Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>CN(C)C=O>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 140 °C
Yield: 91.75 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in N,N-dimethylformamide (70 mL) respectively and heated to 140° C. Then lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.68 g, yield: 91.75%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([OH:10])[CH3:9])=[N:6][C:5]([Cl:11])=[C:4]([Cl:12])[N:3]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[C:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([Cl:12])=[C:5]([Cl:11])[N:6]=1)(=[O:10])[CH3:9]
Reactant: CC(O)c1nc(Cl)c(Cl)nc1N
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)c1nc(Cl)c(Cl)nc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 6 ml of acetone there was dissolved 90 mg of 2-amino-5,6-dichloro-3-(1-hydroxyethyl)pyrazine prepared in Step A above, after which there was added 360 mg of manganese dioxide, and the reaction mixture was stirred for 3 days at room temperature. The manganese dioxide was filtered off, and the precipitate washed three times with acetone, and then filtered. The filtrate was concentrated under vacuum and passed through a silica gel column, then eluted first with hexane, followed by 10% dichloromethane in hexane, with product in the first three fractions (53 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([O:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:31])=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:31])=[O:14])=[C:11]([O:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(C)Oc1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccccc1C(C)Oc1cc(OCc2ccccc2)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 4-benzyloxy-2-(1-o-tolylethoxy)benzoic acid (2.5 g) in dichloromethane (50 mL) is treated with a 2 M solution of oxalyl chloride in dichloromethane (6.5 mL) and stirred at 25° C. for 3.5 hours. The mixture is evaporated to give 4-benzyloxy-2-(1-o-tolylethoxy)benzoyl chloride as a brown liquid (2.73 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31].BrCCOC(=O)C.[H-].[Li+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:31][CH2:30][OH:29])[CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31]
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Agent: CC(=O)OCCBr
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Product: C=C(C)C1N(CCO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (150 mg, 0.26 mmol) and acetic acid 2-bromo-ethyl ester (867 mg, 5.22 mmol) was added LiH (63 mg, 7.9 mmol). The mixture was stirred at room temperature for 20 h, then diluted with ethyl acetate (10 mL), quenched with water (10 mL). The organic layer was separated, washed with water for 5 times, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give product (57 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][CH:16]3[CH2:20][O:19]C(C)(C)[O:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)=[CH:5][C:4]=2[N:3]=1.[ClH:41].Cl.NC1C2N=C(COCC)N(CC(O)CO)C=2C2C=CC(ON3CCCCC3)=CC=2N=1>>[ClH:41].[ClH:41].[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][CH:16]([OH:17])[CH2:20][OH:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC1COC(C)(C)O1
Agent: CCOCc1nc2c(N)nc3cc(ON4CCCCC4)ccc3c2n1CC(O)CO
Agent: Cl
Product: CCOCc1nc2c(N)nc3cc(OC4CCNCC4)ccc3c2n1CC(O)CO

Procedure:
Using the method described in Example 373, tert-butyl 4-{[4-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (7.00 g, 12.6 mmol) was converted into 5.22 g of 3-[4-amino-2-(ethoxymethyl)-7-(piperidinyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol dihydrochloride, which was isolated as a tan powder, mp 278-280° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2c(-c3nc(/C=C/C(=O)O)cs3)cnn2C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a mixed solution of the compound (200 mg, 0.49 mmol) obtained in step 4 in THF (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (0.972 ml, 0.97 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, and 1N hydrochloric acid was added until the mixture became pH 2-3. The mixture was extracted with ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure to give (E)-3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acrylic acid (180.7 mg, 0.471 mmol, 97%) as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(F)c(Cl)c2)cn1
Yield: 5 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-chloro-4-fluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (8 mg, 5%) which was obtained as a white solid. MS (ESI): m/e=353.9 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]([C:5]1[S:6][C:7]([CH2:10][N:11]2[CH2:15][C:14](=[O:16])[N:13](CC3C=CC(OC)=CC=3OC)[S:12]2(=[O:29])=[O:28])=[CH:8][CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]([C:5]1[S:6][C:7]([CH2:10][N:11]2[CH2:15][C:14](=[O:16])[NH:13][S:12]2(=[O:28])=[O:29])=[CH:8][CH:9]=1)=[O:4]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)N(C)CCc4ccccc4)s3)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCc1ccccc1)C(=O)c1ccc(CN2CC(=O)NS2(=O)=O)s1

Procedure:
A solution of the title E compound, 5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylic acid methyl-phenethyl-amide (70 mg, 0.13 mmol) in CH2Cl2 (2 mL) is stirred with TFA (2 mL) at RT for 4 h. The volatiles are evaporated and the residue is stirred in equal volumes of MeCN/water (4 mL). The mixture is filtered through a 0.2μ Acrodisc and the solvents are evaporated to dryness. The residue is trituated from Et2O to afford 5-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2-carboxylic acid methyl-phenethylamide as an off white solid: [M−1]−=392.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1nc(-c2ccc(N(C)C)cc2)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of methyl 2-[4-(dimethylamino)phenyl]quinazoline-4-carboxylate (2.02 g, 6.57 mmol, 1.00 equiv) in ethanol (60 mL) and a solution of NaOH (1.32 g, 33.00 mmol, 5.00 equiv) in water (20 mL). The resulting solution was stirred for 6 h at 50° C. in an oil bath. The reaction mixture was cooled to room temperature. The mixture was concentrated under vacuum. The residue was dissolved in 20 mL of water. The pH value of the solution was adjusted to 5-6 with acetic acid. The solids were collected by filtration. This resulted in 800 mg (41%) of 2-[4-(dimethylamino)phenyl]quinazoline-4-carboxylic acid as a red solid. (ESI) m/z 294 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12].[Li+].[OH-].C(O)C>C1COCC1>[CH3:12][C:8]1[C:7]2[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[CH:6]=2)[NH:10][N:9]=1
Reactant: CCOC(=O)c1cc(OC)c2[nH]nc(C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C(=O)O)cc2c(C)n[nH]c12
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 7-methoxy-3-methyl-1H-indazole-5-carboxylate (516 mg, 2.08 mmol) in THF (17 mL) was added 1 M LiOH (4.2 mL, 4.2 mmol) and the mixture was heated at reflux overnight. Analysis indicated the presence of small amounts of unreacted starting material; therefore, a small amount of ethanol was added to assist in solubilizing materials. Heating was continued for an additional 2 hours before concentrating to dryness. The residue was triturated with 1 N HCl, the solids were isolated by filtration, washed with water and air dried overnight to provide the title compound as an off-white solid (417 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)(=[O:27])=[O:26].[OH-].[NH4+:34]>>[NH2:34][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:22])([CH3:23])[CH3:21])=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)(=[O:27])=[O:26])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (130 mg, 0.255 mmol) and ammonium hydroxide (3 mL), the title compound was obtained as an off-white solid (48 mg, 38% yield). MS (ESI): 490 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1.CO.C(Cl)Cl.CCOC(C)=O.CO>[ClH:22].[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: Fc1ccc(CC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(t-butoxycarbonyl)-4-(4-fluorophenylmethyl)piperidine (11.2 g, 38.2 mmol) was dissolved in 4M HCl in dioxane (50 mL). The reaction was stirred for 15 min and then conc. in vacuo to a white solid. The solid was dissolved in 3% MeOH/CH2Cl2 in EtOAc/MeOH while warming once all solids were dissolved hexanes was added. The crystallization was allowed to cool to room temperature and then placed at 4° C. for 16 h. The white solids were filtered off to yield 8.4 g of product. MS (ESI) 194 (M−HCl+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si](C=[N+]=[N-])(C)C>CO>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
1-(Benzyloxycarbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1-JJ, 1.07 g, 2.9 mmol, Small Molecules, Inc., Hoboken, N.J. USA) was dissolved in 10 mL of dry methanol and trimethylsilyl diazomethane (2.0 M in diethyl ether, Aldrich) was added dropwise with stirring at rt until a slight yellow color persisted. The solution was then concentrated under reduced pressure, and flash chromatography (0-50% EtOAc/hexanes elution) gave 1-benzyl 4-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (compound II-JJ) as a colorless oil: [M+Na]+=401.2 (35%); [M-Boc+H]+=279.1 (100%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[I:15]Cl>C(O)(=O)C>[I:15][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[OH:1]
Reactant: ClI
Reactant: O=C(O)c1cc2ccccc2cc1O
Solvent: CC(=O)O
Product: O=C(O)c1cc2ccccc2c(I)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
3-Hydroxynaphthalene-2-carboxylic acid (0.5 g, 2.7 mmol) was suspended in acetic acid (5 mL) and with stirring iodine monochloride (135 μL, 2.7 mml) was added. The suspension was stirred at room temperature for 1 hour, filtered and washed with water. Drying afforded 0.72 g (85%) of 4-iodo-3-hydroxynaphthalene-2-carboxylic acid as a solid.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17]>C1COCC1.ClCCl>[C:15]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH:16]=[CH2:17]
Reactant: OCc1ccco1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCc1ccco1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Furfuryl alcohol (5.3 mL, 1 eq.) was dissolved in THF (100 mL) in a dry, round bottomed flask and stirred with triethylamine (10.7 mL, 1.25 eq.). The solution was cooled to 0° C. and acryloyl chloride (5 mL, 1 eq.) was added dropwise. The mixture was stirred for 3 h at 20° C. The reaction was worked up by diluting with dichloromethane (50 mL) and filtered through a celite plug to remove the triethylammonium chloride, and the solvent was removed under vacuum. The residue was purified by silica column chromatography using tert-butylmethyl ether-hexane (1:7) (furfuryl acrylate Rf 0.51) to give an oil (7.9 g 84.5% yield). IR (cm−1): 1728 (C═O st), 3147, 3124 (═C—H st), 810, 748 (C—H δ, furan ring). 1H NMR (CDCl3, 300 MHz): δ 6.39 (dd, 1H, H-1A, J1A,1B=17.3 Hz, J1A,2=1.47 Hz), 6.10 (dd, 1H, H-1B J1B,2=10.41 Hz), 5.79 (dd, 1H, H-2), 5.10 (s, 2H, CH2) ppm. Furan ring: 6.40 (bd, 1H, H-3′, J3′,4′=3.2 Hz), 6.33 (dd, 1H, H-4′, J4′,5′=1.9 Hz), 7.39 (m, 1H, H-5′) ppm. 13C NMR (CDCl3, 75 MHz): δ 131.1, 128.0 (C-1/C-2), 165.6 (C-3), 58.0 (CH2) ppm. Furan ring: 149.4 (C-2′), 110.6, 110.5 (C-3′, C-4′), 143.2 (C-5′) ppm. CI-Mass Spectrometry. m/z: 152 (M+), 97 [(OCH2-fur)+], 81 (main peak) [(CH2-fur)+], 55 [(CH2CHCO)+]. HRMS: Theoretical molecular weight for C8H8O3 (M+) 152.047344, experimental molecular weight: 152.046924.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:34].ClC([O-])=O>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: -60 °C
Yield: 89.2 %

Procedure:
At RT, triethylamine (260 μL, 1.86 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (300 mg, 0.93 mmol) in THF (6 mL), and the reaction was cooled to −60° C. external temperature. Neopentyl chloroformate (132 μL in 1.0 mL THF, 0.89 mmol) was added dropwise over a period of 5 minutes. Once the addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in CH2Cl2 to give (R)-neopentyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 9) (345 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.44-8.42 (m, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.59 (d, J=0.5 Hz, 2H), 7.38-7.32 (m, 2H), 6.94-6.90 (m, 2H), 4.28-4.19 (m, 3H), 4.12-4.01 (m, 1H), 3.89 (d, J=9.0 Hz, 1H), 3.71-3.64 (m, 2H), 2.49 (s, 3H), 2.25-2.20 (m, 1H), 2.06-2.00 (m, 1H), 0.89 (s, 9H) ppm. LC/MS: m/z 435.5 (M+H)+ at 2.73 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]12([C:11]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]O)[C:14]([SH:21])=[N:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O-])([O-])=O.[Na+].[Na+]>Cl>[C:1]12([C:11]3[N:15]4[C:14]([S:21][CH2:19][CH2:18][CH2:17][CH2:16]4)=[N:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OCCCCn1c(S)nnc1C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C1CCn2c(nnc2C23CC4CC(CC(C4)C2)C3)SC1

Procedure:
A solution of 4-[3-(1-adamantyl)-5-mercapto-4H-1,2,4-triazol-4-yl]butan-1-ol (3-36) (60 mg) in conc. HCl (6 mL) was heated at 65° C. for 20 h. The cooled solution was added dropwise to 10% aqueous Na2CO3 (75 mL). The gum that precipitated was extracted four times with CH2Cl2. The combined extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by reverse phase HPLC on a C-18 silica gel column using an acetonitrile-0.1% trifluoroacetic acid gradient. Fractions containing the product were combined and rendered basic with excess 10% sodium carbonate. After removing most of the acetonitrile in vacuo, the basic solution was extracted five times with CH2Cl2. The combined extracts were dried (MgSO4) and evaporated in vacuo to give 3-(1-adamantyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3]thiazepine (3-37).
Reaction SMILES: Cl[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[CH3:18][NH2:19].CO>O1CCCC1.C(OCC)(=O)C>[CH3:18][NH:19][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CN
Reactant: COC(=O)c1nc(-c2ccccc2)cnc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ncc(-c2ccccc2)nc1C(=O)OC
Temperature: 92.5 °C
Yield: 24 %

Procedure:
To a solution of methyl 3-chloro-6-phenylpyrazine-2-carboxylate (0.13 g, 0.53 mmol) in tetrahydrofuran (3 mL) was added 0.65 mL of 2.0 N methylamine in THF (1.30 mmol). The reaction was heated in a sealed high-pressure test tube to 90-95° C. overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed 2.0 N aqueous hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (30 mL), and saturated aqueous sodium chloride (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a yellowish product. Trituration with methanol (2 mL) gave a solid, which was filtered and washed with ether to afford afford methyl 3-(methylamino)-6-phenylpyrazine-2-carboxylate (31 mg, 24%) as yellow solid: MS (EI) for C13H13N3O2: 244 (MH+). This intermediate ester was directly used in the next step.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:18][C@H:17]2[NH:19]C(=O)OC(C)(C)C)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:18][C@H:17]2[NH2:19])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
HCl in Dioxane (390 ml) was added to a solution of tert-butyl ((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)carbamate (Intermediate U, 78 g, 0.23 mol) in 1,4-dioxane (780 mL) at 0° C. and stirred at RT for 12 h. After completion, the solvent was evaporated and the residue was triturated with diethyl ether (1 L) followed by hexane (1 L) to give (trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine hydrochloride (55 g, 87%) as off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25](=[NH:28])[NH:26][OH:27])[CH:22]=[CH:21][C:20]=1[OH:29])(=[O:18])=[O:17])[CH3:2].[CH2:41](O)[CH2:42]CC.[ClH:46]>>[ClH:46].[CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:37])=[O:38])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25](=[NH:28])[NH:26][OH:27])[CH:22]=[CH:21][C:20]=1[OH:29])(=[O:18])=[O:17])[CH2:2][CH2:41][CH3:42]
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)NO)ccc1O
Reactant: CCCCO
Agent: Cl
Product: CCCCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)NO)ccc1O

Procedure:
Method 1) A solution of 1.499 g of ethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate in 20 mL of 34% hydrogen chloride n-butanol solution was stirred at 60° C. for 3 hours. After being concentrated under reduced pressure, the reaction mixture was recrystallized from n-butanol-diisopropyl ether to give 1.472 g of n-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate hydrochloride as a white crystal.