H:2]([C:7]([NH2:23])=[O:9])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](O)[C@]3(O)C(=O)OC)C2)C1
Agent: [NH-]CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC[C@H](N)C(N)=O
Reaction time: 0.5 h

Procedure:
To a DMF solution (1 ml) of Boc-Nle (22 mg, 0.095 mmol) was added 318 μl of a 1M solution of HOBT (in NMP) followed by 280 μl of a 1M solution of DCC (in NMP). After 30 min., intermediate (11) (0.0624 mmol) was added in a 3.5 ml DMF. The pH of the reaction was adjusted ~7.5 with diisopropylethylamine. After stirring for 18 hrs the reaction was concentrated to an oil and the Boc protecting group removed by treating the oil with a 1:1 solution of TFA: CH2Cl2 (20 ml). After 5 min. the reaction was concentrated to dryness. Purification was achieved by preparative HPLC on a C-18 reverse phase support (Waters, Delta Pak). Buffer A=0.1% TFA-H2O; B=0.1% TFA-CH3CN. The crude product was loaded in 100% A buffer (100 ml) and a step gradient of 100% A to 30% A was used at a flow rate of 75 ml/min. Homogeneous product fractions were pooled and freeze-dried to yield (12).
Reaction SMILES: [Cl:1][CH:2]([Cl:27])[C:3]([NH:5][CH:6]([CH2:25][F:26])[CH:7]([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][Br:23])[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:4].[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>O1CCCC1.CCOCC>[Br-:23].[Cl:1][CH:2]([Cl:27])[C:3]([NH:5][CH:6]([CH2:25][F:26])[CH:7]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[O:18][C:19]([CH2:20][CH2:21][CH2:22][N+:31]1[CH:32]=[CH:33][N:29]([CH3:28])[CH:30]=1)=[O:24])=[O:4]
Reactant: Cn1ccnc1
Reactant: CS(=O)(=O)c1ccc(C(OC(=O)CCCBr)C(CF)NC(=O)C(Cl)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1cc[n+](CCCC(=O)OC(c2ccc(S(C)(=O)=O)cc2)C(CF)NC(=O)C(Cl)Cl)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A solution of 4-bromo-butyric acid 2-(2,2-dichloro-acetylamino)-3-fluoro-1-(4-methanesulfonyl-phenyl)-propyl ester (1.8 g, 1 equivalent) and 1-methylimidazol (0.56 mL, 2 equivalents) was stirred in tetrahydrofuran (6 mL) at room temperature overnight. The solution was diluted with ether and the precipitates were collected by filtration and stirred in a mixture of ethyl acetate and hexanes (1:1) at room temperature for 24 hours. The purified title methylimidazolium bromide was collected by filtration and dried under reduced pressure at 50° C. for 7 hours to give a pale powder (1.2 g, 56% yield); H1-NMR (CDCl3/CD3OD). δ=2.2 ppm (m, 2H), 2.6 ppm (m, 2H), 3.0 ppm (s, 3H), 3.9 ppm (s, 3H), 4.2-4.5 ppm (m, 5H), 6.0 ppm (d, 1H), 6.4 ppm (s, 1H), 7.2 ppm (d, 1H), 7.4 ppm (s, 1H), 7.6 (d, 2H), 7.8 ppm (d, 2H), 9.4 ppm (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)CC)(C)C.Cl.[CH3:35][NH:36][O:37][CH3:38]>CN(C=O)C.C(OCC)(=O)C>[CH3:38][O:37][N:36]([CH3:35])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Indazole-3-carboxylic acid (15 g, 0.0925 mol) was dissolved in DMF (40 mL) at room temperature. Carbonyldiimidazole (17 g, 0.104 mol) was added. A solution of diisopropylethylamine (18 mL, 0.104 mol) and N,O-dimethylhydroxylamine HCl (10 g, 0.104 mol) in DMF (10 mL) was added in portions. The reaction was stirred at room temperature overnight. The reaction was taken up in ethyl acetate and washed repeatedly with 2-N HCl, water, and brine. The organic layer was evaporated to a yellow oil, and passed through a pad of silica gel with hexane/ethyl acetate (1:2). The resulting solid was washed with ethyl acetate to give the desired product as a white solid (11.40 g, 0.056 mol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCCCO)cc1
Yield: 77.1 %

Procedure:
4-(4-nitrophenyl)butanol (compound 19, 1.7 mL, 10.2 mmol) was dissolved in methanol (20 mL) to which 10% Palladium on carbon (0.2 g) was added and the mixture was hydrogenated using hydrogen gas (30 psi) at ambient temperature for 1 hr. The mixture was filtered through celite filter aid and solvent was evaporated from the filtrate under vacuum to give 1.3 g (77% yield) of crude product. Mass spectrum (M+H)+ calcd for C10H15NO 166.1. found 166.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[O:14][N:13]=1)=O)C>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:10][OH:9])[CH:16]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2cccc(Cl)c2)on1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
Lithium aluminum hydride (320 mg, 8.4 mmol) was slowly added to a solution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (2.0 g, 8.4) in THF (100 mL) at room temperature. After 1 hour, the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was then purified by flash column chromatography using 15-40% ethyl acetate in hexane to afford [5-(3-chloro-phenyl)-isoxazol-3-yl]-methanol (1.32 g, 75%, yellow solid). 1H NMR (CDCl3) δ (ppm): 7.78 (s, 1H), 7.68 (m, 1H), 7.43 (m, 2H), 6.63 (s, 1H), 4.84 (d, 2H), 2.23 (t, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH2:25]([NH:27][CH3:28])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:27]([CH2:25][CH3:26])[CH3:28])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCNC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N(C)CC
Yield: 86.3 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.54 g (0.026 mol) of N-ethylmethylamine in 30 ml of DMF were reacted at room temperature for 16 hours affording a residue which was kugelrohr distilled at 80 Pa, pot temperature 104° C., to give 4.7 g of oil. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent afforded 4.0 g of oil which was purified by kugelrohr distillation at 67 Pa, pot temperature 107° C., to give
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:33]=[CH:32][C:13]2=[N:14][N:15]([C:17]3[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=3[OH:31])[N:16]=[C:12]2[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)=[O:35].OO.[OH2:39]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C1(C)C(C)=CC=CC=1>[CH2:1]([S:9]([C:10]1[CH:33]=[CH:32][C:13]2=[N:14][N:15]([C:17]3[CH:22]=[C:21]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=3[OH:31])[N:16]=[C:12]2[CH:11]=1)(=[O:35])=[O:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=CO
Reactant: O
Reactant: CCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCS(=O)(=O)c1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 500-mL round-bottom flask are charged 30 g (0.062 mol) of 5-n-octylthio-2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole, 35 g (0.28 mol) of xylene, 6.4 g (0.12 mol) of formic acid and 0.21 g (0.0006 mol) of sodium tungstate dihydrate. The reaction mixture is heated to 50° C. and 19 g (0.28 mol) of 50% hydrogen peroxide is then added dropwise over a one-hour period such that the reaction temperature remains between 70-80° C. After holding at this temperature for two hours, 100 g of water and 100 g of xylene are added. The aqueous layer is removed and the xylene phase is washed once with 10% aqueous sodium sulfite solution, 10% aqueous potassium carbonate solution, 10% aqueous sodium chloride solution and water. Xylene is partially stripped under vacuum and 50 g of methanol are added. The yellow solution is cooled to 0-5° C. and filtered after crystallization occurs. The wetcake is washed with 100 g of cold methanol and dried to a constant weight. The title compound is obtained as yellow needles in a yield of 30.1 g (97%). The structure of the product is verified by 1HNMR and mass spectroscopy.
Reaction SMILES: C(OCC)(=O)C[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=O)([C:5]([O:7][CH2:8][CH3:9])=O)O.[H][H]>C(O)C>[OH:7][CH2:5][CH2:3][CH:10]1[CH2:15][CH2:14][O:13][CH2:11]1.[OH:13][CH2:11][CH:10]1[CH2:9][CH2:8][O:7][CH2:5][CH2:3]1
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Reactant: [H][H]
Solvent: CCO
Product: OCC1CCOCC1
Product: OCCC1CCOC1
Yield: 1 %
Yield: 42 %

Procedure:
400 ml of triethyl citrate were hydrogenated at 200° C. and 200 bar together with 1100 ml of ethanol and 60 g of catalyst B (4-mm pellets) until the take-up of hydrogen had ceased. The reaction product was freed from ethanol and distilled under reduced pressure, giving 80 g (42%) of 3-(2'-hydroxyethyl)tetrahydrofuran and 1.8 g (1%) of 4-hydroxymethyltetrahydropyran.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:23][CH3:24])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:23][CH3:24])=[C:18]([NH:19][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1c(N)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)aniline (10 g, 28 mmol), in DCM (100 mL) was added pyridine (6.6 g, 83.7 mmol) and the mixture was cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (5.9 g, 27.9 mmol) in DCM (100 mL) was added dropwise to the mixture. The reaction was stirred at rt for 4 h. Then the reaction was washed with water (200 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:1) to afford the title compound of Step H (8.7 g, 58.2% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (d, J=5.6 Hz, 1H), 7.70-7.75 (m, 1H), 7.63-7.67 (br, 1H), 7.46-7.55 (m, 1H), 7.15-7.19 (m, 2H), 6.95-7.03 (m, 2H), 6.58 (d, J=5.6 Hz, 1H), 3.35-3.40 (m, 4H), 1.44 (d, J=6.4 Hz, 6H). m/z (ES+): 537 [M+H]+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][N:20]([CH3:46])[CH:21]1[C:30]2[CH2:29][O:28][C:27]([CH:31]=[O:32])=[CH:26][C:25]3=[CH:33][N:34]([Si](C(C)C)(C(C)C)C(C)C)[CH:35]=[C:23]([C:24]=23)[CH2:22]1>O1CCCC1.O.C(OCC)(=O)C>[CH3:19][N:20]([CH3:46])[CH:21]1[C:30]2[CH2:29][O:28][C:27]([CH:31]=[O:32])=[CH:26][C:25]3=[CH:33][NH:34][CH:35]=[C:23]([C:24]=23)[CH2:22]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(C=O)OCC3=C2C(=C1)CC3N(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C1CC2=CNC=C3C=C(C=O)OCC1=C32
Reaction time: 3 h
Yield: 88 %

Procedure:
Tetra-n-butylammoniumfluoride (1 mol/l tetrahydrofuran solution) 2.2 ml was added to compound (45) 496 mg in tetrahydrofuran 10 ml with cooling in ice. The mixture was stirred for 3 h, diluted with water and ethyl acetate and, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (2:1) to give colorless crystals, 273.2 mg. This was recrystallized from acetone-isopropyl ether to give the titled compound as colorless crystals, m.p.175-176° C., 2654 mg. Yield 88%.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[NH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9][C:8]1=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH:2]([CH3:6])[C:3]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:7][C:8](=[O:17])[NH:9][CH2:10]2)=[O:4]
Reactant: O=C1NCc2ccccc2N1
Reactant: CC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2c(c1)CNC(=O)N2

Procedure:
2-Bromopropionyl bromide (10.6 g) is added dropwise to a stirring mixture of 3,4-dihydro-2(1H)-quinazolinone (3.2 g) and anhydrous aluminum chloride (7.9 g) in carbon disulfide (60 ml). The reaction mixture is refluxed for four hours, the carbon disulfide decanted and the residue treated with aqueous hydrochloric acid (6N). The acidic residue is poured into ice water, and the precipitate filtered, washed with water and dried, affording the desired product as a solid, which is used in the next step without further purification.