Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:22]1[C:30]2[S:29][N:28]=[CH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[C:31]([OH:33])=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:22]1[C:30]2[S:29][N:28]=[CH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[C:31]([OH:33])=[O:32]
Reactant: O=C(O)c1ccc2cnsc2c1F
Reactant: CSc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Nc2c(C(=O)O)ccc3cnsc23)c(F)c1
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
To a solution of 2-fluoro-4-methylsulfanyl-phenylamine (628 mg, 4.0 mmol) in anhydrous THF (15 mL) at −78° C. was added a 1.0M solution of LHMDS in hexanes (6.0 mL, 6.0 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and a suspension of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid (394 mg, 2.0 mmol) in anhydrous THF (15 mL) was added dropwise. The resultant mixture was stirred at −78° C. for 30 minutes, then allowed to reach room temperature and stirred for 18 hours before being quenched by addition of a 1M aqueous HCl (ca. 50 mL) and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, MeOH in DCM) to give the title compound as a brown solid (200 mg, 30%). LCMS (method B): RT=3.67 min, [M+H]+=335
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:15])([F:16])[F:17])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 90.2 %

Procedure:
To a solution of 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid (21.0 g, 84.3 mmol) in DMF (200 mL) was added potassium carbonate (35.0 g, 253 mmol) and methyl iodide (24.0 g, 169 mmol). The mixture was stirred at 60° C. and after stirring for 6 h the reaction mixture was cooled to 23° C. and was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc and water. The aqueous phase was extracted with EtOAc (2×250 mL and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (SiO2 heptane-EtOac=4/1) to give the titled compound (20.0 g, 90% yield). 1H-NMR (400 MHz, CDCl3) δ (ppm); 8.27 (s, 1H), 8.11 (s, 1H), 3.99 (s, 3H), 2.71 (s, 3H); MS (ES) [M−H] 261.9.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[Cl:24][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=1)[CH2:11][C:10]2([CH3:22])[CH3:23]
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Temperature: 120 °C
Yield: 40.3 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.82 g, 2.0 mmol), pyrrolidine (0.28 g, 4 mmol), copper (I) iodide (230 mg, 1.2 mmol), N,N-dimethyl glycine hydrochloride (220 mg, 1.6 mmol) and potassium carbonate (0.83 g, 6 mmol) in dimethylsulfoxide (20 mL) was heated for 12 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) to afford 6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.31 g, 40%) as a white solid: MS (ESI) M+1=385.2.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:6][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:5]3[N:4]=[N:3][C:2]([N:25]([CH3:26])[CH3:24])=[CH:7][CH:6]=3)[CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nn1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(N(C)C)nn1
Temperature: 140 °C

Procedure:
3-Chloro-6-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridazine (100 mg, 0.30 mmol) was dissolved in 2 mL dimethylforamide and dimethyl-amine hydrochloride (124 mg, 1.5 mmol) and cesium carbonate (396 mg, 1.2 mmol) were added. The reaction mixture was heated in the microwave at 140° C. for 60 min. After cooling to room temperature the reaction mixture was treated with 50 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography (methylene chloride/methanol 100:0->90:10 gradient) and the desired product was obtained as a white solid (57 mg, 55%), MS: m/e=338.1 (M+H+).
Reaction SMILES: COC([N:5]1[C:13]([NH2:14])=[C:12]2[C:7]([CH:8]=[C:9]([Cl:15])[CH:10]=[CH:11]2)=[N:6]1)=O>COC(OC(OC)=O)=O>[NH2:14][C:13]1[C:12]2[C:7](=[CH:8][C:9]([Cl:15])=[CH:10][CH:11]=2)[NH:6][N:5]=1
Reactant: COC(=O)n1nc2cc(Cl)ccc2c1N
Agent: COC(=O)OC(=O)OC
Product: Nc1n[nH]c2cc(Cl)ccc12

Procedure:
Analogously to Example 1, 0.1 mol of 3-amino-6-chloroindazole in 50 ml of pyrocarbonic acid dimethyl ester gives 3-amino-6-chloroindazole-2-carboxylic acid methyl ester (melting point: 198°-200° C; 90% of theory) in 30 minutes at 30°-50° C.
Reaction SMILES: [CH3:1][C:2]1([C:5]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([N+:24]([O-])=O)=[CH:16][N:15]=3)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3]1.C1COCC1.[H][H]>[Pd]>[NH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][CH:10]2[CH2:11][CH2:12][N:7]([C:5]([C:2]3([CH3:1])[CH2:4][CH2:3]3)=[O:6])[CH2:8][CH2:9]2)=[N:15][CH:16]=1
Reactant: CC1(C(=O)N2CCC(Oc3ncc([N+](=O)[O-])c4ccccc34)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C(=O)N2CCC(Oc3ncc(N)c4ccccc34)CC2)CC1
Temperature: 40 °C

Procedure:
Charge a 3 gallon autoclave with (1-methyl-cyclopropyl)-[4-(4-nitro-isoquinolin-1-yloxy)-piperidin-1-yl]-methanone (368.0 g, 1.04 moles), THF (4.42 L, 54.32 moles), and 5% Pd on carbon (dry, 40.50 g, 19.03 moles). Seal the autoclave and introduce hydrogen to 50 psi. Stir the contents at 1000 rpm at room temperature under 50 psi of hydrogen for 4.5 hours. Filter and rinse with additional THF (2.0 L, 24.58 moles). Treat the filtrate with carbon (20-40 mesh, 42.00 g) and heat to 40° C. for 1 hour. Add additional carbon (60 mesh, 47.00 g) and continue heating for 1 hour. Filter carbon through a micro fiber paper and a bed of Hyflo Super Cel® and rinse with a minimal amount of THF. Remove solvent to obtain [4-(4-amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone, 348 g (103%) as a dark orange-red oil/foam. 1H NMR (500 MHz, CDCl3): δ 0.59 (t, J=6.0 Hz, 2H), 0.96 (t, J=6.0 Hz, 2H), 1.34 (s, 3H), 1.88-1.94 (m, 2H), 2.06-2.10 (m, 2H), 3.61-3.70 (m, 2H), 3.93-4.00 (m, 2H), 5.48-5.50 (m, 1H), 7.52 (s, 1H), 7.58 (t, J=7.0 Hz, 1H), 7.73 (t, J=7.0 Hz, 1H), 7.81 (d, J=7.0 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H).
Reaction SMILES: C(O)C.Cl[C:5]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([CH3:21])[N:9]2[CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:8]1[N:9]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10]2[C:6]([N:7]=1)=[C:5]([C:25]1[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=1)[N:13]=[C:12]([NH2:14])[N:11]=2
Reactant: Cc1nc2c(Cl)nc(N)nc2n1C1CCOCC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: Cc1nc2c(-c3ccncc3)nc(N)nc2n1C1CCOCC1
Temperature: 150 °C
Yield: 99.1 %

Procedure:
Anhydrous ethanol (4 mL) was added to an argon-purged vial containing 6-chloro-8-methyl-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-amine (140 mg, 0.52 mmol), pyridine-4-yl-boronic acid (97 mg, 0.79 mmol, 1.5 equiv.), K2CO3 (109 mg, 0.79 mmol, 1.5 equiv.), and Pd(PPh3)4 (30 mg, 0.026 mmol, 0.05 equiv.) and the mixture was heated for 30 min in the microwave oven at 150° C. After cooling to ambient temperature, the reaction mixture was diluted with methanol (8 mL), filtered through a Nylon 0.45 μm filter and the filtrate concentrated in vacuo. Preparative HPLC purification of the residue afforded, after evaporation and drying, the desired compound as an orange solid (160 mg, 99% yield). TFA salt. 1H NMR (300 MHz, CD3OD) δ, ppm: 9.09 (d, J=6.6 Hz, 2H), 8.95 (d, J=6.2 Hz, 2H), 4.61-4.52 (m, 1H), 4.11 (dd, J=11.5, 4.5 Hz, 2H), 3.61 (app t, J=11.3 Hz, 2H), 2.96-2.82 (m, 2H), 2.68 (s, 3H), 1.84 (dd, J=12.7, 2.3 Hz, 2H); MS (EI) m/z 311.3 (MH)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[C@@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.I[CH2:37][C:38]#[N:39].C(#N)C>O1CCCC1>[C:38]([CH2:37][N:5]1[C@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:33])=[O:34])[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][C:8]=2[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[C:4]1=[O:3])#[N:39]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC#N
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 50 mg, 105 μmol) in tetrahydrofuran (3.0 mL). After 20 min, 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. After 2 h, a second portion of 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. After 2 h, a third portion of 2-iodoacetonitrile (8 μL, 0.11 mmol) is added. The mixture is stirred over night, treated with acetonitrile and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 8 mg; ESI mass spectrum [M+H]+=515; Retention time HPLC: 1.01 min (Z018_504).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C@@H:10]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH2:9]1)C1C=CC=CC=1.[C:29]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[F:19][C:15]1[CH:14]=[C:13]([C@@H:11]2[C@@H:10]([CH2:20][OH:21])[CH2:9][N:8]([C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:38][CH2:39][CH3:40])=[O:37])[CH2:12]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCCCC(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CCCCC(=O)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C

Procedure:
A 240 mg portion of [(3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yl]methanol obtained by eliminating benzyl from (3R,4S)-1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidine in the same manner as in Reference Example 17 was dissolved in 2.4 ml of dichloromethane, mixed with 235 mg of monoethyl adipate, 229 mg of WSC and 199 mg of HOBt and stirred at room temperature for 3Hours. The reaction solution was washed with water and dried with anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the residue by a silica gel column chromatography (chloroform-methanol), 320 mg of ethyl 6-[(3S,4R)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-6-oxohexanoate was obtained as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:11][CH:10]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=C(c1cccc(OC)c1)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(C(=CCBr)c2ccccc2C)c1
Reaction time: 8 h

Procedure:
A mixture of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene (18.3 g, 0.077 mol), carbon tetrachloride (80 ml), benzoylperoxide (0.15 g) and N-bromosuccinimide (14.2 g, 0.080 mol) was heated at reflux temperature for 5 h. The reaction mixture was left overnight at room temperature, filtered and the filtrate was evaporated in vacuo to give 3-bromo-1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene in a quantitative yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[NH:15]([C:17](OC)=[O:18])[NH2:16]>CO.C(O)C>[CH2:10]([O:9][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[CH2:4][CH2:3][CH2:2][NH:1][C:17](=[O:18])[NH:15][NH2:16])[CH3:11]
Reactant: COC(=O)NN
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CO
Solvent: CCO
Product: CCO[Si](CCCNC(=O)NN)(OCC)OCC
Reaction time: 2 h

Procedure:
A mixture of 44.2 g (0.20 mole) 3-aminopropyltriethoxysilane and 18.0 g (0.20 mole) methyl hydrazinocarboxylate under nitrogen was gradually heated to 150° C. with a slow distillation of the evolved methanol/ethanol from the reaction. After 2 hours at 150° C., 9.1 g. of distillate had been collected, and the reaction mass was cooled to ambient. The pale yellow oil was decanted from the small amount of white solid; yield 51 g (91%). IR (neat) 3320, 1640 (br), 1540 (br), 1070 (br), 940, 790 cm-1. NMR (CDCl3) 0.4-1.0 (m; 2H), 1.2 (t; 9H), 1.3-2.0 (m; 2H), 2.9-3.5 (m; 2H), 3.5-4.1 (m; 8H), 6.3 (br; 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH2:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:24]([CH2:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH:23][C:32](=[O:33])[CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NC(=O)COc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A mixture of 1 g (3.1 mmol) 4-(3-amino-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, 0.793 g (4.65 mmol) phenoxyacetyl chloride and 2.2 g (21.7 mmol) triethylamine in 20 ml THF was stirred at room temperature for 30 min. The mixture was evaporated and 100 ml DCM were added. The organic phase was washed with 2×50 ml 0.1 M Na2CO3 aq. The combined aqueous phase was extracted with 2×100 ml DCM. The combined organic phases were dried with MgSO4 and evaporated to dryness. The residue was purified over silica eluting with ethyl acetate/hexane 1/1 to yield 1.15 g (81%) of the title compound as yellow solid. MS(ISP): 455.3 (M−H)−.
Reaction SMILES: Br[CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([S:3][CH2:2][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)=[CH:5][CH:6]=1
Reactant: Clc1ccc(SCBr)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(OCSc2ccc(Cl)cc2)c1
Yield: 71 %

Procedure:
The synthesis was effected by reaction of 1-bromomethylthio-4-chlorobenzene and 3-trifluoromethylphenol in the same manner as described in preparation 3(b); yield 71%, b.p. 118°-122° C./0,01 mmHg. 1H NMR (CDC13); δ 5.13 (CH2), 7.1-7.5 (2×Ph), MS [70 eV 70, m/z (% rel. int)]: 318. (2,M), 159 (37), 157 (100), 145 (21) 121 (7), 108 (8), 75 (14)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][CH2:20][CH2:19][N:11]1[CH2:10][CH2:9][CH:8]([O:7][C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)[CH2:13][CH2:12]1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(OC2CCN(CCOC3CCCCO3)CC2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of 4-(4-trifluoromethylphenoxy)-piperidine (1.87 g, 7.63 mmol), 2-(2-bromoethoxy)-tetrahydropyran (1.75 g, 8.4 mmol), potassium carbonate (1.16 g, 8.38 mmol), sodium iodide (1.2 g, 8.01 mmol) in DMF (30 ml) was stirred at 100° C. for 1 hour. The reaction mixture was allowed to return to room temperature, poured into water and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 1-[2-(tetrahydropyran-2-yloxy)ethyl]-4-(4-trifluoromethylphenoxy)piperidine (1.69 g, yield 59%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=2.[O:13]1CCOCC1.[Se](=O)=O>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: C1COCCO1
Reactant: Cc1c(Br)cnc2ncccc12
Agent: O=[Se]=O
Solvent: O
Product: O=Cc1c(Br)cnc2ncccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-4-methyl-[1,8]-naphthyridine (1.5 g, 6.7 mmol), dioxane (16 mL) and water (0.6 mL) was treated with selenium dioxide (3.0 g, 27 mmol) and stirred at 80° C. for 1 h. The mixture was cooled to RT, diluted with satd. aq. NaHCO3, extracted 3× with EtOAc, and the combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum. Filtration through a pad of silica gel eluting with EtOAc gave 0.70 g of the title compound as a yellow solid. 1H NMR (CDCl3) δ 10.62 (s, 1H), 9.32 (s, 1H), 9.28 (d, 1H), 1.18 (d, 1H), 7.66 (dd, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:28]=2[N:29]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH:34][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)=[CH:19][CH:18]=3)=[O:22])=[CH:30][C:28]=2[N:29]=1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
Add oxalyl chloride (0.16 mL, 1.82 mmol) and 3 drops of DMF to a stirring suspension of 4′-fluoro-biphenyl-4-carboxylic acid (0.197 g, 0.910 mmol) in CH2Cl2 (2.0 mL). Stir the reaction mixture at room temperature for 2 h, Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4′-fluoro-biphenyl-4-carbonyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.05 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (2×20 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (3×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white solid (0.106 g, 38%). mass spectrum (m/e): 459.0 (M+1), 457.0 (M−1). 1H NMR (400 MHz, CDCl3): δ 7.95-7.90 (m, 3H), 7.63 (d, J=8.0 Hz, 2H), 7.60-7.54 (m, 2H), 7.52 (d, J=1.2 Hz, 1H), 7.36 (dd, J=8.8, 1.6 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.18-7.11 (m, 2H), 4.21-4.11 (m, 1H), 3.07 (s, 3H), 2.97 (d, J=11.6 Hz, 2H), 2.32 (s, 3B), 2.21-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.83-1.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([CH:18]=C)=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[OH:41]>C(Cl)Cl>[Cl:20][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1)[CH:18]=[O:41]
Reactant: C=Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Reactant: CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of 4-chloro-2-(2,6-dichloro-4-vinyl-phenyl)-thiazolo[5,4-c]pyridine (0.168 g, 0.48 mmol) in DCM (3.8 mL) and MeOH (1 mL) was cooled to −78° C. and degassed with nitrogen then compressed air before the ozone generator was turned on. After 10 minutes, a persistent grey colour remained so the ozone generator was turned off and the reaction mixture was degassed with nitrogen. Triphenylphosphine (0.125 g, 0.48 mmol) was added and the mixture warmed to ambient temperature and stirred for 1 hour. The reaction mixture was partitioned between DCM and water. The organic layer dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-12% EtOAc in pentane to give the desired compound as an off-white solid (0.138 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 10.04 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 7.99-7.98 (m, 3H).