Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](\[NH2:7])/[CH3:6].N1C=CC=CC=1.[F:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH2:20][CH2:21][CH2:22][C:23]([NH:7]/[C:5](/[CH3:6])=[CH:4]\[C:3]([O:2][CH3:1])=[O:8])=[O:24]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C(Cl)CCCOc1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C(/C)NC(=O)CCCOc1cccc(F)c1
Yield: 27.5 %

Procedure:
To a solution of (Z)-methyl-3-aminobut-2-enoate (1.70 g, 14.8 mmol) and pyridine (1.20 g, 15.2 mmol) in DCM (25 mL) was added a solution of 4-(3-fluorophenoxy)butanoyl chloride (3.28 g, 15.1 mmol) in DCM (5 mL) with stirring and the mixture was stirred for 1 h. It was then washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (1.20 g, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[N:29][C:5]2[O:6][CH2:7][CH2:8][C@@H:9]3[C@@:14]([CH3:15])([C:4]=2[CH:3]=1)[N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]1([CH2:26][CH2:25][CH2:24]1)[S:10]3(=[O:28])=[O:27].[C:31]([C:33]1[CH:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1)#[N:32].O.[Cl-].C[NH+]1CCOCC1>C1COCC1.CO>[C:31]([C:33]1[CH:34]=[CH:35][C:36]([C:39]([NH:1][C:2]2[CH:30]=[N:29][C:5]3[O:6][CH2:7][CH2:8][C@@H:9]4[C@@:14]([CH3:15])([C:4]=3[CH:3]=2)[N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[C:11]2([CH2:26][CH2:25][CH2:24]2)[S:10]4(=[O:27])=[O:28])=[O:40])=[N:37][CH:38]=1)#[N:32]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)cnc3OCC[C@H]2S(=O)(=O)C12CCC2
Agent: C[NH+]1CCOCC1
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(NC(=O)c4ccc(C#N)cn4)cnc3OCC[C@H]2S(=O)(=O)C12CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl ((4a′R,11b′R)-10′-amino-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate (0.086 g, 0.197 mmol) in THF/MeOH (3/0.9 mL) was added 5-cyano-2-pyridinecarboxylic acid (0.035 g, 0.236 mmol) and 4-(4,)dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate, 99+% (0.070 g, 0.236 mmol) and the resulting mixture was stirred at rt for 1.5 h. The reaction was quenched with sat. NaHCO3 and extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel chromatography using a gradient 0-3% MeOH/DCM solvent system to afford a white solid as tert-butyl ((4a′R,11b′R)-10′-(5-cyanopicolinamido)-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate as a white solid. MS m/z=588.9 (M+Na).
Reaction SMILES: [CH:1]([Si:4]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[O:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:18]3[CH:19]=[C:20]([O:23][C@H:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C@@H:27]([NH2:34])[CH2:26][CH2:25]4)[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:10][CH2:9]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:44][C:45](=O)[NH:46][C:47]1[N:48]([C:56]2[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=2)[N:49]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:51]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:52]([C:50]1[CH:51]=[C:47]([NH:46][C:45]([NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]4[N:18]([C:14]([N:11]5[CH2:10][CH2:9][CH:8]([CH2:7][CH2:6][O:5][Si:4]([CH:35]([CH3:37])[CH3:36])([CH:1]([CH3:2])[CH3:3])[CH:38]([CH3:40])[CH3:39])[CH2:13][CH2:12]5)=[N:15][N:16]=4)[CH:19]=3)[CH2:25][CH2:26]2)=[O:44])[N:48]([C:56]2[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=2)[N:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CCO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Yield: 81 %

Procedure:
A mixture of Intermediate 66c (178 mg, 0.316 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 128 mg, 0.316 mmol) in 1,4-dioxane (3 mL) and DIPEA (83 μL, 0.474 mmol) was stirred at 95° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a brown foam (208 mg, 81%). LCMS (Method 3): Rt 5.96 min, m/z 819 [MH+].
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH3:17])[CH2:9]2.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:15][CH2:16][CH3:17])[CH2:9]2)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCCN(CCCCc1ccccc1)C1CCc2c(N)cccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCCCc1ccccc1)C1CCc2c(cccc2NC(C)=O)C1
Reaction time: 3 h

Procedure:
0.90 g (0.0022 mol) of 5-amino-2-[N-(4-phenylbutyl)-N-n-propyl-amino]-tetraline-dihydrochloride (Example 4.5.4) and 1.00 g (0.0099 mol) of triethylamine are mixed with 15 ml of absolute methylene chloride with stirring and cooling with ice and 0.20 g (2.55 mmol) of acetylchloride in 5 ml of absolute methylene chloride are added. After 3 hours at ambient temperature or 30 minutes refluxing, the mixture is extracted three times with 5 ml of water, dried with sodium sulphate and concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue is crystallised from diethylether/petroleum ether.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][C:8]1[CH:12]([CH:13]2[CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:11][C:10](=[O:21])[C:9]=1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30].CCN(CC)CC>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:20][O:19][N:16]1[CH2:17][CH2:18][CH:13]([CH:12]2[C:8]([O:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:9]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[C:10](=[O:21])[NH:11]2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)Cl
Reactant: CON1CCC(C2NC(=O)C(c3c(C)cc(C)cc3C)=C2O)CC1
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)NC1C1CCN(OC)CC1
Reaction time: 0.25 h

Procedure:
Ethyl chloroformate (216 mg, 2 mmol) was added dropwise to a mixture of 4-hydroxy-5-(1-methoxy-piperidin-4-yl)-3-(2,4,6-trimethyl-phenyl)-1,5-dihydro-pyrrol-2-one (400 mg, 1.2 mmol), Et3N (606 mg, 6 mmol) and DMAP (60 mg, 0.5 mmol) in acetone (20 ml). The mixture was stirred for 15 min and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel. Yield: 260 mg of carbonic acid ethyl ester 2-(1-methoxy-piperidin-4-yl)-5-oxo-4-(2,4,6-trimethyl-phenyl)-2,5-dihydro-1H-pyrrol-3-yl ester (title compound P1.12) as a solid, mp 154-155° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)(=[O:10])[CH3:9].C(OC(C)C)(C)C>C(O)=O>[CH3:16][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[C:19]([CH2:1][N:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:18]=1
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: CC(=O)Nc1ccc(C)cc1CN1CCNCC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of formic acid (3.77 mL) at −10° C. was treated with 1-methylpiperazine (11.10 mL) dropwise whilst maintaining the temperature at −10° C. The reaction mixture was then allowed to warm to room temperature and treated with 4-acetamidobenzaldehyde (4.08 g). After stirring at 130° C. for 15 minutes the temperature was increased to 155° C. and stirring continued for 2.5 hours. The reaction mixture was allowed to cool to room temperature and treated with diisopropyl ether (50 mL). The insoluble material was washed with diethyl ether to give the title compound (3.98 g) as buff crystalline solid, m.p. 106–108° C. MS: 248 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:21]([O:24]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[CH3:32][C@@H:33]1[NH:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[C:34]1=[O:48]>C(#N)C>[C:4]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:21]([N:38]2[CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][N:42]3[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]3)[C:34](=[O:48])[C@@H:33]2[CH3:32])=[O:24])[CH:3]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H]1NCCN(CCCN2CCCCC2)C1=O
Solvent: CC#N
Solvent: c1ccncc1
Product: C[C@H]1C(=O)N(CCCN2CCCCC2)CCN1C(=O)Nc1cccc(-c2ccccc2)c1
Yield: 176.3 %

Procedure:
A solution of 3-aminobiphenyl (21 mg, 0.13 mmol) and pyridine (11 mg, 0.14 mmol) in acetonitrile (0.5 ml) was added dropwise at 0° C. to a solution of bis-(trichloromethyl)-carbonate (14 mg, 47 μmol) in acetonitrile (0.5 ml). The reaction mixture was allowed to reach room temperature, then a solution of (S)-3-methyl-1-(3-piperidin-1-yl-propyl)-piperazin-2-one (30 mg, 0.13 mmol) in acetonitrile (0.5 ml) was added dropwise. After 30 min the reaction mixture was evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (36 mg, 66%). Colorless gum, MS (ISP)=435.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17](=[O:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[N:22][O:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17](=[O:28])[C:18]2[C:23]([C:24]([F:26])([F:25])[F:27])=[N:22][O:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:38]([CH3:37])=[CH:39][CH:40]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 11 (60 mg, 0.118 mmol) in CH2Cl2 (2.0 mL) stirred at room temperature was added 4-methyl-benzoyl chloride (24.1 mg, 0.153 mmol), followed by Et3N (18 mg, 0.117 mmol). The reaction mixture was stirred at room temperature for 1 h. More 4-methyl-benzoyl chloride (24 mg, 0.153 mmol), and Et3N (18 mg, 0.117 mmol) were added. After another hour, the reaction mixture was purified by SiO2 chromatography directly (EtOAc:heaxanes/1:4) to afford 12 (52 mg, 70%). MS (ESI): 628 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:11][CH3:12])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][Cl:14])=[CH:19][CH:20]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(=O)c1ccc2ocnc2c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2ocnc2c1
Yield: 16 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(benzo[d]oxazol-5-yl)propan-1-one (0.6 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.42 g, 1.5 eq) to give 0.23 g desired product (15%, Z/E=1/1) as a white solid.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S([O-])(=O)=O)=C[CH:2]=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[C:21]([OH:28])[CH:20]=1.C(OCC)(=O)C>COC(OC)(C)C>[F:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[NH:25][C:1]([CH3:6])([CH3:2])[O:28][C:21]=2[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: NC(=O)c1ccc(F)cc1O
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: COC(C)(C)OC
Product: CC1(C)NC(=O)c2ccc(F)cc2O1
Temperature: 83 °C
Yield: 701.1 %

Procedure:
Pyridinium toluene-4-sulfonate (49 mg, 0.19 mmol) was added to a mixture of 4-fluoro-2-hydroxybenzamide (0.3 g, 1.93 mmol) in 2,2-dimethoxypropane (5 mL) and heated at 83° C. for 20 hours. The reaction mixture was reduced in vacuo and ethyl acetate (30 mL) added. The mixture was washed with 10% potassium carbonate solution (2×20 mL), brine (20 mL), dried (MgSO4), and reduced in vacuo to give a white solid. The material was chromatographed on silica, eluting with 40-70% ethyl acetate in isohexane, to give the desired compound as a white solid (0.26 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[N:10]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[N:10]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)O)cc1
Reaction time: 0.75 h

Procedure:
A mixture of benzyl l-benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxylate (518 mg, 1.0 mmol) and 10% Pd/C (50 mg) in methanol (25 mL) is stirred under hydrogen atmosphere for 45 minutes. The mixture is filtered over celite and the filtrate is collected and concentrated under reduced pressure to give 1-benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxylic acid as a glassy solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33]>C(#N)C.CCOC(C)=O>[C:32]([O:35][CH2:36][C:37]([NH:14][C:13]1[C:12]2[C:7](=[N:8][C:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:10]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH:11]=2)[N:6]([CH3:30])[C:5](=[O:31])[C:4]=1[C:1](=[O:3])[CH3:2])=[O:38])(=[O:34])[CH3:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 90 °C

Procedure:
To the product of Example 2 (120 mg) in acetonitrile (2 mL) was added acetoxyacetyl chloride (0.2 mL). The reaction was heated to 90° C. in a CEM microwave reactor for a total of 34 minutes. The reaction was diluted with EtOAc and was washed with saturated aqueous NaHCO3 solution. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-60% EtOAc in hexane affording the title compound. HPLC/MS: 572.1 (M+1), 574.1 (M+3); Rt=4.06 min.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH:24]=[N:23][N:22]=[C:21]2[C@H:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH:24]=[N:23][N:22]=[C:21]2[C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=2)=[O:3])=[CH:17][CH:16]=1
Reactant: Clc1ccc(Cn2cnnc2[C@H]2CCCN2)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirring solution of 1-isocyanato-4-(trifluoromethyl)benzene (46.3 mg, 0.2474 mmol) in 8 mL of CH2Cl2 at 0° C. was slowly added a solution of (R)-4-(4-chlorobenzyl)-3-(pyrrolidin-2-yl)-4H-1,2,4-triazole (0.050 g, 0.1903 mmol) in dichloromethane (2 mL). The resulting mixture was stirred 0° C. for 30 minutes, then at room temperature overnight. The reaction mixture was concentrated in vacuo. Flash chromatography purification ((Hex/EtOAc with 10% of MeOH) afforded the desired product (68 mg, 79.4%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>C(N(CC)CC)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: NCC(O)CO
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc(NCC(O)CO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 9.6 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.41 g of 3-amino-1,2-propanediol, and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 0.28 g of 3-(4-nitro-3-methylphenylamino)propane-1,2-diol (9) was obtained.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCC>O.O(C(C)C)C(C)C>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7]1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Clc1ccc2ccccc2n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)OC(C)C
Solvent: O
Product: Oc1ccc(N2CCN(c3ccc4ccccc4n3)CC2)cc1
Yield: 70 %

Procedure:
A mixture of 10.2 parts of 4-(1-piperazinyl)phenol dihydrobromide, 5.7 parts of 2-chloroquinoline, 6.3 parts of potassium carbonate and 80 parts of 1-butanol is stirred and refluxed overnight. The reaction mixture is diluted with water and 2,2'-oxybispropane is added; the product is crystallized. It is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 6.4 parts (70%) of 4-[4-(2-quinolinyl)-1-piperazinyl]phenol; mp. 198.1° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[C:69]([C:70](O)=[O:71])=[C:68]([CH3:73])[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:69]5[C:65]([CH3:64])=[N:66][O:67][C:68]=5[CH3:73])=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: Cc1noc(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2c(C)noc2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3,5-dimethyl-4-isoxazolecarboxylic acid (0.141 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-({1-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperidin-4-yl}oxy)-7-methoxyquinazolin-4-amine as a white solid (0.107 g). 1H NMR Spectrum: (DMSO d6 373K) 1.80 (m, 2H), 2.01 (m, 2H), 2.20 (s, 3H), 2.40 (s, 3H), 3.47 (m, 2H), 3.75 (m, 2H), 3.96 (s, 3H), 4.76 (m, 1H), 7.23 (m, 1H), 7.23 (s, 1H), 7.40 (m, 1H), 7.58 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: (M+H)+ 526.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([O:18][C:19]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][C:20]=2[CH:21]=O)[CH2:17][CH2:16]1.[C:32]1([C@H:38]2[C@@H:43]([NH2:44])[CH2:42][CH2:41][CH2:40][NH:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)C.C(=O)([O-])O.[Na+].[Cl:54]CCCl>>[ClH:54].[ClH:54].[CH:15]1([O:18][C:19]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][C:20]=2[CH2:21][NH:44][C@H:43]2[CH2:42][CH2:41][CH2:40][NH:39][C@H:38]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:17][CH2:16]1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: FC(F)(F)Oc1ccc(OC2CC2)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
Sodium triacetoxyborohydride (411 mg, 1.94 mmol) was added to a mixture of 2-cyclopropoxy-5-(trifluoromethoxy)benzaldehyde (Description 9, 159 mg, 0.646 mmol), (2S3S)-2-phenylpiperidin-3-amine (prepared by the method described in WO 95/08549, 171 mg, 0.97 mmol) and acetic acid, (111 μl, 1.94 mmol) in 1,2-dichloroethane (5 mL) and the mixture was stirred at room temperature for 2.5 h. The mixture was poured into aqueous sodium hydrogen carbonate (satd., 50 mL) and extracted with ethyl acetate. The combined organic fractions were washed with aqueous sodium hydrogen carbonate (satd., 2×50 mL) and brine (50 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (97:3:0.3). The residue was dissolved in ethanol (2 mL) and ethanolic hydrogen chloride (5M, 0.5 mL) was added. The solid was collected and recrystallised from ethanol. The solid was collected and dried in vacuo to give the title compound as a yellow solid (144 mg, 46%). m.p. 168-171° C. 1H NMR (360 MHz, CD3OD) δ0.66-0.67 (1H, m), 0.80-0.82 (3H, m), 1.99-2.03 (1H, m), 2.27-2.35 (1H, m), 2.43-2.54 (2H, m), 3.30 (1H, m), 3.57-3.68 (1H, m), 3.75-3.80 (2H, m), 4.06-4.14 (2H, m), 5.05-5.06 (1H, d, J 2.7 Hz), 7.26 (1H, d, J 2.0 Hz), 7.30-7.39 (2H, m), 7.50-7.57 (3H, m), and 7.61 (2H, m). m/z (ES+) 407 (M+1).