Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1.[NH3:31]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:31])[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(N3CCOCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCOCC3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 70 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-morpholinopyrimidin-4-amine (34 mg, 0.080 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)-2-morpholinopyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (22 mg, 0.056 mmol, 69.8% yield). 1H NMR (300 MHz, d6-DMSO) δ 11.91 (s, 1H); 9.16 (s, 1H); 8.50 (s, 1H); 8.08 (d, J=4.97 Hz, 1H); 7.67 (s, 1H); 7.51 (s, 1H); 6.85 (d, J=8.77 Hz, 1H); 3.85 (s, 3H); 3.74 (s, 4H); 3.66 (s, 4H); 2.36 (s, 3H). m/z (ESI, +ve ion) 396.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[CH:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([OH:23])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)C>[OH:23][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[CH:13]=[N:14][NH:15][C:3]=23)=[CH:16][CH:17]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cn[nH]c2c1Nc1ccc(O)cc1
Yield: 54.5 %

Procedure:
Ethyl 7-chloro-1H pyrazolo[4,3-b]pyridine-6-carboxylate (1.0 g, 0.004 mole) and p-aminophenol (1.0 g, 0.009 mole) were stirred together in ethyl acetate (200 ml) under nitrogen for 48 hours, the temperature being maintained between -10° and -5° C. The ethyl acetate was removed under reduced pressure to give a yellow solid. This solid was dissolved in aqueous ethanol and the pH adjusted to pH8 with 10% sodium carbonate solution. The resulting solid was filtered off washed with water and dried. Recrystallization from methanol/ethyl acetate gave the title compound as a pale yellow solid (650 mg, 50%), m.p. 286°-287° C. (decomposition)
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][CH:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:22]#[N:23])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: CSc1ccc(C=Nc2ccc(F)cc2)cc1
Product: CSc1ccc(C(C#N)Nc2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methylthiobenzaldehyde and 4-fluoroaniline as starting materials, 4-fluoro-N-(4-methylthiobenzylidene)aniline was obtained in a yield of 89%. This aniline compound and trimethylsilyl cyanide were then reacted together in a similar manner to that described in Example 1(ii), to give the title compound as a slightly yellow powder (yield 47%).
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[P:17]([O:24][CH2:25][CH2:26][C:27]#[N:28])[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[C:27]([CH2:26][CH2:25][O:24][P:17]([C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:8]=1)[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)#[N:28]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: N#CCCOP(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCOP(c1nc([N+](=O)[O-])n[nH]1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a stirred solution of 3-nitro-1,2,4-triazole (2.57 g, 22.57 mmol) and triethylamine (12.58 mL, 9.14 g, 90.28 mmol) in CH2Cl2 (40 mL) was added dropwise Chloro(2-Cyanoethoxy)morpholinophosphine (5.82 g, 22.57 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a yellow oil (5.98 g, 79%). 31P NMR (CDCl3) δ 126.9.
Reaction SMILES: C[Si](C)(C)C#CC=C1CCNCC1.[CH3:14][O:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([N:24]2[CH2:29][CH2:28][C:27](=[CH:30][C:31]#[C:32][Si](C)(C)C)[CH2:26][CH2:25]2)[N:19]=[CH:18][CH:17]=1.Br[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40](F)[CH:39]=1.IC1C=C(F)C=CC=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:44][C:42]1[CH:41]=[C:40]([C:32]#[C:31][CH:30]=[C:27]2[CH2:28][CH2:29][N:24]([C:20]3[N:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[C:21]=3[C:22]#[N:23])[CH2:25][CH2:26]2)[CH:39]=[CH:38][CH:43]=1
Reactant: COc1ccnc(N2CCC(=CC#C[Si](C)(C)C)CC2)c1C#N
Reactant: Fc1cc(F)cc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#CC=C1CCNCC1
Agent: Fc1cccc(I)c1
Solvent: O
Product: COc1ccnc(N2CCC(=CC#Cc3cccc(F)c3)CC2)c1C#N
Yield: 20.4 %

Procedure:
The title compound was prepared in the same way as the Compound of Example 274 but replacing Compound 274c with Compound 294a and 1-bromo-3,5-difluorobenzene with 3-iodofluorobenzene and adding 1 molar equivalent of tetrabutylammonium fluoride monohydrate to the starting reaction mixture. Purification by automated flash chromatography (Horizon™-Biotage) PE-EtOAc 100:30, then by CHCl3 followed by a final purification by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient afforded a colourless oil. Yield: 20.4%. LCPREP. Colourless oil. Yield: 20.4%
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1)=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[N:23]1[CH:22]=[CH:21][N:19]2[CH:20]=[C:15]([CH:14]3[CH2:8][CH2:9][CH2:10][CH2:11][S:12]3)[CH:16]=[CH:17][C:18]=12
Reactant: O=S(CCCCCl)Cc1ccc2nccn2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: c1cn2cc(C3CCCCS3)ccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
8.68 g of potassium t-butoxide was added to 80 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4:1 (v/v)] mixture, followed by the cooling with ice. A solution of 9.51 g of the 6-((4-chlorobutyl)sulfinylmethyl)imidazo[1,2-a]pyridine prepared in the Preparative Example 8 in 30 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4: 1 (v/v)] mixture was dropped into the obtained mixture. The obtained mixture was stirred for one hour, followed by the addition of ice-water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained oil was solidified by allowing to stand, followed by the addition of ether. The obtained mixture was filtered to give 5.84 g of the title compound as a dark-creamy powder (yield: 71%). The NMR spectroscopic analysis of this powder revealed that the powder was a mixture comprising two diastereomers at a ratio of about 2:1.
Reaction SMILES: [OH:1][C:2]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)=[CH:3][C:4]([C:6]1[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:16])=[O:5].[OH-].[Na+].Cl>C(O)C>[OH:1][C:2]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)=[CH:3][C:4]([C:6]1[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:13])[CH3:14])[CH:9]=[CH:8][C:7]=1[OH:16])=[O:5]
Reactant: COC(=O)c1ccc(C(O)=CC(=O)c2cc([Si](C)(C)C)ccc2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)c1ccc(O)c(C(=O)C=C(O)c2ccc(C(=O)O)cc2)c1
Yield: 50.5 %

Procedure:
To a solution of 148 mg (0.4 mmol) of methyl 4-[1-hydroxy-3(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoate in 20 ml of ethanol was added 2 ml of 2N-sodium hydroxide solution at room temperature with stirring. The mixture was stirred at room temperature for 1 day and acidified with 10%-hydrochloric acid to pH 4. A deposited precipitation was extracted with AcOEt. The extract was washed with H2O and saturated aq.NaCl, dried over MgSO4, and evaporated. The residue was recrystallized from methanol to give 72 mg of yellow needles (yield 51%), m.p. 207°-209° C.
Reaction SMILES: C([C:3]([CH2:10][CH3:11])([C:7]([O-:9])=[O:8])[C:4]([O-:6])=[O:5])C.BrCCBr.S(=O)(=O)(O)O>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:3]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:10][CH2:11]1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: BrCCBr
Product: O=C(O)C1(C(=O)O)CC1
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
In 50% NaOH 187 ml was dissolved 15 g of diethylmalonate at room temperature. Benzyltriethylammoniumchloride (21.3 g) was added and the resulting mixture was stirred for 10 minutes. 1,2-Dibromoethane (12.3 g) was added to the reaction solution and the resulting mixture was stirred for more than 18 hours at room temperature. The reaction mixture was neutralized by adding dropwise conc. sulfuric acid and then extracted with ethyl acetate. The extract was distilled under reduced pressure to give 6.2 g of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]([O:17]CC)=O)[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][NH2:22].CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]([NH:22][CH3:21])=[O:17])[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: CCOC(=O)CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Reaction time: 72 h
Yield: 42.3 %

Procedure:
In 1.5 ml of methylene chloride were dissolved 0.5 g of ethyl (3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazin-4-yl)acetate and 0.16 g of 40% methylamine-methanol and the mixture was allowed to stand at room temperature for 3 days. The solvent was then distilled off and the residue was recrystallized from methylene chloride-hexane to give 0.2 g of 2-(3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazin-4-yl)-N-methylacetamide. This compound has the following physicochemical properties.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:18]=[C:17]2[N:8]([C:9](=S)[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1.ClC1C=CC(N=C=S)=C(C=1)[C:26]#[N:27].N1C=CC=C1C(NN)=O.CN>>[CH3:26][N:27]=[C:9]1[N:8]2[N:7]=[C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)[N:18]=[C:17]2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10]1
Reactant: N#Cc1cc(Cl)ccc1N=C=S
Reactant: S=c1[nH]c2ccccc2c2nc(-c3ccc[nH]3)nn12
Agent: CN
Agent: NNC(=O)c1ccc[nH]1
Product: CN=c1[nH]c2ccccc2c2nc(-c3ccc[nH]3)nn12
Temperature: 150 °C

Procedure:
A mixture of 2-(2-pyrrolyl)-5-thiono-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazoline (4.28 g), prepared from 5-chloro-2-isothiocyanatobenzonitrile and 2-pyrrolecarbohydrazide as described in Example 39, is placed in a stainless steel pressure vessel with 40% aqueous methylamine saturated at 0° with methylamine gas (225 ml) and heated 6 hours at an outside temperature of 150° C. The reaction mixture is cooled to room temperature and the solid collected, washed with water and air dried. Recrystallization from aqueous methanol, then water affords pure 5-methylimino-5,6-dihydro-2-(2-pyrrolyl)-[1,2,4]triazolo-[1,5-c]quinazoline, mp 220°-221°.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[N:5]([CH2:8][C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[C:6]=[S:7].C(O)C>N1C=CC=CC=1>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH2:8][N:5]1[CH:1]=[N:3][N:4]=[C:6]1[SH:7]
Reactant: NNC=O
Reactant: S=C=NCc1ccco1
Solvent: c1ccncc1
Solvent: CCO
Product: Sc1nncn1Cc1ccco1
Yield: 83.7 %

Procedure:
A solution of formic acid hydrazide (439 mg, 7.809 mmol) in pyridine (20 ml) was added to a solution of 2-isothiocyanatomethyl-furan (1 g, 7.185 mmol) in pyridine (20 ml). Reaction took place at room temperature overnight, and ethanol (20 ml) was added directly to the reaction and placed in 80 C bath overnight. Solvent was evaporated and the title compound (1.09 g, 83%) was obtained from purification by SPE chromatography on silica gel with 500 ml 20%, 250 ml 25%, 250 ml 30%, 250 ml 35%, 250 ml 40%, and 250 ml 50% ethyl acetate in hexanes. 1H NMR (CD3OD), δ (ppm): 14.0 (bs, 1H), 8.19 (s, 1H), 7.52 (q, 1H), 6.52 (m, 1H), 6.42 (m, 1H), 4.90 (s, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([NH2:21])[CH2:9][C@@H:8]1[CH2:22][CH3:23])=[O:6])([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH:29]=O>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[C@H:10]([NH:21][CH2:29][C:28]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:26]([C:25]([F:24])([F:38])[F:39])[CH:27]=2)[CH2:9][C@@H:8]1[CH2:22][CH3:23])=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[C@H]1C[C@@H](N)c2cc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Product: CC[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)ccc2N1C(=O)OC(C)C

Procedure:
treating said cis-4-amino-2-ethyl-6-trifluoromethyl-3,4,-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester first with 3,5-bis-trifluoromethyl-benzaldehyde under acidic conditions followed by a reducing agent to form cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4,-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl.C(OCC)(=O)C>[C:43]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][C:6]3[CH:7]=[C:2]([F:1])[C:3]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[N:4][CH:5]=3)=[O:23])=[CH:12][N:13]=2)[CH2:18][CH2:19]1)(=[O:45])[CH3:44]
Reactant: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)cn2)CC1
Reaction time: 0.33 h

Procedure:
To a solution of N-((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)-6-(piperazin-1-yl)nicotinamide 46-3 (35 mg, 0.076 mmol) and DIEA (27 μL, 0.155 mmol) in DCM (1.0 mL) was added acetyl chloride 46-4 (7 μL, 0.095 mmol). After 20 minutes stirring, the mixture was diluted with ethyl acetate, washed with water, and dried over Na2SO4. After evaporation of the solvents followed by preparative reverse phase HPLC separation gave 6-(4-acetylpiperazin-1-yl)-N-((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)nicotinamide as a solid 46. MS m/z 503.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.76 (d, 1H), 8.58 (d, 1H), 8.54-8.50 (m, 1H), 8.29 (bs, 1H), 8.07 (d, 1H), 7.97 (dd, 1H), 7.60 (dd, 1H), 6.62 (d, 1H), 4.63 (s, 2H), 3.72-3.65 (m, 4H), 3.61-3.55 (m, 4H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:18]I.O>O1CCCC1>[CH3:1][S:2][CH:3]([CH3:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5]
Reactant: CSCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(C)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 40.8 %

Procedure:
To 5.00 g of 2-methylthio-4'-(trifluoromethyl)acetophenone dissolved in 50 ml of tetrahydrofuran was added under ice-cooling 0.855 g of a 60% aqueous solution of sodium hydride, and the mixture was reacted at room temperature with stirring until no bubbles were produced. After an addition of 3.34 g of methyl iodide, the mixture was stirred at room temperature for a further 2 hours. The resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography- using n-hexane to obtain 2.16 g of an oily product of 2-methylthio-4'-(trifluoromethyl)propiophenone (yield: 40.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH2:35]Cl)[CH:34]=1.O>CN(C=O)C>[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][N:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:32]=[N:31][CH:30]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: ClCc1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 20 h

Procedure:
300 mg (0.98 mmol) of the compound from Example 4A and 953 mg (2.93 mmol) of cesium carbonate were dissolved in 4 ml of DMF, and 261 mg (1.10 mmol) of 3-bromo-5-(chloromethyl)-pyridine hydrochloride were added. The mixture was stirred initially at 40° C. for 20 h and then at 70° C. for 24 h. To bring the reaction to completion, a further 130 mg (0.55 mmol) of 3-bromo-5-(chloromethyl)pyridine hydrochloride and 450 mg (1.38 mmol) of cesium carbonate were then added, and the reaction was stirred at 70° C. for another 20 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 263 mg (56% of theory) of the target compound.
Reaction SMILES: C(O)(=O)/C=C/C(O)=[O:5].[CH3:9][N:10]1[C:16]2=[C:17]3[C:22](=[N:23][C:24]4=[CH:25][CH:26]=[CH:27][C:14](=[C:15]24)[O:13][CH:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:11]1)[CH2:21][CH2:20][CH2:19][CH2:18]3.CC(C)([O-])C.[K+].CI.[Cl-].[NH4+]>O1CCCC1>[CH3:9][N:10]1[C:16]2=[C:17]3[C:22](=[N:23][C:24]4=[CH:25][CH:26]=[CH:27][C:14](=[C:15]24)[O:13][CH:12]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:11]1=[O:5])[CH2:21][CH2:20][CH2:19][CH2:18]3
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CN1CC(c2ccccc2)Oc2cccc3nc4c(c1c23)CCCC4
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C(c2ccccc2)Oc2cccc3nc4c(c1c23)CCCC4
Temperature: 0 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
1,3,9,10,11,12-hexahydro-1-methyl-3-phenyl-2H-quino[4,3,2-ef][1,4]benzoxazepine fumarate (4.20 g) was suspended in dry tetrahydrofuran (75 ml), chilled with ice/water, and potassium tert-butoxide (1.50 g) was added. The mixture was stirred for 1 hr, methyl iodide (1.90 g) was added, and the mixture was stirred overnight. The reaction mixture was poured into ammonium chloride solution, and the organic layer was separated. The aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. Recrystallization of the residue from methanol gave 3.37 g (77%) of product, mp 188°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][C:20]=1[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH:30][C:10]([C:7]3[CH:6]=[C:5]([CH2:4][C:3]4[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=4[F:1])[O:9][N:8]=3)=[O:12])=[CH:24][NH:25]2)=[CH:21][C:20]=1[CH3:31]
Reactant: Cc1cc2c(CCN)c[nH]c2cc1Cl
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(CCNC(=O)c3cc(Cc4cc(F)ccc4F)on3)c[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
A mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.180 g, 0.752 mmol), 2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine intermediate 142 (0.157 g; 0.752 mmol), HATU (0.286 g; 0.753 mmol) and N,N diisopropylethylamine (0.324 mL; 1.88 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane and eluent 1 to 10% ethyl acetate in dichloromethane) and by preparative HPLC method 2 to yield 0.0051 g (2%) of N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: C1([N:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(N)=O)=NC=C(N5CCC[C@@H](NC(N(C)C)=O)[C@H]5C)N=4)=[CH:14][CH:13]=3)([CH3:11])[CH2:7][CH2:6]2)CCC1.C1(P([C:54]2C=CC=C[C:55]=2[C:60]2C=CC=CC=2)C2CCCCC2)CCCCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:60]1([N:5]2[CH2:6][CH2:7][C:8]([C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=3)([CH3:11])[CH2:9][CH2:10]2)[CH2:55][CH2:54]1
Reactant: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Reactant: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C(N)=O)c(Nc2ccc(C3(C)CCN(C4CCC4)CC3)cc2)n1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC1(c2ccc(N)cc2)CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 402 %

Procedure:
To a suspended of 4-(4-bromophenyl)-1-cyclopropyl-4-methylpiperidine (341) (16.0 g, 54.5 mmol), (dicyclohexylphosphino)biphenyl (1.9 g, 5.4 mmol) and Pd2(dba)3 (2.5 g, 27.2 mmol) in anhydrous THF (100 mL) was added LiHMDS (1M, 109 mL, 109 mmol). The resulting mixture was purged with N2 and then stirred at 60° C. for overnight under N2 atmosphere. After cooled down to RT, the mixture was diluted with water (100 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 50% EtOAc in PE to give 4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342) (5 g, 40%) as a white solid. Proton NMR (CDCl3): δ 7.16 (2H, d, J=8.5 Hz), 6.69 (2H, d, J=8.6 Hz), 3.58 (2H, s), 2.82-2.65 (2H, m), 2.64-2.49 (2H, m), 2.14-2.04 (2H, m), 1.77-1.65 (2H, m), 1.21 (3H, s), 0.96-0.82 (1H, m), 0.56-0.28 (4H, m) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2Cl)c1

Procedure:
1-(2,4-Dichloro-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 1-bromomethyl-2,4-dichloro-benzene following General Procedure A.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13]>>[C:1]1([CH2:7][C:8]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Product: C[C@H](NC(=O)Cc1ccccc1)C(=O)O

Procedure:
Following General Procedure B" above, title compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102-104° C.