Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:20][O:19][C:10]1[C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[C:2]([C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])=[O:1]
Reactant: COC(=O)C#CC(O)c1ccc(OC)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C#CC(=O)c1ccc(OC)c(OC)c1OC
Reaction time: 1 h

Procedure:
A solution of 7 g (25 mmol) of methyl 4-hydroxy-4-(2,3,4 -trimethoxyphenyl)-2-butynoate in 40 ml of methylene chloride was added dropwise at 0° to a suspension of 62 g (0.71 mol) of manganese dioxide in 140 ml of methylene chloride. The reaction mixture was stirred at 0° for 1 hour, filtered over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/hexane yielded methyl 3-(2,3,4 -trimethoxybenzoyl)propiolate of melting point 74°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=O)[N:21]=4)=[C:13]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:31]>CO>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][CH:19]=[C:20]([C:22]([NH2:31])=[O:24])[N:21]=4)=[C:13]([NH:27][CH:28]([CH3:29])[CH3:30])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1csc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)n1
Reactant: N
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nc(C(N)=O)cs1
Temperature: 80 °C

Procedure:
The ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate (Example 20) (200 mg, 0.455 mmol) was taken in a sealed tube, to it methanol (2 mL) was added, followed by addition of methanolic ammonia (10 mL). The reaction mixture was heated at 80° C. for 3 h. The reaction mixture was concentrated. The crude material was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent. The material obtained was further purified on preparative TLC to obtain 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxamide. 1H NMR: 400 MHz, DMSO-d6: δ 1.33 (d, J=6.40 Hz, 6H), 3.64-3.72 (m, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.63 (bs, 1H), 7.69 (bs, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.14 (s, 1H), 8.32 (s, 1H), 8.35 (d, J=6.80 Hz, 1H), 8.49 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.35 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 1.933 min; LCMS (ES-API), m/z 411.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.137 min; Purity: 99.8%.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])/[C:3](/[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1)=[CH:4]\[C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]2)[N:9]=1.[H-].[Na+].[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36]>O1CCCC1>[CH3:33][N:34]([CH3:39])[S:35]([N:6]1[CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:15])([F:16])[F:17])[CH2:12][CH2:13]2)[N:9]=[C:5]1/[CH:4]=[C:3](/[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1)\[C:2]([F:1])([F:29])[F:30])(=[O:37])=[O:36]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: FC(F)(F)/C(=C\c1nc(CC2(C(F)(F)F)CC2)c[nH]1)c1ccc(-n2cccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC2(C(F)(F)F)CC2)nc1/C=C(/c1ccc(-n2cccn2)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
In a 250-mL round-bottom flask, a mixture of 1-{4-[(Z)-1-(trifluoromethyl)-2-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)vinyl]phenyl}-1H-pyrazole (5.05 g, 11.8 mmol) and 60 wt % sodium hydride (0.89 g, 22 mmol) were mixed with tetrahydrofuran (80 mL). After bubbling ceased, dimethylsulfamoyl chloride (2.6 mL, 24.26 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with water and extracted with diethyl ether. The combined organic extracts were washed with brine, dried (potassium carbonate), and concentrated in vacuo to afford an orange solid. Chromatography over silica eluting with 25-40% ethyl acetate/hexanes afforded N,N-dimethyl-4-{[1-(trifluoromethyl)cyclopropyl]methyl}-2-{(1Z)-3,3,3-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]prop-1-en-1-yl}-1H-imidazole-1-sulfonamide, as a yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:9]=1)=[O:6].C[Si]([C:34]#[CH:35])(C)C>CC#N.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:28]([C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:34]=1[CH3:35])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)[CH:9]=1)=[O:6])#[CH:29]
Reactant: Cc1ccc(C(=O)Nc2cc(CN3CCN(C)CC3)cc(C(F)(F)F)c2)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)Nc2cc(CN3CCN(C)CC3)cc(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-iodo-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide (951 mg, 1.84 mmol), PdCl2(PPh3)2 (65 mg, 0.092 mmol) in MeCN (75 mL) and Et3N (20 mL) at room temperature was added trimethylsilylacetylene (0.8 mL, 5.52 mmol) followed by CuI (18 mg, 0.092 mmol). The resulting mixture was allowed to stir at room temperature for 2 h at which time the reaction mixture was concentrated under reduced pressure followed by reconstitution in MeOH (100 mL). To this mixture was added enough K2CO3 to saturate the mixture and the mixture was allowed to stir for about 1.5 h. The mixture was filtered through a pad of Celite. To the filtrate was added silica gel (˜20 mL) and the mixture was concentrated under reduced pressure, and purified via automated flash chromatography (silica gel, 0% to 15% MeOH in CH2Cl2, gradient elution) to afford 3-ethynyl-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide.
Reaction SMILES: [N:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=C)[CH:17]=3)[NH:12][C:11]=2[C:21]([NH2:23])=[O:22])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+].O.C([O-])(O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:21]([NH2:23])=[O:22])=[C:10]2[S:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)(=[O:8])=[O:9])=[O:25]
Reactant: C=Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1[nH]c2ccc(C=O)cc2c1S(=O)(=O)N1CCOCC1

Procedure:
3-(Morpholin-4-ylsulfonyl)-5-vinyl-1H-indole-2-carboxamide (207 mg, 0.617 mmol, 1.0 equiv), sodium periodate (660 mg, 3.09 mmol, 5.0 equiv) and osmium tetraoxide (16 mg, 0.062 mmol, 0.1 equiv) were dissolved in 18 mL of a 5:1 solution of acetone:water and stirred for 18 hours. The mixture was poured into aqueous saturated NaHCO3 and extracted three times with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 338.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[CH:15][NH:16]4)(O)[CH2:6]2)[CH2:3][CH2:2]1>Cl.O>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]=[C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[CH:15][NH:16]4)[CH2:6]2)[CH2:2][CH2:3]1
Reactant: OC1(c2cccc3[nH]ccc23)CCCN(CC2CC2)C1
Agent: Cl
Solvent: O
Product: C1=C(c2cccc3[nH]ccc23)CN(CC2CC2)CC1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A solution of 10 g of the product of Example 25 in 300 ml of 1 N hydrochloric acid was refluxed for 6 hours and was then cooled to room temperature and was diluted with 300 ml of water. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous sodium chloride and evaporated to dryness under reduced pressure. The 9.1 g of residue were chromatographed over silica gel and eluted with a 95-5 chloroform-methanol mixture to obtain 5.4 g of 4-[1-cyclopropylmethyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole with an Rf=0.10.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[C:40]2[CH3:48])[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[CH3:48][C:40]1[N:39]([CH:36]2[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)=[O:16])[CH2:4]3)[CH2:38][CH2:37]2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: Cc1nc2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4c(C)nc5ccccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 69.8 %

Procedure:
The title compound was prepared from 60 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5), 50 mg of 1-1-piperidin-4-yl-2-methyl-1-H-benzoimidazole (from Step B) and 80 mg of sodium triacetoxyborohydride in 4 mL THF and 1 mL of DMF, using a procedure analogous to that described in Example 95, Step D to provide 61 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([C:4]([OH:6])=[O:5])[CH3:3].[CH3:15][C@H:16](NC)[C@H](O)C1C=CC=CC=1>>[CH3:15][CH2:16][O:5][C:4]([C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:1])[CH3:3])=[O:6]
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
Clofibric acid (1.073 g, 5 mmol) and ephedrine (0.826 g, 5 mmol) were molten in a hot mortar until a free-flowing clear liquid was obtained. The mixture solidified at room temperature and was grinded to obtain a yellow powder in quantitative yield. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=9.36 (br s, 2H), 7.30 (m, 5H), 7.19 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.75 Hz, 2H), 5.10 (s, 1H), 3.12 (m, 1H), 2.52 (s, 3H), 1.41 (s, 6H), 0.85 (d, J=6.58 Hz), 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=176.8, 155.5, 141.8, 128.5, 128.0, 126.9, 125.8, 123.4, 119.2, 80.2, 69.8, 59.5, 30.7, 25.8, 9.6. mp 131° C., T5%onset 166° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:11][CH2:10]1.[O:30]=[C:31]1[CH2:36][O:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.C([BH3-])#N.[Na+]>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]2[O:20][CH2:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([NH:8][CH2:41][C:39]4[CH:38]=[CH:37][C:34]5[O:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=5[N:40]=4)[CH2:14][CH2:13]3)[C:22]=2[CH:23]=1
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one trifluoroacetate (Intermediate 46) (0.4 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (80 mg, 0.44 mmol) and sodium cyanoborohydride were reacted as described under Example 21, but, the reaction was stirred at room temperature overnight after sodium cyanoborohydride addition to give the title compound as a free base, 30 mg (17%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:26]CC2C=CC(OC)=C(OC)C=2)[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:6]=[C:7]([NH2:26])[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(CCCCCCN3CC[C@H](F)C3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(N)c2[nH]nc(CCCCCCN3CC[C@H](F)C3)c2n1
Yield: 39.2 %

Procedure:
A solution of (S)-5-butyl-N-(3,4-dimethoxybenzyl)-3-(6-(3-fluoropyrrolidin-1-yl)hexyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (119 mg, 0.232 mmol) in trifluoroacetic acid (1 mL, 12.98 mmol) was heated in a Biotage Initiator microwave (using initial absortion setting high) at 120° C. for 2.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in 3:1 chloroform:IPA (50 mL) and washed with aqueous sodium hydroxide (0.1 M, 50 mL). The organic phase was separated and the aqueous back extracted with 3:1 chloroform:IPA (30 mL). The combined organic extracts were dried (hydrophobic frit) and concentrated in vacuo. The material (223 mg) was dissolved in MeOH:DMSO (1:1) (2 mL) and purified by MDAP (Method B). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as an orange solid (33 mg).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH:16][CH2:17][C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)=[N:13][CH:12]=[N:11][C:10]=3[NH:9][C:8]=2[Si](CC)(CC)CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:30]N1C(=O)CCC1=O>CN(C=O)C>[I:30][C:8]1[NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[C:15]=2[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC[Si](CC)(CC)c1[nH]c2ncnc(NC[C@@H]3CCCO3)c2c1-c1ccccc1
Solvent: CN(C)C=O
Product: Ic1[nH]c2ncnc(NC[C@@H]3CCCO3)c2c1-c1ccccc1

Procedure:
A solution of 1.00 g (2.5 mmol) of (S)-[5-phenyl-6-(triethylsilanyl)-7-H-pyrrolo[2,3-d]pyrimidine-4-yl]-(tetrahydrofuran-2-ylmethyl)-amine and 830 mg (3.7 mmol) of N-iodosuccinimide in 10 ml DMF was stirred at 45° C. for 1 h. The reaction mixture was partitioned between dichloromethane (120 ml) and a 4:1 mixture of brine and saturated aqueous sodium thiosulfate (35 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (1×) and brine (1×), dried over Na2SO4, filtered and concentrated. The residue was dissolved in dichloromethane (10 ml), and hexanes (200 ml) was added slowly. A solid precipitate formed. The solid was filtered off and dried under high vacuum to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 1.51 (m, 1 H), 1.69-1.91 (m, 3 H), 3.19-3.69 (m, 4 H), 3.99 (m, 1 H), 5.27 (t, J=4.4 Hz, 1 H), 7.37-7.56 (m, 5 H), 8.42 (s, 1 H), 13.21 (s, 1 H). Mass Spectrum (ESI) m/e=421.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20](O)=[O:21])[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:68])([F:67])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[CH2:65][NH2:66]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([NH:66][CH2:65][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=2[C:58]([F:57])([F:67])[F:68])=[O:21])[N:10]=1
Reactant: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)NCc1ccccc1C(F)(F)F
Yield: 24.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid (Intermediate-11, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.072 g, 0.410 mmol) to afford 0.035 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 4.62-4.71 (br s, 2H), 7.30 (d, J=8.7 Hz, 1H), 7.46-7.52 (m, 2H), 7.56-7.59 (m, 2H), 7.65-7.75 (m, 3H), 8.02 (dd, J=2.4 Hz, 1H), 8.28 (s, 1H), 8.90 (br s, 1H), 12.58 (s, 1H); MS (m/z): 519.30 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:12].CC1(C)O[C:21](=[O:22])[CH2:20][C:18](=[O:19])[O:17]1>O>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]2[C:5]=1[O:12][C:21](=[O:22])[C:20]([C:18]([OH:19])=[O:17])=[CH:7]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cccc(OC(F)(F)F)c1O
Solvent: O
Product: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
3-(Trifluoromethoxy)salicylaldehyde (0.250 g, 1.21 mmol) and Meldrum's acid (0.200 g, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 0.197 g of 8-(trifluoromethoxy)-3-carboxy-coumarin in a 60% yield: LCMS (ESI) m/z 275 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][B-](F)(F)F)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].[K+]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:43][N:40]5[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[CH2:38][CH2:39]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Agent: [K+]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and potassium (4-tert-butoxycarbonyl-piperazin-1-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=1.26 min; Mass spectrum (ESI+): m/z=591 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]1.[C:16](#N)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].ICC>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]1
Reactant: COC1(c2cccc(F)c2F)CCNC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Product: CCN1CCC(OC)(c2cccc(F)c2F)C1
Temperature: 110 °C
Yield: 27 %

Procedure:
A mixture of 3-(2,3-difluorophenyl)-3-methoxypyrrolidine (0.4 g, 1.87 mmol), acetonitrile (5 ml), sodium carbonate (0.52 g, 3.74 mmol) and iodoethane (0.28 g, 1.87 mmol) was heated at 110° C. in a sealed tube under microwave irradiation for 10 minutes. Water (30 ml) was added and the aqueous phase was extracted with ethyl acetate (2×50 ml), the combined organic phases was dried (MgSO4) and evaporated to give the crude product (0.45 g). Purification by flash chromatography (ethyl acetate/methanol 1:1) and by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.12 g, 27%). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 94-98° C. MS m/z (rel. intensity, 70 eV) 241 (M+, 5), 226 (54), 211 (27), 141 (50), 71 (bp).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.C(O)(C)C.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:22][CH:23]=1)[NH:24][C:2]1[CH2:3][C:4]3[C:9]([C:1]2=1)=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: O=C1Cc2ccccc2C1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)-c1ccccc1C3
Temperature: 82 °C
Yield: 96.7 %

Procedure:
8.21 g of 2-indanone (Aldrich, 98%, Mw=132.16, 60.88 mmol), 40 mL of isopropanol, 10.84 g of p-methoxyphenylhydrazin hydrochloride (Aldrich, 98%, Mw=174.63, 60.83 mmol) were charged at room temperature in a 250 mL flask equipped with magnetic stirrer. The slurry was brought to reflux (82° C.), (a black slurry was obtained), and kept at reflux for 1 hour. The dark brown viscous suspension was then cooled to room temperature; 200 mL of water saturated with NaHCO3 were added into the reactor (final pH ca. 7.5-8), the resulting mixture was filtered and the residue washed with plenty of water. The dark green solid on the filter was dried in vacuo at 70° C. for 4 hours (14 g, 98.9% pure by GC, 96.7% yield of pure product).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH2:6][C@H:7]1[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:4]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][CH2:2][C:3]([NH:5][CH2:6][C@H:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNC(=O)CO)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CO)NC[C@@H]1CNCCO1
Temperature: 25 °C

Procedure:
(R)-tert-butyl 2-((2-hydroxyacetamido)methyl)morpholine-4-carboxylate (1.0 equiv.) was dissolved in DCM:TFA (4:1, 0.5 M) and stirred at room temperature. After one hour the solution was concentrated to yield (S)-2-hydroxy-N-(morpholin-2-ylmethyl)acetamide. LCMS (m/z) (M+H)=175.1, Rt=0.12 min.