Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][CH2:8][C:9]([OH:11])=[O:10].NN.C([O-])([O-])=O.[K+].[K+].C(O)COCCO>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)CCCc1cccs1
Temperature: 190 °C
Yield: 84.7 %

Procedure:
3.6 g (0.019 mol) of 4-(2-thienyl)-4-keto-butyric acid, 2.74 ml (0.07 mol) of hydrazine 98%, 3.69 g (0.066 mol) of potash and 42 ml of diethylene glycol are placed in a two-necked flask equipped with a magnetic stirrer. The medium is heated for 7 h at 190° C. The medium is a clear uniform yellow. When it has cooled to room temperature it is hydrolysed with 200 ml of water. The diethylene glycol is extracted with 5 times 100 ml of ether. The aqueous phase is then acidified to pH 1 and extracted. The acid is absorbed in a solution of soda 5% washed with ether then acidified and absorbed for the last time in ether which is dried over MgSO4 and concentrated. 2.74 g of a clear yellow oil is obtained. Yield=85%.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:19]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([CH2:37][O:38][CH3:39])[O:17]2)=[C:9]([NH:40][CH2:41][CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:8]=1)(=O)=O.[C-:55]#[N:56].[K+]>CN(C)C=O>[Si:22]([O:21][C@@H:20]1[C@H:19]([O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:31])[CH3:32])[C@@H:18]([CH2:37][O:38][CH3:39])[O:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([CH2:6][C:55]#[N:56])=[N:8][C:9]=2[NH:40][CH2:41][CH:42]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC#N)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 67.5 °C
Yield: 80.3 %

Procedure:
A stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (3.0 g, 3.76 mmol) (preparation 16) in anhydrous N,N-dimethylformamide (20 ml) was treated with potassium cyanide (0.37 g, 5.69 mmol) and heated to 65-70° C. for 3 hr. The mixture was cooled to room temperature and partitioned between diethyl ether and water. The organic phase was separated and the aqueous phase extracted again with diethyl ether. The combined organic solutions were then washed with brine, dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of diethyl ether:pentane (1:1) to afford the title compound as a foam (2.2 g). MS: 751 (MNa+).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=2[S:5][CH:6]=1.[C:12](C(O[Na])=O)([F:15])([F:14])[F:13].CN1CCCC1=O>[Cu]I.O>[CH3:11][C:7]1[C:4]2[S:5][CH:6]=[C:2]([C:12]([F:15])([F:14])[F:13])[C:3]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O[Na])C(F)(F)F
Reactant: Cc1cccc2c(Br)csc12
Agent: [Cu]I
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc2c(C(F)(F)F)csc12
Reaction time: 1 h

Procedure:
A mixture of 2 g of 3-bromo-7-methylbenzo[b]thiophene, 4.8 g of CF3COONa, 3 g CuI and 20 ml of 1-methylpyrrolidone are vigorously stirred and heated at 160°. After a short while evolution of gas commences. Stirring is continued for one hour at 160° and a further hour at 180°. After cooling the reaction mixture is poured into water, extracted with ether/hexane (1/1) and the organic phase washed, dried and concentrated under vacuum. The raw product is chromatographed over silica gel (eluant: n-hexane) and the title compound obtained as a colourless oil.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:19]([N:21]1[CH2:32][CH2:31][CH2:30][C@H:22]1[C:23]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl.C(ON[C@H](C(N[C@H](C(N1CCC[C@H]1C(NCC(N)=O)=O)=O)CCCNC(=N)N)=O)C(=C=O)C(C)C)C1C=CC=CC=1.[N+](C1C=CC([O:84][C:85](=O)[C@@H:86]([CH2:98][C:99]2[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=2)[NH:87][C:88]([O:90][CH2:91][C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)=[O:89])=CC=1)([O-])=O>CN(C)C=O>[ClH:1].[CH2:91]([O:90][C:88]([NH:87][C@@H:86]([C:85]([NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:19]([N:21]1[CH2:32][CH2:31][CH2:30][C@H:22]1[C:23]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])=[O:9])[CH2:4][CH:5]([CH3:6])[CH3:7])=[O:84])[CH2:98][C:99]1[CH:100]=[CH:101][CH:102]=[CH:103][CH:104]=1)=[O:89])[C:92]1[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Agent: CC(C)C(=C=O)[C@H](NOCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reaction time: 24 h

Procedure:
The L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride obtained from de-protection of 6.43 g. of Nα -benzyloxy-carbonyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride, 4.3 g. of Nα -benzyloxycarbonyl-D-phenylalanine p-nitrophenyl ester (prepared as for the L-isomer, J. Org. Chem. 27, 3409 (1962)) and 30 ml. of dimethylformamide is stirred until solution is complete. The solution is allowed to stand at 25° C. for 24 hours, filtered from a small amount of fine solid and again allowed to stand at 25° C. for 24 hours. The solution is evaporated to dryness at 40° C. under reduced pressure. The residue is dissolved in methanol (40 ml.) and ethyl acetate (30 ml.) and dropped into 300 ml. of stirred dry diethyl ether. The granular solid which precipitates is separated by decanting and the precipitation is repeated. The solid is separated and dried at 45° C. under reduced pressure to give 6.5 g. of product suitable for use but showing by ultraviolet absorption 0.37% of p-nitrophenol; [α]D23 -54.6° (c 1.0, methanol); ultraviolet in methanol λmax 257 E11 5.8.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C1(C)C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>CCOCC.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:26][NH:27][CH:28]=2)=[CH:15][CH:16]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a mixture of 5.63 g of a 60% sodium hydride/oil suspension in 200 mL of dry ether under nitrogen is added from an additional funnel a mixture of 23.5 g (122 mmol) of ethyl p-chlorocinnamate and 19.4 g (122 mmol) of (p-tolylsulfonyl)methyl isocyanide in solution in 180 mL of ether and 80 mL of dimethylsulfonide. The addition time is about 20 minutes and results in gentle refluxing of the mixture. After another 10 minutes stirring, the mixture is diluted with 100 mL of water. The mixture is extracted four times with ether which is then dried over magnessium sulfate followed by concentrated in vacuo. The resulting solid is recrystallized from ethylene dichlorite to give 7.8 g of crystals, m.p. 137°-138° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[NH:16][C:15](=[O:24])[CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([Br:35])[C:33]=1[Br:34])[CH2:29]Br>CN(C)C=O.O>[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[N:16]([CH2:29][C:28]2[CH:27]=[C:26]([Br:25])[C:33]([Br:34])=[C:32]([Br:35])[CH:31]=2)[C:15](=[O:24])[CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1cc(Br)c(Br)c(Br)c1
Reactant: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2n1Cc1cc(Br)c(Br)c(Br)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.675g. of 80% w/w suspension; freed of mineral oil as in Example 1) in dimethylformamide (100ml.) under a nitrogen atmosphere was added 4-(2-benzyloxyethyl)-6-fluoro-1,2-dihydro-2-oxoquinoline (6.0g.). The mixture was stirred at 40° C. for one hour and then treated at this temperature with 3,4,5-tribromobenzylbromide (9.1g.). The mixture was stirred overnight at ambient temperature and then diluted with water (200 ml.) and the product extracted with ethyl acetate (3 × 150ml.). The combined organic extracts were washed with water (2 × 100ml.), dried (MgSO4), and evaporated. The residue was a mixture of O- and N-substituted products. Chromatography of this residue on silica gel using a 50:50 v/v mixture of ether and petroleum ether (b.p. 40°-60° C.) as eluant gave 4-(2-benzyloxyethyl)-6-fluoro-1-(3,4,5-tribromobenzyl)-1,2-dihydro-2-oxoquinoline, as an oil, Infra-Red Spectral Absorption ν max. 1665 cm.-1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.[CH3:38][C:39]([CH3:41])=O>>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:39]([CH3:41])[CH3:38])[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)=O
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CN(C(C)C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized by following the Reductive Amination Procedure using N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide and acetone. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.06 Hz, 6H) 1.44-1.80 (m, 6H) 1.95 (br. s., 2H) 2.27 (m, 6.09 Hz, 1H) 2.89 (t, J=7.33 Hz, 2H) 3.50 (t, J=7.33 Hz, 2H) 3.92 (s, 3H) 4.08 (t, J=13.89 Hz, 2H) 4.29-4.42 (m, 1H) 4.72-4.89 (m, 1H) 7.19 (d, J=6.82 Hz, 1H) 8.05 (s, 1H) 8.25 (d, J=13.39 Hz, 1H) 8.29-8.32 (m, 1H) 8.40 (d, J=7.07 Hz, 1H). [M+H] calculated for C27H34F3N7O3, 562. found 562.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C@H:4]1[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[C:16]1[S:17][CH:18]=[CH:19][N:20]=1
Reactant: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1nccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1CCNC[C@H]1c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Stir tert-butyl trans-4-methoxy-3-thiazol-2-yl-piperidine-1-carboxylate (4.8 g, 16.1 mmol) in dichloromethane (80.4 mL) and add trifluoroacetic acid (7.30 mL, 96.51 mmol). Stir the mixture at ambient temperature overnight. Remove the solvent under reduced pressure, and purify the residue via SCX (50 g cartridge) eluting with 2N NH3/MeOH. Concentrate the appropriate fractions under reduced pressure to give the title compound (3.2 g, 85.3%) as a waxy solid. MS (m/z): 199 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Br[C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:6]1[CH:5]=[C:4]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC1(C)OB(c2cc(Cl)c(OCC(F)(F)F)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 74.2 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (530 mg, 1.43 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (275 mg, 1.57 mmol), K2CO3 (395 mg, 2.86 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.029 mmol) in THF (3 mL) and H2O (3 mL) was heated at 80° C. in a sealed tube for 3 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel elute with PE to give 1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (360 mg; yield 74%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.Cl.[NH2:16][NH2:17].O.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:17][N:16]=1
Reactant: CCOC(=O)C(=O)CC(=O)COC
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(COC)n[nH]1

Procedure:
Ethyl 5-methoxy-2,4-dioxopentanoate (2.168 g, 11.52 mmol) was dissolved in ethanol (100 ml) and hydrazine dihydrochloride (4.84 g, 46.1 mmol) was added. The resulting mixture was refluxed for 2 h. 200 ml of water was added and the pH of the mixture was neutralized with NaHCO3. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried with Na2SO4, filtered and evaporated. The product was used in the next step without further purification. 1H-NMR (400 MHz; DMSO-d6): δ 1.29 (t, 3H), 3.26 (s, 3H), 4.27 (q, 2H), 4.42 (s, 2H), 6.72 (s, 1H), 13.62 (s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][OH:34]>C(O)C>[OH:34][N:33]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: CO[C@@H](Cc1ccc(C#CCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O
Reactant: NO
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCCOc2ccc(C(=NO)c3ccccc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionic acid from Example 42, (1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS (ES) for C27H25NO5 [M+H]+: 444.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4](=[CH2:11])[CH2:5][CH2:6][C:7](OC)=[O:8].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][CH2:6][C:7](=[O:8])[N:18]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])[CH2:11]1)=[O:12]
Reactant: C=C(CCC(=O)OC)C(=O)OC
Reactant: COc1ccc(CN)c(OC)c1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(=O)N(Cc2ccc(OC)cc2OC)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methylenepentanedioic acid dimethyl ester (19.2 g) in toluene (195 ml) was added 2,4-dimethoxybenzylamine (16.6 ml), and the mixture was stirred for 3 days at reflux. This reaction solution was cooled to room temperature, and then washed with a 1M aqueous solution of hydrochloric acid, water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the titled compound (26.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH3:9][O:10][C:11]1[C:24]2[O:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([C:25](Cl)=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:25]([CH:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[C:24]=3[O:23][C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:26])=[N:6]1)[CH3:8]
Reactant: CCn1nnc(N)n1
Reactant: COc1cccc2c1Oc1ccccc1C2C(=O)Cl
Product: CCn1nnc(NC(=O)C2c3ccccc3Oc3c(OC)cccc32)n1

Procedure:
The title compound, white solid, m.p. 239-240° C. (dec.) and MS: (pos. ions): m/e=352.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and (RS)-4-methoxy-9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[C:16](=[O:23])[NH:15][N:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].I[CH3:25]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[C:16](=[O:23])[N:15]([CH3:25])[N:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CI
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reaction time: 0.5 h

Procedure:
6 mmol of a 60% suspension of sodium hydride in mineral oil was added to a suspension of 5 mmol of compound 1 in about 40 ml of dimethylformamide, under a flow of nitrogen at room temperature. After stirring this mixture for 30 minutes, 7 mmol of iodomethane was added and the resulting mixture was stirred for another 4 hours, after which the solvent was evaporated. The residue was partitioned between ethyl acetate and water, the organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane). Crystallized from petroleum ether (60-95° C.). M.p. 110-112° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Na]>O.CC(O)C>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:10]2[C:7]3[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=3[C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2c(N)ccc(OC)c2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CCN1CCc2c(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc(OC)c2CC1
Temperature: 120 °C

Procedure:
3-Ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamine (50.01 mg, 0.2270 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (67.4 mg, 0.227 mmol) and 10-camphorsulfonic acid (79.1 mg, 0.340 mmol) were charged to 2 ml IPA in a microwave tube. The reaction was heated to at 120° C. for 40 minutes. Pour reaction into water (50 ml) and saturated sodium bicarb (90 ml) and extract 3 times with 25 ml portions of methylene chloride. Dry combined organic over magnesium sulfate, filter and evaporate to a brown oil (102 mg). The crude reaction was purified on silica gel (12 g Isco column) using a gradient of 0-10% methanol in methylene chloride and then isocratic 20% methanol in methylene chloride to yield 2-[5-Chloro-2-(3-ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a beige foam. 1H-NMR (CDCl3) δ 11.10 (br s, 1H), 8.42 (br s, 1H), 8.02 (s, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 6.95 (m, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.43 (s, 1H), 3.89 (s, 3H), 3.12 (br s, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.93 (br s, 1H), 2.60-2.41 (m, 6H), 1.00 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])=[CH:4][CH:3]=1.C[Si]([C:20]#[N:21])(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]#[N:21])[CH:11]=[CH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc[n+]([O-])c1-c1ccc(F)cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C#N)nc1-c1ccc(F)cc1
Yield: 66.7 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-methylpyridine 1-oxide (24 g, 0.118 mol) in tetrahydrofuran (200 mL) were added trimethylsilyl cyanide (19.2 mL, 0.153 mol) and dimethylcarbamoyl chloride (14.1 mL, 0.153 mmol), and the mixture was heated under reflux for 2 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (16.7 g, 67%) as a white solid. Under reduced pressure, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9) to give the title compound (3.0 g, 12%) as a white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([I:26])=[C:22]([CH3:27])[CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[NH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>C(#N)C>[I:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:28])=[CH:21][C:22]=1[CH3:27]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1I
Reactant: NCc1cccnc1
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1I
Yield: 96.1 %

Procedure:
To a solution of 2,2,2-trichloro-1-[10-(4-iodo-3-methylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]ethanone of Step B (1 g, 1.74 mmol) in dry acetonitrile (30 mL) at room temperature under nitrogen was added dimethyl sulfoxide (0.62 mL, 8.72 mmol) followed by 3-(aminomethyl)pyridine (0.36 mL, 3.49 mmol) and the reaction mixture heated to reflux for 36 hours. The cooled reaction mixture was concentrated in vacuo to a small volume then partitioned between ethyl acetate (50 mL) and 1 M sodium hydroxide (50 mL). The organic layer was separated, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using ethyl acetate as solvent afforded a white foam (0.94 g). Recrystallization from ethyl acetate/hexane gave the title compound (0.77 g, 79%) as white solid, m.p. 176-177° C.