Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)[C:22]([CH3:38])=[CH:21][N:20]=1>N1C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=5)[C:22]([CH3:38])=[CH:21][N:20]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(N)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 90 °C

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (91 mg, 0.35 mmol) and tert-butyl 4-(2-amino-5-methylpyrimidin-4-yl)benzoate (50 mg, 0.175 mmol), pyridine (2 mL) was added. The reaction was heated at 90° C. for twenty four hours. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in EtOAc and filtered. The filtrate was washed with saturated aqueous NaHCO3 (×3). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 4-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoate. ESI-MS m/z calc. 509.2, found 510.5 (M+1)+. Retention time 2.18 minutes.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][CH2:6][CH2:5]2)[CH2:3][C:2]1(C(O)=O)[C:8]([OH:10])=[O:9]>N1C=CC=CC=1>[CH2:1]1[C:4]2([CH2:7][CH2:6][CH2:5]2)[CH2:3][CH:2]1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C1(C(=O)O)CC2(CCC2)C1
Solvent: c1ccncc1
Product: O=C(O)C1CC2(CCC2)C1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of spiro[3.3]heptane-2,2-dicarboxylic acid (1.737 g, 9.43 mmol) in pyridine (20 mL) was heated at 115° C. overnight, cooled to RT and concentrated to dryness. The residue was treated with 6M HCL, extracted with DCM (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford spiro[3.3]heptane-2-carboxylic acid (1.21 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 2.85 (m, 1H), 2.15-2.03 (m, 4H), 1.96 (t, J=7.3 Hz, 2H), 1.84 (t, J=7.3 Hz, 2H), 1.76-1.70 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:19]=[C:18]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]([F:31])[F:30])[N:17]=[C:16]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[N:15]=3)[CH2:9][CH2:8]2)[C:3]1=[O:38].C(N(C(C)C)C(C)C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50].C(=O)(O)[O-].[Na+]>ClCCCl>[F:30][CH:29]([F:31])[C:21]1[N:20]([C:18]2[N:17]=[C:16]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:15]=[C:14]([O:13][C@H:10]3[CH2:11][CH2:12][C@H:7]([N:4]4[CH2:5][CH2:6][C@H:2]([NH:1][S:49]([CH3:48])(=[O:51])=[O:50])[C:3]4=[O:38])[CH2:8][CH2:9]3)[CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1
Reactant: N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3S)-3-amino-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]pyrrolidin-2-one (75 mg), N-ethyl-N-isopropylpropan-2-amine (73 μL), and 1,2-dichloroethane (750 μL) was added methanesulfonyl chloride (17 μL), followed by stirring at room temperature for 1 hour. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain N-{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}methanesulfonamide (82 mg) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([Cu])#[N:10]>CN(C=O)C>[Br:8][C:4]1[N:3]=[C:2]([C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Br)n1
Temperature: 100 °C
Yield: 28 %

Procedure:
Take up 2,6-dibromopyridine (0.500 g, 2.11 mmol) and CuCN (0.189 g, 2.11 mmol) in DMF (5.3 mL). Heat at 100° C. for 22 hours. Cool to room temperature. Add water (50 mL) and extract with ethyl acetate (3× 100 mL). Wash the organic layer with brine (1× 75 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 15-40% ethyl acetate in hexanes to give the title compound (0.108 g, 30.0%): GC/MS, MS ES+ 182 (M−H)+, time 8.78 min, % of total 100%; TLC [silica gel 60 F254, 30% ethyl acetate in hexanes] Rf=0.29.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([O:14][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
BocSer(Bzl) 60 g (0.2 mol) was added to 400 ml of ethyl acetate, to which triethylamine 21 g (0.2 mol) and benzyl bromide 35.4 g (0.2 mol) were added and reacted under refluxing condition for 4 hours. After cooled, the salt produced was separated by filtration. The filtrate was washed with an aqueous NaHCO3 solution and an aqueous NaCl solution and then dried over Na2SO4 and concentrated to dryness to obtain 54 g of white powder (Yield: 68%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[Cl-].[NH4+:10].[OH-].[Na+]>CO.O>[N:10]1[CH:7]=[CH:8][C:3]([NH:4][CH2:5][CH3:6])=[CH:1][CH:2]=1
Reactant: [NH4+]
Reactant: C=Cc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNc1ccncc1

Procedure:
A slurry of vinyl pyridine (161.4 mL, 1.5 mol) and ammonium chloride (240.7 g, 4.5 mol) in 1:1 MeOH/H2O (1.2 L) was heated to reflux for 18 h. The resulting homogenous solution was basified to pH13 with 3N NaOH and extracted repeatedly with CH2Cl2. The organic extracts were combined and concentrated to give a green oil, which was fractionally distilled to give 2-1 as an amber liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:31][CH:30]([NH2:32])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl.C(O)C>[C:21]([O:25][C:26]([N:28]1[CH2:31][CH:30]([NH:32][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=3[F:19])=[CH:6][N:5]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CN(C(=O)OC(C)(C)C)C2)nc1N
Temperature: 80 °C

Procedure:
To a stirred suspension of chloropyrimidine (700 mg, 2.34 mmol, Example 289) in methylene chloride (30 mL), amine (525 mg, 5.64 mmol, Example 318) in ethanol (30 mL) was added and the mixture heated at 80° C. for 4.5 hours. The solvent was removed and the residue was dissolved in ethyl acetate and the mixture was washed successively with 0.5N hydrochloric acid and water. The organic layer was dried with sodium sulfate and concentrated to give a white solid. 1.0 g, 98%. MS (ES) MH+=436.
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14](C(=O)C(C)(C)C)[N:13]=[CH:12]4)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:2]2[CH2:3][CH:4]3[CH:7]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][N:13]=[CH:12]5)[CH:1]2[CH2:6][CH2:5]3)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3C4CCC3NC4)ccc21
Product: Clc1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1

Procedure:
Reaction of Intermediate 14 with 4-chlorobenzaldehyde affords the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:30][C:31]1([CH3:55])[CH2:40][CH2:39][C:38]2[N:37]=[CH:36][N:35]=[C:34]([N:41]3[CH2:47][C:46]4[CH:48]=[C:49](B(O)O)[CH:50]=[CH:51][C:45]=4[O:44][CH2:43][CH2:42]3)[C:33]=2[CH2:32]1>>[CH3:30][C:31]1([CH3:55])[CH2:40][CH2:39][C:38]2[N:37]=[CH:36][N:35]=[C:34]([N:41]3[CH2:47][C:46]4[CH:48]=[C:49]([C:2]5[CH:3]=[C:4]6[NH:10][CH:9]=[N:8][C:5]6=[N:6][CH:7]=5)[CH:50]=[CH:51][C:45]=4[O:44][CH2:43][CH2:42]3)[C:33]=2[CH2:32]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: Brc1cnc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6nc[nH]c6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 6-bromo-1-(triphenylmethyl)-1H-imidazo[4,5-b]pyridine (reagent preparation 15) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.64 (s, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 8.22 (brs, 1H), 7.75 (d, 1H), 7.58 (dd, 1H), 7.06 (d, 1H), 4.67 (s, 2H), 4.35 (m, 2H), 3.85 (m, 2H), 2.72 (m, 2H), 2.46 (s, 2H), 1.61 (m, 2H), 0.85 (s, 6H); MS (EI) for C25H26N6O: 427 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([F:14])[CH:3]=1.[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:10](=[O:13])[N:11]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[N:12]=2)=[C:4]([F:14])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]nc(-c2ccc(Br)cc2F)[nH]1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2F)n(COCC[Si](C)(C)C)c1=O

Procedure:
Compound 59b (0.26 g, 1.0 mmol) was treated with SEMCl using the procedure described in Example 51, Step C to obtain compound 59c as a yellow oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H33BrFN3O3Si2: 518.1 (M+H). Found: 518.1.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>N.CO>[C:29]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:37])=[O:36])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc(-c2ccccc2)c1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Biphenyl-3-sulfonyl chloride (25 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (2.0 mg). MS m/z 405 [M+H]+.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9].[F:13][C:14]([F:24])([F:23])[C:15]1[S:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:24])([F:23])[C:15]1[S:19][C:18]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=2)[CH:8]=[O:9])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)s1
Reactant: O=Cc1ccnc(Br)c1
Agent: OBO
Product: O=Cc1ccnc(-c2ccc(C(F)(F)F)s2)c1

Procedure:
2-(5-(trifluoromethyl)thiophen-2-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and (5-(trifluoromethyl)thiophen-2-yl)boronic acid (29.4 mg, 62.3 mg theoretical, 47.2%). LC-MS m/z 258.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([O:26]CC4C=CC=CC=4)[CH:22]=3)[CH2:17]2)[CH:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([OH:26])[CH:22]=3)[CH2:17]2)[CH:3]=1
Reactant: COc1cc2nc(N3CCc4cc(OCc5ccccc5)c(OC)cc4C3)cc(N)c2cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1O)CCN(c1cc(N)c3cc(OC)c(OC)cc3n1)C2
Reaction time: 1.5 h
Yield: 24.7 %

Procedure:
A suspension of the product of part (A) (3.0 g) in methanol (400 ml) was warmed at about 50° until the majority of the product dissolved. The reaction mixture was then transferred to a hydrogenator and hydrogenated under a hydrogen pressure of 2.068×105Pa (30 psi) in the presence of 5% Pd/C (400 mg) at room temperature with stirring for 1.5 hours. The reaction mixture was filtered through "Arbacel" (a microcrystalline cellulose filtration aid), and evaporated to yield impure 4-amino-6,7-dimethoxy-2-(6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline (600 mg). The catalyst was then stirred in methylene chloride/methanol (4:1, 200 ml) for 30 minutes, and the mixture was filtered and the filtrate evaporated to yield a further 1.05 g of the impure product. The total of the impure product (1.65 g) was dissolved in methylene chloride/methanol (4:1, 300 ml) and shaken with 10% sodium carbonate solution (50 ml). The organic phase was washed (H2O), dried and evaporated. Medium pressure chromatography of the residue on silica (Merck "Art.9385") eluting with methylene chloride containing gradually increasing amounts of ethanol (1-25%) followed by collection and evaporation of appropriate fractions gave the title compound. The compound was slurried in boiling methylene chloride (20 ml), cooled, precipitated with hexane, filtered, and the solid washed with hexane and dried to give the pure title compound as a quarter-hydrate (900 mg), m.p. 250°- 251°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH3:17])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Cc1ccsc1-c1nn(N)c(=O)c2ccccc12
Product: Cc1ccsc1-c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 14B and 2-(4-chlorophenyl)acetic acid was processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H), 8.37-8.40 (m, 1H), 7.89-8.05 (m, 2H), 7.72 (d, J=5.1 Hz, 1H), 7.61-7.63 (m, 1H), 7.34-7.46 (m, 4H), 7.11 (d, J=5.1 Hz, 1H), 3.71 (s, 2H), 2.09 (s, 3H); MS (APCI) M/Z 410 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[C:8]([CH3:14])[CH:7]=2)[CH2:5][CH2:4]1.[Cl:15][C:16]1[N:17]=[C:18](Cl)[C:19]2[NH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN1C(=O)CCC1.O>[Cl:15][C:16]1[N:17]=[C:18]([O:13][C:9]2[C:8]([CH3:14])=[CH:7][C:6]([CH:3]3[CH2:5][CH2:4]3)=[CH:11][C:10]=2[CH3:12])[C:19]2[NH:24][CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Reactant: Clc1nc(Cl)c2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To a stirred suspension of NaH (25 mg, 0.64 mmol) in dry NMP (1.5 mL) was added 4-cyclopropyl-2,6-dimethylphenol (103 mg, 0.64 mmol) and the resolution mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.64 mmol) in dry NMP (1.7 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1-2:1), to give the product as a light yellow solid (20.2 mg, 8%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:14][CH2:15][CH:16]=O)[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>C(O)C.O>[CH2:1]([O:8][CH2:9][C@H:10]([O:14][CH2:15][CH:16]=[N:24][OH:25])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CC[C@H](COCc1ccccc1)OCC=NO
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
{[(2R)-1-(Benzyloxy)pent-4-en-2-yl]oxy}acetaldehyde (C3) (7.76 g, ≦32.88 mmol) was dissolved in a 2:1 mixture of ethanol and water (127 mL). Sodium acetate (13.6 g, 166 mmol) was added, and the mixture was stirred for 15 minutes. Hydroxylamine hydrochloride (98%, 7.05 g, 99.4 mmol) was then added, and the reaction mixture was heated to 60° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as a colorless oil, presumed from the 1H NMR spectrum to be a mixture of E and Z oximes. Yield: 7.12 g, 28.6 mmol, 87% over two steps. 1H NMR (400 MHz, CDCl3) δ 2.30-2.37 (m, 2H), 3.47-3.65 (m, 3H), {[4.20 (dd, half of ABX pattern, J=12.9, 5.8 Hz) and 4.25 (dd, half of ABX pattern, J=12.9, 5.6 Hz)] and 4.45-4.49 (br m), total 2H}, 4.55 and 4.56 (2 s, total 2H), 5.05-5.14 (m, 2H), 5.75-5.87 (m, 1H), 6.93-7.01 and 7.47-7.55 (2 br m, total 1H), 7.27-7.39 (m, 5H).
Reaction SMILES: [NH:1]([C:8](=[O:43])[C:9]([C:20]1[CH:42]=[CH:41][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33]C(=O)OC(C)(C)C)=[O:25])=[CH:22][CH:21]=1)([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24]([C:23]1[CH:41]=[CH:42][C:20]([C:9]([CH3:10])([C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:43])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:21][CH:22]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccccc1)(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
To a solution of tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-1-methyl-2-oxoethyl]benzoyl}amino)phenyl]-carbamate (14 mg, 0.024 mmol) in CH2Cl2 (3 mL) at room temperature was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature 30 min and concentrated. Purification by reverse phase HPLC (10% to 95% MeCN in water) gave 2-(4-{[(2-aminophenyl)amino]carbonyl}-phenyl)-2-methyl-N,N′-diphenylmalonamide (12 mg, TFA salt, 84%) as a white solid: 1H NMR (600 MHz, CDCl3) δ 9.77 (s br, 1H), 9.18 (s br, 2H), 7.87 (d, J=6.2 Hz, 21-1), 7.45-7.42 (m, 6H), 7.34-7.28 (m, 5H), 7.17-7.04 (m, 5H), 6.18 (s br, 21-1), 2.05 (s, 3H); ESIMS calcd 479.2 (M++H), found 479.2 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15]Br)=[CH:11][CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[N:8]=2)=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][N:28]=[N+:29]=[N-:30])=[CH:11][CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[N:8]=2)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
In a 25 mL pear-shaped flask, 3-bromomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (150.6 mg, 0.341 mmol) and sodium azide (66.6 mg, 1.02 mmol) were combined with DMF (2 mL) to give a light yellow solution. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with H2O (25 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (2×25 mL), dried over MgSO4, and concentrated in vacuo to give 3-azidomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (134.7 mg, 97.8%) as a yellow oil which contained DMF as an impurity. 1H NMR (DMSO-d6) δ ppm 8.89 (d, J=8.2 Hz, 1H) 7.78-8.27 (m, 1H) 7.26-7.76 (m, 5H) 4.30 (s, 2H) 3.52 (s, 2H). MS calcd. for C18H12F3N5O3 [(M+H)+] 404.0, obsd. 404.0, [(M+H-N2)+] 376.0, obsd. 376.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=[O:20])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:30][N:31]([CH3:42])[C:32]1[CH:41]=[CH:40][C:35]2[C:36]([CH3:39])=[CH:37][O:38][C:34]=2[CH:33]=1.[OH-].[Na+]>C(OC(=O)C)(=O)C>[CH3:42][N:31]([CH3:30])[C:32]1[CH:41]=[CH:40][C:35]2[C:36]([CH3:39])=[C:37]([C:11]3([C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:2]=4[CH3:1])[C:13]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:19](=[O:21])[O:20]3)[O:38][C:34]=2[CH:33]=1
Reactant: Cc1coc2cc(N(C)C)ccc12
Reactant: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCn1c(C)c(C2(c3oc4cc(N(C)C)ccc4c3C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 40 °C
Yield: 66.3 %

Procedure:
3.5 g of (2-methyl-1-n-octylindol-3-yl)-(2-carboxyphenyl)ketone and 1.6 g of 6-dimethylamino-3-methylbenzofuran are suspended in 45 ml of acetic anhydride and heated to 40° C. After 2 hours the reaction product is poured onto ice, basified with concentrated sodium hydroxide solution and filtered off. The crude product is recrystallized from toluene/methanol to give 3.25 g of the 3-(6-dimethylamino-3-methyl-benzofuran-2-yl)-3-(2-methyl-1-n-octylindol-3-yl)phthalide compound of the formula ##STR28## having a melting point of 157°-158° C. The phthalide compound gives a green colour on acid-modified silica gel.