Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH2:11].C(O)C>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:11][CH3:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNCc1ccc(Cl)nc1
Temperature: 20 °C

Procedure:
A mixture of the product of Example 4(b), 2-chloro-5-chloromethylpyridine, (8.1 g, 0.05 mol), methylamine (60 ml of a 30% w/v solution in water, 0.5 mol) and ethanol (100 ml) was heated, with stirring, under reflux for 5 hours. The reaction mixture was then cooled to ambient temperature (20° C.) and the solvent removed by evaporation under reduced pressure to give a brown oil. The product, N-(6-chloro-3-pyridylmethyl)-N-methylamine, was isolated from this oil by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with 10% v/v methanol/dichloromethane as eluent, as a brown oil (5.96 g, 76.1%).
Reaction SMILES: [CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[OH:10])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[O:10][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCCCC1(C(=O)OCC)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccc(C)cc1

Procedure:
6.42 grams of ethyl 1-n-butyl-2-hydroxy-cyclopentane carboxylate obtained in Example 16 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.66 ml of pyridine was slowly added, then 6.12 ml of 4-methyl-benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 11.77 g of brown liquid. MS: m/e 332(M+′), 287(M+—OCH2CH3), 213(M+—CH3C6H4CO), 197(M+—CH3C6H4CO2), 119 (base), 91.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([F:26])=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)(=[O:51])[CH3:50]>CN(C)C=O>[C:49]([N:52]1[CH2:57][CH2:56][N:55]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[C:17]([F:26])=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH3:25])=[CH:19]5)=[N:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:27][CH3:28])[CH2:54][CH2:53]1)(=[O:51])[CH3:50]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCBr
Reactant: CC(=O)N1CCNCC1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline (310 mg of a sample containing triphenylphosphine oxide (approx. 12% w/w), 0.61 mmol) and 1-acetylpiperazine (258 mg, 2.02 mmol) in N,N-dimethylformamide (5 ml) was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (202 mg, 67%) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>O1CCCC1>[C:16]([Si:13]([CH3:15])([CH3:14])[N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[CH:3]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Ic1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine 634 (1.11 g, 4.6 mmol) was dissolved in tetrahydrofuran (120 mL). Sodium hydride (60% dispersion in mineral oil, 0.13 g, 5.5 mmol) was added, followed by tert-butyldimethylsilyl chloride (0.85 g, 5.5 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound as a white solid (636, 100 mg, 15%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:35](=O)([O:41]C(C)(C)C)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3.03 g (8.70 mmol) of Compound 27 obtained in Example 27 was dissolved in 200 ml of dimethylformamide, 109 mg of dimethylaminopyridine and 3.0 ml of di-tert-butyl carbonate were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 3.44 g (88%) of 2-[4-[N-acetyl-N-(tert-butoxycarbonyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: ClC1C=C(C#N)C2C=C[N:8]([C:11]3[N:12]([CH2:22][CH3:23])[C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=3[CH:17]([CH3:19])[CH3:18])C=2C=1.N1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[N:27]1>>[CH2:22]([N:12]1[C:11]([N:8]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[N:27]2)=[C:16]([CH:17]([CH3:18])[CH3:19])[C:15](=[O:20])[NH:14][C:13]1=[O:21])[CH3:23]
Reactant: CCn1c(-n2ccc3c(C#N)cc(Cl)cc32)c(C(C)C)c(=O)[nH]c1=O
Reactant: c1ccc2[nH]ncc2c1
Product: CCn1c(-n2ncc3ccccc32)c(C(C)C)c(=O)[nH]c1=O

Procedure:
This compound was made by a procedure similar to that used to prepare 6-chloro-1-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-1H-indole-4-carbonitrile (90), except that 1H-indazole was used instead of 6-chloro-1H-indole-4-carbonitrile. LC-MS shows 299.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 8.97 (br, 1H), 8.31 (s, 1H), 7.83 (d, 2H), 7.54 (m, 1H), 7.36 (m, 2H), 3.42 (m, 1H), 3.20 (m, 1H), 1.90 (m, 1H), 1.15 (dd, 6H), 1.00 (t, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:15][CH2:16][C:17]3[S:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[N:21]=3)[CH:11]=2)[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[N:21]=[C:17]([CH2:16][NH:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13]3)[S:18][CH:19]=1
Reactant: COC(=O)c1ccc2cc(NCc3nc(-c4ccccc4Cl)cs3)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(NCc3nc(-c4ccccc4Cl)cs3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The crude 6-{[4-(2-chloro-phenyl)-thiazol-2-ylmethyl]-amino}-naphthalene-2-carboxylic acid methyl ester from Step A is dissolved in THF (1 mL). A solution of 1 M LiOH in H2O (1 mL) is added and the mixture is stirred for 12 h at rt. The mixture is acidified with 1 M HCl (1 mL) and extracted into EtOAc (20 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound G1 as a white solid: MS calcd. for C21H16ClN2O2S (M+H+) 395.9. found 396.0.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(C3C(=O)N(C(C)=O)c4ccccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
A solution of 1-acetyloxindole (251 mg, 1.6 mmol), ( J. Med. Chem. 1986, 1838), in DMF (3 ml) was added to a suspension of sodium hydride (50 mg, 2.4 mmol) in DMF (10 ml) and the mixture stirred for 10 minutes at ambient temperature. 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (108 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), in DMF (3 ml) was added and the mixture stirred for 1.5 hours at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (70/30). The purified product was recrystallised from methylene chloride/ether, collected by filtration, washed with ether and dried under vacuum to give 4-(1-acetyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (77 mg, 47%).
Reaction SMILES: [N:1]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][CH2:26][C@H:2]1[C:3]([NH:5][C@H:6]([C:12]([NH:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10])=[O:4].[H][H]>CO.[Pd]>[N:1]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][CH2:26][C@H:2]1[C:3]([NH:5][C@H:6]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)O

Procedure:
Boc-Pro-Gln-Gly-OBzl (4.0 g, 8.2 m mol) was dissolved in 90% methanol (60 ml), and hydrogen gas was passed through the solution in the presence of a spoonful of Pd-C for 6 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was solidified by the addition of ether and recrystallized from methanol-ether.
Reaction SMILES: C1(C)C=CC([C:7]([C@:9](C(O)=O)([OH:24])[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=[O:8])=CC=1.[F:29][C:30]1[C:35]([C@@H:36]([NH:38][CH2:39][C@@H:40]([OH:42])[CH3:41])[CH3:37])=[CH:34][CH:33]=[C:32]([F:43])[N:31]=1>[OH-].[Na+]>[F:29][C:30]1[C:35]([C@@H:36]([N:38]2[CH2:39][C@H:40]([CH3:41])[O:42][C:7](=[O:8])[C:9]2=[O:24])[CH3:37])=[CH:34][CH:33]=[C:32]([F:43])[N:31]=1
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Reactant: C[C@H](O)CN[C@@H](C)c1ccc(F)nc1F
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1CN([C@@H](C)c2ccc(F)nc2F)C(=O)C(=O)O1
Temperature: 145 °C
Yield: 115.4 %

Procedure:
(S)-1-[(S)-1-(2,6-difluoropyridin-3-yl)ethylamino]propan-2-ol (+)-di-p-toluoyl-D-tartrate (199 g) was dissolved in 5 N aqueous sodium hydroxide (450 mL), water (1,000 mL), and 50% toluene-THF (2,000 mL), and the organic layer was separated. The aqueous layer was washed with 50% toluene-THF (800 mL) three times. The organic layers were combined and concentrated under reduced pressure. Then, diethyl oxalate (200 mL) was added to the residue, and the reaction solution was heated and stirred at 140 to 150° C. Three hours later, the reaction solution was diluted with toluene (500 mL) and then ice-cooled while stirring. The precipitated crystals were collected by filtration, washed with toluene and diethyl ether, and then air-dried to obtain 103 g of the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH:11]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C(c1ccc2nc(Oc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 80 °C

Procedure:
A suspension of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine (54 mg, 0.14 mmol), methyl-4-hydroxybenzoate (21.7 mg, 0.14 mmol) and potassium carbonate (21.6 mg, 0.16 mmol) in 1 mL of DMF was heated at 80° C. overnight. The mixture was concentration in vacuo and the residue partitioned between water and DCM. After extracting the aqueous layer, the combined DCM extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified using PTLC and eluting with 5% MeOH (2N NH3)/DCM to provide methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate. MS (ESI) m/z 451.17 [M+H]+.
Reaction SMILES: N[C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:19]>N([O-])=O.[Na+]>[OH:19][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCc2ccc(N)cc2CC1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Product: CCOC(=O)N1CCc2ccc(O)cc2CC1

Procedure:
To ethyl 7-amino-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate was added a 5% aqueous sulfuric acid solution, followed by stirring under ice-cooling. An aqueous solution (30 ml) of 10.22 g of sodium nitrite was added dropwise in portions thereto, and followed by stirring at the same temperature for 0.5 hours and then stirring at 60° C. for 3 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain a crude purified product having ethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a main component. The crude purified product was recrystallized from ethyl acetate twice to obtain 15.66 g of ethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:22]#[N:23])=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)C#N
Reactant: CSc1ccc(N=Cc2ccc(C)cc2)cc1
Product: CSc1ccc(NC(C#N)c2ccc(C)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methylbenzylidene)-4-methylthioaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 73%).
Reaction SMILES: [C:1]([CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[I-].[Na+].[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1.O>[C:1]([C:6]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1CCCCCCC1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC1(C(=O)OCC)CCCCCCC1=O
Temperature: 110 °C

Procedure:
A solution of 2-carboethoxy-cyclooctanone (92.2 g, 0.5 mole) in toluene (1.6 l) is treated with sodium iodide (1 g) and 60% sodium hydride in mineral oil (23.3 g, 0.58 mole). The mixture is heated at 110° C. The mixture is treated with ethyl α-bromoacetate (98.0 g, 0.58 mole) dropwise and the mixture is warmed to 65° C. for 18 hours. The mixture is cooled and water (500 ml) was added. The layers are separated and the aqueous is extracted with toluene (2×1 l). The extracts are dried (MgSO4) and filtered. The filtrate is concentrated at reduced pressure and distilled to yield pure 2-carboethoxy-2-carboethoxymethylcyclooctanone with a bp of 193°-195° C. at 16 mm.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:6]([F:20])=[CH:5][N:4]=1.[CH:21]1([C:24]2[C:29]([N:30]3[C:34]([CH3:35])=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH2:36])=[C:26]([F:37])[CH:25]=2)[CH2:23][CH2:22]1>CC(O)C>[CH:21]1([C:24]2[C:29]([N:30]3[C:34]([CH3:35])=[N:33][N:32]=[N:31]3)=[CH:28][C:27]([NH:36][C:3]3[N:8]=[C:7]([NH:9][CH:10]4[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]4)[C:6]([F:20])=[CH:5][N:4]=3)=[C:26]([F:37])[CH:25]=2)[CH2:22][CH2:23]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Reactant: Cc1nnnn1-c1cc(N)c(F)cc1C1CC1
Agent: Cl
Solvent: CC(C)O
Product: Cc1nnnn1-c1cc(Nc2ncc(F)c(NC3CC(C)(C)NC(C)(C)C3)n2)c(F)cc1C1CC1
Temperature: 70 °C
Yield: 57.9 %

Procedure:
A mixture of 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine hydrochloride (416 mg, 1.29 mmol, 1 equiv), 4-cyclopropyl-2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)benzenamine (300 mg, 1.29 mmol, 1 equiv), and PTSA monohydrate (196 mg, 1.03 mmol, 0.8 equiv) in IPA (13 mL) were heated to 70° C. for 6 days. After cooling to ambient temperature, the crude mixture was concentrated to dryness and taken in water, EtOAc, and 1N NaOH. The layers were separated. The organic layer was washed with 1N NaOH 2×, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by trituration from EtOAc:hexane to give compound N2-(4-cyclopropyl-2-fluoro-5-(5-methyl-1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine (361 mg, 58%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>CO.C(#N)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To 2-fluoro-6-nitrobenzoic acid (712 mg, 3.85 mmol) in methanol/acetonitrile (10 mL/10 mL) was dropwise added TMSCHN2 at 0° C. under N2 until yellow color persistent, and stirred additional 30 min. Then the reaction was quenched with HOAcat 0° C. until the yellow color disappears. Partial of the solvent was removed o rotary vacuum, the residue was dissolved in small amount of EtOAc, purified on flash chromatography eluting with 30˜50% EtOAc/hexanes (600 mL) to afford the expected product, methyl 2-fluoro-6-nitrobenzoate, (716 mg, 94% yield) which was used in step-2; 1H NMR (400 MHz, CDCl3) δ ppm 3.96 (s, 3 H), 7.40-7.48 (m, 1 H), 7.58 (td, J=8.31, 5.54 Hz, 1 H), 7.94 (d, J=8.31 Hz, 1 H); Mass spec. 200.05 (MH+), Calc. for C8H6FNO4 199.03.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.O>CN1CCCC1=O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:37][CH2:36][C:35]4[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: NCc1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Cc2cnc(NCc3ccc(Cl)cc3)nc2)c2cc(Cl)cnc21
Yield: 73.3 %

Procedure:
To 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (610, 0.060 g, 0.13 mmol, prepared as described in Example 74, Scheme 191) in N-methylpyrrolidinone (1.80 mL) was added p-chlorobenzylamine (61, 0.20 g, 1.4 mmol). The reaction was irradiated with microwave on 300 watts, 150° C. for 15 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (613, 0.05 g, 74%). MS (ESI) [M+H+]+=524.3.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12](=[O:24])[CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=3[CH3:23])[CH2:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[C:35]2[NH:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[NH:31][CH2:30][C:29]=2[CH:28]=[N:27]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]1([CH2:5][N:6]2[CH2:7][CH2:8][N:9]([C:12](=[O:24])[CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:31]4[CH2:30][C:29]5[CH:28]=[N:27][N:26]([CH3:25])[C:35]=5[NH:34][C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]4=5)=[O:19])=[CH:16][C:15]=3[CH3:23])[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1CC(=O)N1CCN(CC2CCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CC(=O)N1CCN(CC2CCC2)CC1
Yield: 32 %

Procedure:
WSCD (76 mg, 0.39 mmol) and DMAP (7 mg, 0.06 mmol) were added to a solution of 4-[2-(4-cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid from Example E85.2 (100 mg, 0.30 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (61 mg, 0.30 mmol) in dichloromethane (20 ml) and DIEA (0.16 ml, 0.91 mmol). The mixture was heated at reflux for 20 h and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 6% methanol:94% dichloromethane to 1% 35% ammonia:7% methanol:92% dichloromethane) to give an off-white solid identified as the title compound (50 mg, 32%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[ClH:35].[Cl:36][CH2:37][C:38]1[CH:39]=[N:40]C=CC=1.Cl>>[ClH:36].[ClH:35].[CH2:1]([O:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][C:24]2[CH:25]=[N:40][CH:39]=[CH:38][CH:37]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: ClCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCc3cccnc3)cc2OCc2ccccc2)n1
Yield: 53.2 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 3-(chloromethyl)pyridine hydrochloride (27.6 mg, 0.17 mmol were reacted according to the method of Example 43 to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(pyridin-3-ylmethylthio)pyridin-2-amine dihydrochloride (44.2 mg, 53.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 8.68 (dd, 1H), 8.65 (d, 1H), 8.11 (m, 1H), 7.80-7.75 (m, 2H), 7.60-7.55 (m, 3H), 7.45-7.34 (m, 3H), 6.75 (s, 1H), 5.30 (s, 2H), 4.34 (s, 2H), 2.28 (d, 3H); Mass spectrum (apci) m/z=238.0 (100), 330.0 (70), 421.0 (60).