Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][SH:26])[N:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30]Cl.[C:32]([O-:35])(=[S:34])[CH3:33].[K+]>CN(C)C=O.O.CC(C)=O>[C:32]([S:34][CH2:30][S:26][CH2:25][C:23]1[N:22]=[N:21][N:20]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:24]=1)(=[O:35])[CH3:33]
Reactant: SCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Reactant: ClCBr
Reactant: CC([O-])=S
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SCSCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of 1-trityl-1,2,3-triazol-4-ylmethylmercaptan (3.00 g: 8.40 mMol.) in dimethylformamide (10 ml) is added sodium hydride (60% dispersion in oil: 370 mg: 9.25 mMol.), and the mixture is stirred for 5 minutes at room temperature. The reaction mixture is added to a solution of bromochloromethane (15 ml) in dimethylformamide (15 ml) at -30° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. To a solution of the residue in acetone (30 ml) is added potassium thioacetate (1.92 g: 16.8 mMol.), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated. The residue is purified by silica chromatography (toluene: ethyl acetate=10:1) and crystallized from ether to give 4-acetylthiomethylthiomethyl-1-trityl-1,2,3-triazole (2.65 g) as colorless crystals. Yield: 71%. mp. 106° C.
Reaction SMILES: [Cl:1][C:2]1[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](Br)[CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:22][C:23]1[CH:28]=[C:27]([C:10]2[C:2]([Cl:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[N:6]([CH3:20])[C:5](=[O:21])[CH2:4]3)[CH:26]=[N:25][CH:24]=1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2Cl
Reactant: Brc1cncc(Br)c1
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2Cl
Temperature: 120 °C

Procedure:
To 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (525 mg, 1.71 mmol), prepared as described in Example 27a, was added 3,5-dibromopyridine (CAS#625-92-3, 1.2 g, 5.1 mmol), 1,2-dimethoxyethane (5.0 mL), and 2 M aqueous sodium carbonate (2.05 mL, 4.1 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (0.93 g, 0.10 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3.55%) to furnish 5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 336.9753 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (a, 3H), 3.62 (s, 2H), 6.85 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.95-8.04 (m, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.70 (d, J=2.3 Hz, 1H).
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:29])[C:5](=[O:28])[NH:6]2.N(OCCC(C)C)=O.[I:38]CI>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[N:8]=[C:7]3[C:3]([N:4]([CH3:29])[C:5](=[O:28])[NH:6]3)=[C:2]([I:38])[N:10]=2)=[N:12]1
Reactant: ICI
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Agent: CC(C)CCON=O
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Temperature: 85 °C

Procedure:
1.725 g (3.358 mmol) of the compound from example 41 were dissolved in 7 ml of diiodomethane and admixed with 7.19 ml (53.732 mmol) of isopentyl nitrite. The reaction mixture was heated to 85° C. for 16 h and, after cooling, concentrated on a rotary evaporator. The residue was by means of preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, gradient 55:40:5→0:95:5). 64 mg of the title compound were obtained (4% of theory).
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C([Li])CCC.[C:35]1([C:41]2[N:42]=[C:43]([CH2:52]Br)[O:44][C:45]=2[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Na+].[I-]>C1COCC1.O.C(OCC)(=O)C>[C:35]1([C:41]2[N:42]=[C:43]([CH2:52][O:1][C@H:2]3[C:11]4[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:8]=[CH:9][CH:10]=4)[CH2:5][CH2:4][CH2:3]3)[O:44][C:45]=2[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2O)(c1ccccc1)c1ccccc1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [I-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2OCc1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.6 %

Procedure:
To a solution of (1R)-1-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.5 g) in THF (20 ml) were added n-butyllithium (2.8 ml, 1.5M solution in hexane), (4,5-diphenyloxazol-2-yl)methyl bromide (1.8 g) and NaI (1.2 g) at -78° C. under N2. The solution was warmed to the room temperature and stirred for 6 hours. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-(4,5-diphenyloxazol-2-yl)methyloxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.65 g). MS (m/z): 636 (M+ +1) IR (Neat): 3400 cm-1NMR (CDCl3, δ): 1.09 (9H, s), 1.6-2.2 (4H, m), 2.6-3.2 (2H, m), 4.65 (1H, m), 4.75 (1H, d, J=13.2 Hz), 4.84 (1H, d, J=13.2 Hz), 6.31 (1H, d, J=8 Hz), 6.75 (1H, t, J=8 Hz), 6.98 (1H, d, J=8 Hz), 7.2-7.8 (10H, m)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.CS(C)=O.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20]>O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CC(C)N1CCNCC1
Reactant: Clc1ccc(-c2ccc(Cl)nc2)cc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1
Temperature: 100 °C
Yield: 85.2 %

Procedure:
A mixture of 2-chloro-5-(4-chlorophenyl)pyridine (500 mg, 2.23 mmol), DMSO (2.0 mL) and 1-isopropylpiperazine (3 mL, 23.4 mmol) was stirred and heated on a 100° C. oil-bath overnight. The reaction mixture was poured into water (75 mL), and the solid was isolated by filtration, washed with water and dried. The crude product was purified by column chromatography on silica gel (Kiselgel 60, mesh 0.040-0.63) eluting with a mixture of ethyl acetate and methanol (4:1). Collecting the proper fractions afforded 600 mg (85%) of 1-[5-(4-chlorophenyl)pyridin-2-yl]-4-isopropylpiperazine.
Reaction SMILES: Cl.[O:2]1C=CC=C1C=CC(=N)OCC.C(O)C.N#CN.[CH:20]1([NH:26][C:27](=[N:37][C:38]#[N:39])[CH:28]=[CH:29][C:30]2C=C[CH:33]=[CH:32][C:31]=2Cl)CCC[CH2:22][CH2:21]1>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:20]([NH:26][C:27](=[N:37][C:38]#[N:39])[CH:28]=[CH:29][C:30]1[O:2][CH:33]=[CH:32][CH:31]=1)[CH2:21][CH3:22]
Reactant: N#CN=C(C=Cc1ccccc1Cl)NC1CCCCC1
Reactant: CCOC(=N)C=Cc1ccco1
Agent: Cl
Agent: N#CN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCNC(C=Cc1ccco1)=NC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(2-furyl)-2-propenimidate HCl in an amount of 1.34 g. is dissolved in 3 ml. of ethanol and then an equimolar amount of triethylamine is added to the ice-cooled resulting solution. To this solution, cyanamide (0.25 g.) is added and stirring is continued for 1 hour at room temperature. After removal of solvent from the mixture, the resulting residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with water and dried with MgSO4. To the residue, after removal of ethyl acetate, MeOH (3 ml.) and n-butylamine (1.1 g.) are added with slight warming and stirring is continued for 1 hour. The mixture is evaporated and resulting residue is submitted to column chromatography (KIESEL GEL 40 T : ethyl acetate for eluent). The thus obtained crystals, which are recrystallized from acetone have the formula: ##STR11## and the following characteristics:
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].C(N(CC)CC)C.[I-].[C:39]([N:42]1[CH2:47][CH2:46][N:45]([C:48]([NH+]2C=CN(C)C2)=[O:49])[CH2:44][CH2:43]1)(=[O:41])[CH3:40]>C(Cl)Cl>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:48]([N:45]5[CH2:46][CH2:47][N:42]([C:39](=[O:41])[CH3:40])[CH2:43][CH2:44]5)=[O:49])[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Reactant: CC(=O)N1CCN(C(=O)[NH+]2C=CN(C)C2)CC1
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)N5CCN(C(C)=O)CC5)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
To a solution of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (25 mg, 0.063 mmol) and triethylamine (0.013 mL, 0.095 mmol) in CH2Cl2 (2 mL) was added 3-(4-acetyl-piperazine-1-carbonyl)-1-methyl-3H-imidazol-3-ium iodide (Intermediate 6) (15 mg, 0.063 mmol) and the mixture stirred at room temperature under argon for 18 h. Partitioned between CH2Cl2 (10 mL) and sat. NaHCO3(aq) (2 mL) and the organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo to give 1-(4-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperazin-1-yl)-ethanone as a pale yellow powder (9 mg, 25% yield). 1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 2.14 (s, 3H) 2.24-2.33 (m, 2H) 3.04 (t, 2H) 3.25-3.91 (m, 13H) 3.99 (s, 3H) 4.18 (s, 2H) 5.74-5.78 (m, 1H) 7.79 (d, 1H) 8.14 (d, 1H) 8.60 (s, 1H) LCMS: [M+H]+=550.2, Rt(1)=1.58 min.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[C:21](Cl)=[O:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3].[NH:12]1[CH:13]=[CH:14][CH:15]=[N:10][C:11]1=[O:18]
Reactant: CN(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN1CCC(OC(=O)N(C)c2ccc(Cl)c(Cl)c2)N(c2nnc(C(C)(C)C)s2)C1=O
Product: O=c1nccc[nH]1
Temperature: 25 °C

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-methyl-N-(3,4-dichlorophenyl)carbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 horus. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tertrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[N-methyl-N-(3,4-dichlorophenyl)carbamoyloxy]-2(1H-pyrimidinone.
Reaction SMILES: [K].C1C2C(=CC=CC=2)C=CC=1.[CH2:12]1[C:21]2[C:16]3[C:17](=[CH:22][CH:23]=[CH:24][C:15]=3[CH2:14][O:13]1)[CH:18]=[CH:19][CH:20]=2>C1COCC1>[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:17]2[C:16]=1[C:21]([CH2:12][OH:13])=[CH:20][CH:19]=[CH:18]2
Reactant: c1cc2c3c(cccc3c1)COC2
Agent: [K]
Solvent: c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: Cc1cccc2cccc(CO)c12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
A 3-L 4-neck flask equipped with an overhead stirrer, a thermocouple, a condenser, a nitrogen inlet, and a 1-L addition funnel was charged with potassium (30 g, 0.764 mol) and THF (1 L). The metal suspension was heated to 60° C. for 30 min and then stirred to room temperature. To the reaction mixture was then added naphthalene (2 g, 0.015 mol), the suspension was stirred at room temperature for 10 min and then cooled to −20° C. to afford a blue suspension. A solution of 1H,3H-Benzo[de]isochromene (26 g, 0.153 mol) in THF (500 ml) was slowly added via the addition funnel, with addition controlled so that the reaction temperature did not exceed −15° C. After stirring for 5 h at −20° C., the suspension was removed from the cooling bath, warmed with stirring to 0° C., and then allowed to stand without stirring (potassium metal settling). The solution was decanted and the residual potassium was cooled and carefully decomposed with isopropyl alcohol (IPA) under N2. The decanted solution was carefully treated with water (20 mL) under nitrogen and stirring was continued for 20 min. Additional water and ether were added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over MgSO4 and condensed in vacuo to yield a crude material. The crude material was purified by flash chromatography (7.5/2.5 hexane/EtOAc) to yield 8-methyl-1-napthalenemethanol as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([C:19]([F:22])([F:21])[F:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C)C=O.O>[C:30]1([CH2:29][O:1][C:2]2[CH:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]([C:19]([F:22])([F:20])[F:21])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl 2-hydroxy-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 51; 230 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (5 mL) and cesium carbonate (264 mg, 0.81 mmol) and benzyl bromide (0.12 ml, 1.01 mmol) were added. The mixture was heated at 40° C. for 18 hours. Ethyl acetate (10 ml) and water (10 ml) were added and the organic layer was separated and washed with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (1:1 cyclohexane/ethyl acetate-10% 7M NH3 in methanol/dichloromethane) gave the title compound as oil. 232 mg.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].CCOCC>C(N(CC)CC)C>[CH3:6][S:7]([O:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCCCBr
Reaction time: 1 h

Procedure:
A mixture containing 13.9 ml. of 3-bromo-1-propanol, 7.6 ml. of methane sulfonyl chloride and 100 ml. ether was formed. The mixture was mixed together and 14 ml. of triethylamine was added over a period of 45 minutes at 5°-10° C. and then stirred at 5°-10° C. for 1 hour. The mixture was allowed to come to room temperature and was stirred for an additional 15 minutes. To the mixture was added 100 ml. of water and the ether solution dried over magnesium sulfate and evaporated to yield 14.5 g. of a colorless oil. nD30 1.4749.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH2:20]([NH:22][C:23](=S)[NH:24][NH2:25])[CH3:21]>C(O)C>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:23]([NH:22][CH2:20][CH3:21])=[N:24][N:25]=3)[N:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCNC(=S)NN
Reactant: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCNc1nnc2ccc(-c3cccc(N(CC)C(C)=O)c3)nn12

Procedure:
A solution of 7.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 6.0 g 4-ethyl-3-thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then worked up and the product chromatographed as described in Example 70. Recrystalization of the product from dichloromethane-hexane afforded 2.1 g yellow flakes, mp 171°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH3:10].[NH2:12][C:13]([NH2:15])=[S:14].[I:16]I.CO>O>[IH:16].[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:12]=1
Reactant: COc1ccccc1C(C)=O
Reactant: NC(N)=S
Reactant: II
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1csc(N)n1
Product: I
Yield: 83 %

Procedure:
The starting compound was prepared as follows: 15 gm of o-methoxy-acetophenone was intimately admixed with 15.2 gm of thiourea in a resin flask, and 27.7 gm of iodine were added in small portions to the mixture. After all of the iodine had been added, the reaction mixture was heated overnight on an oil bath at 100°0 C. After cooling, first 50 ml of methanol and then 400 to 500 ml of water were added to the reaction mixture. The solidified mass was comminuted in a motar, the suspension was filtered, and the filter cake was washed first with water, then with some ethanol and then with ether, and finally dried. 27.7 gm (83% of theory) of 2-amino-4-(2'-methoxy-phenyl)-thiazole hydroiodide were obtained, which could be used as the starting compound without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].C(Cl)Cl.CO>[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]2=[O:27])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CCn1ccn(-c2ccc(OCc3ccccc3)cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN1CCN(c2ccc(O)cc2)C1=O

Procedure:
Prepared from 1-(4-benzyloxyphenyl)-3-[2-(ethoxycarbonyl)ethyl]-3H-imidazol-2-one by hydrogenation in the presence of palladium on charcoal in ethanol at 40° C. and a hydrogen pressure of 50 psi. Rf value: 0.20 (silica gel; methylene chloride/methanol=100:2)
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.N[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2.Cl.[NH3:35]>CCO.CO>[CH3:17][C:15]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([C:7]2[C:2]([NH:35][C:31]3[C:32]4[CH:33]=[CH:25][NH:26][C:27]=4[CH:28]=[CH:29][CH:30]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:16]=1
Reactant: N
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: Nc1cc2ccccc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1nc(-c2cccnc2Nc2cccc3[nH]ccc23)c2nc[nH]c2n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 5 %

Procedure:
6-(2-Fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (270 mg, 0.862 mmol) and 4 aminoindole (159.3 mg, 1.205 mmol) were suspended in EtOH (5.0 mL) and then aqueous hydrochloric acid, (5N, 0.21 mL, 1.1 mmol) was added. The reaction flask was fit with a reflux condenser, placed in a preheated oil bath (100° C.), and stirred for 3 hours. Then, the reaction was cooled to room temperature, diluted with 2N ammonia in MeOH (4.0 mL), and allowed to stand overnight. Then, the material was concentrated, treated with DMF and filtered. The solid was washed with DCM, and the filtrate was concentrated and purified on prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min). The fractions with product were collected, concentrated, and filtered through a silica gel plug (about 1 inch) with 10:1 DCM/2N ammonia in MeOH to give N-(3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indol-4-amine (13.7 mg, 5%). MS (ESI pos. ion) m/z 342 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 13.60 (s, 1H), 12.44 (s, 1H), 11.16 (s, 1H), 9.77 (d, J=7.04 Hz, 1H), 8.61 (s, 1H), 8.37 (dd, J=4.69 Hz, 1.76 Hz, 1H), 8.05 (dd, J=6.85 Hz, 1.56 Hz, 1H), 7.37 (t, J=2.64 Hz, 1H), 7.11-7.04 (m, 2H), 7.01 (dd, J=7.82 Hz, 4.69 Hz, 1H), 6.72 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28].O([CH2:40][CH:41]([F:43])[F:42])S(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.O>C(#N)C>[F:31][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[N:22]([CH2:40][CH:41]([F:43])[F:42])[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)[nH]c2nccnc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)n(CC(F)F)c2nccnc12

Procedure:
Isobutyric acid 7-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 2.7) (0.335 g), 2,2-difluoroethyl triflate (0.32 g) and Hunigs base (0.2 ml) were stirred in acetonitrile (12 ml) at ambient temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The phases were separated and the organic phase was washed with water, aqueous sodium hydrogen carbonate (saturated) and brine, dried over anhydrous sodium sulfate and concentrated to give Compound No. B24 of Table B (0.280 g).