Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH:16][C:31](=[O:33])[CH3:32])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)C1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanamine (500 mg, 1.56 mmol) in DCM (5 mL) was added pyridine (185 mg, 2.3 mmol). After stirring for 5 min at RT, a solution of acetyl chloride (147.2 mg, 1.88 mmol) in DCM (0.5 mL) was added into the reaction mixture, which was stirred at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated aq NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with ether to yield N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide (500 mg). 1H NMR (CDCl3, Free base) δ (ppm): 8.42 (d, 2H), 7.25 (s, 1H), 7.15 (d, 1H), 6.92 (d, 2H), 6.9 (d, 1H), 6.2 (d, 1H), 5.3 (q, 1H), 4.4 (dd, 1H), 4.25 (dd, 1H), 3.58 (dd, 2H), 2.6 (m, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 2.3 (m, 2H), 2.03 (s, 3H). Separation by chiral HPLC provided enantiomers II-1a-b.
Reaction SMILES: Cl.[C:2](SCC1C=CC=CC=1)(=[NH:4])[CH3:3].[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:24][S:23][C:22]([NH2:25])=[N:21]2)[CH:17]=[CH:18][CH:19]=1.C(SCC1C=CC=CC=1)(=N)C>C(O)C.O>[NH2:25][C:22]1[S:23][CH2:24][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][C:2](=[NH:4])[CH3:3])[CH:19]=[CH:18][CH:17]=2)[N:21]=1
Reactant: NC1=NC(c2cccc(N)c2)CS1
Reactant: CC(=N)SCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=N)Nc1cccc(C2CSC(N)=N2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
0.15 g of benzyl ethanimidothioate hydrochloride and then 5 cm3 of ethanol are added, under an inert atmosphere and at a temperature in the region of 0° C., to a stirred solution of 0.14 g of 4-(3-aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine in 15 cm3 of ethanol. The mixture is stirred for 1 hour at about 0° C. and then for 2 hours at a temperature in the region of 20° C. A further 0.030 g of benzyl ethanimidothioate is added to complete the reaction, after which the mixture is maintained at a temperature in the region of 45° C. for 24 hours. The reaction medium is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 30 cm3 of water and the solution is washed with 30 cm3 of dichloromethane. The aqueous solution is concentrated under the above conditions and the solid obtained is then triturated from diethyl ether, filtered, air-dried and purified by chromatography at atmospheric pressure on a column of silica gel (particle size 40-63μ; mass 63 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (12/3/0.5 by volume). The fractions containing the expected product are collected. These fractions are combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.100 g of [3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine is obtained in the form of a white solid melting at 180° C. 1H NMR spectrum (250 MHz, (CD3)2SO-d6, with addition of a few drops of CD3COOD-d4, δ in ppm): 2.28 (unres. mult.: 3H); 3.18 (dd, J=12.5 and 8.5 Hz: 1H); 3.80 (dd, J=12.5 and 8.5 Hz: 1H); 5.30 (t, J=8.5 Hz: 1H); 7.21 (broad d, J=8.5 Hz: 1H); 7.27 (broad s 1H); 7.36 (broad d, J=8.5 Hz: 1H); 7.49 (broad t, J=8.5:Hz: 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3C=CC=C[CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:7]=1.[CH3:35]CO>[Pd]>[CH3:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3([CH3:35])[CH2:30][CH2:29]3)=[O:26])[CH2:21][CH2:20]2)=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:7]=1
Reactant: Cc1cc(-n2cnnn2)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCO
Agent: [Pd]
Product: Cc1cc(-n2cnnn2)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OC2(C)CC2)CC1

Procedure:
A solution of benzyl 4-[(1R,2S)-2-(2-{[3-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate (920 mg, 1.99 mmol) in 5 ml of EtOH was treated with 200 mg of Pd/C under a balloon of H2 gas for 3.5 hours. The suspension was filtered through a plug of celite and the filtrate was concentrated to afford the title compound as a crude product to be used for the next step. LC/MS (m/z): 329 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]1(=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1>C1(C)C=CC=CC=1>[Cl:7][C:6]12[C:2]([Cl:11])([Cl:1])[C:3]([Cl:10])([CH:14]3[CH:13]1[C:12](=[O:23])[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]3=[O:22])[C:4]([Cl:9])=[C:5]2[Cl:8]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Hexachlorocyclopentadiene (60 g.), 1,4-naphthoquinone (31.6 g.), and 30 ml. of toluene were mixed, heated to reflux temperature, and maintained at this temperature for 4 hours. After cooling to room temperature and extracting the excess hexachlorocyclopentadiene with Skelly "B" solvent, the mixture solidified slowly. This crude brown solid was recrystallized repeatedly from benzene/Skelly "B" mix-solvent (70/30) to yield white crystals, m.p. 116°-118° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][N:30]([CH3:39])[C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][N:30]([CH3:39])[C:31]([CH:33]1[CH2:34][CH2:35][N:36]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:37][CH2:38]1)=[O:32]
Reactant: CN(C)C(=O)C1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(=O)N(C)C)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 49.4 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and piperidine-4-carboxylic acid dimethylamide (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0, 95:5, 90:10, to 85:15) to afford 326 as a white solid (69 mg, 51%). LCMS (Method G): RT=5.48 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.19 (m, 1 H); 7.73-7.68 (m, 1 H); 7.29-7.25 (m, 2 H); 4.35 (m, 4 H); 3.91-3.83 (m, 7 H); 3.75 (s, 2 H); 3.06 (s, 3 H); 2.95 (s, 6 H); 2.54 (m, 1 H); 2.18 (m, 2 H); 1.92-1.79 (m, 2 H) and 1.71 (m, 4 H)
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([F:24])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([F:24])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1F
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.72 (1H, d, J=1.6 Hz), 7.07-7.13 (2H, m), 7.33-7.41 (2H, m), 7.51 (1H, d, J=2.0 Hz), 7.95 (1H, s), 8.62 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H10ClFN4O, 329; Found, 329.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CCN(CC)CC.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>CO>[F:15][C:16]([F:23])([F:22])[C:17]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:18]
Reactant: OCCNCCO
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N(CCO)CCO)C(F)(F)F
Reaction time: 20 h

Procedure:
(Kamal, A.; et al J. Med. Chem. 2002, 45, 4679-4688) Diethanolamine (3.57 g, 34 mmol) was dissolved in methanol (20 mL) and treated with Et3N (4.7 mL, 34 mmol) and ethyl trifluoroacetate (4.90 g, 34 mmol) for 20 h at rt, followed by adding another 1 mL CF3COOEt. After another 20 h, removal of volatile solvents under high vacuum yielded N-trifluoroacetyl-diethanolamine compound 6 as light yellow oil, which was used without further purification.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].Cl>CN(C=O)C.CO>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:5][C:6]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a slurry of NaH (1.38 g, 60% in mineral oil, 34.41 mmol) in DMF (20 mL) at 0° C. was added a solution of 3-(dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (1-2; 4.15 g, 15.64 mmol) and 2-cyanoacetamide (1.45 g, 17.2 mmol) in MeOH (1.5 mL) and DMF (40 mL) dropwise over 40 min. The resulting mixture was stirred at 90° C. for 4 h and cooled to rt. The mixture was poured into dilute HCl aqueous solution (240 mL, 0.25 M) and filtered, washed with water (40 mL) and dried in vacuo to afford 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (1-3). 1H-NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.15-7.28 (m, 7H), 7.05-7.07 (m, 2H), 2.36 (s, 3H). LRMS m/z (M+H) Calcd: 287.3, found: 287.1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][CH2:9][CH2:10][OH:11].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:8][CH2:9][CH2:10][O:11][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: OCCBr
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCBr
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
2,2-Dimethylpropionyl chloride (10 mL, 81.2 mmol) was added over 10 min to an ice-cooled solution of 2-bromoethanol (5.48 mL, 77.4 mmol) and DIPEA (20.8 mL, 121.8 mmol) in DCM (150 mL). The reaction mixture was stirred in the ice bath for a further 15 min, then at RT for 16 h. The reaction mixture was washed successively with 1M HCl, saturated aqueous NaHCO3 and water. The organic fraction was dried (Na2SO4) then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 1-6% EtOAc in cyclohexane) affording the title compound as a colourless oil (10.58 g, 65%). 1H NMR (CDCl3, 300 MHz): 4.37 (2H, t, J=6.0 Hz), 3.52 (2H, t, J=6.0 Hz), 1.23 (9H, s).
Reaction SMILES: [C:1]1([N:7]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Mg]Br.C1C[O:44][CH2:43][CH2:42]1>>[C:43]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:44])[CH3:42]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1ccccc1
Temperature: 120 °C

Procedure:
In a capped vial (1 mL) containing a solution of phenylazide (6.6 mg, 55 μmol) in dry THF (300 μL), was added [RhCl(cod)]2 (0.27 mg, 0.55 μmol), and 1,2-bis(diphenylphosphino)ethane (0.66 mg, 1.65 μmol), and was shaken until the solution was homogeneous. After addition of a solution of methyl magnesium bromide (18.5 μL of 3M solution in ether, 55 μmol), the resulting mixture was transferred to the micro-autoclave, which was pre-charged with [11C]CO. The micro-autoclave was heated at 120° C. for 5 min under 35 MPa and the crude product was transferred to a reduced pressure vial. The radioactivity was measured before and after the vial was flushed with N2 (the [11C]CO-trapping efficiency of 96% was determined based on these values). The solution was dissolved in ammonium formate (0.5 mL, pH=3.5) and heated at 120° C. for 1 min. A small amount of crude product was collected and analyzed by the reversed phase HPLC. Yield of product: 91%. The product was identified by HPLC with an added authentic reference compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:12]=[CH:13]/[N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>CCO.C1COCC1.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1cc(/C=C/N2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(CCN2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Yield: 41 %

Procedure:
Pd/C (10% by wt, 0.090 g) was added to a degassed solution of 2-{(E)-2-[3-amino-5-(trifluoromethyl)phenyl]vinyl}-1H-isoindole-1,3(2H)-dione (0.900 g, 2.71 mmol) in EtOH (56 mL) and THF (40 mL). The mixture was hydrogenated (50 psi) at rt until LC/MS indicated reaction was complete. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, 1:1 EtOAc:hexanes) to afford the desired product as a white solid (0.371 g, 40%). LCMS: (FA) ES+ 335.3 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[Cl:11][CH2:12][NH:13][CH:14]([CH2:17][O:18][CH3:19])[CH:15]=[O:16]>C1C=CC=CC=1>[Cl:11][CH2:12][N:13]([CH:14]([CH2:17][O:18][CH3:19])[CH:15]=[O:16])[C:9]([NH:8][C:6]1[S:7][C:3]([CH2:2][Cl:1])=[N:4][N:5]=1)=[O:10]
Reactant: COCC(C=O)NCCl
Reactant: O=C=Nc1nnc(CCl)s1
Solvent: c1ccccc1
Product: COCC(C=O)N(CCl)C(=O)Nc1nnc(CCl)s1

Procedure:
5-Chloromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-chloromethylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-chloromethyl-3-(5-chloromethyl-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32][Cl:33]>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:30][CH2:31][CH2:32][Cl:33])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCCl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.48 g) in ethanol (5 ml) was added caesium carbonate (0.977 g) and reaction mixture heated to 85° C. for 10 min. before addition of 1-bromo-3-chloropropane (0.74 ml). Heating was continued for 24 h before cooling to room temperature and concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed with water(twice), then with KHSO4 solution and brine. The organics were dried (MgSO4), concentrated and the residue purified by silica gel chromatography (eluting with 20% ethyl acetate in isohexanes) to deliver the sub-title compound as a pale yellow foam (0.50 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([NH:15][S:26]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=3)(=[O:28])=[O:27])=[CH:14][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CCc2ccc(N)cc2CC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN1CCc2ccc(NS(=O)(=O)c3ccc(NC(C)=O)cc3)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
400 mg (1.96 mmol) of 3-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-amine and 1.86 mmol of 4-acetylaminobenzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, 0.82 ml (5.87 mmol) of triethylamine was added dropwise, and the mixture was stirred at room temperature overnight. After the solvent had been evaporated off, 20 ml of water were added, and the mixture was acidified with 1 mol of hydrochloric acid and extracted with 50 ml of diethyl ether. The aqueous phase was made basic at pH 9-10 with 1 mol of sodium hydroxide solution and then extracted with diethyl ether. The residue obtained after drying with sodium sulfate and after removal of the solvent was converted into the hydrochloride with ethereal hydrochloric acid. Yield: 280 mg (35% of theory)
Reaction SMILES: [C:1]([Si:5]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3Cl)[NH:18][N:17]=2)[C:9]=1[F:26])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CCOC(C)=O>[Si:5]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][CH:23]=3)[NH:18][N:17]=2)[C:9]=1[F:26])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncnc(Cl)c23)c1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncncc23)c1F

Procedure:
A solution of tert-butyl-[2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,5,6-trifluoro-4-pyridyl]-dimethyl-silane (398 mg, 1.00 mmol), triethylamine (100.7 mg, 138.7 μL, 0.9953 mmol) in EtOAc (19 mL) was subjected to hydrogenation using H-cube apparatus. The following conditions were used to transform the starting material to subtitle product; 1×500 μL injection at 100 μL/min @ 70° C. followed by 4×4000 μL injection of reagent solution run at 150 μL/min @ 70° C. The product fractions were combined, diluted with EtOAc, washed with water (3×), brine, dried (MgSO4), filtered and concentrated in vacuo to give the sub title product as an orange solid (172 mg, 43.2% Yield). H1 NMR (400 MHz, DMSO) δ 14.59 (1H, s), 9.66 (1H, s), 9.10 (1H, m), 0.96 (9H, s) and 0.48 (6H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=2)[CH:10]=1)=O.O.[NH2:26][NH2:27].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:3]([NH:26][NH2:27])=[O:2])[CH:6]=[N:7][C:8]=2[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:12][C:13]=1[F:18]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Temperature: 85 °C
Yield: 64.9 %

Procedure:
5-(4-Chloro-3-fluoro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid methyl ester (97 mg, 267 μmol) was dissolved in ethanol (2 mL) to give a light yellow solution. Hydrazine monohydrate (134 mg, 130 μl, 2.67 mmol) was added under argon. The reaction mixture was stirred under argon at reflux temperature (85° C.) for 5 h. Subsequently the reaction mixture was poured into 10 mL saturated aqueous Na2CO3 solution and extracted with isopropyl acetate (2×20 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give the title compound (63 mg, 65%) as off-white solid; MS (ESI) 361.8 (M−H)−.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])(O)(=O)=O.[CH2:18]([SH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH3:15][C:14]([NH2:17])([CH3:16])[CH2:13][S:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(N)COS(=O)(=O)O
Reactant: CCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCSCC(C)(C)N
Temperature: 25 °C
Yield: 99.3 %

Procedure:
In a mixed solvent of 10 ml of water and 10 ml of ethanol was suspended 1.38 g (10 mmol) of potassium carbonate. To the suspension were added 0.85 g (5 mmol) of 2-amino-2-methylpropyl hydrogensulfate and 0.73 g (5 mmol) of 1-octanethiol, and the resulting mixture was gently refluxed for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the desired compound was extracted three times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 1.08 g of 2-methyl-1-n-octylthio-2-propylamine was obtained. The purity was measured in terms of area percentage by gas chromatography and found to be 91%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>ClCCl>[C:45]([NH:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1)(=[O:47])[CH3:46]
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 27 mg (0.21 mmol) N-ethyldiisopropylamine and 70 mg (0.69 mmol) acetic anhydride. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 100 mg (92%) of the title compound as white solid. MS m/e (%): 537 (M+, 68), 282 (100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:8])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].O1CCC[CH2:12]1>>[CH3:1][O:2][C:3]([C:5]1([O:8][CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)C1(O)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1(OC)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1-Hydroxy-cyclopropanecarboxylic acid methyl ester (1.1 6 gm, 10 mmol) was dissolved in 10 ml of tetrahydrofuran and cooled under a nitrogen atmosphere to 0° C. Sodium hydride (0.52 gm, 60% oil dispersion) was added portionwise followed by lodomethane (1 ml) and stirred for 18 hrs. The reaction mixture was quenched with ammonium chloride and extracted with ethylacetate to obtain 2 gm of title product. (MH+=130)