Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH2:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]3[CH:15]=2)[CH2:28][CH2:29]1
Reactant: FC(F)(F)c1ccc2nc(CCl)cn2c1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2nc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)cn2c1
Yield: 77.4 %

Procedure:
A mixture of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (0.452 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.468 g), diisopropylethylamine (Aldrich; 0.299 g), and THF (4 mL) is stirred at reflux for 21 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue chromatographed on silica gel using methanol/dichloromethane (2.5/97.5) to give 0.64 g of 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine. The methanesulfonate salt is prepared by dissolving 2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine in ethyl acetate/hexane and adding methanesulfonic acid (0.143 g) dissolved in methanol. The mixture is concentrated under reduced pressure and the residue is crystallized from ethyl acetate to give 0.691 g of the title compound; mp 161-162° C.; MS m/z 428; IR (mineral oil) 1162, 1225, 1033, 1130, 1142, 1337 cm-1. 1H NMR (CDCl3) δ 2.78, 3.09, 3.83, 6.96, 7.18, 7.31, 7.35, 7.66, 7.68, 8.47.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([CH3:17])[CH:4]=1.C([OH:22])(C)(C)C.C(Cl)Cl.CC(=CC)C.[O-]Cl=O.[Na+]>O.CCOCC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][C:6]([C:7]([OH:22])=[O:8])=[C:5]([CH3:17])[CH:4]=1
Reactant: CC(C)(C)O
Reactant: COCCCOc1cc(C=O)c(C)cc1OC
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COCCCOc1cc(C(=O)O)c(C)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 4-methoxy-5-(3-methoxy-propoxy)-2-methyl-benzaldehyde (1.25 g, 5.25 mmol) in a 3:1 mixture of tert-butanol/CH2Cl2 (60 mL) is added 2-methyl-2-butene (25.0 mL), followed by dropwise addition of a solution of NaClO2 (5.81 g, 51.4 mmol) and NaH2PO4 (4.07 g, 33.6 mmol) in water (45 mL) over 15 min at room temperature, and stirring is continued overnight. The reaction mixture is poured into ice/saturated aqueous NaHCO3 solution, the water phase is washed with AcOEt, then acidified and extracted with AcOEt. The combined organics are washed with brine, dried (Na2SO4) and concentrated to give a yellow solid. The crude product is stirred for 30 min in a 95:5 mixture of hexaneldiisopropyl ether (25 mL), the precipitate is filtered off, washed with a 95:5 mixture of hexane/diisopropyl ether and dried to give the title compound as yellowish solid. MS: 253.0 [M−H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.23 min. 1H-NMR (CDCl3): δ 1.96 (m, 2H), 2.51 (s, 3H), 3.27 (s, 3H), 3.48 (m, 2H), 3.84 (s, 3H), 4.00 (m, 2H), 6.89 (s, 1H), 7.41 (s, 1H) ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:22]=1[CH3:38].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:22]=3[CH3:38])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (143 mg, 0.543 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (148 mg, 0.54 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (140 μL, 0.54 mmol), and NMP (780 μL, 8.1 mmol). The reaction was heated in a microwave at 160° C. for three h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dd, J=4.3, 0.8 Hz), 7.93 (3H, d, J=5.5 Hz), 7.86 (1H, br. s.), 7.60-7.69 (1H, m), 7.38-7.46 (1H, m), 7.29-7.36 (2H, m), 6.31 (1H, br. s.), 3.91 (4H, br. s.), 3.68-3.81 (4H, m), 3.25 (4H, br. s.), 2.95 (4H, br. s.), 2.38 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>OCC(CO)O>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NCCN=C2c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: c1ccc(-c2nccnc2-c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 22 %

Procedure:
Next, 18.3 g (78.2 mmol) of 2,3-diphenyl-5,6-dihydropyrazine and 4.4 g of potassium hydroxide are added to 200 mL of dissolved glycerin, and stirring with heating is performed at 190° C. for 20 minutes. After cooling, extraction with ether is performed several times, the ether is removed, and purification by column chromatography is performed with the use of an ethyl acetate/hexane solvent. By removing the ethyl acetate/hexane solvent, a ligand Hdppr (2,3-diphenylpyrazine) is obtained (apricot-orange powder, yield: 22%). The reactions in the step 1 are shown by a formula (107).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:6]2[O:11][CH:10]=[CH:9][C:7]=2[N:8]=1.ClC1N=C(Cl)C2OC=CC=2N=1.N1CCNCC1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1.C(Cl)Cl>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:14][CH2:13]2)[C:6]2[O:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: Clc1nc(N2CCNCC2)c2occc2n1
Reactant: CS(=O)(=O)Cl
Agent: C1CNCCN1
Agent: Cl
Agent: Clc1nc(Cl)c2occc2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(c2nc(Cl)nc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a flask was added 2-chloro-4-(piperazin-1-yl)furo[3,2-d]pyrimidine, hydrochloride salt (0.325 g, 1.18 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [Ark Pharm] with piperazine), DCM (7 mL), pyridine (7.00 mL) and MsCl (0.101 mL, 1.29 mmol). The mixture was stirred overnight at rt. The mixture was warmed to about 35° C. and stirred for about 5 h. The solvent was removed in vacuo and the residue dissolved in DCM (20 mL). The organics were washed with water (about 20 mL) and with saturated aqueous NaHCO3 (about 20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with an elution gradient EtOAc/hexanes (50 to 75%) to give 2-chloro-4-(4-(methylsulfonyl)piperazin-1-yl)furo[3,2-d]pyrimidine (0.162 g, 43%): LC/MS (Table 2, Method a) Rt=1.11 min; MS m/z 317.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CN1CCCc2cc(N)ccc21
Product: CN1CCCc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc21

Procedure:
Using the procedure outlined in Example 25, the title compound was prepared from N-methyl-6-amino-1,2,3,4-tetrahydroquinoline (International Patent Application, Publication number WO 94/14801) (75 mg, 0.46 mmol) and 4-biphenylcarboxylic acid (140 mg, 0.71 mmol) as a yellow gum. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.03 (d, 2H), 7.6-7.8 (m, 5H), 7.4-7.55 (m, 3H), 7.2-7.35 (m, 2H), 6.59 (d, 1H), 3.21 (m, 2H), 2.89 (s, 3H), 2.79 (m, 2H), 1.99 (m, 2H).
Reaction SMILES: C([C:4]1[C:12]2[C:7](=[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]3=[CH:10][CH:11]=2)[N:6]([CH:17]2[CH2:22][CH:21]=[C:20]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:19]=[CH:18]2)[N:5]=1)(O)=O.[C:27](OCC)(=[O:29])C>>[CH3:27][O:29][C:14]1[CH:15]=[CH:16][C:8]2[C:9]([CH:13]=1)=[CH:10][CH:11]=[C:12]1[C:7]=2[N:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[N:5]=[CH:4]1
Reactant: CCOC(C)=O
Reactant: NS(=O)(=O)C1=CCC(n2nc(C(=O)O)c3ccc4ccccc4c32)C=C1
Product: COc1ccc2c(ccc3cnn(-c4ccc(S(N)(=O)=O)cc4)c32)c1
Temperature: 295 °C
Yield: 20 %

Procedure:
4,5-Dihydro-4- [3-(carboxy)-1H-benz[g]indazol-1-yl]benzenesulfonamide from Step 3 (1.00 g, 2.5 mmol) was placed in a round bottomed flask and heated to 295° C. for 0.5 hour. The residue was dissolved in a small amount of ethyl acetate and purified by flash chromatography, eluting with 40% ethyl acetate in hexane to give 4-[7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide as a white solid (200 mg, 20%): 1H NMR (CD3OD): 8.28 (1H, s), 8.18 (2H, d, J=8.66 Hz), 7.81 (1H, s), 7.77 (2H, d, J=8.66 Hz), 7.59 (1H, d, J=8.86 Hz), 7.52 (1H, d, J=9.27 Hz), 7.46 (1H, d, J=2.62 Hz), 7.0 (1H, dd, J=9.27, 2.62 Hz), 3.91 (3H, s) . Mass spectrum M+H =354. Elemental analysis Calc'd. for C18H15N3O3S: C, 61.18; H, 4.28; N, 11.89; S, 9.07. Found: C, 60.93; H, 4.23; N, 11.73; S, 8.93.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH3:8].[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([C@@H:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])[CH3:8])=[CH:17][CH:16]=3)=[O:15])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: C[C@@H](c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc([C@H](C)N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 80.8 %

Procedure:
Using (S)-4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)ethyl]benzoic acid (162 mg) described in Preparation Example 44 and 1-(3,5-dimethylpyridin-2-yl)piperazine (126 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (215 mg) was obtained.
Reaction SMILES: O=O.[C:3]1([NH:9][C:10](=S)[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH3:19].O>CC([O-])=O.CC([O-])=O.[Cu+2].CO>[C:3]1([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[NH:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CO
Solvent: O
Product: N=C(Nc1ccccc1)Nc1ccccc1
Yield: 94.2 %

Procedure:
Air is used as the oxygen-containing gas in the following example. 0.1 mol of diphenylthiourea, 1.2 mol of ammonia, and 0.02 mmol of Cu(OAc)2 are reacted with air (pressure of 5 bar) in a solvent mixture of 40 g of water and 40 g of methanol. Diphenylguanidine is obtained in a 94.2% yield at a reaction temperature of 50° C. and a reaction time of 70 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:28]([NH:30][C:31](=[N:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH:45]=1)OC1C=CC=CC=1)#[N:29]>>[C:28]([NH:30][C:31]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:25])=[N:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]2[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]2)[CH:45]=1)#[N:29]
Reactant: COc1ccc(CN(CCN(C)CCCCCCN)c2ccccn2)cc1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: COc1ccc(CN(CCN(C)CCCCCCNC(=NCCCOc2cccc(CN3CCCCC3)c2)NC#N)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.56 g (1.52 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=669 ([M+H]+, 5), 121 (100); IR (KBr): 2163 cm-1 (C≡N). For analytical purposes a sample is converted into the tartaric acid salt in an ether/ethanol solvent mixture; m.p.: 79° C. (ether/ethanol).
Reaction SMILES: CCCCC.[C:6]([Li])([CH3:9])([CH3:8])[CH3:7].[Cl:11][C:12]1[C:20]2[N:19]=[C:18]([NH:21][C:22]3[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=3[O:30][CH3:31])[N:17]([CH3:32])[C:16]=2[C:15]([C:33](OC)=[O:34])=[CH:14][CH:13]=1>C(OCC)C.O>[Cl:11][C:12]1[C:20]2[N:19]=[C:18]([NH:21][C:22]3[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=3[O:30][CH3:31])[N:17]([CH3:32])[C:16]=2[C:15]([C:33](=[O:34])[C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Reactant: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: CCOCC
Product: COc1cc(Cl)cc(C)c1Nc1nc2c(Cl)ccc(C(=O)C(C)(C)C)c2n1C
Reaction time: 1 h

Procedure:
A n-pentane solution of tert-butyl lithium (1.46 M, 0.5 ml) was added to a solution of methyl 4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate (100 mg, 0.23 mmol) in diethyl ether (5 mL) at −78° C. and stirred for 1 h. The reaction mixture was diluted with water (5 mL), stirred at room temperature for 0.5 h and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. The resultant was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 31 mg (0.073, mmol, 32%) of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:9]([CH2:10][NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][C:5]=1[O:17][CH3:18].[CH2:19]=O>[Pd].CO>[ClH:1].[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:9]([CH2:10][N:11]([CH3:19])[CH2:12]3)[C:8]=2[CH:7]=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: C=O
Reactant: COc1ccc2c(c1OC)CC[C@@H]1CNC[C@@H]21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1OC)CC[C@@H]1CN(C)C[C@@H]21
Yield: 75 %

Procedure:
A solution of the product of example 46, formalin (5 mL), NaOAc.3H2O (0.45 g), and MeOH (95 mL) in the presence of Pd/C catalyst (0.45 g, 5%, wet) was hydrogenated under 3 atmospheres H2 pressure. The resulting solution was filtered and evaporated to dryness. Water/1N KOH were added and the solution was extracted with ether. The combined extracts were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, evaporated, and converted to the HCl salt. The crude product was triturated with ether/MeOH, filtered, and dried to yield 0.70 g gray powder, (75%); mp 228°-30° C.; M+ 247.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[CH:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:24])[CH:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Yield: 38.8 %

Procedure:
8-Bromo-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (3.52 g, 9.16 mmol) and 26 mL of POCl3 were heated to 120° C. for 4 h. The bulk of the POCl3 was distilled (˜18 mL), and the reaction cooled. The solution was poured slowly onto warm water to get a gummy solid. The water was decanted and the solids washed with several portions of water. A final wash with toluene and drying under vacuum afforded 1.43 g of material (3.55 mmol, 38.8%). 1H NMR (300 MHz, DMSO): 9.58(s, 1H), 8.39(d, 1H, J=8.48 Hz), 8.15(d, 1H, J=7.67 Hz), 7.70(d, 1H, J=8.88 Hz), 7.66(d, 1H, J=2.42 Hz), 7.51(dd, 1H, J=8.48, 7.67 Hz), 7.44(d, 1H, J=8.88, 2.42 Hz), 6.90(s, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[C:12]2[C:21](=[O:36])[N:22](CC3C=CC(OC)=CC=3OC)[CH:23]([CH3:24])[C:11]=2[C:10]=1[F:37].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[C:12]2[C:21](=[O:36])[NH:22][CH:23]([CH3:24])[C:11]=2[C:10]=1[F:37].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: COc1ccc(CN2C(=O)c3c(-c4cnn(C)c4)nc(N[C@@H]4CCCC[C@@H]4N)c(F)c3C2C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CC1NC(=O)c2c(-c3cnn(C)c3)nc(N[C@@H]3CCCC[C@@H]3N)c(F)c21
Temperature: 60 °C

Procedure:
A mixture of 6-((1R,2S)-2-aminocyclohexylamino)-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (20 mg, 0.039 mmol) and TFA (1 mL) was heated at 60° C. for 2 h. Following reaction, the mixture was purified by preparative HPLC eluting with water (0.05% TFA) and ACN (15-25% gradient, 0.035% TFA) to give the title compound as a TFA salt (10 mg, 71%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.59 Hz, 3 H), 1.46 (d, J=7.02 Hz, 2 H), 1.60-1.84 (m, 5 H), 3.68 (br s, 1 H), 3.89 (s, 2 H), 4.44 (br s, 1 H), 4.71 (q, J=6.65 Hz, 1 H), 6.52 (br s, 1 H), 6.73 (d, J=6.53 Hz, 1 H), 7.72 (br s, 2 H), 8.24-8.32 (m, 1 H), 8.46 (s, 1 H), 8.82 (s, 1 H). [M+H] calc'd for C18H23FN6O, 359; found, 359.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH2:16][CH2:17][O:18][CH:19]=[CH2:20]>>[CH:19]([O:18][CH2:17][CH2:16][NH:15][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1)=[CH2:20]
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: C=COCCN
Product: C=COCCNC(C)Cc1cccc(C(F)(F)F)c1
Yield: 32 %

Procedure:
N-(2-vinyloxyethyl)-α-methyl-β-(3-trifluoromethylphenyl)-ethyl amine was prepared from 3-trifluoromethylphenylacetone and 2-aminoethylvinylether according to the method of Example 1. The product was obtained in 32% yield as a colorless oil, b.p. 81°-83°/0.5 mm; ND25 1.4650.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.Cl.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[C:34]([CH2:35][NH2:36])=[CH:33][C:32]([C:37]([F:40])([F:39])[F:38])=[N:31]2)[CH:27]=[CH:28][CH:29]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[C:34]([CH2:35][NH:36][C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([C:2]4([OH:1])[CH2:3][O:4][CH2:5]4)=[CH:11][CH:10]=3)=[O:21])=[CH:33][C:32]([C:37]([F:38])([F:39])[F:40])=[N:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Nc1ccc(C2(O)COC2)cc1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C2(O)COC2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of phenyl 4-(3-hydroxyoxetan-3-yl)phenylcarbamate (100 mg, 0.35 mmol, 1.0 eq) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (119.3 mg, 0.35 mmol, 1.0 eq) in DCM (10 mL) was added TEA (106 mg, 1.049 mmol, 3.0 eq) at RT and stirred at 40° C. overnight. The mixture was diluted with DCM (30 mL) and washed with water (10 mL), brine (10 mL) and dried over anhydrous Na2SO4 and concentrated. Crude product was purified by CC using MeOH/CHCl3 (1:9) to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(3-hydroxyoxetan-3-yl)phenyl)urea (100 mg; 61%) as a white solid (TLC system: MeOH/CHCl3 (1:9); Rf: 0.45).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:9]=3[CH:8]=2)=[N:3]1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:22]([O:16][C:15]1[C:9]2[CH:8]=[C:7]([C:4]3[O:5][CH2:6][C:2]([CH3:17])([CH3:1])[N:3]=3)[O:11][C:10]=2[CH:12]=[CH:13][CH:14]=1)[C@H:23]1[O:25][CH2:24]1
Reactant: CC1(C)COC(c2cc3c(O)cccc3o2)=N1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)COC(c2cc3c(OC[C@@H]4CO4)cccc3o2)=N1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4,4-dimethyloxazolin-2-yl)-4-hydroxybenzo(b)furan (1.50 g), (S)-glycidyl nosylate (1.68 g) and potassium carbonate (2.69 g), a crude product of the title compound was quantitatively obtained as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1F
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A mixture of 4-cyano-2-fluorobenzyl bromide (250 g, 1.17 mol), sarcosine tert-butyl ester hydrochloride (212.2 g, 1.17 mol) and potassium carbonate (484 g, 3.50 mol) in acetone (2 L) was stirred 24 hours at 50° C. and 18 hours at RT. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up with water (1 L) and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with water (1 L), dried (MgSO4) and concentrated under vacuum to give the title compound as a yellow-brown oil (325 g, quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 7.82 (dd, J=9.9, 1.4 Hz, 1H), 7.70 (dd, J=7.9, 1.5 Hz, 1H), 7.64 (m, 1H), 3.78 (s, 2H), 3.23 (s, 2H), 2.27 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 279.2 (M+H)+.
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]2)=[CH:7][CH:6]=1.Cl>O.O1CCOCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:20]([F:21])([F:22])[F:23])=[N:11]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
Add a solution of LiOH (122 mg, 5.03 mmol) in H2O (3 mL) to a stirred solution of ethyl 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (550 mg, 1.68 mmol) in 1,4-dioxane (10 mL). Stir overnight at ambient temperature. Acidify to pH 5 with 1 N HCl and extract with CH2Cl2 and 2× with 20% iPrOH in CHCl3. Dry the combined organic layers with MgSO4, filter and concentrate under reduced pressure to obtain 140 mg of the title compound as a white solid. Acidify the aqueous layer to pH 2-3 with 1 N HCl, and extract twice with 20% iPrOH in CHCl3. Dry the combined organics over MgSO4, filter, and add the solution to the initially obtained 140 mg white solids. Concentrate to afford the title compound as a white solid (426 mg, 85%). ES/MS m/z 299.0 (M−1).