Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]([C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:21]([C:18]3[CH:19]=[N:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)(=[O:22])=[O:23])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: Nc1cc(F)cc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2cc(F)cc3cccnc23)cn1
Yield: 26.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-ylamine (Intermediate 48) (125 mg, 0.77 mmol), 6-cyano-pyridine-3-sulfonyl chloride (Intermediate 19) (187 mg, 0.92 mmol), pyridine (121 mg, 1.54 mmol), DMAP (cat.) and DCM (10 ml) gave the title compound (67 mg, 26%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [CH2:1]([N:8]1[CH2:42][CH2:41][C:11]2([N:15]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:14](=[O:33])[N:13]=[C:12]2[NH:34][CH2:35][CH:36](OC)OC)[CH2:10][CH:9]1[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:42][CH2:41][C:11]2([C:12]3=[N:34][CH:35]=[CH:36][N:13]3[C:14](=[O:33])[N:15]2[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=2)[CH2:10][CH:9]1[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CNC1=NC(=O)N(c2cc(F)ccc2-c2ccc(S(C)(=O)=O)cc2)C12CCN(Cc1ccccc1)C(C)C2)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CC2(CCN1Cc1ccccc1)c1nccn1C(=O)N2c1cc(F)ccc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 110 °C

Procedure:
To a solution of 8-benzyl-4-[(2,2-dimethoxyethyl)amino]-1-[4-fluoro-4′-(methylsulfonyl)biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (50 mg, 0.08 mmol) in toluene (2.0 ml) was added p-toluenesulfonic acid (20 mg, 0.01 mmol). The reaction was sealed and allowed to stir at 110° C. The reaction was purified via reverse phase chromatography and neutralized with sodium bicarbonate. The product was extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound as cis and trans mixture-1′-benzyl-6-[4-fluoro-4′-(methylsulfonyl)biphenyl-2-yl]-2′-methylspiro[imidazo[1,5-a]imidazole-7,4′-piperidin]-5(6H)-one. LCMS (M+H) 544.9. 1H NMR (400 MHz, CD3OD) δ 7.98 (m, 1H), 7.89 (m, 1H), 7.66 (m, 3H), 7.55 (m, 1H), 7.46 (m, 1H), 7.40 (dt, J=8.8, 2.8 Hz, 0.5H), 7.32 (dt, J=9.2, 2.8 Hz, 0.5H), 7.22 (m, 5H), 6.91 (m, 0.5H), 6.79 (m, 0.5H), 4.10 (m, 1H), 3.12 (s, 1.5H), 3.06 (s, 1.5H), 3.02 (s, 1H), 2.81 (m, 1H), 2.71-2.40 (m, 2H), 2.04-1.85 (m, 1H), 1.78-1.57 (m, 3H), 1.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.Cl>CC(O)C>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)c1ccccc1N
Agent: Cl
Solvent: CC(C)O
Product: NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 60 °C

Procedure:
A mixture of 2-aminobenzamide (681 mg, 5.0 mmol), 2,4,5-trichloropyrimidine (2.75 g, 15 mmol, 3 equiv.) and concentrated HCl (aq) (1.72 mL, 20 mmol, 4 equiv.) in 2-propanol (100 mL) is heated at 60° C. for 12 h. The 2-propanol solvent is removed in vacuo. The resulting residue is neutralized to approximately pH=7 by adding 1 N NaOH (aq) followed by partition between EtOAc and water. Upon partition between EtOAc and water, a significant amount of precipitate is produced. This precipitate is collected by vacuum filtration and washed with small amounts of EtOAc and water, providing the product 2-(2,5-dichloropyrimidin-4-ylamino)benzamide; ESMS m/z 283.0 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH:29][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:3]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CO
Product: COc1ccc(CCNc2nc(N3CCOCC3)c3nc[nH]c3n2)cc1OC
Temperature: 192.5 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
As shown in Scheme 3 above, a mixture of 2,6-dichloropurine (1.90 g, 10 mmol) and morpholine (2.34 g, 30 mmol) in water (25 mL) was heated under reflux for 15 min. Solidified reaction mixture was cooled to room temperature. Solid was filtered out and washed with water, methanol and ether. The 2-chloro-6-morpholin-4-yl-9H-purine was obtained in 96% yield (2.30 g). A mixture of 2-chloro-6-morpholin-4-yl-9H-purine (1.92 g, 8 mmol) and 2-(3,4-dimethoxyphenyl)ethylamine (4.35 g, 24 mmol) in sealed tube and under nitrogen was stirred at 190-195° C. for 1 hour. The reaction mixture turned to clear solution initially and then formed a slurry. The reaction mixture was cooled to room temperature diluted with methanol (8 mL) and the solid was collected by filtration, washed with methanol and Et2O and dried to afford 2.30 g (74% yield) of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl)amine.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([C:9]([NH2:11])=[O:10])[C:6]([NH2:8])=[NH:7].Cl.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=O>C(O)C>[NH2:7][C:6]1[NH:8][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:14][C:5]=1[C:9]([NH2:11])=[O:10]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: N=C(N)CC(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(Br)cc2)[nH]c1N
Reaction time: 0.33 h
Yield: 8.8 %

Procedure:
Under ice-cooling, sodium ethoxide (2.1 g, 30 mmol) was added to a suspension of malonamamidine hydrochloride (4.1 g, 30 mmol) in dehydrated ethanol (50 mL), and then the mixture was stirred for 20 minutes. Moreover, 2,4′-dibromoacetophenone (4.2 g, 15 mmol) was added thereto, and the whole was stirred at room temperature for 5 hours. After the insoluble solid was filtered out, the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography to give the title reference compound (0.37 g) as a black solid (Yield 9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3[NH2:25])[NH:18][N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:33]([C:35]1[O:36][C:37](=[O:60])[C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]3[O:55][C:54]([CH3:57])([CH3:56])[C:53]([CH3:59])([CH3:58])[O:52]3)[CH:46]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH3:34].Cl>CN(C=O)C.CCOC(C)=O>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:33]([C:35]3[O:36][C:37](=[O:60])[C:38]4[C:43]([C:44]=3[C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]5[O:52][C:53]([CH3:59])([CH3:58])[C:54]([CH3:57])([CH3:56])[O:55]5)[CH:46]=3)=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH3:34])[N:17]=[C:16]([C:11]3[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[C:24]=12
Reactant: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
In a 100 ml round bottomed flask 3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G18, 400 mg, 1,194 mmol) was dissolved in 7 ml of dry DMF then K2CO3 (254 mg, 1.837 mmol) was added. After stirring for 5 min a solution of 3-(1-bromoethyl)-4-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1H-isochromen-1-one (Intermediate C26, 420 mg, 0,918 mmol) in 7 ml of dry DMF was added and the clear brown mixture was heated at 60° C. for 30 min. The mixture was cooled to r.t. then 30 ml of HCl 0.5 M and 50 ml of EtOAc were added and stirred for 15 min. Phases were separated and the crude material was purified by chromatography eluting with DCM\MeOH (80/20) in DCM to give the title compound (820 mg) as a brown oil. This material was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH:31][NH:32][C:33]([NH2:35])=[O:34])=O)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@@:10]([CH3:27])([CH2:28][C:29]3[NH:35][C:33](=[O:34])[NH:32][N:31]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(=O)NNC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2n[nH]c(=O)[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
259 mg (0.50 mmol) of 2-(2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetyl)hydrazinecarboxamide (Example 76, Step A) was suspended in 2 N aqueous sodium hydroxide (16 mL) and heated at reflux for 3.25 h. Upon cooling to room temperature, the mixture was acidified with conc. HCl until strongly acidic and then extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 75% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19][S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH2:13]3)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19][S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH2:13]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc([N+](=O)[O-])c3)cc2C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N)c3)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
A solution of Intermediate 3 (430 mg, 1.19 mmol) in ethanol (10 ml) was treated with 10% palladium on charcoal (paste) (100 mg), and then stirred under an atmosphere of hydrogen at room temperature and pressure for 24 h. The mixture was filtered through a bed of kieselguhr and washed through with ethanol. The filtrate was removed under reduced pressure to give the title compound as a colourless solid (320 mg, 81%); mass spectrum: (ES−): Found 329 (MH−); C18H22N2O2S requires 330; 1H-NMR (400 MHz, CDCl3) δ 1.36 (6H, m), 2.94 (2H, m), 3.17 (1H, m), 3.35 (2H, m), 3.77 (2H, bs), 4.31 (2H, m), 6.67 (1H, m), 6.87 (1H, m), 6.95 (1H, m), 7.22 (2H, m), 7.39 (2H, m).
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.N1C=CC=CC=1.Cl>O>[CH3:1][NH:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1
Reactant: C1CNCCN1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Yield: 74.3 %

Procedure:
A mixture of 1.95 g of 1-methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 3.05 g of anhydrous piperazine and 20 ml of dry pyridine is refluxed for 6 hours. The solvent is stripped off in vacuo, the residue is taken up in 20 ml of water, the pH is brought to 7-8 with half-concentrated hydrochloric acid, with cooling, and the precipitate is filtered off with suction, washed with ice-water and dried at 100° C. in vacuo. 1.8 g of 1-methylamino-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 276°-278° C. are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].[CH2:9](Br)[CH:10]=[CH2:11]>CC(C)=O>[CH2:11]([O:7][CH2:6][CH2:5][N:4]([CH3:8])[CH3:3])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOCCN(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (17.5 g) and dimethyl formaldehyde (400 mL) were added to a 2-L round-bottom flask. After cooling the flask to 0° C. by immersing in an ice bath, 2-dimethylaminoethanol (0.398 mol) was added. After stirring for about 30 minutes and adding allyl bromide (0.4378 mol), the mixture was stirred for 3 hours after raising the temperature of the reactor to room temperature. Upon completion of reaction, the reaction was terminated by adding water to the flask and the product was extracted using diethyl ether. The extract was concentrated under reduced pressure and used in the next step without further purification. After filtration under reduced pressure, 2-(allyloxy)-N,N-dimethylethanamine was obtained through fractional distillation. Structural analysis was performed by NMR spectroscopy.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[O:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=O)[CH2:16][CH2:15]1>O1CCCC1>[O:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[CH:3][C:1]#[N:2])[CH2:16][CH2:15]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CCOc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Diethyl cyanomethylphosphonate (1.15 eq.) is slowly added to a suspension of sodium hydride (1.15 eq.) in anhydrous tetrahydrofuran at 0° C. The reaction medium is stirred for 10 minutes at 0° C. and then cooled to −78° C. 4-Chromanone dissolved in tetrahydrofuran is added. The temperature is then returned slowly to 20-25° C. over 2 hours 30. After removal of the solvent, the compounds are extracted with ethyl acetate. The organic phase is washed with a large amount of a saturated solution of sodium chloride, concentrated and purified (Z/E mixture) on a silica column (AcOEt/PE 3/7).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:42]=[CH:41][C:13]([C:14]([NH:16][S:17]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC(Cl)(Cl)Cl)=[O:32])=[C:22]([CH3:39])[C:21]=2[CH3:40])(=[O:19])=[O:18])=[NH:15])=[CH:12][CH:11]=1)=[O:5])[CH3:2].O>[Zn].CC(O)=O>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:42]=[CH:41][C:13]([C:14]([NH:16][S:17]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:22]([CH3:39])[C:21]=2[CH3:40])(=[O:19])=[O:18])=[NH:15])=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C(=N)NS(=O)(=O)c2c(C)cc(OCCCC(=O)OCC(Cl)(Cl)Cl)c(C)c2C)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(C(=N)NS(=O)(=O)c2c(C)cc(OCCCC(=O)O)c(C)c2C)cc1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 32.6 %

Procedure:
Zn powder (0.32 g) was added to a mixture of 4-ethoxycarbonylpropoxy-N-{4-[3-(2,2,2-trichloroethoxycarbonyl)propoxy]-2,3,6-trimethylbenzenesulfonyl}benzamidine (0.65 g), water (2 ml), and AcOH (18 ml) under ice-water cooling. The reaction mixture was stirred at room temperature for 3.25 hours, and then evaporated. The resulting precipitate was removed by filtration, and was washed with AcOEt and isopropyl ether (IPE). The filtrate, AcOEt, and IPE were combined, and then washed with water. The organic phase was dried over MgSO4, and evaporated. The resulting residue was purified by chromatography over silica gel (CHCl3-MeOH as eluent) to give 4-ethoxycarbonylpropoxy-N-[4-(3-carboxypropoxy)-2,3,6-trimethylbenzenesulfonyl]benzamidine (0.17 g) as an oil compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][OH:33]>C(#N)C>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]([CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:31][CH2:32][OH:33])[CH2:11][CH2:12]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N(CC1CCN(CCO)CC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 56 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (60 mg, 0.184 mmol) in acetonitrile (10 mL) was added potassium carbonate (76 mg, 0.552 mmol) followed by 2-bromoethanol (29.9 mg, 0.239 mmol). The reaction mixture was heated in the seal tube at 80° C. for 4 hours. The reaction mixture was then filtered and evaporated. 2,2,2-Trifluoro-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide (40 mg, 0.103 mmol, 55.8% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.07-7.37 (m, 5H), 3.75-3.87 (m, 2H), 3.57-3.66 (m, 1H), 3.49-3.57 (m, 1H), 3.46 (t, J=6.06 Hz, 1H), 3.36-3.41 (m, 3H), 3.19 (t, J=3.79 Hz, 1H), 2.78-3.04 (m, 2H), 2.56-2.76 (m, 1H), 2.48 (ddd, J=3.54, 6.51, 10.17 Hz, 1H), 1.96-2.15 (m, 1H), 1.87 (td, J=2.91, 10.80 Hz, 2H), 1.63 (dt, J=5.24, 10.23 Hz, 1H), 1.39-1.57 (m, 3H); LC-MS Rt=0.76 min; MS (ESI): 371.2 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([NH:44][C:13]([NH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:45]=[CH:46][CH:47]=1
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 53 %

Procedure:
The title compound was prepared as described in Example 159B, using phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from the previous step (0.139 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.116 g, 53%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (s, 1H), 8.55 (s, 1H), 7.54-7.62 (m, 7H), 7.39 (m, 2H), 7.19 (d, 1H), 6.96 (d, 1H), 6.86 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 551 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[C:19]([CH2:18][N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:20]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cc2c([nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC#N)CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A 125-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with ethyl 4,5,6,7-tetrahydro-1H-indole-2-carboxylate 104g (5.76 g, 29.8 mmol) and DMF (50 mL). The solution was cooled to 0° C. using an ice bath. Sodium hydride, NaH (60% dispersion in mineral oil, 1.43 g, 35.8 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. After that time, bromoacetonitrile (1.43 g, 35.8 mmol) was added. The mixture was stirred at room temperature for 14 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and water (450 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 55% yield (3.80 g) of 104h as a yellow semi-solid: 1H NMR (300 MHz, CDCl3) δ 6.66 (s, 1H), 5.29 (s, 2H), 4.28 (q, 2H, J=7.2 Hz), 2.62 (t, 2H, J=6.3 Hz), 2.49 (t, 2H, J=6.3 Hz), 1.92 (m, 2H), 1.75 (m, 2H), 1.33 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 233.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18]([O:21]C)[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:24])[CH2:10][CH2:9]1.[BrH:25]>C(O)(=O)C>[BrH:25].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18]([OH:21])[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:24])[CH2:10][CH2:9]1
Reactant: COc1cc2c(cc1F)CCN(C)C2C1(c2ccccc2Cl)CC1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCc2cc(F)c(O)cc2C1C1(c2ccccc2Cl)CC1

Procedure:
A mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (18.0 g) in acetic acid (150 ml) and 48% aqueous hydrobromic acid (150 ml) was heated under reflux under argon for 220 minutes. The solvent was removed in vacuo, and the residue dried by azeotropic distillation with propan-2-ol and crystallised from propan-2-ol to yield 1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (18.56 g), m.p. 240° C. (dec).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].Cl>CN(C=O)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1)#[N:22]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
Diethyl malonate (44.6ml, 293 mmol) was added dropwise over 1.5 hours to a suspension of sodium hydride (11.7 g of a 60% suspension in mineral oil, 293 mmol) in DMF under argon and the reaction mixture was stirred at ambient temperature for 30 minutes. The resulting solution was added dropwise over 1 hour to a solution of 2-chloro-5-cyano-1-nitrobenzene (24.3 g, 133 mmol) in DMF (75 ml) cooled with a dry ice/acetone bath. The temperature of the cooling bath was adjusted to prevent the freezing of the red reaction mixture. After the addition was completed, the reaction was left to rise to ambient temperature over 2 hours. The resulting red solution was poured slowly into a stirred mixture of ice (100 ml) and 1M hydrochloric acid (10 ml). The resulting yellow precipitate was collected by filtration, washed with water until the filtrate was at pH7.0 and then dried under vacuum to give diethyl (4-cyano-2-nitrophenyl)malonate (39.6 g, 97%).