Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[C:21]([CH2:24][C:25]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1)(O)=[O:22]>>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[N:1]1[C:21](=[O:22])[CH2:24][C:25]2([CH2:29][CH2:28][CH2:27][CH2:26]2)[C:30]1=[O:31]
Reactant: O=C(O)CC1(C(=O)O)CCCC1
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Product: O=C1CC2(CCCC2)C(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 200 °C

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.1 g, 0.37 mmol; prepared in a manner similar to that described in Example 23) and 1-(carboxymethyl)cyclopentane-1-carboxylic acid (0.064 g, 0.37 mmol) was heated at 200° C. in a sealed tube until the starting materials had been consumed (the reaction was followed by tlc using a 1:1 mixture of ethyl acetate and hexane as eluant). The warm mixture was poured into an ice/water mixture (10 ml) and the resulting solid was collected by filtration. The crude product was recrystallised from ethyl acetate/hexane (the hot solution required filtration to remove traces of undissolved solids) to give 2-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-azaspiro[4.4]nonane-1,3-dione (0.03 g) as an off-white solid, m.pt. 215–220° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.7–2.2 (m, 8H) (4× cyclopentyl CH2), 2.9 (s, 2H) (—COCH2—), 4.35 (s, 2H) (ArCH2—), 7.3–7.45 (m, 2H) (2×ArH), 7.5–7.6 (m, 1H) (ArH), 7.8–8.1 (m, 3H) (3×ArH), 8.3 (d, 1H) (ArH), 12.7 (s, 1H) (CONH); m/z (M+H)+. 406, 91.4% purity.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]=[C:6]2[S:5][C:4]=1[CH3:12])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([Br:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(#N)C>[Br-:35].[CH2:34]([N:11]1[CH2:10][CH2:9][CH2:8][N+:7]2[C:3]([CH2:1][CH3:2])=[C:4]([CH3:12])[S:5][C:6]1=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCC1=C(C)SC2=NCCCN21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCN1CCC[n+]2c1sc(C)c2CC
Product: [Br-]
Temperature: 0 °C
Yield: 18.9 %

Procedure:
3-Ethyl-2-methyl-6,7-dihydro-[5H]-thiazolo[3,2-a]pyrimidine (1.8 g., 0.01 mole) (prepared by basification of the hydrobromide salt with sodium carbonate) and cetyl bromide (3.3 g., 0.011 mole) were refluxed in acetonitrile solution for 16 hours. The solvent was evaporated and the residual oil solidified by stirring under dry ether at 0° C. Recrystallization from a mixture of acetonitrile and ether gave 8-cetyl-3-ethyl-2-methyl-6,7-dihydro[5H]thiazolo[3,2-a]pyrimidinium bromide, (0.92 g., 20%), m.p. 63°-66° (Found: C, 61.4; H, 9.6; N, 5.6. C25H47N2SBr requires C, 61.6; H, 9.7; N, 5.7%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[N+]([O-])(O)=O.[NH2:18][C:19]([NH2:21])=N.[OH-].[Na+].[CH2:24](O)CCC>>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[CH:4]=[CH:3][N:18]=[C:19]([NH2:21])[CH:24]=2)[CH:8]=1
Reactant: CCCCO
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: N=C(N)N
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: Nc1cc(-c2cccnc2)ccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
3-(Dimethylamino)-1-(pyridine-3-yl)prop-2-en-1-one (15.4 g, 0.088 mol), guanidine nitrate (10.7 g, 0.088 mol), and sodium hydroxide (3.5 g, 0.088 mol) were dissolved in n-butanol (120 mL). The mixture was heated to reflux with stirring and maintained for 16 hours. The reaction mixture was then cooled to room temperature. The solid was collected and washed with water (400 mL). The desired product was dried under vacuum for three days and 12.7 g of yellow crystals of desired product was obtained (yield: 85%); 1H NMR (500 MHz, CDCl3) δ 5.15 (br., 2H), 7.09 (d, 1H), 7.44 (m, 1H), 8.33 (d, 1H), 8.42 (d, 1H), 8.73 (d, 1H), 9.22 (s, 1H). LC-MS (m/z) calculated, 172.2. found 173.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>CC(O)=O>[O:17]=[C:8]1[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6](=[O:23])[C:5]2[C:10](=[CH:11][C:12]([C:13]([F:15])([F:16])[F:14])=[C:3]([CH2:2][N:1]3[CH:26]=[CH:30][CH:29]=[CH:28]3)[CH:4]=2)[NH:9]1
Reactant: COC1CCC(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(Cn3cccc3)cc2c1=O
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (100 mg, 0.28 mmol) in conc. CH3CO2H (8 mL) was added 2,5-dimethoxytetrahydrofurane (41.3 μL, 0.31 mmol) and the reaction mixture was stirred for 20 min at reflux temperature. Subsequently, the solvent was evaporated and the crude brown residue was recrystallized from EtOAc/cyclohexane to yield N-(2,4-dioxo-6-pyrrol-1-ylmethyl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (108 mg, 0.27 mmol, 95%) as a light-brown solid. 1H-NMR (DMSO-d6, 400 MHz) 3.12 ppm (s, 3H, SO2—CH3); LC-MS rt=3.757 nm; MS: m/z 402.9 [M+H]+Column: SunFireC18, 4.6*50 nm, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5].[CH:13]([NH2:16])([CH3:15])[CH3:14].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.CC(O)=O>[F:1][C:2]1[C:9]([CH2:10][NH:16][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: CC(C)N
Reactant: N#Cc1c(I)ccc(C=O)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NCc1ccc(I)c(C#N)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A solution of Example 220A (1.00 g, 3.6 mmol) in MeOH (15 mL) was treated with isopropylamine (0.31 mL, 3.6 mmol) and sodium cyanoborohydride (227 mg, 3.6 mmol), and the mixture was stirred overnight at rt. HOAc (1 mL) was added and the reaction was stirred for 5 h, then treated with 1N NaOH and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 8% MeOH/CH2Cl2 to give the desired product (372 mg). MS (ESI(+)) m/e 318.9 (M+H)+.
Reaction SMILES: C1COCC1.C(N(CC)CC)C.[CH2:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH:18]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:19]([OH:21])=[O:20]>O>[CH:14]1([C@@H:18]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][CH2:13]1
Reactant: Cc1ccc(C(C(=O)O)C2CCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc([C@@H](C(=O)O)C2CCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2.4 l of THF and 129.7 g (1.28 mol) of triethylamine are added, with stirring, to a suspension of 560 g (2.57 mol) of the compound from Example I in 4.8 l of water. The resulting solution is heated to 60° C., 155.4 g (1.28 mmol) of (S)-(-)-phenethylamine are added and the resulting suspension is stirred for 2 h at 60° C. The reaction mixture is cooled to 20° C., the precipitate is filtered off by suction, washed with 2.4 l of water/THF (2:1) and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH3:34])[C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:27])([F:1])[F:28])=[N:4][N:5]=4)[N:8]=3)[CH2:17][CH2:16]2)=[CH:19][CH:20]=1
Reactant: CNCCOC
Reactant: O=C(O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[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
Product: COCCN(C)C(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A mixture of 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid (79 mg, 0.20 mmol), N-(2-methoxyethyl)methylamine (21 mg, 0.24 mmol), DIPEA (0.105 mL, 0.61 mmol) and HATU (92 mg, 0.24 mmol) in DMA (3 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give N-(2-methoxyethyl)-N-methyl-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (77 mg, 82%) as a solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[F:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](Cl)=[O:51])=[CH:48][CH:47]=1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:50]([C:49]1[CH:53]=[CH:54][C:46]([F:45])=[CH:47][CH:48]=1)=[O:51]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)c3ccc(F)cc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and 4-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]=2[N:10]=[CH:9]1.[Cl:22][C:23]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:13]1[CH2:14][CH2:15][C:16]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH:9]=[N:10][C:11]=2[CH:12]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:26]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: CCOC(=O)C1NCCc2c1ncn2-c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A mixture of ethyl 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-4-carboxylate hydrochloride (0.050 g, 0.18 mmol), 2-chloro-3-trifluoromethyl benzoic acid (0.045 g, 0.20 mmol), HATU (0.077 g, 0.20 mmol), and DIPEA (0.035 mL, 0.20 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3×10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH (NH3):DCM) gave the title compound (26 mg, 30%). 1H NMR (500 MHz, CDCl3) δ 8.58-8.45 (m, 1H), 8.10-7.98 (m, 1H), 7.94-7.82 (m, 1H), 7.82-7.72 (m, 1H), 7.63 (dd, J=7.6, 1.3 Hz, 1H), 7.55-7.28 (m, 3H), 6.23 (dd, J=12.3, 6.3 Hz, 1H), 5.25-5.00 (m, 1H), 4.48-4.06 (m, 2H), 4.01-3.60 (m, 3H), 3.50-2.85 (m, 3H). MS (ESI): mass calculated for C22H18ClF3N4O3, 478.1. m/z found 479.2 [M+H]+.
Reaction SMILES: [Zn:1].[Br:2]C[C:4]1[CH:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[C:7](C2C=CC=CC=2)=[CH:8][CH:9]=1.ClC1C2C(=CC=CC=2)N=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)N=1>O1CCCC1>[Br-:2].[CH3:19][O:18][C:16]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][C:5]=1[C:34]1[CH:33]=[CH:32][C:31]([CH2:23][Zn+:1])=[CH:36][CH:35]=1)=[O:17]
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: COC(=O)c1cc(CBr)ccc1-c1ccccc1
Reactant: [Zn]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(C[Zn+])cc1
Product: [Br-]
Reaction time: 6 h

Procedure:
[[2'-(methoxycarbonyl)(1,1'-biphenyl)-4-yl]-methyl] zinc bromide was prepared in advance from 400 mg of zinc in 1 ml of tetrahydrofuran and 1.53 g of methyl 4-(bromomethyl)(1,1'-biphenyl)-2-carboxylate (KNOCHEL, J. Org. Chem., 1988, Vo. 53, p. 5789 to 5791) and 240.69 mg of 4-chloro-2-phenyl-quinazoline and 115 mg of palladium tetrakis(triphenyl-phosphine) complex were added to the solution. The mixture stood at 50° C. for 6 hours and the reaction medium was poured into a water/ice/acetic acid mixture. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with water and water saturated with sodium chloride, dried and evaporated. After chromatography on silica (eluant: ethyl acetate-hexane 1-9 then 2-8), 260 mg of expected product melting at 120° C. to 121° C. after crystallization from isopropyl ether were obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(OCC)(=O)C>[NH:1]1[C:5]2=[N+:6]([O-:18])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 0 °C

Procedure:
1H-pyrrolo[2,3-b]pyridine (2.8 g, 24 mmol) was dissolved in ethyl acetate (24 mL) and cooled to 0° C. A solution of 3-chloroperbenzoic acid (77%, 6.7 g, 30.1 mmol) in ethyl acetate (24 mL) was added drop-wise then the reaction mixture warmed to 25° C. over 16 h. The reaction mixture was cooled to 0° C., filtered, and the solids dried to give crude 1H-pyrrolo[2,3-b]pyridine 7-oxide, 3-chlorobenzoic acid complex (4.1 g, 58%) as an off-white solid. This was used directly in the next step without purification. LCMS (EI/CI) m/z: 135 [M+H].
Reaction SMILES: Cl[CH:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[CH:3]1[CH:11]=[O:12].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-:25].[K+].[K+]>>[F:9][CH:8]([F:10])[C:4]1[C:3]([C:11]([OH:12])=[O:25])=[C:2]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:22])([F:23])[F:13])[CH:16]=2)[N:6]([CH3:7])[N:5]=1
Reactant: O=C([O-])[O-]
Reactant: CN1N=C(C(F)F)C(C=O)C1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [K+]
Product: Cn1nc(C(F)F)c(C(=O)O)c1Oc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared using 5-chloro-3-(difluoromethyl)-1-methyl-4H-pyrazole-4-carbaldehyde and 3-trifluoromethylphenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.Cl.Cl.[NH2:27][C:28]1[CH:29]=[C:30]([CH:58]=[CH:59][CH:60]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:39]=[C:38]([CH2:40][O:41][C:42]3[CH:55]=[CH:54][C:45]([CH2:46][CH:47]4[S:51][C:50](=[O:52])[NH:49][C:48]4=[O:53])=[CH:44][CH:43]=3)[N:37]([CH3:56])[C:36]=2[CH:57]=1.C(N(CC)CC)C>CN(C)C=O>[O:52]=[C:50]1[NH:49][C:48](=[O:53])[CH:47]([CH2:46][C:45]2[CH:54]=[CH:55][C:42]([O:41][CH2:40][C:38]3[N:37]([CH3:56])[C:36]4[CH:57]=[C:32]([O:31][C:30]5[CH:29]=[C:28]([NH:27][C:1]([NH:20][CH2:19][C:18]6[CH:21]=[CH:22][C:15]([C:14]([F:23])([F:24])[F:13])=[CH:16][CH:17]=6)=[O:2])[CH:60]=[CH:59][CH:58]=5)[CH:33]=[CH:34][C:35]=4[N:39]=3)=[CH:43][CH:44]=2)[S:51]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)NCc4ccc(C(F)(F)F)cc4)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (130 mg) in anhydrous N,N-dimethylformamide (8 ml) was added 4-(trifluoromethyl)benzylamine (135 mg) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and triethylamine (153 mg) and the mixture was stirred at 60° C. for 1 hour and then allowed to stand at room temperature overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. The product insoluble in methanol was isolated by filtration and further purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=50:50→60:40 as the eluant to afford the title compound (102 mg, mp 127.9-132.4° C.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[CH2:14]([OH:16])[CH3:15].[CH2:17]=O>ClCCl>[CH2:14]([O:16][CH2:1][N:2]([CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:17])[CH3:15]
Reactant: CCO
Reactant: C=O
Reactant: CNCc1cccc2ccccc12
Solvent: ClCCl
Product: CCOCN(C)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21 g of N-methyl-1-naphthylmethylamine and 9 g of abs. ethanol are treated under ice-cooling in portions with 3.6 g of paraformaldehyde and the mixture stirred for 1 hour at room temperature. The reaction mixture is treated with dichloromethane, filtered and concentrated. The pure product is obtained as a pale yellow oil following vacuum distillation (1.3 mbar/135°-138°).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([C:30]([F:33])([F:32])[F:31])[N:19]=1)([CH3:17])([CH3:16])[CH3:15].[Br-].[Na+].C(N(CC)C(C)C)(C)C>CN(C)C=O>[ClH:1].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]3)[CH2:28][CH2:29]2)[CH:21]=[C:20]([C:30]([F:31])([F:32])[F:33])[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(N2CCN(CCCCn3ncc(=O)[nH]c3=O)CC2)cc(C(F)(F)F)n1
Product: Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
13.4 g of 2-(4-chloro-butyl)-2H-[1,2,4]triazine-3,5-dione (65.8 mmol) and 18.97 g of 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethyl-pyrimidine (65.8 mmol) were dissolved in 400 mL of dimethylformamide. After addition of 33.9 g of sodium bromide (329 mmol) and 115 mL of N,N-diisopropylethylamine (658 mmol), the reaction was stirred for 48 h at room temperature. Then the solvent was removed under reduced pressure and the obtained residue was trituated with 400 mL of ethyl acetate and the obtained solution was filtered. The filtrate was evaporated to dryness and the remaining oily residue was treated with 100 mL of diethyl ether, filtered and the filtrate was again evaporated to dryness. The crude product was purified three times via silica gel chromatography (ethyl acetate-methanol 0-100%; dichloromethane-methanol 0-5%; dichloro-methane-methanol 0-2%) to yield the free base of the title compound. This product was transferred into its hydrochloride salt via treatment with HCl/diethyl ether (yield 2.56 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([Cl:9])(C)[CH2:6][N:7]=1.[Cl:11][C:12]1[C:17]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.[C:24](#N)C>>[Cl:11][C:12]1[C:17]([S:18]([NH:21][C:22]([NH:1][C:2]2[N:7]=[C:6]([CH3:24])[C:5]([Cl:9])=[C:4]([CH3:10])[N:3]=2)=[O:23])(=[O:19])=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CC1=NC(N)=NCC1(C)Cl
Reactant: O=C=NS(=O)(=O)c1cccnc1Cl
Reactant: CC#N
Product: Cc1nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)nc(C)c1Cl

Procedure:
To a stirred suspension of 1.4 g of 2-amino-5-chloro-5,6-dimethylpyrimidine in 20 ml of dry acetonitrile at room temperature is added 2.2 g of 2-chloropyridine-3-sulfonylisocyanate. The mixture is stirred for several hours, evaporated to dryness and the residue is mixed with 30 ml of water and enough 10% sodium hydroxide to adjust the pH to 11. This mixture is filtered and the filtrate adjusted to pH 7 by the addition of 10% hydrochloric acid and then refiltered. Acidification of this filtrate to pH 2 causes the desired compound to precipitate. The desired compound is filtered off and dried.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][C@@H:34]([C:38]([OH:40])=O)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C.N1CCCC1>ClCCl>[N:13]1([C:38]([C@@H:34]2[O:35][CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:33]2)=[O:40])[CH2:14][CH2:15][CH2:16][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (1.47 g, 4.3 mmol) was added to a solution of (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1 g, 4.3 mmol) and diisopropylethylamine (1.11 g, 8.6 mmol) in anhydrous dichloromethane (20 mL) at room temperature. Pyrrolidine (0.45 mL, 5.62 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between water and dichloromethane. The organics were dried over sodium sulfate and concentrated under reduced pressure and the resulting residue was purified via column chromatography (100-200 mesh silica gel, 0-0.5% methanol in dichloromethane) to afford (R)-tert-butyl 2-(pyrrolidine-1-carbonyl)morpholine-4-carboxylate (0.62 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][CH2:15][CH3:16])[C:7]([CH2:17]O)=[CH:6]2.O=S(Cl)[Cl:21]>C(Cl)Cl>[ClH:21].[Cl:21][CH2:17][C:7]1[C:8]([NH:13][CH2:14][CH2:15][CH3:16])=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: CCCNc1nc2ccc(OC)cc2cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCNc1nc2ccc(OC)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a stirred solution of (6-methoxy-2-(propylamino)quinolin-3-yl)methanol SLA 28174 (1.45 g, 5.88 mmol) in dry CH2Cl2 (115 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (8.53 mL, 118 mmol). The mixture was stirred for 2 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times), to give 3-(chloromethyl)-6-methoxy-N-propylquinolin-2-amine hydrochloride SLA 28178 (1.28 g, 82% yield) as a yellow solid.