Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:26])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of ethyl 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanate (3.58 g), 2N aqueous sodium hydroxide solution (10.0 mL), tetrahydrofuran (10 mL) and methanol (10 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (3.34 g, yield 99%) as pale-yellow crystals. melting point 234-235° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:29][CH:28]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (800 mg, 3.34 mM) and triethylamine (1.5 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-chiorophenyl isocyanate (641 mg/ml, 5.01 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally crystallized with methanol-ether (1:6) to give 8f as solid. Yield: 1.06 g, 80.70%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([OH:16])[C:11](I)=[N:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:26]([C:28]1[CH:42]=[CH:41][C:31]([CH2:32][N:33]2[CH2:36][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:34]2)=[CH:30][C:29]=1[F:43])#[CH:27].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([C:8]1[CH:9]=[C:10]2[O:16][C:26]([C:28]3[CH:42]=[CH:41][C:31]([CH2:32][N:33]4[CH2:36][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:34]4)=[CH:30][C:29]=3[F:43])=[CH:27][C:11]2=[N:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reactant: Oc1cc(Cc2ccccc2)c(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3cc4nc(Cl)c(Cc5ccccc5)cc4o3)c(F)c2)C1
Reaction time: 16 h

Procedure:
In a sealed flask was combined 5-benzyl-6-chloro-2-iodopyridin-3-ol (1.50 g, 4.3 mmol), PdCl2(PPh3)2 (0.30 g, 0.43 mmol), copper(I) iodide (0.17 g, 0.87 mmol), N-ethyl-N-isopropylpropan-2-amine (6.1 mL, 35 mmol), methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (1.2 g, 4.8 mmol) and DMF (10 mL, 129 mmol). The flask was flushed with argon, sealed and placed in an oil bath for 16 h at 80° C. The reaction was concentrated to remove solvent, and the resulting black mixture was adsorbed onto silica. Flash chromatography (100% EtOAc) afforded a yellow oil that was further purified on a Varian HF Mega Bond Elut SCX column (eluted with 2M ammonia in MeOH). Trituration with of the resulting solids with ether afforded an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.83-7.90 (1H, m), 7.49 (1H, s), 7.27-7.40 (5H, m), 7.22-7.24 (1H, m), 7.12-7.19 (2H, m), 4.20 (2H, s), 3.72 (3H, s), 3.65 (2H, s), 3.52-3.59 (2H, m), 3.32-3.38 (3H, m); MS (ESI) m/z: Calculated: 464.1; Observed: 465.1 (M++1).
Reaction SMILES: [Cl-].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S+:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[CH:6][CH:5]=1.C(O)C.[CH3:32][N:33]([C:35]1[CH:36]=[CH:37][C:38]([N:41]=[N:42][C:43]2[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:47][CH:48]=2)=[CH:39][CH:40]=1)[CH3:34]>O>[CH3:32][N:33]([CH3:34])[C:35]1[CH:36]=[CH:37][C:38]([N:41]=[N:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([O-:52])(=[O:51])=[O:50])=[CH:45][CH:44]=2)=[CH:39][CH:40]=1.[CH3:2][N:3]([CH3:28])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S+:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[CH:8][CH:9]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: CN(C)c1ccc(-c2cc(-c3ccccc3)[s+]c(-c3ccccc3)c2)cc1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)[O-])cc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-(4'-dimethylaminophenyl)-2,6-diphenylthiapyrylium chloride, 8.07 g, in a hot mixture of water, 400 mls, and ethanol, 100 mls, is added a solution of Methyl Orange, E. K. 432, 6.8 g, in hot water, 200 mls, with stirring. The mixture is stirred for 10 minutes and then is cooled and filtered, the filtrate being orange-red in color. The solid product is taken up in boiling nitromethane, filtered hot, evaporated down somewhat, and diluted with ethanol. The solid which crystallizes out overnight is filtered off. Yield: 9.3 g. of product having structural formula II noted above and exhibiting light absorption maxima (when dissolved in ethanol) at 582 and 427 nm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[O:11]=[C:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1>C1COCC1>[OH:11][C:12]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2nccs2)CC1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
Thiazole (21.3 g, 250 mmol) in THF (160 mL) was cooled to −70° C. and then n-BuLi (100 mL, 250 mmol) was added slowly over 5 minutes, keeping the temperature at −60° C. or lower. The resulting slurry was stirred for 45 minutes at this temperature and then the product of Step 1 (48.55 g, 228 mmol) in THF (50 mL) was added dropwise, maintaining the temperature at −60° C. The solution was stirred for one hour and then the cooling bath removed. At −20° C., 2M HCl (114 mL) was added and upon warming to RT the homogeneous solution was diluted with EtOAc (150 mL). The phases were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were washed with aqueous saturated NaHCO3 (150 mL), brine (150 mL) and then concentrated to a thick syrup. This was dissolved in EtOAc (140 mL) and then treated with hexane (210 mL) and the slurry filtered to afford tert-butyl 4-hydroxy-4-(1,3-thiazol-2-yl)azepane-1-carboxylate as a white solid (68.0 g, 220 mmol) and the material was then subjected to chiral chromatography to afford tert-butyl (4R)-4-hydroxy-4-(1,3-thiazol-2-yl)azepane-1-carboxylate (14.5 g, 48.6 mmol).
Reaction SMILES: [NH2:1][CH:2](N1C(=O)C2=CC=CC=C2C1=O)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[NH2:25]N.[ClH:27]>CO>[ClH:27].[ClH:27].[NH2:25][CH:3]([CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][NH2:1]
Reactant: NN
Reactant: NC(CCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: NCC(N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Amino-2-benzyloxymethyl-1-phthalimido-ethane (3.0 g, 9.7 mmol) is dissolved in 50 ml dry methanol and hydrazine hydrate (968 mg, 19.3 mmol) is added. After being refluxed for 4 hours, the reaction mixture is stirred for 24 hours at ambient temperature and 50 ml 2N hydrochloric acid was added. The phthalhydrazide is removed by filtration and the 1,2-diamino-1-benzyloxymethyl-ethane-dihydrochloride is purified by recrystallisation from dry ethanol.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][C:4]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[C:18](OCC)(=[O:24])[C:19](OCC)=[O:20]>>[N:11]1([C:4]2[CH:5]=[C:6]3[C:7](=[CH:8][C:3]=2[C:2]([F:1])([F:16])[F:17])[NH:9][C:19](=[O:20])[C:18](=[O:24])[NH:10]3)[CH:12]=[CH:13][CH:14]=[CH:15]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(-n2cccc2)c(C(F)(F)F)cc1N
Product: O=c1[nH]c2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared by the method of Example 1f from 0.8 g (3.3 mmol) of N-(2-trifluoromethyl-4,5-diaminophenyl)pyrrole and 32 g (221 mmol) of diethyl oxalate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])([O-:14])=[O:13]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1c(O)ccc2ccccc12

Procedure:
Fluorination can be accomplished by nitrating 2-hydroxynaphthalene (Formula I) with one equivalent of nitric acid in an inert organic solvent, to form 1-nitro-2-hydroxynaphthalene, reacting this with dimethyl sulfate in dilute alkali to form 1-nitro-2-methoxynaphthalene, hydrogenating the methyl ether over Raney nickel, for example, to form 1-amino-2-methoxynaphthalene, diazotizing this in aqueous fluoroboric acid to yield the 1-diazonium fluoroborate, and thermally decomposing the latter in the presence of copper powder to yield 1-fluoro-2-methoxynaphthalene (Formula IV).
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12](O)=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][N:7]=3.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:12]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:1]=[N:2][N:3]=[C:4]2[CH:13]=1
Reactant: Oc1cc2nnnn2c2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2nnnn2c2ncccc12

Procedure:
Tetrazolo[1,5-a][1,8]naphthyridin-5-ol (0.5 g, 2.67 mmole) was suspended in phosphorous oxychloride (10 mL) and heated at reflux for 4 hours. The reaction mixture was concentrated under vacuum and the residue was poured into water. Dichloromethane was added and the aqueous layer was made basic with sodium bicarbonate. The dichloromethane layer was separated, dried over magnesium sulfate, filtered and then concentrated under vacuum. The resulting solid was recrystallized from toluene to provide 0.3 g of 5-chlorotetrazolo[1,5-a][1,8]naphthyridine as a solid, m.p. 229-230° C. (decomposition). Analysis: Calculated for C8H4ClN5: %C, 46.73; %H, 1.96; %N, 34.06; Found: %C, 46.87; %H, 1.54; %N, 33.93.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([C:8]1[CH:17]=[C:16]2[C:12](=[CH:13][CH:14]=[C:15]2[CH3:18])[C:11]([CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:1]([O:22][CH2:21][CH2:20][CH:19]([C:11]1[C:12]2[C:16](=[CH:17][C:8]([CH:5]([CH3:7])[CH3:6])=[CH:9][CH:10]=1)[C:15]([CH3:18])=[CH:14][CH:13]=2)[CH3:23])(=[O:3])[CH3:2]
Reactant: Cc1ccc2c(C(C)CCO)ccc(C(C)C)cc1-2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)c1ccc(C(C)C)cc2c(C)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.8 g (0.063 mol) of acetyl chloride in 20 ml of dichloromethane were added dropwise at 0° C. to a solution of 12.1 g (0.05 mol) of 3-(7-isopropyl-1-methylazulen-4-yl)butanol and 7.9 g (0.1 mol) of pyridine in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 1 hour. It was then extracted with 30 ml of 2N hydrochloric acid, and the organic phase was washed neutral and dried over sodium sulfate. The residue remaining behind after evaporating off the solvent was chromatographed (silica gel; 9:1 v/v petroleum ether/ethyl acetate). This gave 12.6 g (89%) of the acetate as a highly viscous blue oil. Physical data: IR (KBr): 2959, 2929 (CH); 1741 (C=O); 1555, 1463, 1436, 1387, 1365, 1241, 1047 cm-1. 1H-NMR (CDCl2): δ=1.38 (d, 6H); 2.05 (s, 3H); 2.16 (cm, 2H); 2.68 (s, 3H); 3.08 (cm, 1H); 2.22 (cm, 2H); 4.18 (cm, 2H); 6.95 (d, 1H); 7.30 (d, 1H); 7.40 (d, 1H); 7.64 (d, 1H); 8.18 (s, 1H) ppm. 13C-NMR (CDCl3); δ=1286; 20.85; 24.72 (2C); 30.17; 34.53; 38.28; 64.22; 112.19; 124.41; 125.46; 133.30; 135.13; 136.39; 136.59; 137.28; 140.04; 147.55; 170.90 ppm. MS: m/e=284.4 (C19H24O2+, 50%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.O>CN(C)C=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@H:27]6[N:31]([CH2:43][C:44]([F:47])([F:46])[F:45])[C@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5CC(F)(F)F)cn3)nc2n1C1CCCC1
Temperature: 80 °C
Yield: 64.1 %

Procedure:
A sample of 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (60 mg, 0.123 mmol) was combined with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.035 ml, 0.246 mmol) in dimethylformamide (1 mL) and heated to (80° C.) overnight. The reaction was then poured into water and extracted with ethyl acetate. The aqueous was washed with ethyl acetate. The organics were combined, dried over sodium sulfate, filtered and concentrated which gave a crude material that was purified by silica gel column chromatography which gave 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-9-(2,2,2-trifluoroethyl)-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (45 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.51 (d, J=9.09 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J=2.53 Hz, 1H), 7.52 (dd, J=8.84, 2.78 Hz, 1H), 6.46 (s, 1H), 4.80 (t, J=8.59 Hz, 1H), 4.23 (d, J=13.64 Hz, 1H), 3.47 (m, 3H), 3.16 (s, 6H), 3.06 (m, 3H), 2.83 (dd, J=15.66, 7.07 Hz, 1H), 2.57 (dd, J=12.13, 8.59 Hz, 2H), 2.04 (m, 6H), 1.70 (m, 4H). MS m/z 571.6 (M+H)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: CN1CCN(c2nc(Cl)nc3ccsc23)CC1
Solvent: c1ccncc1
Product: COc1ccc(CNc2nc(N3CCN(C)CC3)c3sccc3n2)cc1
Temperature: 200 °C

Procedure:
To a solution of 2-chloro-4-(4-methyl-piperazin-1-yl)-thieno[3,2-d]pyrimidine (0.11 g, 0.4 mmol) in pyridine (0.34 mL) in a microwave vial was added 4-methoxybenzylamine (0.55 mL, 4.2 mmol). The reaction mixture was heated to 200° C. in the microwave for 1 h, after which pyridine was removed under reduced pressure. The resultant residue was purified by FCC (2 M NH3 in MeOH/CH2Cl2) to yield (4-methoxy-benzyl)-[4-(4-methyl-piperazin-1-yl)-thieno[3,2-d]pyrimidin-2-yl]-amine. The intermediate was then dissolved in trifluroacetic acid (2.5 mL) and heated at 60° C. for 1.5 h. After concentrating, the residue was purified by reverse-phase chromatography (acidic conditions) to afford the desired product as a TFA salt (30 mg). MS: 250.1. 1H NMR (400 MHz, CD3OD) δ ppm 8.26 (d, J=5.6 Hz, 1H), 7.30 (d, J=5.6 Hz, 1H), 4.65-4.12 (m, 4H), 3.60-3.41 (m, 4H), 2.98 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12].ClCCl.ClC1C=CC=C(C(OO)=[O:36])C=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:36])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][CH2:11][OH:12]
Reactant: CSCc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75.9 mg (0.20 mmol) of the compound from Example 7 were introduced into 11 ml of dichloromethane at 0° C., 49.2 mg (0.20 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 50 mg (63% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:23][C:24]=1[CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][C:24]2[S:23][C:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:21][C:20]=2[CH3:19])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccccc2)sc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccccc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with (4-methyl-2-phenyl-thiazol-5-yl)-methanol [PCT Int. Appl. (2002), WO 02/80899 A1] in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-[2-methyl-4-(4-methyl-2-phenyl-thiazol-5-ylmethoxy)-phenyl]-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][N:13]=[C:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15]1>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][N:13]=[C:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CC(c2ccccc2)Oc2ccccc21
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CC(c3ccccc3)Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of p-toluenesulfonyl chloride (83 g) in 125 ml pyridine was added dropwise at 5°-10° to 2,3-dihydro-4-(hydroxyimino)-2-phenyl-4H-1-benzopyran (52 g) in 230 ml pyridine. The reaction mixture was then stirred for 20 hours at room temperature, poured into ice-water to separate out the title compound, which was filtered, washed several times with water, then once with ether, and finally dried in air. Yield: 85.5 g; m.p. 141°-143°.
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21](=[O:23])[CH3:22])=[C:15]([N+:24]([O-])=O)[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1>[Fe].O>[NH2:24][C:15]1[CH:14]=[C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:18]([O:19][CH3:20])=[CH:17][C:16]=1[C:21](=[O:23])[CH3:22]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Yield: 90 %

Procedure:
A mixture of iron powder (27 g, 0.48 g atoms), ammonium formate (31 g, 500 mmol), 1-(4-benzyloxy-5-methoxy-2-nitrophenyl)ethanone (36 g, 120 mmol), toluene (500 mL) and water (500 mL) was heated to reflux overnight. The mixture was filtered through celite and washed with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford 1-(2-amino-4-benzyloxy-5-methoxyphenyl)ethanone (29.3 g, 90%). 1H NMR (CDCl3): δ 7.41-7.30 (m, 5H), 7.13 (s, 1H), 6.16 (br s, 2H), 6.10 (s, 1H), 5.13 (s, 2H), 3.83 (s, 3H), 2.51 (s, 3H). LC/MS (M+H=272).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:3])[NH2:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:17][CH2:16][CH2:15][NH2:18])(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccccc1OCC1CO1
Reactant: NCCN
Product: NCCNCC(O)COc1ccccc1C(N)=O
Reaction time: 1 h

Procedure:
1-(o-Carbamoylphenoxy)-2,3-epoxypropane (20 g.) is added to ethylenediamine (125 ml.) and the mixture is stirred at laboratory temperature for 1 hour and then evaporated to dryness under reduced pressure. The residue is stirred with water (150 ml.), the mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallised from acetonitrile and there is thus obtained as residue 1-(o-carbamoylphenoxy)-3-(β-aminoethyl)aminopropan-2-ol, m.p. 91°-93° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][C@H:21]1[CH2:26][NH:25][CH2:24][C@@H:23]([CH3:27])[NH:22]1.N12CCC(CC1)CN2>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:25]4[CH2:24][CH:23]([CH3:27])[NH:22][CH:21]([CH3:20])[CH2:26]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: C1CN2CCC1CN2
Product: CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC(C)N1
Temperature: 140 °C
Yield: 20.9 %

Procedure:
A mixture of 2.8 g (0.01 mol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.14 g (0.01 mol) of cis-2,6-dimethylpiperazine and 2.2 g of diazabicyclo[2.2.2]octane is heated at 140° C. for 5 hours. The solvent is distilled off under high vacuum, 30 ml of water are added to the residue, the suspension is adjusted to pH 8 with 2N HCl and the precipitate which has separated out is extracted by boiling with 30 ml of methanol. 0.75 g (21% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-1-piperazinyl)quinoline-3-carboxylic acid, of decomposition point 234°-236° C., is obtained. Mass spectrum: 359 (M+), 290, 289 (100%, M+ -70), 245,70.