Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[O:12]=[C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=[C:14]1[C:29]([O:31]C)=O>C(Cl)Cl>[O:12]=[C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[N:15]=[C:14]1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31]
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
A solution of aniline (0.360 mL, 3.95 mmol) in methylene chloride (10 mL) was cooled on an ice water bath then treated with a solution of trimethyl aluminum (2 M in toluene, 2.0 mL, 4.0 mmol). After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. At that point, methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (0.595 g, 2.00 mmol) was added and the reaction was heated at reflux for 18 h. After that time, the reaction was cooled to room temperature and carefully quenched with HCl aqueous solution (1 N, 5 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×10 mL). The combined organic extracts were washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. The residue was recrystallized from ethyl acetate/hexanes to give 0.214 g (30%) of 4-oxo-N-phenyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide as yellow crystals.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][C@@:15]([C:30]1[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=[C:32]([F:43])[CH:31]=1)([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13].[C:44]([O-])([O-])=O.[K+].[K+].CI>CC#N>[F:43][C:32]1[CH:31]=[C:30]([C@:15]([NH:14][C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[N:3][N:2]([CH3:44])[N:1]=2)=[O:13])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCCCCCc1nn[nH]n1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1nnc(CCCCCNC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)n1
Temperature: 80 °C
Yield: 17 %

Procedure:
To a solution of (R)-1-(5-(2H-tetrazol-5-yl)pentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (12 mg, 0.019 mmol) in MeCN (115 μL) at rt was added K2CO3 (3.2 mg, 0.023 mmol) followed by MeI (1.5 μL, 0.023 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was quenched by addition of H2O and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-(2-methyl-2H-tetrazol-5-yl)pentyl)urea (Example 260, 2 mg, 18% yield) as white solid. 1H NMR (500 MHz, CDCl3) ppm 7.17-7.08 (m, 5H), 6.99-6.85 (m, 5H), 6.67 (d, J=5 Hz, 2H), 5.98-5.75 (m, 1H), 4.23 (s, 3H), 3.82 (d, J=15 Hz, 1H), 3.68 (d, J=15 Hz, 1H), 3.10-3.07 (m, 2H), 2.85-2.82 (m, 2H), 1.77-1.71 (m, 2H), 1.46-1.40 (m, 2H), 1.32-1.26 (m, 2H); LC/MS: RT=3.218 min [M+H] 621.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.[C:19](Cl)(Cl)=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:19](=[O:20])[O:14][C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]23)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)O)cc1
Reactant: O=C(Cl)Cl
Product: COc1ccc(-n2c(=O)oc(=O)c3ccccc32)cc1

Procedure:
The starting material, N-(4-methoxyphenyl)isatoic anhydride was prepared from 2-(4-methoxyphenylamino)benzoic acid and phosgene according to the procedure of Example 1, part (b).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([C:23](=O)C)[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)[C:6](=[C:26]([O:33][CH2:34][CH3:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]1=[O:36])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].IC.O>CS(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([CH3:23])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)/[C:6](=[C:26](/[O:33][CH2:34][CH3:35])\[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[C:5]1=[O:36])(=[O:3])[CH3:2]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc(N(C(C)=O)S(=O)(=O)c3ccccc3)cc21)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: CCO/C(=C1\C(=O)N(C(C)=O)c2ccc(N(C)S(=O)(=O)c3ccccc3)cc21)c1ccccc1

Procedure:
10 g (20 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone (Example 1e) are dissolved in 150 ml of DMSO and combined with 2.2 g (20 mmol) of potassium tert. butoxide with stirring. After 15 minutes' stirring 1.9 ml (31 mmol) of iodomethane are added. The mixture is stirred for 3 hours at ambient temperature. Then another 2.2 g (20 mmol) of potassium tert. butoxide and 1 ml (16 mmol) of iodomethane are added. The mixture is stirred for 18 hours at ambient temperature. Then water is added. The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness. The residue is chromatographed on silica gel (petroleum ether/dichloromethane, 7:3).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(C(C)C)C(C)C)C.C1(C)C=CC=CC=1>O>[C:10]1(=[O:15])[N:2]([CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC1CCC(O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1

Procedure:
75.5 g (0.5 Mol) of 4-aminocyclohexanolhydrochloride and 74.0 g (0.5 Mol) of phthalic acid anhydride are mixed with 65 g (0.5 Mol) of ethyl-diisopropyl-amine and 1000 ml of toluene and boiled for 36 hours with a water separator. Then water is added, the toluene phase is separated off and the aqueous phase is extracted several times with chloroform. The organic phases are combined, dried and concentrated. The concentration residue is recrystallised from isopropanol.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].Cl[CH2:7][C:8]1[N:9]([CH2:35][CH2:36][CH3:37])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:34])(=[O:33])[NH:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:12]=1.O>C(O)(C)C>[CH:2]([O:3][CH2:7][C:8]1[N:9]([CH2:35][CH2:36][CH3:37])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([S:26](=[O:34])(=[O:33])[NH:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][N:12]=1)([CH3:4])[CH3:1]
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CCl
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1COC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.1 %

Procedure:
Sodium isopropoxide (87 mg, 1.05 mmol) was added to a stirred suspension of 4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Method 116; 100 mg, 0.21 mmol) in isopropanol (20 ml). The reaction was stirred for 48 hours at ambient temperature, and was then poured into water (80 ml) and extracted with EtOAc (3×30 ml). The extracts were combined washed with brine (2×40 ml), dried and the volatiles removed by evaporation. The residue was purified by reverse phase HLPC (C18 column) eluting with aqueous ammonia/water/acetonitrile (5:90:5 decreasing in polarity to (5:0:95) to give the title compound (18 mg, 17%) as a brown gum. M/z 503.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]2([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[O:9]2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(c1cccc(F)c1)C1CCCCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: Fc1cccc(C2OC3(CCN(Cc4ccccc4)CC3)N3CCCCC23)c1

Procedure:
Utilizing the procedure described in Example 1 above, 11 g of alpha-(3-fluorophenyl)-2-piperidinemethanol is reacted with 10 g of N-benzyl-4-piperidone to obtain hexahydro-1'-benzyl-1-(3-fluorophenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 113°-115° C. after recrystallizaton from petroleum ether.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:17][C@H:18]([OH:37])[C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:45]>O1CCOCC1>[ClH:45].[NH2:8][C@H:9]([C:13]([NH:15][C@@H:16]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:17][C@H:18]([OH:37])[C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 135 mg (0.27 mmol) of (2S,3S,5S)-5-(N-(N-(t-butyloxycarbonyl)valinyl) amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane was added 8 ml of 4M HCl in dioxane. The resulting mixture was stirred at ambient temperature for 1 h and concentrated in vacuo to provide the crude desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[N:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[N:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2scnc2c(=O)n1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2scnc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (1 equiv) in dichloromethane is added to a solution of 6-benzyl-5-(1-{[2-(dimethylamino)ethyl]amino}-propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-4, 1 equiv) and N,N-diisopropylethylamine (1 equiv) in dichloromethane, and the resulting mixture is stirred under ambient conditions for 1 h. The reaction mixture is washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with CH2Cl2 to 5% NH3—EtOH/CH2Cl2 gives N-[1-(6-benzyl-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-5-yl)propyl]4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH2:6][C:7]1[C:15]([F:16])=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[C:9]([F:17])[CH:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:32][S:33](Cl)(=[O:35])=[O:34].[CH2:37]1COC[CH2:38]1>CCOC(C)=O>[CH2:37]([NH:13][CH2:11][CH3:10])[CH3:38].[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH2:6][C:7]1[C:15]([F:16])=[CH:14][C:10]([C:11]([NH:13][S:33]([CH3:32])(=[O:35])=[O:34])=[O:12])=[C:9]([F:17])[CH:8]=1
Reactant: NC(=O)c1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Reactant: C1CCOC1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCNCC
Product: CS(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Reaction time: 0.29 h

Procedure:
To 4-((3,4-dichlorophenoxy)methyl)-2,5-difluorobenzamide (Preparation 24, 60 mg, 0.18 mmol) in THF (2 mL) was added a THF solution of lithium hexamethyldisilazide (1 M, 0.362 mL, 0.362 mmol) over 2 minutes. After stirring for 15-20 minutes, methanesulphonyl chloride (0.028 mL, 0.362 mmol) was added and the solution was stirred for 18 hours at room temperature. The reaction mixture was then diluted with EtOAc and washed twice with water. The organic layer was dried over sodium sulphate and evaporated to yield a yellow oil (65 mg), which was purified by preparative HPLC to yield the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].C(Cl)Cl.O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](O)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CO>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:6][C@H:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CNCC[C@H](O)c1cccs1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CNCC[C@H](OS(=O)(=O)c1ccc(C)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (5.0 g, 29.2 mmol), methylene chloride (50 mL), p-toluenesulfonic acid hydrate (5.55 g, 29.2 mmol) and methanol (20 mL) is stirred 1 h at 25° C., then concentrated to dryness. The residue (10.8 g) which solidifies after a few hours is finally recrystallised from butanol (30 mL) affording a white powder (6.0 g, 60%); 1H-NMR (DMSO-d6, 400 MHz): 8.1 (1H, s, broad), 7.5 (2H, dm), 7.42 (1H, dd), 7.1 (2H, dm), 7.0 (2H, m), 4.92 (1H, dd), 2.97 (2H, m, symm.), 2.57 (3H, s), 2.28 (3H, s), 2.0 (2H, m); 13C-NMR (DMSO-d6, 100 MHz): 149.3, 145.5, 137.6, 128.0, 126.6, 125.4, 124.4, 123.0, 66.1, 45.8, 35.1, 32.7, 20.7.
Reaction SMILES: C[C:2]([N:5]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([Cl:16])[CH:10]=1)[C:6](=[O:8])[O-:7])([CH3:4])C.[CH2:17](Br)C.O1[CH2:24][CH2:23][CH2:22]C1>C(OCC)C>[CH2:2]([N:5]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([Cl:16])[CH:10]=1)[C:6](=[O:8])[O:7][C:23]([CH3:22])([CH3:24])[CH3:17])[CH3:4]
Reactant: C1CCOC1
Reactant: Cc1ccc(N(C(=O)[O-])C(C)(C)C)cc1Cl
Reactant: CCBr
Solvent: CCOCC
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C)c(Cl)c1

Procedure:
Sodium hydride, 2.0 grams (0.05 mole) was washed repeatedly with heptane, then was stirred in 100 ml of tetrahydrofuran. To this was added 10.0 grams (0.41 mole) of 1,1-dimethylethyl(3-chloro-4-methylphenyl)carbamate (prepared in Example 4, Step A). The reaction was stirred for 5 minutes and 9.0 grams (0.083 mole) of ethyl bromide in 25 ml of tetrahydrofuran was added dropwise. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was taken up in 500 ml of diethyl ether and washed with three 50 ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 10.8 grams of 1,1-dimethylethyl N-ethyl-N-(3-chloro-4-methylphenyl)carbamate as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=[C:3]1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[Na].[CH2:29](N(CC)CC)C.S(Cl)(Cl)=O>C(Cl)Cl.CO>[CH3:29][O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[C:5]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:4]=2)=[CH:27][CH:26]=1
Reactant: Cn1c(-c2ccc(C(=O)O)cc2)nc(-c2ccccc2)c1-c1ccncc1
Reactant: CCN(CC)CC
Agent: [Na]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a suspension of 4-[1-methyl-4-phenyl-5(4-pyridyl)-imidazol-2-yl]benzoic acid, sodium salt (20 mg, 0.06 mmol) [See Ex. 5 above] in CH2Cl2 (2 mL) was added triethylamine (24 mL, 0.17 mmol), followed by thionyl chloride (10 mL, 0.14 mmol). The reaction mixture was stirred at rt for 30 min, at which time MeOH (0.5 mL) was added. The mixture was stirred at rt for an additional 2 h and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gra-dient of 0-1% MeOH/CHCl3 and recrystallized from EtOAc to afford the title compound as an off-white crystalline solid (1.6 mg, 8%): mp 208-209° C.
Reaction SMILES: C1OCC2C1=CC=CC=2.ON1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]>C(#N)C>[CH:12](=[O:21])[C:13]1[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:15]=[O:16].[C:15]1([C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][O:21]1)=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: c1ccc2c(c1)COC2
Solvent: CC#N
Product: O=C1OCc2ccccc21
Product: O=Cc1ccccc1C=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 7 %
Yield: 80 %

Procedure:
A mixture of 10 mmol of phthalan (isocoumaran), 1 mmol of N-hydroxyphthalimide (NHPI), and 5 ml of acetonitrile was stirred at 60° C. under a nitrogen monoxide atmosphere (1 atm) for 6 hours. Gas chromatographic analysis of products in the reaction mixture revealed that phthalan was converted, at a rate of 90%, into phthalaldehyde (yield: 80%), and phthalide (1-phthalanone) (yield: 7%).
Reaction SMILES: C(OC(=O)C)(=O)C.CS(C)=O.[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:31]1[CH:32]=[N:33][C:34]([Cl:37])=[CH:35][CH:36]=1)([CH3:30])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=1)[OH:21])([CH3:15])([CH3:14])[CH3:13]>C(OCC)(=O)C>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:31]1[CH:32]=[N:33][C:34]([Cl:37])=[CH:35][CH:36]=1)([CH3:30])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=1)=[O:21])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(C)(c1ccc(Cl)nc1)C(O)c1ccc(Cl)c(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)NC(C)(C(=O)c1ccc(Cl)c(F)c1)c1ccc(Cl)nc1
Reaction time: 18 h
Yield: 96.8 %

Procedure:
Acetic anhydride (2.3 ml, 24.7 mmol) was added to a dimethyl sulfoxide (8 ml) solution of the compound (1.14 g, 2.75 mmol) obtained in Step 4 above under ice cooling and the resulting mixture was gradually returned to room temperature while being stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with 6% aqueous sodium perchlorate solution, 10% aqueous sodium thiosulfate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=4:1 (v/v)] to give the title compound (1.10 g, 97%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>C1COCC1.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:5]1[C@@H:4]([CH2:3][CH2:2][O:1][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[CH2:8][O:7][C:6]1([CH3:10])[CH3:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CCOc2ccc(C(F)(F)F)cn2)COC1(C)C
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To a stirred solution of tert-butyl (S)-4-(2-hydroxyethyl)-2,2-dimethyl-oxazolidine-3-carboxylate (300 mg; CAS 147959-18-0) in THF (4 ml) under an argon atmosphere was added sodium hydride (59 mg, 60% dispersion in oil). The resulting suspension was heated at 50° C. for 20 min and then cooled to 0° C. A solution of 2-chloro-5-trifluoromethyl-pyridine (222 mg) in THF (2 ml) was then added dropwise and the resulting mixture was heated at 70° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated brine, the phases were separated and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-oxazolidine-3-carboxylic acid tert-butyl ester (393 mg, 82%) as a colourless oil. MS (ISP): 391.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([NH:29][CH:30]2[CH2:37][C@H:36]3[N:38]([CH3:39])[C@H:32]([CH2:33][CH2:34][CH2:35]3)[CH2:31]2)=[O:28])=[CH:25][C:24]=1[F:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:41]=[CH:40][C:26]([C:27]([NH:29][CH:30]5[CH2:37][C@H:36]6[N:38]([CH3:39])[C@H:32]([CH2:33][CH2:34][CH2:35]6)[CH2:31]5)=[O:28])=[CH:25][C:24]=4[F:42])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1[C@@H]2CCC[C@H]1CC(NC(=O)c1ccc(N)c(F)c1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Solvent: CO
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4C[C@H]5CCC[C@@H](C4)N5C)cc3F)ncc21
Temperature: 160 °C
Yield: 27.5 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 108 mg, 0.35 mmol) and 4-amino-3-fluoro-N-(9-methyl-9-azabicyclo[3.3.1]non-7-yl)benzamide (Intermediate 162; 102 mg, 0.35 mmol) were combined with p-toluenesulphonic acid monohydrate (167 mg, 0.88 mmol) in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation for 25 minutes at 160° C. The cooled reaction mixture was diluted with methanol (10 mL) and loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed with methanol (2×5 mL) and eluted with 7 N methanolic ammonia (10 mL). Product containing fractions were evaporated and the resultant material purified by base modified reverse phase preparative HPLC to give the title compound as a white solid (54 mg, 28%).
Reaction SMILES: [CH:1]1([C:4](O)=O)C[CH2:2]1.[Br:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([NH:15][CH3:16])=[C:10]([CH3:17])[CH:9]=1.[C:18]([O-])(O)=O.[Na+]>O=P(Cl)(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([CH3:17])[C:11]2[N:15]=[C:16]([CH:4]3[CH2:1][CH2:2]3)[N:14]([CH3:18])[C:12]=2[CH:13]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C1CC1
Reactant: CNc1c(C)cc(Br)cc1N
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)cc2c1nc(C1CC1)n2C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of cyclopropanecarboxylic acid (356 μl) and 5-bromo-N′,3-dimethylbenzene-1,2-diamine (600 mg) was added POCl3 (10 ml), and the mixture was heated at 120° C. After 3 h, the mixture was poured into saturated aqueous NaHCO3 solution, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (450 mg) as brown solid.