Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.C[Si](C)(C)N[Si](C)(C)C.[CH2:18]([NH2:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[CH2:18]([NH:28][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCN
Reactant: O=C1CONC(=O)N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCCCCCCCCCNC1=NC(=O)NOC1
Yield: 91.1 %

Procedure:
A solution of 5.0 g (0.043 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 0.025 g of ammonium sulfate, 35 ml of hexamethyldisilazane and 19.5 g (0.123 mole) of n-decylamine in 200 ml freshly distilled dry dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield approximately 10 g (92 percent) of 5-decylamino-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:13][N:14]([CH3:26])[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O.CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[N:14]([CH3:13])[CH3:26])=[CH:18][CH:19]=2)=[CH:6][N:7]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Temperature: 110 °C
Yield: 46.4 %

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (625.1 mg, 2.694 mmol), [4-(dimethylcarbamoyl)phenyl]boronic acid (520 mg, 2.694 mmol), sodium carbonate (571.1 mg, 5.388 mmol) and palladium; triphenylphosphane (311.3 mg, 0.2694 mmol) in a mixture of acetonitrile (3 mL) and water (3 mL) was heated at 110° C. in the microwave for 30 minutes. The reaction was diluted with EtOAc and water and the layers separated. The aqueous later was extracted further with EtOAc (2×) and the combined organics dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, 0-100% EtOAc/Petroleum ether) to give the desired product as a yellow solid (375 mg, 46% Yield). 1H NMR (400.0 MHz, DMSO) d 3.02 (3H, s), 3.15 (3H, s), 4.04 (3H, s), 7.54 (2H, m), 7.97 (2H, m), 8.71 (1H, s) ppm; MS (ES+) 301.13
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:13]=1)[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: NCCCn1ccnc1
Solvent: C1COCCO1
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1ccnc1
Reaction time: 0.67 h

Procedure:
5-Chloroisatoic anhydride (26.7 g) was added in portions to a stirred solution of 3-imidazol-1-ylpropylamine (17.2 g) in dioxan (150 ml) over a period of 15 minutes. Stirring was continued for 40 minutes before the solution was evaporated in vacuo to give 5-chloro-2-amino-N-(3-imidazol-1-ylpropyl)benzamide as a buff coloured solid, used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C(OCC)(=O)C>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCCc1ccc(O)cc1
Yield: 99.2 %

Procedure:
4-(4-methoxyphenyl)butanoic acid (5.0 g) was dissolved in 48% hydrobromic acid (50 mL) and acetic acid (80 mL), then the solution was refluxed by heating for 6 hours. Ethyl acetate (300 mL) is added into the reaction solution, then organic layer was washed with water (100 mL) and saturated sodium chloride solution (50 mL), dried on anhydrous sodium sulfate, filtered and vacuum concentrated, then washed with n-hexane to give the above-identified compound (4.6 g, yield 99%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]([C:11]([CH3:13])=O)=[CH2:10]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:10][CH:9]=[C:11]2[CH3:13]
Reactant: Nc1ccccc1F
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2c(F)cccc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a stirred solution of 2-fluoroaniline (1 g. 9.0 mmol.) in acetic acid (10 ml), activated silferc (1.4 g. ferric chloride 9.0 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.7 g, 9.9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.2 g. 9.0 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 65%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([N:60]2[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]2)=[O:10])=[CH:6][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH:3]=1
Reactant: COc1ccc(COc2cc(Cl)c(C(=O)O)cc2OCc2ccc(OC)cc2)cc1
Reactant: CN1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Cl)c(C(=O)N3CCN(C)CC3)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a solution of 6-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid (94 g: 218 mMol.) in tetrahydrofuran (1 liter) are added dicyclohexylcarbodiimide (50 g: 1.1 Eq.) and N-hydroxybenzotriazole (33 g: 1.1 Eq.), and the mixture is stirred at room temperature for 90 minutes. To the reaction mixture is added N-methylpiperazine (48 ml: 2 Eq.) and the resulting precipitate is filtered off. The filtrate is concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium hydroxide and water, dried and concentrated in vacuum. The residue is treated in dichloromethane and ether to remove a small amount of insoluble material and concentrated under reduced pressure to give 1-(6-chloro-3,4-bis(p-methoxybenzyloxy)benzoyl-4-methylpiperazine (108 g). Yield: 97%.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>>[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)([O:12][CH:10]([CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11])(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)OC(C)CCOc2ccccc2)cc1
Yield: 98 %

Procedure:
10 g of the 4-phenoxy-2-butanol was reacted with 13.9 g of p-toluenesulfonyl chloride in 21.2 ml of 5N-sodium hydroxide in accordance with the method described in Norris, J. Am. Chem. Soc. 38, 642 (1907) to obtain 18.9 g of 4-phenoxy-2-butyl tosylate having a boiling point of 170° C. to 171° C. at 2 mmHg in a yield of 89%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCOCC1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (4.04 g, 33.08 mmol), in acetonitrile (50 ml) was added K2CO3 (10.1 g), followed by N-(2-chloroethyl)morpholine hydrochloride (6.16 g). The reaction mixture was heated to reflux overnight, additional N-(2-chloroethyl)morpholine hydrochloride (0.6 g) and K2CO3 (0.5 g) were added and the mixture was refluxed for another 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was treated with DARCO®, filtered and the solvent was stripped. The residue was partitioned between saturated NaHCO3 (150 ml) and ethyl acetate (300 ml). The layers were separated and the organic layer was washed with 1N NaOH, dried over MgSO4, filtered and stripped to afford, as an amber oil, 6.41 g of 4-[2-(4-morpholinyl)ethoxy]benzaldehyde.
Reaction SMILES: N1C=CN=C1.[C:6]([C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7].CN(C)C=O.[CH3:20][Si:21]([CH3:24])([CH3:23])Cl>CCCCCC>[C:6]([C:8]1([O:14][Si:21]([CH3:24])([CH3:23])[CH3:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7]
Reactant: C#CC1(O)CCCCC1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CC1(O[Si](C)(C)C)CCCCC1
Reaction time: 0.02 h

Procedure:
A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexane-1-ol are mixed with 500 g of dimethylformamide with cooling in an ice bath. A 152 g portion of trimethylchlorosilane is added with cooling and stirring in about one minute. The mixture is stirred for one hour and allowed to stand overnight. One liter of hexane is added. The lower layer is separated, diluted with water and extracted with hexane. The hexane layers are washed several times with water and then combined and dried over magnesium sulfate. Filtration and then evaporation of the hexane gives 198.5 g of product which is distilled giving 168 g of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[O:9][C:10](=O)[C:5]=2[CH:4]=1)[CH3:2].[NH2:29][CH2:30]C(O)=O>C(O)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[CH2:30][NH:29][C:10](=[O:9])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: NCC(=O)O
Reactant: CCc1cc2c(=O)oc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Solvent: CC(=O)O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CNC2=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 48.4 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-2H-thieno[2,3-d][1,3]oxazine-1(4H)-yl)methyl]biphenyl-2-carbonitrile (2 g), glycine (0.46 g) and acetic acid (20 mL) was stirred at 100° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@@H:16]4[CH2:25][CH2:24][C:19]5(OCC[O:20]5)[CH2:18][C@H:17]4[CH3:26])=[N:13][CH:12]=[C:11]([C:27]#[N:28])[C:7]=3[NH:8][C:9]=2[CH:10]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@@H:16]4[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][C@H:17]4[CH3:26])=[N:13][CH:12]=[C:11]([C:27]#[N:28])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: C[C@@H]1CC2(CC[C@H]1Nc1ncc(C#N)c3[nH]c4cc(Cl)ccc4c13)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1CC(=O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3cc(Cl)ccc3c12
Reaction time: 8 h

Procedure:
To a stirred solution of 7-chloro-1-{[(7R,8R)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (147 mg, 0.37 mmol) in acetone (15 mL) was added pTsOH.H2O (176 mg, 0.93 mmol). The mixture was left to stir overnight, diluted with EtOAc, and washed with aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate), and concentrated to afford the title compound. LRMS (APCI) calc'd for (C19H17ClN4O) [M+H]+, 353.1. found 353.0.
Reaction SMILES: COC1C=C([C:11](=O)[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3CCC[C@H:18]3[CH2:17]2)=O)C=CC=1OC.C(OC(N1CCCCC1C(O)=O)=O)(C)(C)C.[Cl:42][C:43]1[CH:55]=[CH:54][C:46]([C:47]([CH2:49][CH2:50][C:51]([OH:53])=O)=[O:48])=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([C:47](=[O:48])[CH2:49][CH2:50][C:51]([N:19]2[CH2:20][CH2:21][N:16]3[CH2:14][CH2:13][CH2:12][CH2:11][CH:17]3[CH2:18]2)=[O:53])=[CH:54][CH:55]=1
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Product: O=C(CCC(=O)N1CCN2CCCCC2C1)c1ccc(Cl)cc1

Procedure:
463 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using 1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(4-chlorobenzoyl)propanoic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]=2)[O:3]1.[ClH:23]>CC(OC)(C)C.CCOCC>[ClH:23].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:22])[O:3][B:4]([C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: CC1(C)OB(C2=CCNCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HCl in Et2O (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et2O to give the title compound (1.434 g, 90%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[Br:16][C:17]1[CH:18]=[N:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=1>>[Br:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([N:13]2[CH2:12][CH2:11][N:10]([C:4]3[C:3]([CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][N:5]=3)[CH2:15][CH2:14]2)=[O:24])=[N:21][CH:22]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Yield: 99.7 %

Procedure:
Using 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (528 mg) described in Preparation Example 80 and 5-bromopyrimidine-2-carboxylic acid (406 mg) and by the reaction and treatment in the same manner as in Example 97, (5-bromopyrimidin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (750 mg) was obtained. Using this compound (750 mg) and (R)-4-methyl-2-oxazolidinone (303 mg) and by the reaction and treatment in the same manner as in Example 1, (R)-3-[2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyrimidin-5-yl]-4-methyloxazolidin-2-one was obtained. The obtained (R)-3-[2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyrimidin-5-yl]-4-methyloxazolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.4 mL) was added, and the precipitate was collected by filtration to give the title compound (509 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.O>C1(C)C(C)=CC=CC=1>[CH3:14][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[N:9]=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=1
Reactant: CN(C)CCCOc1ccccc1N
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: CN(C)CCCOc1ccccc1N=Cc1cccc(C(F)(F)F)c1
Yield: 52.6 %

Procedure:
A solution of 19.4g of 2-(3-dimethylaminopropoxy)aniline and 17.4g of m-trifluoromethylbenzaldehyde in 100ml of xylene is refluxed for about 6 hours. The water formed in the reaction is collected in a Dean-Stark tube. The solvent is removed under reduced pressure and the residue fractionated to yield 18.4g of the title compound as an oil, boiling point 155°-160° C. at 0.2-0.3 mm. of Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20](/N=C/N(C)C)=[O:21])=NC=1.NN>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:20][O:21]3)[N:9]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(-c2nc[nH]n2)nc1
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cn1
Agent: NN
Product: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Yield: 83 %

Procedure:
5-Bromo-2-(1H-1,2,4-triazol-3-yl)pyridine. A solution of (E)-5-bromo-N-((dimethylamino)methylene)picolinamide (0.604 mg, 2.36 mmol) and hydrazine (2.12 g, 66.1 mmol) was stirred at 25° C. for 3 h. The reaction was concentrated and diluted with water. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (0.442 g, 83% yield). MS (ESI) m/z 226.1 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[O:6][CH:7]=[C:8]([OH:18])[C:9]2[C:10]=1[N:11]=[C:12]1[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]1>[O-2].[O-2].[Mn+4]>[O:18]=[C:8]1[C:9]2[C:10]([N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)=[C:5]([CH2:4][C:3]([OH:19])=[O:2])[O:6][CH2:7]1
Reactant: COC(=O)Cc1occ(O)c2c3ccccc3nc1-2
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(O)CC1=C2N=c3ccccc3=C2C(=O)CO1

Procedure:
Oxidation of 4-hydroxypyrano[3,4-b]indole acetic acid methyl ester 15 with manganese dioxide, followed by hydrolysis, afforded 4-oxopyrano[3,4-b]-indole acetic acid 18. When 15 was treated with urea in acidified aqueous tetrahydrofuran, a quantitative conversion to 4-ureidopyrano[3,4-b]indole acetic acid methyl ester 13 was achieved.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]#[N:34])[N:19]=3)[C:15](=[O:35])[C@@H:14]([NH:36][C:37](=[O:49])[C@@H:38]([N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH3:39])[C:8]3([CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[O:7][C:6]=2[CH:50]=1.[CH3:51][N:52](C=O)C>[NH4+].[Cl-].[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:51]([C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]#[N:34])[N:19]=3)[C:15](=[O:35])[C@@H:14]([NH:36][C:37](=[O:49])[C@@H:38]([N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH3:39])[C:8]3([CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[O:7][C:6]=2[CH:50]=1)#[N:52]
Reactant: CN(C)C=O
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2nn(-c3ccccc3C#N)c3ccccc23)c2ccc(Br)cc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2nn(-c3ccccc3C#N)c3ccccc23)c2ccc(C#N)cc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 94 %

Procedure:
A solution of tert-butyl (S)-1-((S)-8-bromo-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (50 mg, 67.2 μmol, Eq: 1.00) in DMF (1.5 mL) was degassed with argon and Zn(CN)2 (15.8 mg, 134 μmol, Eq: 2) and Pd(Ph3P)4 (23.3 mg, 20.2 μmol, Eq: 0.3) were added. The mixture was heated in microwave at 110° C. for 30 min., cooled, diluted with sat. NH4Cl and extracted with EtOAc. The combined extracts were washed with H2O, then concentrated and the residue was purified by preparative TLC to give tert-butyl (S)-1-((S)-8-cyano-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (43.5 mg, 94%)
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.Cl.O1CCOCC1>>[ClH:26].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:6]3[CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[CH:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)CCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 122 %

Procedure:
Following the general procedure for Example 18, the product from step 1 (0.62 g, 1.59 mmol) was treated with a 1:1 mixture of concentrated HCl/dioxane (28 mL) to afford the title compound (0.40 g, 68%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:22]1(B(O)O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:30]1([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15])[CH:5]=[N:6][CH:7]=2)[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cccc3ccccc23)c1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.00 mmol) in benzene (2.0 mL) were added aqueous sodium carbonate (2.0 M, 1.0 mL), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) and 1-naphthaleneboronic acid (189 mg, 1.10 mmol). The reaction mixture was refluxed overnight, then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (196 mg, 62%). MS (CI/NH3) m/z 319 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.71-1.92 (m, 3H), 2.00-2.10 (m, 1H), 2.27-2.38 (m, 1H), 2.51 (s, 3H), 2.66-2.75 (m, 1H), 3.09-3.17 (m, 1H), 3.98-4.14 (m, 2H), 7.34-7.57 (m, 5H), 7.72-7.96 (m, 3H), 8.36-8.43 (m, 1H).
Reaction SMILES: CO.[Li+].[BH4-].C([O:7][C:8]([C:10]1[CH:11]=[C:12]2[CH2:17][CH2:16][CH2:15][N:13]2[N:14]=1)=O)C>C1COCC1>[N:14]1[N:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[CH:11][C:10]=1[CH2:8][OH:7]
Reactant: CCOC(=O)c1cc2n(n1)CCC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2n(n1)CCC2
Temperature: 40 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
MeOH (2.73 mL) was added to the THF (180 mL) solution of LiBH4 (1.63 g) under a nitrogen atmosphere at room temperature, and then 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid ethyl ester (8.11 g) was added to the suspension and stirred for 2 h at 40° C. The mixture was quenched with 1 mol/L HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3 was added to the solution to adjust pH to 8 and the mixture was extracted with AcOEt. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as brown crystals (4.87 g, 78%).