Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>Cl.N1C=CC=CC=1.ClCCl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ccc(-c2ccccn2)c(OC)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1ccc(-c2ccccn2)c(O)c1
Temperature: 160 °C
Yield: 65.7 %

Procedure:
A mixture of 2-(2,4-dimethoxyphenyl)pyridine (14 g) in pyridine hydrochloride (121 g) is heated to 160° C. and the resulting melt is heated at 160° C. for 7 hours. The mixture is then cooled, diluted with dichloromethane, washed with hydrochloric acid (2 M) and water, dried and evaporated. The residual oil is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (1:1 v/v), to give 2-(2,4-dihydroxyphenyl)pyridine (8.0 g) in the form of a solid, m.p. 170-172° C. [NMR(CDCl3):- 6.3(1H,s),6.4(1H,d),7.3(1H,m), 7.8(1H,d),7.9(1H,t),8.0(1H,d),8.5(1H,d).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:25][N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([C:21]([NH:23][CH3:24])=[O:22])=[CH:6]2.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[CH3:1][O:2][C:3]1[C:4]([CH2:25][N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:7]([C:21]([NH:23][CH3:24])=[O:22])=[CH:6]2
Reactant: CNC(=O)c1cc2c(CN3CCN(C(=O)OC(C)(C)C)CC3)c(OC)ccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc2c(CN3CCNCC3)c(OC)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-{[5-methoxy-2-[(methylamino)carbonyl]-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (3.4 mg, 0.063 mmol, Intermediate 58) was dissolved in DCM (2 mL) before TFA (1 mL) was added. The reaction mixture was stirred for 2 h at RT before completed. The solvent was evaporated and the obtained oil was dissolved in methanol and the solvent was evaporated. The obtained brown solid was stored under vacuum for 24 h. Quantitative yield was obtained. MS (ESI+) for C22H26N4O4S m/z 443 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[C:8]([F:20])[CH:7]=1>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([F:20])[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(O)c(F)c1
Reaction time: 18 h
Yield: 105.1 %

Procedure:
(E)-3-(4-Benzyloxy-3-fluoro-phenyl)-acrylic acid methyl ester (0.37 g, 1.2 mmol) obtained in Step B was dissolved in EtOAc (4 mL) and MeOH (2 mL). The solution was added with 10% Pd/C (0.03 g), and the mixture was stirred under hydrogen atmosphere for 18 hours. The reactant was filtered by using celite, and the filtrate was washed with EtOAc to obtain the title compound (0.25 g, 98%).
Reaction SMILES: CO.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[C:11]([O:15]OC(C)(C)C)(C)(C)C>>[C:5]1([CH:3]([CH3:4])[O:15][CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCc1ccccc1
Solvent: CO
Product: COC(C)c1ccccc1
Temperature: 90 °C
Yield: 35 %

Procedure:
Into a pressure vessel methanol (84 μL, 1 mmol, 1 eq) was added and diluted with ethylbenzene (1.225 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing ethylbenzene under vacuum, the residue was analyzed by GC/MS and 1H NMR to determine the yield and consumption of starting materials. 1H NMR Yield: 35%.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][N:4]([CH3:32])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]2)[N:8]=[C:7]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])[N:6]=1.[C-:35]#[N:36].[Na+].BrBr>[Na].C(=O)(O)[O-].C(Cl)Cl.O>[C:35]([C:10]1[C:5]([N:4]([CH2:3][C:2]([CH3:34])([CH3:33])[CH3:1])[CH3:32])=[N:6][C:7]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:8][C:9]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)#[N:36]
Reactant: [C-]#N
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)cc(N3CCCN(C)CC3)n2)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)c(C#N)c(N3CCCN(C)CC3)n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 3-[4-[(2,2-dimethyl-propyl)-methyl-amino]-6-(4-methyl-[1,4]diazepan-1-yl)-pyrimidin-2-ylamino]-N-methoxy-4-methyl-benzamide (140 mg, 0.29 mmol) and sodium cyanide (0.044 g, 0.89 mmol) in sat. aq. sodium-bicarbonate (1 mL) and methylene chloride (3 mL) was added bromine (0.045 mL, 0.87 mmol). The resulting mixture was stirred for 16 h at room temp, then diluted with water and extracted with methylene chloride (2×15 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure, and the product was purified by HPLC. C26H38N8O2 MS m/e=495 (M+H). Deprotection was performed as described in Example 75.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.BrC1C2C(=CC=CC=2)C=C(NC(C2(C3C=CC4OC(F)(F)OC=4C=3)CC2)=O)N=1.[CH3:62][C:63]1[NH:64]C2C([CH:71]=1)=CC(B(O)O)=CC=2>>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]6[C:30](=[CH:31][CH:32]=5)[NH:64][C:63]([CH3:71])=[CH:62]6)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(Nc1cc2ccccc2c(-c2ccccc2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1cc2cc(B(O)O)ccc2[nH]1
Agent: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Product: Cc1cc2cc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)cc4ccccc34)ccc2[nH]1

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-phenylisoquinolin-3-yl)cyclopropanecarboxamide was made by the procedure shown above starting from N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide and 2-methyl-1H-indol-5-ylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.Cl>O.C(O)C>[ClH:1].[OH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Temperature: 25 °C

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 3-aminophenol (32 mg, 0.290 mmol), and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and the resulting crystals was filtered, washed with water, with water:ethanol (2:1) and dried to give a tan crystals (22 mg, 30%). 1H NMR (DMSO-d6): 10.17 (s, 1H), 9.36 (d, J=1.5 Hz, 1H), 8.72–8.66 (m, 2H), 7.66–7.62 (m, 1H), 7.20 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.45–6.41 (m, 1H).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[CH2:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)[CH3:16].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([CH2:15][CH3:16])=[CH:18][CH:19]=1)[CH2:12]2
Reactant: CCc1ccc(CN)cc1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1ccc(CN2Cc3cc(Br)cc(Cl)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.06 g, 3.00 mmol), 4-ethyl-benzylamine (0.575 mL, 4.0 mmol), and K2CO3 (0.967 g, 7.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.442 g, 41%). GC-MS: m/z 364 (M)+, 336 (M−28)+. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 2.64 (q, 2H) 4.20 (s, 2H), 4.73 (s, 2H), 7.21 (m, 4H), 7.44 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccs2)OCCNc2ccc(Br)cc21
Reaction time: 3 h
Yield: 84.5 %

Procedure:
To a solution of 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one (5 g, 14.6 mmol) in anhydrous THF (100 mL) was added lithium aluminum hydride (0.2 g, 5.2 mmol) at rt under nitrogen. After addition, the mixture was stirred for 3 hrs and treated with aqueous ammonium chloride solution (200 mL). Ethyl acetate (300 mL) was added. Organic layer was separated, dried (MgSO4), and concentrated to afford 7-bromo-5-methyl-5-thien-2-yl-1,2,3,5-tetrahydro-4,1-benzoxazepine as an oil (4 g, 85%). A white solid as a HCl salt: 1H NMR (DMSO-d6): δ 7.52 (dd, J=5.0, 0.8 Hz, 1H), 7.31 (dd, J=8.5, 2.1 Hz, 1H), 7.12 (d, J=2.1 Hz, 1H), 6.95-7.04 (m, 2H), 6.78 (dd, J=3.5, 0.9 Hz, 1H), 3.61-3.85 (m, 4H), 3.12 (m, 2H), 2.93 (s, 3H); MS (ESI) m/z 324/326 ({M+H]+); Anal. calcd for C14H14BrNOS HCl: C, 46.62; H, 4.19; N, 3.88. Found: C, 46.70; H, 3.99; N, 3.83.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[N:30]([C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36])=[C:31]=[O:32]>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][CH:41]=[CH:42][C:33]=1[NH:30][C:31]([N:16]([C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[CH:15]=[CH:14][N:13]=1)[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[O:32]
Reactant: CC(C)c1ccc(-c2ccnc(NCc3cccs3)n2)cc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)N(Cc1cccs1)c1nccc(-c2ccc(C(C)C)cc2)n1
Temperature: 100 °C
Yield: 2.6 %

Procedure:
To a solution of [4-(4-isopropyl-phenyl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine (50 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (33 μL, 0.24 mmol) and methyl 2-isocyanatobenzoate (32 mg, 0.18 mmol). The resulting reaction mixture was heated in a CEM Exployer PLS™ microwave at 100° C. for 30 min. After cooling to room temperature the solvent was evaporated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 to give 2 mg of 2-{3-[4-(4-isopropyl-phenyl)-pyrimidin-2-yl}-3-thiophen-2-ylmethyl-ureido}-benzoic acid methyl ester. LCMS m/z: 488 (M+1)+.
Reaction SMILES: ClC1C=CC=C(Cl)[C:3]=1[N:9]1C=C2C(NC3C=C(NC)N=CN=3)=NC=CC2=N1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[C:40]3=[CH:41][N:42]([C:44]4[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=4[Cl:51])[N:43]=[C:39]3[CH:38]=[CH:37][N:36]=2)[CH:31]=[C:30]([CH3:52])[N:29]=1.CN>>[Cl:51][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]([Cl:50])[C:44]=1[N:42]1[CH:41]=[C:40]2[C:35]([NH:34][C:32]3[CH:31]=[C:30]([CH3:52])[N:29]=[C:28]([NH:9][CH3:3])[N:33]=3)=[N:36][CH:37]=[CH:38][C:39]2=[N:43]1
Reactant: CNc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(Cl)n1
Agent: CN
Product: CNc1nc(C)cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)n1
Yield: 33 %

Procedure:
Following the procedure described for N-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]-N′-methylpyrimidine-4,6-diamine, (2-chloro-6-methylpyrimidin-4-yl)-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]amine and methylamine were reacted to afford the title compound as a yellow solid (24 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 9.16 (s, 1H), 7.94 (d, J=6.4 Hz, 1H), 7.81-7.80 (m, 2H), 7.70 (dd, J=9.0, 7.3 Hz, 1H), 7.65 (s, 1H), 7.15 (dd, J=6.4, 1.0 Hz, 1H), 2.82 (d, J=4.8 Hz, 3H), 2.25 (s, 3H). LCMS (Method B): RT=2.90 min, m/z: 400 [M+H+].
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[C:13]([F:31])[CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[C:13]([F:31])[CH:12]=1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)cc2F)CC1
Reactant: ON=C1CCCCCC1
Product: Fc1cc(Cl)ccc1C1CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH3:13])[C:8]([CH3:12])=[N:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:26](OCCCCC)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(O)(=O)C>[C:1]([N:4]1[C:5]2[C:10](=[N:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2)[CH:11]=[N:26]1)(=[O:3])[CH3:2]
Reactant: CCCCCON=O
Reactant: CC(=O)Nc1cc(C)c(C)nc1C
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2nc(C)c(C)cc21
Reaction time: 12 h

Procedure:
The reaction was run similar to that described by D. Chapman and J. Durst, J. Chem. Soc. Perkin I, 2398 (I980). A 12.40 g sample of the 5-(acetylamino)-2,3,6-trimethylpyridine was combined with 22 mL of acetic anhydride, 22 mL of acetic acid, and 13 g of potassium acetate in 200 mL of benzene. The mixture was brought to relux. A solution of an excess of amyl nitrite, (11 g) in benzene (40 mL), was added to the refluxing solution over a period of 2 hours and refluxing was continued an additional 12 hours. The reaction was cooled and stirred, with 200 mL of 5% aqueous sodium carbonate, for 3 hours. The organic phase was separated, dried with anhydrous sodium sulfate, concentrated under vacuum and chromatographed (silica gel: methylene chloride/ether) to give 4.94 g of 1-acetyl-5,6-dimethylpyrazolo [4,3-b] pyridine. ##STR6##
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:8]([O:10]CC)=O)[C:3]([O:5]CC)=O.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].CC[O-].[Na+].[Na]>C(O)C>[CH3:13][C:2]1([CH3:1])[C:3](=[O:5])[NH:21][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:8]1=[O:10]
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Reactant: Nc1ccccc1N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC1(C)C(=O)Nc2ccccc2NC1=O
Yield: 64.7 %

Procedure:
43.0 g of diethyl dimethylmalonate and thereafter 24.7 g of o-phenylenediamine were added to a sodium ethylate solution freshly prepared from 10.5 g of sodium and 400 ml of abs. ethanol under argon. The reaction mixture was heated continuously to 180° C. in the course of 2 hours, whereby ethanol was distilled off continuously. After cooling the dried residue was triturated with dilute hydrochloric acid, the precipitate was filtered off and washed with water and ethanol. After drying in a high vacuum there were obtained 30.2 g of 2,3,4,5-tetrahydro-3,3-dimethyl-2,4-dioxo-1H-1,5-benzodiazepine as a brownish powder, m.p.>270° C. This product was added portionwise under argon to 17.0 g of sodium hydride (about 55%) in 300 ml of abs. dimethylformamide at 0° C. After the exothermic reaction had faded away 27.6 ml of methyl iodide were added and the reaction mixture was warmed to room temperature. Thereafter, it was poured on ice and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried and concentrated up to crystallization. There were obtained 29.5 g of 2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-2,4-dioxo-1H-1,5-benzodiazepine, m.p. 159°-160° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([OH:19])=O)=[CH:7][CH:6]=1)(=[O:3])[NH2:2]>O>[O:19]=[C:17]1[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:20]=[CH:21][C:5]([CH2:4][C:1]([NH2:2])=[O:3])=[CH:6][C:7]1=2
Reactant: NC(=O)Cc1ccc(Oc2ccccc2CC(=O)O)cc1
Solvent: O
Product: NC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 81.4 %

Procedure:
To 59 mg of 2-(4-carbamoylmethylphenoxy)phenylacetic acid was added 1.8 g of polyphosphoric acid, and the mixture was stirred under a dry atmosphere at 100° C. for 50 minutes. After being cooled, the resulting mixture was dissolved in water and then extracted with ethyl acetate. The extract was washed with a 1% sodium hydroxide solution and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was recrystallized from acetone/n-hexane to give 45 mg (yield: 76%) of (10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-acetamide as light yellow crystals having a melting point of 151.5°-154° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1>C(O)C>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH3:11])[CH:3]=2)=[CH:19][CH:18]=1)#[N:27]
Reactant: Cc1cc(Cl)n2nccc2n1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Solvent: CCO
Product: Cc1cc(NCc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
3.35 g (20 mmol) 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (prepared according to Y. Makisumi, Chem. Pharm. Bull. 1962, 10, 620) and 4.17 g (20 mmol) 4-aminomethyl-2'-cyanobiphenyl were heated with reflux in 40 ml dry ethanol for 4 hours. The solvent was distilled off in vacuo, and the remaining oil solidified after stirring with a mixture of 20 ml hexane and 20 ml t-butylmethylether to give a reddish powder of the pure title compound, m.p. 221°-223° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:8][CH2:7]1.O.[S:37]([C:41]1[CH:47]=[CH:46][C:44](C)=[CH:43][CH:42]=1)([OH:40])(=[O:39])=[O:38]>C(OCC)(=O)C>[C:3]1([CH3:2])[C:4]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:26][CH:27]=[CH:28][CH:29]=1.[C:47]1([CH3:2])[C:41]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:42][CH:43]=[CH:44][CH:46]=1.[F:35][C:2]([F:1])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:10][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1N=C(NCCOCCO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-4-{[2-(2-hydroxyethoxy)ethyl]amino}-1,3-thiazol-2(5H)-one (4.3 g) in ethyl acetate (40 ml) was added tosylic acid monohydrate (3.11 g), and the mixture was stirred at room temperature for 2 hr. The precipitate was collected by filtration, washed with ethyl acetate, and recrystallized from 2-butanone/heptane to give the title compound (4.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27]CC2C=CC=CC=2)=[O:26])[C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:45]>[C].[Pd].CCOCC>[ClH:45].[CH2:1]([O:3][C:4]([C@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O

Procedure:
Catalytic reduction of benzyl 3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) obtained in Example 21 is carried out using 10% palladium-carbon as a catalyst in a manner similar to that described in Example 17. The oily product is dissolved in ether, and 0.5 ml of hydrogen chloride-ethyl acetate solution (5N) is added dropwise to the solution to give 0.18 g of 3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:3]1.[C:16]1([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH:22]([NH:29][C:12](=[O:14])[C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:15])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Solvent: CC#N
Product: Cn1cc(C(=O)C(=O)NC(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
N-Benzhydryl-2-(1-methyl-1H-indol-3-yl)-2-oxo-acetamide was synthesized following scheme II above starting from (1-methyl-1H-indol-3-yl)-oxo-acetic acid and C,C-diphenyl-methylamine. Yield (11%). HPLC ret. time 3.79 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 9.56 (d, J=9.1 Hz, 1H), 8.65 (s, 1H), 8.24 (m, 1H), 7.61 (m, 1H), 7.43-7.26 (m, 12H), 6.32 (d, J=9.1 Hz, 1H), 3.90 (s, 3H); ESI-MS 369.1 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH:17]=O)[CH:7]=[CH:6]2.C(OP([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(OCC)=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH:17]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:7]=[CH:6]2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc2ccc(C=O)cc2c(OC)c1OC
Product: CCOC(=O)C=Cc1ccc2cc(OC)c(OC)c(OC)c2c1

Procedure:
6,7,8-Trimethoxynaphthalene-2-carboaldehyde (985 mg) and ethyl diethylphosphonoacetate (1.05 mL) were treated in the same manner as in Preparation Example 17 to obtain the title compound.