Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[C:12]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:15]=[C:14]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:13]=1.O>O1CCCC1.CCCCCC>[C:1]([NH:5][C:12]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:15]=[C:14]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Reactant: CC(C)(C)N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)Nc1cc(N2CCCC2)nc(N2CCCC2)n1
Reaction time: 17 h

Procedure:
A mixture of 21.7 g of t-butylamine in 100 mL of tetrahydrofuran is cooled to about -40° and treated over about 15 min with 170 mL of 1.6M n-butyllithium in hexane. The mixture is warmed to 0° for 2 hr, then recooled to -40° and treated over 30 min with a mixture of 25 g of 4-chloro-2, 6-di-1-pyrrolidinylpyrimidine and 50 mL of tetrahydrofuran. The mixture is allowed to warm to 20°-25° and is stirred for 16-18 hr. Water (50 mL) is then added and the mixture is concentrated under reduced pressure. The residue is partitioned between methylene chloride and aqueous 10% sodium bicarbonate. The organic phase is washed with saline, dried over anhydrous sodium sulfate and concentrated. Chromatography (silica gel, 5% ethyl acetate/hexane) gives the title compound, NMR (CDCl3) 4.78, 4.25, 3.53-3.49, 3.40, 1.93-1.86 and 1.41 6.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](N(CC)C(C)C)(C)[CH3:29].BrCC>C1COCC1>[CH2:28]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:29]
Reactant: Clc1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(-c3ccccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 100 mg of 3-(S)-benzyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 3 equiv. of N,N-diisopropylethylamine were added followed by 2 equiv. of bromoethane. The reaction was be shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM and washed with 1N aqueous NaOH solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Treatment with 1 equiv. 2M HCl in dioxane and concentration in vacuo gave 16 mg of its hydrochloride salt. Yield 27%, ES MS (+) m/z 405
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:13])[CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[C:16](OC)([CH3:18])[CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:17][C:16]1([CH3:18])[O:13][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][O:12]1
Reactant: COC(C)(C)OC
Reactant: O=[N+]([O-])c1ccc(C(O)CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.8 %

Procedure:
A mixture of 1-(4-nitrophenyl)ethane-1,2-diol (7.0 g, 38.3 mmol), 2,2-dimethoxypropane (16 g, 153.2 mmol) and 4-methylbenzenesulfonic acid (2.6 g, 15.32 mmol) in acetone (100 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated and then dissolved in ethyl acetate (300 mL). The organic layer was separated, washed by water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to afford the title compound (4.0 g, 40%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:18])(=[O:17])[C:7]=2[CH:19]=1)#N.C(O)=[O:21]>O>[CH:5]1[C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:18])(=[O:17])[C:7]=2[CH:19]=[C:3]([CH:1]=[O:21])[CH:4]=1
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Reactant: O=CO
Solvent: O
Product: O=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Reaction time: 3 h

Procedure:
Mix 267 mg (1 mmole) 3-cyano-dibenzo[b,f]thiepin-5,5-dioxide with Raney allowy (500 mg) and a mixture of 4 ml formic acid and 1 ml water at the reflux temperature. After 3 hours, add 200 mg additional Raney alloy and heat for one hour to obtain complete reduction. Filter the reaction mixture while hot to remove the alloy, and wash with ethyl acetate to remove any occluded solvent. Wash the organic layer containing the product with water and with saturated sodium chloride solution. Separate the organic layer containing the product to produce a residue of a pale yellow oil, which crystallizes in a small volume of ethyl acetate, m.p. 167°-171° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](O)=[C:29]([F:34])[CH:28]=1)=[O:26]>>[F:34][C:29]1[CH:28]=[C:27]([C:25](=[O:26])[CH3:24])[CH:32]=[CH:31][C:30]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])[CH2:6][CH2:7]1
Reactant: CC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Product: CC(=O)c1ccc(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Yield: 21 %

Procedure:
Prepared in analogy to Example 4 from (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) and 3-fluoro-4-hydroxyacetophenone. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 21%). MS (m/e): 478.4 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]([CH2:14][F:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:17]O>>[CH3:17][O:4][C:3](=[O:5])[C:2]([NH2:1])([CH2:14][F:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: NC(CF)(Cc1ccc(O)cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)(CF)Cc1ccc(O)cc1
Temperature: 90 °C
Yield: 70 %

Procedure:
With ice cooling, a suspension of 2-amino-2-fluoromethyl-3-(4-hydroxyphenyl)propionic acid (10.0 g) in absolute methanol (400 ml, dried over magnesium) is saturated with HCl gas. After heating at 90° C. overnight, the solvent is removed under reduced pressure, and the residue is dried for 3 hours under the vacuum of an oil pump. After dissolving in absolute methanol (400 ml) and saturating with HCl gas, the mixture is heated at 90° C. overnight again. After evaporation of the solvent, the residue is dissolved in water and a solution of sodium carbonate is added with stirring until pH ~10. The suspension is extracted 3 times with ether; the combined ether extracts are filtered, washed carefully with water, dried (Na2SO4) and evaporated to give pure methyl-2-amino-2-fluoromethyl-3-(4-hydroxyphenyl)propionate (7.5 g, 70%) as white crystals, m.p. 130° C.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[CH2:3][C:2]([CH3:1])([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)[CH3:5]
Reactant: CNC
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Product: CN(C)CC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with dimethyl amine to provide the title compound: H1 NMR (400 MHz, CDCl3) 1.50 (s, 6H), 2.00 (s, 6H), 2.40 (s, 2H), 7.55 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21]C)=[O:20])[CH2:15][CH2:14]1)[C:7]([C:23]([F:26])([F:25])[F:24])=[CH:6]2.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)[C:7]([C:23]([F:26])([F:25])[F:24])=[CH:6]2
Reactant: COC(=O)C1CCN(c2nc3ccc(OC)cc3cc2C(F)(F)F)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)C1CCN(c2nc3ccc(O)cc3cc2C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 9.4 %

Procedure:
To a solution of methyl 1-(6-methoxy-3-(trifluoromethyl)quinolin-2-yl)piperidine-4-carboxylate (300 mg, 0.815 mmol) in DCM (5 mL) was added BBr3 (0.4 mL, 4.08 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 20 hours. Water (10 mL) was added to the mixture dropwise at 0° C. The mixture was concentrated in vacuo, then diluted with EtOAc (150 mL), filtered and concentrated in vacuo. Purification by prep-HPLC (0.1% TFA as additive) to give Compound 41 (26 mg, yield 9.4%) as a solid. 1H NMR (MeOD 400 MHz): δ 8.51 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.8 Hz, 1H), 7.21 (d, J=2.8 Hz, 1H), 3.55-3.49 (m, 2H), 3.13-3.02 (m, 2H), 2.58-2.49 (m, 1H), 2.09-2.00 (m, 2H), 1.93-1.82 (m, 2H). MS (ESI): m/z 340.7 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][C:37]1[C:38]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([F:36])[C:38]([CH2:46][CH2:47][N:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(CCN2CCOCC2)c(F)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(CCN2CCOCC2)c(F)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 47.8 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-fluoro-2-(methyloxy)-4-[2-(4-morpholinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (92 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and neutralized with 1 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography, followed by MeOH re-crystallization to give the title compound (61 mg, 0.086 mmol, 47%). 1H NMR (400 MHz, CDCl3) δ ppm 9.51 (d, J=6.97 Hz, 1H), 9.28 (s, 1H), 8.61 (d, J=2.20 Hz, 1H), 8.24-8.32 (m, 2H), 7.88 (dd, J=8.62, 2.38 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=8.80 Hz, 1H), 7.32-7.39 (m, 1H), 7.16-7.23 (m, 1H), 7.14 (d, J=8.80 Hz, 1H), 6.90-7.00 (m, 3H), 6.74 (d, J=6.60 Hz, 1H), 6.69 (d, J=5.13 Hz, 1H), 4.12 (s, 3H), 3.91 (s, 3H), 3.73-3.80 (m, 4H), 2.78-2.86 (m, 2H), 2.58-2.65 (m, 2H), 2.52-2.58 (m, 4H). MS (ESI): 710 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C[C:18]1([CH3:26])[O:23]C(=O)CC(=O)O1.[CH3:27][C:28]1[CH:32]=[C:31]([NH2:33])[NH:30][N:29]=1>CN1CCCC1=O>[CH3:27][C:28]1[NH:29][N:30]=[C:31]2[C:32]=1[C:2]1([CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:3]1)[CH2:26][C:18](=[O:23])[NH:33]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)C1
Solvent: CN1CCCC1=O
Product: Cc1[nH]nc2c1C1(CC[C@@H](C(=O)OCc3ccccc3)C1)CC(=O)N2
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To (R)-benzyl 3-oxocyclopentanecarboxylate (0.4 g, 1.833 mmol) were sequentially added N-methylpyrrolidone (3 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (0.264 g, 1.833 mmol) and 3-methyl-1H-pyrazol-5-amine (0.178 g, 1.833 mmol) at room temperature. The contents heated to 80° C. (oil bath temp.) for 75 min, and stirred at room temperature for additional 48 hours. The reaction mixture was partitioned between ethyl acetate (40 mL) and 1N hydrogen chloride (15 mL). The ethyl acetate layer was separated and sequentially washed with 1N sodium hydroxide (15 mL), brine (20 mL), dried over sodium sulfate, concentrated and subjected to preparative HPLC (Phenomex Luna AXIA 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the desired product were isolated and concentrated. The residue that was obtained was partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution. The dichloromethane layer was separated, dried over sodium sulfate and concentrated to yield a solid (33 mg, 0.097 mmol, 5.31%). It was used as such for the subsequent step without further purification. MS (ESI) m/z 340.16 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4]C=[CH:6][CH:7]=1.[CH2:8]([N:12]1[CH:16]=[C:15]([C:17]2[S:21][C:20]([C:22]([NH:24][C@@H:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)=[O:23])=[CH:19][CH:18]=2)[CH:14]=[N:13]1)[CH:9]([CH3:11])[CH3:10].[NH:30]1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)C1>>[CH3:10][CH:9]([CH3:11])[CH2:8][N:12]1[CH:16]=[C:15]([C:17]2[S:21][C:20]([C:22]([NH:24][C@@H:25]3[CH2:29][CH2:28][N:27]([C:7]4[CH:2]=[CH:3][N:4]=[N:30][CH:6]=4)[CH2:26]3)=[O:23])=[CH:19][CH:18]=2)[CH:14]=[N:13]1
Reactant: Brc1cccnc1
Reactant: CC(C)Cn1cc(-c2ccc(C(=O)N[C@@H]3CCNC3)s2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Product: CC(C)Cn1cc(-c2ccc(C(=O)N[C@@H]3CCN(c4ccnnc4)C3)s2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 4-bromopyridazine for 3-bromopyridine and (R)-5-(1-isobutyl-1H-pyrazol-4-yl)-N-(pyrrolidin-3-yl)thiophene-2-carboxamide for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.44 Hz, 6H) 1.90-2.39 (m, 3H) 3.38-3.75 (m, 4H) 3.92 (d, J=7.12 Hz, 2H) 4.43-4.71 (m, 1H) 6.62 (dd, J=6.44, 3.05 Hz, 1H) 7.19 (d, J=3.73 Hz, 1H) 7.71 (d, J=4.07 Hz, 1H) 7.79 (s, 1H) 8.13 (s, 1H) 8.55 (dd, J=8.99, 6.95 Hz, 2H) 8.64 (d, J=2.71 Hz, 1H); MS (ESI(+)) m/e 397 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)C1C=CC=CC=1)(C)C.[C:34]([O:38][C:39]([NH:41][NH2:42])=[O:40])([CH3:37])([CH3:36])[CH3:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:5]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:1]([N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[NH2:42])=[O:2])[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(C)N(c1ccccc1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a phosgene solution (20% solution in toluene) at 0° C. was added piperazine-1-carboxylic acid benzyl ester (0.385 mL, 1.996 mmol) and diisopropylphenyl amine (0.383 mL, 4.397 mmol) in 5 mL of CH2Cl2 dropwise. The resulting pale yellow mixture was stirred 2 h warming to room temperature under Ar. The phosgene solution was removed by vacuum distillation. 20 mL of anhydrous CH2Cl2 was added. The reaction vessel was cooled to 0° C. and hydrazinecarboxylic acid tert-butyl ester and diisopropylethyl amine (0.383 mL, 4.397 mmol) was added in one portion. The reaction was warmed to room temperature and stirred for 1 h. The reaction was quenched with 10 mL of saturated NaHCO3, diluted with 30 mL of EtOAc, then washed with 2×30 mL of saturated NH4Cl solution and 30 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated to provide 720 mg of 4-(N-tert-butoxycarbonyl-hydrazinocarbonyl)-piperazine-1-carboxylic acid benzyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].Cl.Cl[CH2:23][CH2:24][CH2:25][NH2:26].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C1(C)C=CC=CC=1.O>[C:34]([N:26]1[C:7]2[CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=3[C:8]=2[CH2:23][CH2:24][CH2:25]1)(=[O:36])[CH3:35]
Reactant: NCCCCl
Reactant: CC(=O)Cl
Reactant: O=C1Cc2ccc(Cl)cc2C(c2ccccc2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC2=C1CC(c1ccccc1)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 73.3 g (0.23 mol) of 6-chloro-3,4-dihydro-4-phenyl-2(1H)-naphthalenone in 1.5 l of toluene is treated with 32.4 g (0.58 mol) of potassium hydroxide and 83.7 g (0.64 mol) of 3-chloropropylamine hydrochloride and boiled on a water separator for 42 hours. After cooling to room temperature, there are added thereto 79 ml (0.56 mol) of triethylamine and dropwise 29.7 ml (0.42 mol) of acetyl chloride in 250 ml of toluene. The mixture is stirred for 1 hour, extracted with ethyl acetate/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography over silica gel with hexane-ethyl acetate (4:1) and then with hexane-ethyl acetate (1:1) and recrystallization from ethyl acetate gives 4-acetyl-8-chloro-1,2,3,4,5,6-hexahydro-6-phenylbenzo[f]quinoline as beige crystals with melting point 167°-168°.
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4](O)=[O:5].C1(C(Cl)(Cl)[Cl:18])C=CC=CC=1>>[Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)C(F)(F)C(F)(F)Br
Reactant: ClC(Cl)(Cl)c1ccccc1
Product: O=C(Cl)C(F)(F)C(F)(F)Br
Yield: 70.8 %

Procedure:
A mixture of 375.9 g (1.67 mol) of 3-bromotetrafluoropropionic acid, 10 g of ferric chloride, and 488.7 g (2.50 mol) of benzotrichloride was refluxed for 1.5 h, then crude product was removed, bp about 60°. Redistillation gave 287.9 g (71%) of 3-bromotetrafluoropropionyl chloride, bp 67°-68°. IR (CCl4): 5.53 (C=O). ##STR44##
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:31])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:30][C:26]1[CH:25]=[C:24]([C:22]2[CH2:21][C:20](=[O:31])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(Br)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2

Procedure:
) The title compound was prepared from the above described {2-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-5-methyl-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (3.50 g, 6.79 mmol) and TFA (20 mL) in DCM (60 mL) according to general procedure I step 2. Obtained as a light yellow solid (1.79 g, 64%). MS (ISP) 397.1 [(M+H)+] and 399.1 [(M+2+H)+]; mp 198-202° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1.Cl>O>[CH3:21][N:22]1[CH:26]=[C:25]([S:27]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=2)(=[O:29])=[O:28])[N:24]=[CH:23]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: NCCc1ccc(OCC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1cnc(S(=O)(=O)NCCc2ccc(OCC(=O)O)cc2)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
6.3 g (32 mmol) of 4-(2-aminoethyl)phenoxyacetic acid are added to a solution of 9.7 g (79 mmol) of potassium carbonate in 50 ml of water and the mixture is stirred for 5 minutes. A suspension of 5.8 g (32 mmol) of 1-methyl-4-imidazolesulfonyl chloride from Example C-1 in 20 ml of water is slowly added to this suspension. The mixture is heated to 80° C. and stirred at this temperature for 2 hours. After cooling to room temperature, the reaction solution is acidified to pH 4 using 2N hydrochloric acid. The precipitate deposited is separated off, washed several times with water and recrystallized from dilute acetic acid in order to give the title compound of melting point 203°-204° C.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:24][C:25]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1.[F:35][C:36]1([F:42])[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1>>[F:35][C:36]1([F:42])[CH2:41][CH2:40][CH2:39][N:38]([C:2]2[CH:34]=[CH:33][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:24][C:25]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=2)[CH2:37]1
Reactant: FC1(F)CCCNC1
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1)C(=O)O
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(N2CCCC(F)(F)C2)cc1)C(=O)O

Procedure:
The title compound was prepared using analogous conditions described in Example 152 using 2-((1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and 3,3-difluoropiperidine. MS (ESI): mass calcd. for C31H37F2N5O3, 565.2; m/z found, 566.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=9.0, 1H), 7.57-7.51 (m, 1H), 7.34 (d, J=2.1, 1H), 7.25 (dd, J=9.1, 2.3, 1H), 7.13 (d, J=8.7, 2H), 6.96 (d, J=8.8, 2H), 6.28 (d, J=2.2, 1H), 6.25 (d, J=2.2, OH), 5.65 (s, 2H), 5.07 (s, 2H), 3.84 (s, 3H), 3.40 (t, J=5.7, 4H), 3.27-3.23 (m, 2H), 2.08-1.96 (m, 2H), 1.89-1.68 (m, 6H), 0.90-0.83 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Br[CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:1]4[CH2:34][CH2:35][CH2:36][C:37]4=[O:38])[CH:3]=3)[C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: O=C(Cl)CCCBr
Reactant: COc1nn(-c2cccc(N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nn(-c2cccc(N3CCCC3=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 80 °C
Yield: 5.2 %

Procedure:
According to Scheme 9 Step 2: To a solution of 2-(3-aminophenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (100 mg, 0.27 mmol) (1 mL) and NEt3 (78 μL, 0.55 mmol) in DMF was added bromobutyryl chloride (36 μL, 0.30 mmol). The reaction mixture was heated at 80° C. for 4 hours then quenched with water and extracted with ethyl acetate. The organic layers were combined and successively washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified on a prepacked silica column (10 g) 8:2 cyclohexane/Ethyl acetate 80/20 to afford 4-(4-chlorobenzyl)-6-methoxy-2-(3-(2-oxopyrrolidin-1-yl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 4.145 as a white solid (6 mg, 5%).