Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl.O>[Cl:20][C:21]1[CH:28]=[C:27]([CH:26]=[CH:25][C:22]=1[C:23]#[N:24])[O:29][CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(C#N)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 33 mg, 0.092 mmol) in DMSO (1 mL) was added 2-chloro-4-hydroxybenzonitrile (114 mg, 0.092 mmol) and K2CO3 (25 mg, 0.18 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with DCM (10 mL) and water (20 mL). The organic layer was separated and the aqueous layer extracted with DCM (2×10 mL). The combined organic layers were filtered through a phase separation cartridge and reduced to dryness to give a yellow oil which was purified by reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:25]12([CH2:35][NH:36][C:7]([C:6]3[C:2]([Cl:1])=[N:3][N:4]([C:10]4[N:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[CH:5]=3)=[O:9])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.22 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.44 mmol), 1-adamantan-1-ylmethan-amine (36 mg, 0.22 mmol), and BOP (115 mg, 0.26 mmol) The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with CH2Cl2 (5 mL). The CH2Cl2 layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by silica gel column chromatography (gradient from 30% EtOAc/hexane to 60% EtOAc/hexane) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (1H, s), 8.91 (2H, d, J 4.8), 8.18 (1H, bs), 7.56 (1H, t, J 4.8), 2.92 (2H, d, J 5.6), 1.92 (3H, s), 1.60 (6H, m), 1.47 (6H, s). MS (M+1)=372.18; RT=1.35 min. *IC50.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15]C)=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc2c(c(C(=O)O)c1)CCCC2
Yield: 98.1 %

Procedure:
A solution of methyl 3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (0.96 g, 4.46 mmol) in THF (54 mL), water (21 mL) and 1N NaOH (9.4 mL, 9.4 mmol) was stirred overnight at room temperature. The THF was removed in vacuo and the mixture acidified to pH 1with 1N HCl. The resulting precipitate was extracted with EtOAc, dried (MgSO4), filtered and concentrated to give the title compound as a white solid (0.88 g, 98%). 1H NMR (DMSO) δ 13.33 (s, 1H), 7.96 (d, 1H), 7.29 (d, 1H), 3.99 (d, 2H), 2.81 (d, 2H), 1.72 (m, 4H); MS m/z 200.1 (M−H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[C:45]1([C:51]2[CH:52]=[C:53](O)[CH:54]=[CH:55][CH:56]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[C:45]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:50]=[CH:49][CH:48]=[C:47]([O:32][CH2:33][CH2:34][C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][C:38](=[O:44])[NH:39]3)[CH:46]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: O=C1Cc2c(CCO)cccc2N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1Cc2c(CCOc3cccc(-c4ccccc4)c3)cccc2N1
Reaction time: 0.25 h
Yield: 36.1 %

Procedure:
Diethyl azodicarboxylate (1.58 mL, 10 mmol) was added to a solution of triphenylphosphine (2.62 g, 10 mmol) in tetrahydrofuran (20 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (1.77 g, 10 mmol) followed by 3-phenylphenol (1.7 g, 10 mmol). The mixture was stirred at room temperature for one day and the solvent was evaporated. The residue was dissolved in ethyl acetate (150 mL) and the organic solvent was washed with 2 N hydrochloric acid (3×50 mL), saturated sodium bicarbonate solution and brine. The residue was chromatographed on silica gel eluting with ethyl acetate: hexane 2:8 to give 1.19 g (36%) of 4-[2-(biphenyl-3-yloxy)-ethyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][NH:9][C:10](=[NH:12])[NH2:11])=O)=[CH:4][CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[N:11]=[C:10]([NH2:12])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)NNC(=O)c1ccc(Cl)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1nc(-c2ccc(Cl)cc2)n[nH]1
Yield: 52 %

Procedure:
A solution of 2-(4-chlorobenzoyl)hydrazinecarboximidamide (2.1 g) in diphenylether (15 ml) was stirred for 10 min at 170° C. The reaction was then quenched by the addition of hexane (30 ml) and the product was collected by filtration, washed with hexane (3×10 ml) and dried in an oven under reduced pressure to give 3-(4-chlorophenyl)-1H-1,2,4-triazol-5-amine as a light yellow solid (1 g, 52%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[CH3:18])[O:3]1>CO>[CH3:18][C:10]1[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:19])([CH3:1])[O:3]2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:15]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Solvent: CO
Product: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 13 h
Yield: 109 %

Procedure:
A 500-mL round-bottomed flask equipped with a magnetic stirrer was charged with 4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (1n) (8.44 g; 32.1 mmol) and methanol (150 mL). The reaction flask was twice evacuated and back-filled with argon. 10% Palladium on charcoal (50% wet, 425 mg dry weight) was then added to the solution, and the reaction flask evacuated and back-filled with hydrogen three times. The reaction was then stirred under balloon pressure of hydrogen at room temperature for 13 h. After this time, the flask was twice evacuated and back-filled with argon, then filtered through a pad of Celite 521 and the filtrate concentrated in vacuo. The resulting residue was dried under high vacuum for 1 d to afford a quantitative yield (8.16 g) of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1o) as a white solid: mp 110-112° C.; MS (ESI+) m/z 234 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[N:19]=1.[CH3:25]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:25][C:2]1[C:3]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[N:19]=1
Reactant: CC(C)N(C)c1nc2c(nc1Br)CN(C(=O)OC(C)(C)C)CCO2
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nc2c(nc1N(C)C(C)C)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 90 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A mixture of tert-butyl 2-bromo-3-[methyl(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (200 mg), methylboronic acid (119 mg), tetrakis(triphenylphosphine)palladium(0) (58 mg), tripotassium phosphate (423 mg) and DME (3 mL) was stirred under an argon atmosphere at 90° C. for 16 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 3→40% ethyl acetate/hexane) to give the title compound (109 mg, 65%) as a pale-yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15][C:16]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:10][CH2:9]1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1nc(NC[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.2 g, 3 mmol) in 50% TFA in CH2Cl2 (20 mL) was stirred at ambient temperature. After 30 minutes, the mixture was concentrated and the residue was diluted with 1 M aqueous sodium hydroxide. The aqueous layer was extracted with CH2Cl2 (twice). The combined organic layer was dried over Na2SO4, filtered and concentrated to give cis-N2-(4-amino-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (0.88 g, 98%) as a white solid.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:33])[NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:36][CH2:37][CH2:38][CH2:39][OH:40]>CCCCCC.C(OCC)(=O)C>[OH:40][CH2:39][CH2:38][CH2:37][NH:36][C:5]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:33]
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)NCCCO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 65 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 3-amino-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 65%. Melting point: 145-146° C. (hexane-ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Se](=O)=[O:18]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)c1ccc(Br)cc1
Reactant: O=[Se]=O
Solvent: CC(=O)O
Product: O=C(C(=O)c1ccc(Br)cc1)c1ccncc1
Temperature: 135 °C
Yield: 47.5 %

Procedure:
A mixture of 200 mg (0.725 mmol) of l-(4-bromophenyl)-2-(4-pyridyl)-ethanone (from Step A) and 81 mg (0.725 mmol) of selenium(IV) oxide, and 5.5 mL of glacial acetic acid was heated to 135° C. for 2 h. After being cooled to room temperature, the reaction mixture was partitioned between saturated aqueous potassium carbonate and ethyl acetate. The aqueous layer was extracted twice more more with ethyl acetate. The organic layers were combined and washed with water and brine and dried over anhydrous sodium sulfate. Volatiles were removed under reduced pressure and the residue was flash chromatographed over silica gel (gradient elution 2-4% MeOH in DCM) to yield 100 mg of the titled compound, homogeous by TLC; mass spectrum (CI) m/e 290, 292 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[C@:13]([CH2:19][CH2:20][C:21](NC4SC=NN=4)=[O:22])([CH3:18])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[N:31]=[C:32]([NH2:36])[S:33][C:34]=1[CH3:35]>>[CH3:29][C:30]1[N:31]=[C:32]([NH:36][C:21](=[O:22])[CH2:20][CH2:19][C@:13]2([CH3:18])[C:14]([CH3:17])=[CH:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]=3[CH2:12]2)[S:33][C:34]=1[CH3:35]
Reactant: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CCC(=O)Nc1nncs1
Reactant: Cc1nc(N)sc1C
Product: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CCC(=O)Nc1nc(C)c(C)s1

Procedure:
The title compound was prepared in a manner analogous to the preparation of the title compound of Example 171, replacing 2-amino-1,3,4-thiadiazole with 4,5-dimethyl-2-aminothiazole. MS found: (M+H)+=425. 1H NMR (400 MHz, chloroform-D) δ ppm 1.20 (s, 3 H) 1.75-1.86 (m, J=8.65, 6.10 Hz, 1 H) 1.87-1.97 (m, 1 H) 1.91 (s, 3 H) 2.29 (s, 6 H) 2.50-2.57 (m, 2 H) 2.62 (d, J=16.28 Hz, 1 H) 2.80 (d, J=16.00 Hz, 1 H) 6.20 (s, 1 H) 7.19 (t, J=8.65 Hz, 2 H) 7.44 (dd, J=9.16, 4.58 Hz, 1 H) 7.51 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[O-])=[CH:4][C:3]=1[CH3:12].C([Li])(C)(C)C.CO[C:20]1[CH:25]=[CH:24][CH:23]=C[C:21]=1[C:26](=O)[C:27]([O:29]CC)=[O:28].[NH4+].[Cl-].C[CH2:36][O:37][CH2:38][CH3:39]>CCCCC.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[CH3:12])[NH:8][C:9](=[O:11])[C:21]2([CH2:26][C:27]([OH:29])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:39][C:38]=1[O:37][CH3:36]
Reactant: CCOCC
Reactant: Cc1cc(NC(=O)[O-])ccc1Cl
Reactant: CCOC(=O)C(=O)c1ccccc1OC
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccccc1C1(CC(=O)O)C(=O)Nc2cc(C)c(Cl)cc21
Temperature: -70 °C
Reaction time: 1 h

Procedure:
4-chloro-3-methylphenylcarbamate in 45 ml of ether is cooled to −70° C., under an argon atmosphere, 30 ml of 1.5M solution of tert-butyllithium in pentane are added dropwise, the mixture is stirred for 1 hour while allowing the temperature to rise to −10° C., and is stirred for 1 hour 45 minutes at −10° C. The reaction mixture is cooled to −70° C., a solution of 5 g of the compound obtained in step A in 25 ml of THF is added dropwise, the mixture is stirred for 1 hour and allowed to warm to −30° C., and is then stirred overnight while allowing the temperature to return to RT. Saturated NH4Cl solution is added to the reaction mixture, the THF is evaporated off, the resulting aqueous phase is extracted three times with EtOAc, the organic phase is washed with water, with saturated NaCl solution and dried over Na2SO4, the solvent is partially evaporated off and the crystalline product is filtered off by suction. 2.6 g of the expected product are obtained, m.p.=254–256° C.
Reaction SMILES: [NH4+:1].C([O-])(=O)C.ClC(Cl)(Cl)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[O:9].O>CS(C)=O>[Cl:33][C:29]1[CH:28]=[C:27]([C:26]2[C:12]3[C:11](=[CH:16][CH:15]=[C:14]([C:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:13]=3)[NH:10][C:8](=[O:9])[N:1]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: [NH4+]
Reactant: O=C(c1ccc(F)cc1)c1ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c2cccc(Cl)c2)c1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(F)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
Acetic acid, ammonium salt (0.135 mol) was added at room temperature to a mixture of intermediate 4 (0.0675 mol) in DMSO (300 ml). The mixture was stirred at 60° C. for 4 hours, then brought to room temperature and poured out into water. The precipitate was filtered, washed with water, taken up in warm CH3CN, filtered, washed again with CH3CN, then with diethyl ether and dried under a vacuo, yielding 18.5 g (72%) of intermediate 5. The mother layer was purified by column chromatography over silica gel (15-40 μm) (eluent DCM/MeOH:NH4OH 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1.8 g (7%) of 4-(3-chlorophenyl)-6-(4-fluorobenzoyl)-2(1H)-quinazolinone (intermediate 5), mp. 226° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[F:18][CH:19]([F:36])[C:20]1[N:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:25][C:21]=1[C:22](O)=[O:23].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:36][CH:19]([F:18])[C:20]1[N:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])=[CH:25][C:21]=1[C:22]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[O:23]
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Reactant: Nc1cccc2c(NCC(F)(F)F)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)Nc2cccc3c(NCC(F)(F)F)ncnc23)c1
Yield: 5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2,2,2-trifluoroethyl)quinazoline-4,8-diamine (Intermediate-65, 48 mg, 0.20 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 107 mg, 0.40 mmol), oxalyl chloride (50 mg, 0.40 mmol), DMF (1 drop) and DIPEA (127 mg, 0.99 mmol) in CH2Cl2 (2 mL) to afford 5 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.95 (t, 1H), 8.71 (d, 1H), 8.61 (s, 1H), 8.48 (t, 1H), 8.07 (m, 2H), 7.65 (t, 1H), 7.41-7.05 (t, J=54.0 Hz, 1H), 4.42 (m, 4H), 2.50 (m, 1H), 1.05 (d, J=7.2 Hz, 6H); MS [M+H]+: 497.52.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C.[N+](C1C=NC2C(C=1O)=CC=CC=2)([O-])=O>ClCCl.Cl.NCC1(O)CCCCC1>[N+:22]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[NH:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCC1(O)CCCCC1
Agent: Cl
Agent: O=[N+]([O-])c1cnc2ccccc2c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 105.3 %

Procedure:
A suspension of 1-aminomethyl-1-cyclohexanol hydrochloride (20.0 g, 121 mmol) and 4-chloro-3-nitroquinoline (24.0 g, 115 mmol) in dichloromethane (550 mL) was cooled to 0° C., and triethylamine (40 mL, 290 mmol) was added dropwise over a period of 30 minutes. The reaction was allowed to warm to room temperature over two hours. An analysis by HPLC indicated that the 4-chloro-3-nitroquinoline starting material actually contained some 3-nitroquinolin-4-ol, and additional pure 4-chloro-3-nitroquinoline (12.0 g, 57.5 mmol) was added. The reaction was stirred for four hours, and additional 1-aminomethyl-1-cyclohexanol hydrochloride (2.0 g, 12 mmol) was added, and the resulting suspension was stirred for three days. The solvent was removed under reduced pressure, and the residue was triturated in water for one hour and isolated by filtration. The resulting solid was triturated with hot dichloromethane and isolated by filtration from the hot mixture to provide 36.5 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol as a bright yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3[C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[O:44][CH3:45])=[N:34][O:35][C:36]=3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[CH:4][C:5]([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[C:3]([N:24]2[CH2:25][CH2:26][N:27]([C:30]([C:32]3[C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[O:44][CH3:45])=[N:34][O:35][C:36]=3[CH3:37])=[O:31])[CH2:28][CH2:29]2)=[CH:4][C:5]([NH:12][C:13](=[O:23])[C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=2)=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1NC(=O)c1ccc(N(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c(CO)cc2Cl)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of methyl 5-chloro-2-(4-(dimethylamino)benzamido)-4-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)benzoate (108 mg, 0.171 mmol) in MeOH (1 mL) and THF (3 mL) at room temperature was added sodium borohydride (32.3 mg, 0.854 mmol). The resulting reaction mixture was stirred at 40° C. for 2 hours. The product was purified by preparative HPLC(CH3CN/H2O-10 nM ammonium acetate) to give 90 mg (81% yield) of N-(4-Chloro-2-(hydroxymethyl)-5-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)phenyl)-4-(dimethylamino)benzamide. 1H-NMR (CDCl3, 400 MHz): δ 9.39 (1H, s), 8.03 (1H, s), 7.84 (2H, d, J=8.8 Hz), 7.58 (1H, dd, J1=7.5 Hz, J2=1.8 Hz), 7.52-7.45 (1H, m), 7.14 (1H, s), 7.11-6.99 (2H, m), 6.74 (2H, d, J=9.0 Hz), 4.71 (2H, s), 3.82 (3H, s), 3.77 (2H, s), 3.23 (2H, s), 2.97 (2H, s), 3.07 (6H, s), 2.57 (3H, s), 2.46 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=[O:14])[CH2:8][O:9][CH2:10]2)=[CH:5][CH:4]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18].C[O-].[Na+].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=[O:14])[CH:8]([C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])[O:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1F)COCC2=O
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1F)COC(C(=O)C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A solution of 7-methoxy-8-fluoro-isochroman-4-one from Step 2 (370 mg, 1.76 mmol) and ethyl trifluoroacetate (290 mg, 2.04 mmol) in 8 mL of anhydrous tetrahydrofuran was treated with a solution of 25% sodium methoxide in methanol (570 mg, 2.64 mmol). The solution was stirred at room temperature for 16 hours, treated with excess 3N hydrochloric acid, and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 450 mg (88%) of pure 7-methoxy-8-fluoro-3-(trifluoroacetyl)isochroman-4-one which was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([I:12])[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:13]>CC(O)C.O>[Br:1][C:2]1[N:3]=[C:4]([I:12])[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:13])[C:6]=12
Reactant: N
Reactant: Clc1nccn2c(I)nc(Br)c12
Solvent: O
Solvent: CC(C)O
Product: Nc1nccn2c(I)nc(Br)c12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-bromo-8-chloro-3-iodo-imidazo[1,5-a]pyrazine (250.00 mg, 0.696 mmol) in i-PrOH (8 mL) in a Parr bomb was added 7 mL ammonia in water (35%). The resulting solution was stirred at 95° C. overnight. The solvent was removed under reduced pressure and the crude material was passed through a short silica gel column (5% MeOH in DCM as eluent). The fractions were collected and combined, solvent was removed under reduced pressure to give a residue which was used in next step without further purification. MS (ES+): m/z: 338.80, 340.81 [MH+]. HPLC: tR=1.64 min (OpenLynx: polar—5 min).