Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[CH:29]1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:37][C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]([CH3:27])[CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: Cn1cc(C=O)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cn(C)c3ccccc23)CC1
Yield: 48.5 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.5 g) as starting compound and 1-methyl-1 H-indol-3-carboxaldehyde (0.81 g) were reacted and treated in the same manner as in Example 121 to give 1.0 g of 4-amino-5-chloro-N-((1-(5-((1-methyl-1 H-indol-3-ylmethyl)amino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[NH2:13][CH2:14][C:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH2:14][C:15]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NCC1(O)CCCC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1(O)CCCC1
Yield: 43 %

Procedure:
The mixture of 2,5-dibromonitrobenzene (Tokyo Kasei Kogyo Co., Ltd., 5.4 g, 19.2 mmol), 1-(aminomethyl)cyclopentanol hydrochloride (J. Med. Chem. 1981, 24, 12-16, 4.3 g, 28.4 mmol) and N,N-diisopropylethylamine (8.4 mL, 48.1 mmol) in 1-methyl-2-pyrrolidinone (32 mL) was microwaved for 30 min at 200° C. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 as eluent) to afford the title compound (2.6 g, 43%) as an orange amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22](OC)=[O:23].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=[O:23]
Reactant: COC(=O)CC1=C(C)/C(=C/c2ccc(SC)cc2)c2ccc(F)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CSc1ccc(/C=C2/C(C)=C(CC=O)c3cc(F)ccc32)cc1
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
To a solution of the ester from Step 1 (3.39 g, 9.57 mmol) in toluene (75 mL) at -70° C., there was slowly added diisobutyl aluminum hydride (1M) in toluene (12 mL, 12 mmol) and the resulting mixture stirred at -70° C. for 45 minutes. Methanol (10 mL) was added slowly at -70° C., then the mixture was warmed to room temperature and water (100 mL) and 1N aqueous HCl (50 mL) were added. The mixture was shaken and the organic layer collected; the aqueous fraction was extracted with ether and the combined organic fractions washed 3 times with water, dried over MgSO4 and evaporated down to a thick oil. The crude title compound was used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]2[CH2:27][CH2:28][O:29][C:30](=[O:33])[N:31]([CH3:32])[C:25]=2[CH:24]=[CH:23][C:22]=1[O:34][CH3:35]>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:26]3[CH2:27][CH2:28][O:29][C:30](=[O:33])[N:31]([CH3:32])[C:25]=3[CH:24]=[CH:23][C:22]=2[O:34][CH3:35])=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc2c(c1N)CCOC(=O)N2C
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2CCOC(=O)N3C)ncc1Cl
Yield: 4 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 1-Amino-2-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product was isolated as a light yellow solid (4.0 mg, 4%). mp: 160° C. followed by solidification and melt at 250 and discoloration, MS (ESI+): 483 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.21 (s, 1H), 8.35 (br s, 1H), 8.06 (s, 1H), 7.44 (d, J=8 Hz, 1H), 7.20 (br s, 1H), 7.12 (d, J=8 Hz, 1H), 7.01 (t, 1H), 6.98 (d, J=7 Hz, 1H), 6.40 (s, 1H), 6.21 (br s, 1H), 4.39 (t, 2H), 3.83 (s, 3H), 3.42 (s, 3H), 3.04 (d, J=5 Hz, 3H), 2.98 (t, J=6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][C:18]#[CH:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4].Br[CH2:21]C#CC>>[CH3:1][O:2][C:3]([C:5]1([CH2:17][C:18]#[C:19][CH3:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6]1)=[O:4]
Reactant: CC#CCBr
Reactant: C#CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1
Product: CC#CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-But-2-ynyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 5J was prepared essentially similarly as 3-prop-2-ynyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester by substituting 3-bromo-propyne with 1-bromo-but-2-yne
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[Cl:18][C:19]1[C:27]2[N:26]=[CH:25][N:24](C3CCCCO3)[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:34][NH:35][CH3:36].CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CCCCO>[Cl:18][C:19]1[C:27]2[N:26]=[CH:25][NH:24][C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:34][N:35]([CH3:36])[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)c1cc(Nc2ccnc(Cl)n2)n[nH]1
Reactant: CNCc1ccc2c(ncn2C2CCCCO2)c1Cl
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(Cc1ccc2[nH]cnc2c1Cl)c1nccc(Nc2cc(C(F)F)[nH]n2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A vial was charged with 2-chloro-N-(5-(difluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (80 mg, 0.33 mmol), the bis HCl salt of 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)-N-methylmethanamine (138 mg, 0.39 mmol), DIPEA (0.29 mL, 1.63 mmol) and n-BuOH (1.5 mL), sealed and heated at 90° C. for 8 h. The reaction mixture was then cooled to RT, and 4N HCl/dioxane (0.81 mL, 3.26 mmol) was added. The mixture was stirred at 40° C. for 3 h and then concentrated in vacuo. The crude mixture was purified by preparative HPLC to afford 15.1 Mg9 12%) of N2-((4-chloro-1H-benzo[d]imidazol-5-yl)methyl)-N4-(5-(difluoromethyl)-1H-pyrazol-3-yl)-N2-methylpyrimidine-2,4-diamine (II-81).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Brc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)CN1CCC(c2ccc(Br)cc2)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-bromophenyl)piperidine hydrochloride (5 g, 18.1 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.62 g, 19.9 mmol) in ACN (250 mL) was added N,N-diisopropylethyl amine (11 mL, 63.2 mmol). The reaction mixture was heated at 45° C. for 50 min. 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.46 g, 2.0 mmol) was added and heating continued for 1 h. Another 0.46 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.0 mmol) was added and heating continued for 1 h. The reaction mixture was concentrated, diluted with brine and extracted twice with a mixture of hexanes-EtOAc-DCM. The organic layers were combined, concentrated, diluted with toluene and concentrated again. Purification by flash chromatography on silica gel (0 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 322.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.4 Hz, 2 H),7.08 (d, J=8.4 Hz, 2 H),3.06 (m, 2 H),3.00 (q, J=9.7 Hz, 2 H),2.45 (m, 3 H).1.77 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:17])[N:3]=1.[C-:18]#[N:19].[K+]>CS(C)=O.CCOC(C)=O>[NH2:17][C:4]1[N:5]=[C:6]([N:8]([CH2:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([C:18]#[N:19])[N:3]=1
Reactant: [C-]#N
Reactant: CCN(c1ccccc1)c1nc(N)nc(Cl)n1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCN(c1ccccc1)c1nc(N)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-N-ethyl-N-phenyl-[1,3,5]triazine-2,4-diamine (Intermediate 37, 400 mg, 1.60 mmol) was dissolved in anhydrous DMSO (5 mL) before the addition of potassium cyanide (200 mg, 3.07 mmol). The reaction mixture was stirred at 120 C in a pressure tube for 2 h before allowing to cool to room temperature. The product mixture was diluted with EtOAc (20 mL), extracted with water (2×10 mL), saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The desired product was obtained and used directly without further purification (300 mg, 78%). Method C HPLC-MS: MH+ requires m/z=241. Found: m/z=241, Rt=1.27 min (89%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29]CC)=[O:28])[CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>O.CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:23]1[CH2:33][CH2:32][CH:26]([C:27]([OH:29])=[O:28])[CH2:25][CH2:24]1)=[O:5]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(O)C1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 18 h

Procedure:
2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (B)(3.1 g, 0.14 mol), ethyl isonipecotate (1.7 ml, 0.11 mol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (5.1 g, 0.13 mol) and N,N,-diisopropylethylamine (10.0 ml, 0.55 mol) were added to dimethylacetamide (15 ml) and stirred for 18 hours. Water (100 ml) was added to the reaction mixture and the product was extracted into dichloromethane (4×50 ml). The combined organic layers were, filtered, washed with water (3×100 ml), dried over MgSO4, filtered and evaporated in vacuo to yield an orange oil. The oil was purified by flash chromatography (ethyl acetate) to yield 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoyl]piperidine-4-carboxylic acid as the methyl ester (1.5 g, 33%, 96% purity). To a solution of the methyl ester in tetrahydrofuran: water (2:1, 40 ml) was added sodium hydroxide (0.3 g, 0.075 mol) and the reaction was stirred for 18 h. The reaction was concentrated, washed with ethyl acetate (2×20 ml) and acidified with 2M HCl to pH 2. The aqueous layer was extracted with dichloromethane (2×20 ml), and the combined extracts were dried over MgSO4 and evaporated to yield 1-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoyl]piperidine-4-carboxylic acid (D) as a yellow solid (0.6 g, 65%), m/z [M+1]+ 392 (96% purity)
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[CH2:17][NH:18][C:19]1[N:23]([C@@H:24]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]2[OH:26])[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[N:20]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[CH2:17][NH:18][C:19]1[N:23]([C@@H:24]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]2[OH:26])[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[N:20]=1
Reactant: OC[C@H]1O[C@@H](n2c(NCc3cccc(OCCCCOCc4ccccc4)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: OCCCCOc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 100.3 %

Procedure:
2-[3-(4-Benzyloxybutyloxy)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (24 mg) was dissolved in ethanol (2 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at 60° C. under a hydrogen atmosphere for 24 hour. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].II.[I:19](O)(=O)=O.S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([I:19])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: [O-][I+2]([O-])O
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Agent: II
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2c(I)c(OC)ccc12

Procedure:
The process for the key intermediate in the copending application is exemplified as follows: 6-methoxy-1-naphthalenecarboxylic acid methyl ester is reacted with iodine and iodic acid in the presence of 98% sulfuric acid to give 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester, which in turn is reacted with trifluoromethyl iodide and copper powder in a stainless steel autoclave to give 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid methyl ester. Hydrolysis of the latter compound with dilute aqueous sodium hydroxide gives 6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid, one of the key intermediates noted hereinbefore. The latter compound also can be named 5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C@@H:9]2[C@H:14]([CH2:15][OH:16])[CH2:13][CH2:12][O:11][CH2:10]2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](O)[C:19]=1[CH:20]=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:16][CH2:15][C@@H:14]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=2)[C:19]=1[CH:20]=[O:21]
Reactant: O=Cc1c(O)cccc1O
Reactant: CC(C)n1nccc1[C@H]1COCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1nccc1[C@H]1COCC[C@H]1COc1cccc(O)c1C=O
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
To a solution of (±)((3S,4R)-3-(1-isopropyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-yl)methanol (50 mg, 0.22 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.44 mmol) in THF (1 mL) was added PPh3 (120 mg, 0.44 mmol) and DIAD (0.09 mL, 0.44 mmol) at 0° C. After stirred for 30 min, the solution was concentrated and the residue was purified by column (Hexanes/EtOAc=60:40) to give impure product, which was further purified by prep HPLC (eluted with ACN/H2O) to give (±) 2-hydroxy-6-(((3S,4R)-3-(1-isopropyl-1H-pyrazol-5-yl)tetrahydro-2H-pyran-4-yl)methoxy)benzaldehyde (6 mg). 1H NMR (400 MHz, CDCl3) (ppm) 11.90 (s, 1H), 10.36 (s, 1H), 7.79 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.32 (t, J=8.8 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 4.46 (m, 1H), 4.13 (dt, J=11.2, 4.0 Hz, 1H), 3.95 (dd, J=11.2, 3.2 Hz, 1H), 3.81 (dd, J=11.6, 3.2 Hz, 1H), 3.73 (dd, J=9.2, 5.6 Hz, 1H), 3.65 (dt, J=11.6, 3.2 Hz, 1H), 3.57 (t, J=8.8 Hz, 1H), 3.28 (d, J=4.0 Hz, 1H), 2.56 (m, 1H), 1.87 (m, 1H), 1.58 (m, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.29 (d, J=7.6 Hz, 3H); MS (ESI) m/z 334.3 [M+H]+.
Reaction SMILES: Cl.NC1C[C:10]2[C:5](=[CH:6][C:7]([Br:16])=[C:8]([NH2:15])[C:9]=2[N+:12]([O-:14])=[O:13])C1.[CH:17]([N:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH3:22])([CH3:19])C.CCOC(C)=O.CO>CN(C=O)C>[NH2:15][C:8]1[C:9]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5](=[CH:6][C:7]=1[Br:16])[CH2:24][CH:23]([N:20]1[CH2:17][CH2:19][CH2:22][CH2:21]1)[CH2:25]2
Reactant: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(N)C2
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(N1CCCC1)C2
Temperature: 70 °C
Yield: 30.7 %

Procedure:
A mixture of 2,5-diamino-6-bromo-4-nitroindane hydrochloride (1.5 g, 5 mmol), 1-4-dibromobutane (1.3 g, 6 mmol) and diisopropylethylamine (1.9 g, 15 mmol) in DMF (100 mL) was heated at 70° C. for 24 h. The solvent was evaporated and the residue taken up in methylene chloride:water. The aqueous layer was basified with 1N NaOH and back extracted. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a dark syrup. The purified product (0.5 g) was obtained from column chromatography (4:1 EtOAc:methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(P(CCCC)CCCC)CCC.[O:36]=[S:37]1(=[O:47])[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:45][CH2:44][CH2:43][N:40]4[CH2:39][CH2:38][S:37](=[O:47])(=[O:36])[CH2:42][CH2:41]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=S1(=O)CCN(CCCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (5.0 g, 15.6 mmol) was suspended in dichloromethane (150 ml) and tributylphosphine (11.1 ml, 44.6 mmol) was added followed by stirring at ambient temperature for 30 minutes. To this mixture was added 3-(1,1-dioxothiomorpholino)-1-propanol (4.2 g, 21.8 mmol) followed by the addition of 1,1′-(azodicarbonyl)dipiperidine (11.7 g, 46.4 mmol) in portions. The mixture was stirred at ambient temperature overnight then diluted with ether (300 ml) and the precipitate was removed by filtration. The residue was chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give a solid which was triturated with ethyl acetate filtered and dried to give 4-(4-chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (5.4 g, 70%).
Reaction SMILES: Br[C:2]1[C:3]2[CH:4]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][CH:5]3[N:6](C(OC(C)(C)C)=O)[C:7]=2[CH:8]=[CH:9][CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].B(O)O.N#N.[CH3:43][N:44]([CH:46]=O)C>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>[N:44]1[C:43]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]=[C:4]([C:2]2[C:3]3[C@@H:4]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C@@H:5]4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3c(Br)cccc3N(C(=O)OC(C)(C)C)C2CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Product: c1cc2c(c(-c3cnc4ccccc4c3)c1)[C@@H]1CCNCC[C@@H]1N2
Temperature: 80 °C
Yield: 73 %

Procedure:
A 30-mL shaker vial was charged with di(tert-butyl) 10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate (0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol), 3-quiniline boronic acid (0.111 g, 0.642 mmol), and DMF (2 mL). The vial was purged with N2, and tetrakis(triphenylphosphine)palladium (0.025 g, 0.02 mmol) was added and the mixture was agitated at 250 RPM with heating at 80° C. overnight. The mixture was filtered through Celite, washing with MeOH (3-5 mL), and sulfonic acid resin (DOWEX®50W-X2, washed and dried, 4.8 meq/g dry weight) was added (1 g). The vial was then purged with N2, capped and agitated at 250 RPM with heating at 65° C. for 72 h. The mixture was filtered through a scintered funnel and the resin was washed 1:1 methylene chloride/methanol and then consecutively washed with MeOH and THF and 2M pyridine/MeOH to ensure that all excess reagent was removed from the resin (the methanol and THF washes are alternated to swell and then shrink the resin to help expel reagents from inside the resin). The resin was then washed with 4M ammonium hydroxide in methanol (4×2 ml) and THF (2×2 ml) into an accurately weight round-bottomed flask. The filtrate was concentrated to give 0.049 g (73%) of an amber oil: MS (EI) m/z 316 (MH+); HPLC rt=2.67 min (85%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NCCCO
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NCCCO)n2n1)c1cccnc1
Temperature: 120 °C
Yield: 41.3 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and 3-amino-1-propanol (56 μL; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as an off-white solid (22 mg, 40%). HPLC, Rt: 2.05 min. (purity 96.2%). LC/MS, M+(ESI): 380.8, M−(ESI): 378.9.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[O:11][C:10]([CH3:12])=[N:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:3]([OH:5])=[O:4].C([O-])(=O)C.[Na+]>C(O)C>[CH3:12][C:10]1[O:11][C:7]([CH2:6][CH2:2][C:3]([OH:5])=[O:4])=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])[N:9]=1
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)c(CC(Cl)C(=O)O)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccccc2C(F)(F)F)c(CCC(=O)O)o1
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-3-[2-methyl-4-(2-trifluoromethylphenyl)-5-oxazolyl]propionic acid (2.5 g), sodium acetate (0.62 g), 80% ethanol (50 ml) and 10% paladium-carbon (1.0 g) was subjected to catalytic hydrogenation for 8 hours and then the catalyst was filtered off. The filtrate was concentrated, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and iso-propyl ether was added to the residue to give crystals of 2-methyl-4-(2-trifluoromethylphenyl)oxazole-5-propionic acid, yield 1.85 g (82.6%). Recrystallization from ether gave colorless prisms. yield 1.45 g (64.7%), m.p. 118°-119° C.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[N:23][N:22]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:26]([C:24]1[S:25][C:21]([C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[Cl:13])=[N:22][N:23]=1)(=[O:28])=[O:27])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=S(=O)(Cl)c1nnc(-c2cc(Cl)ccc2Cl)s1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2cc(Cl)ccc2Cl)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(2,5-Dichlorophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.27 (s, 1H), 7.80 (d, 1H), 7.75 (d, 1H), 4.03 (q, 2H), 3.35 (s, 2H), 3.21 (t, 2H), 2.71 (t, 2H), 1.15 (t, 3H).