Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:12]>>[C:1]1([P:7](=[O:8])([O-:10])[O-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:12].[Na+:12]
Reactant: O=P(O)(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=P([O-])([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 176.2 %

Procedure:
In 1.58 g (10.0 mmol) of phenylphosphonic acid (manufactured by Nissan Chemical industries, Ltd.), 20 mL (10.0 mmol) of 0.5 N sodium hydroxide was added, stirred at room temperature for 10 minutes, then water was distilled off under reduced pressure and dried to obtain 1.78 g (yield 99%) of the aimed product as white crystal. Decomposition temperature: 480° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
7-Nitro-3,4-dihydro-2H-naphthalen-1-one (200 mg, 1.05 mmol) was dissolved in methanol (5 mL) and NaBH4 ((78 mg, 2.05 mmol) was added in portions. The reaction was stirred at room temperature for 20 min and then concentrated and purified by column chromatography (10-50% ethyl acetate-hexanes) to yield 7-nitro-1,2,3,4-tetrahydro-naphthalen-1-ol (163 mg, 80%). 1H NMR (400 MHz, CD3CN) δ 8.30 (d, J=2.3 Hz, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 4.76 (t, J=5.5 Hz, 1H), 2.96-2.80 (m, 2H), 2.10-1.99 (m, 2H), 1.86-1.77 (m, 2H); HPLC ret. time 2.32 min, 10-99% CH3CN, 5 min run.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:18]([N:20](CC)[CH2:21][CH3:22])[CH3:19].N1CCCC1>C1C=CC=CC=1.CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:20]2[CH2:21][CH2:22][CH2:19][CH2:18]2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCNC1
Product: O=C(c1ccc([N+](=O)[O-])c(F)c1)N1CCCC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
1.00 g (5.40 mmol) 3-Fluoro-4-nitro-benzoic acid were suspended in 55 mL benzene. 1 mL Thionyl chloride and 7 drops DMF were added. The resulting mixture was stirred of 5 h at 70° C. and then concentrated under reduced pressure. The residue was dissolved in 40 mL CH2Cl2. Subsequently 0.75 mL (5.40 mmol) triethylamine and 0.45 mL (5.40 mmol) pyrrolidine were added and the resulting solution was stirred for 1 h at room temperature. The mixture was diluted with CH2Cl2 and washed subsequently with a 0.1 N HCl-solution, with a saturated NaHCO3-solution and with brine. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuo to give crude (3-Fluoro-4-nitro-phenyl)-pyrrolidin-1-yl-methanone as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1ccccc1-c1ncccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1-c1ncccc1N
Temperature: 65 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of 2-(2-methoxyphenyl)-3-nitropyridine (34.3 mg, 0.15 mmol) in EtOAc (5.0 mL) was added tin(II) chloride dihydrate (0.17 g, 0.76 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 65° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH (10 mL), water (10 mL), and brine (10 mL). After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as mostly 2-(2-Methoxyphenyl)-3-pyridinamine. Mass Spectrum (pos.) m/e: 201.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Cl[CH2:30][C:31]([N:33]1[CH2:42][CH2:41][C:36]2([O:40][CH2:39][CH2:38][O:37]2)[CH2:35][CH2:34]1)=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:30][C:31]([N:33]3[CH2:34][CH2:35][C:36]4([O:40][CH2:39][CH2:38][O:37]4)[CH2:41][CH2:42]3)=[O:32])[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cn(CC(=O)N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.6 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide (32.0 g, 79.1 mmol) in DMF (400 mL) was treated with 2-chloro-1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-ethanone (20.8 g, 94.9 mmol) and Cs2CO3 (51.5 g, 158.1 mmol) and the mixture was stirred at room temperature for 19 hours. The reaction was diluted with water (˜1.6 L) and the resultant precipitate was collected by filtration. The solid was washed with water dried under reduced pressure to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide as a beige solid (33.3 g, 72%). LCMS (Method 3) [M+H]+=588.2, RT=3.02 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.85 (s, 1H), 8.78 (dd, 1H, J=1.6, 6.9 Hz), 8.71 (s, 1H), 8.56 (dd, 1H, J=1.8, 4.0 Hz), 8.42 (s, 1H), 7.69 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.30-7.26 (m, 1H), 7.00 (dd, 1H, J=4.2, 6.9 Hz), 6.48 (t, 1H, J=74.0 Hz), 5.06 (s, 2H), 4.00-3.95 (m, 4H), 3.74 (dd, 2H, J=5.8, 5.8 Hz), 3.61 (dd, 2H, J=5.8, 5.8 Hz), 1.74-1.64 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[S:15]2)[S:10][C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:40][C:41]1[CH:42]=[C:43]([NH:50][C:51](=[O:55])[CH2:52][O:53][CH3:54])[CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49]>>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[S:15]2)[S:10][C:9]1=[N:40][C:41]1[CH:42]=[C:43]([NH:50][C:51](=[O:55])[CH2:52][O:53][CH3:54])[CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(c2ccccc2)N(C)C(=C2SC(=S)N(Cc3ccccc3)C2=O)S1
Reactant: CCNc1ccc(NC(=O)COC)cc1N
Agent: COS(=O)(=O)c1ccc(C)cc1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2SC(C)=C(c3ccccc3)N2C)C(=O)N1Cc1ccccc1

Procedure:
Likewise as described in Example 1, intermediate 3′-benzyl-3,5-dimethyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one was alkylated with methyl p-toluenesulfonate and condensed with N-(3-amino-4-ethylaminophenyl)-2-methoxyacetamide to afford the title compound. 1H-NMR (CDCl3): δ 8.00 (1H, br s), 7.42-7.51 (5H, m), 7.30-7.37 (3H, m), 7.19-7.26 (3H, m), 7.11 (1H, d), 6.53 (1H, br s), 5.18 (2H, s), 3.97 (2H, s), 3.47 (3H, s), 3.42 (3H, s), 2.98 (2H, m), 2.06 (3H, s), 1.02 (3H, br t); MS(ESI): 600 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:43]1[CH2:49][CH2:48][CH2:47][C@H:44]1[CH2:45][OH:46]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:43]1[CH2:49][CH2:48][CH2:47][C@H:44]1[CH:45]=[O:46])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 26.5 g of N-benzyloxycarbonyl-leucin. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 400 ml of THF. To this solution was added 7.9 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 33.5 g of WSCD-HCl and 140 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 6.2 ml of a DMSO solution of 2 -M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 300 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 300 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 4.2 g (12.1%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:20]1C=CC=C[CH:21]=1>ClC(Cl)C>[Cl:5][C:6]1[C:7]([CH3:15])=[C:8]2[C:12]([CH2:20][CH2:21][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1C(=O)O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1c(Cl)ccc2c1C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Thionyl chloride (10.0 mL, 1.5 eq) and 3-chloro-2-methyl-benzoic acid (commercially available from Aldrich) (15.6 g, 91.4 mmol) in benzene was refluxed until no more gas evolution was observed. After cooling to rt the mixture was concentrated. The concentrate was diluted with dichloroethane and added to a solution of AlCl3 (12.2 g, 1.0 eq) in dichloroethane at 10–20° C. Ethylene was bubbled through the mixture for 4 h. and the mixture was stirred overnight. The mixture was quenched with 4 N HCl. The resulting layers were separated and the aqueous layer was extracted with Et2O (3×250 mL). The combined organic extract was washed with H2O (3×150 mL), saturated NaHCO3 (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated. Concentrated sulfuric acid was added and the mixture was stirred at 85° C. for 1 h. After cooling to rt, the reaction mixture was quenched with ice-water. The mixture was extracted with Et2O (3×250 mL) and the combined organic extracts were washed with H2O (3×200 mL), saturated NaHCO3 (3×200 mL), brine (1×100 mL), dried over MgSO4 and concentrated. Pure 6-chloro-7-methyl-1-indanone (11.9 g, 72%) was obtained after column chromatography using 20% EtOAc:hexane as eluant. Use of 6-chloro-7-methyl-1-indanone in Method NINETEEN produced 4-(5-chloro-4-methyl-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 152).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13].[C:18]([CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]=1)O)#[N:19]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH:20]([C:18]#[N:19])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]=1)=[O:13]
Reactant: N#CC(O)c1cccc(Oc2ccc(F)cc2)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccc(F)cc2)n1)c1ccc2ccccc2c1

Procedure:
Following the procedure of Example 3, 2-(2-naphthyl)-3-methylbutanoic acid is reacted with cyano [6-(4-fluorophenoxy)-2-pyridyl]methanol to give cyano[6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-naphthyl)-3-methylbutanoate.
Reaction SMILES: [CH2:1]([CH:4]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[Li]CCCC.[CH3:18][Sn:19](Cl)([CH3:21])[CH3:20]>C1COCC1>[CH2:1]([CH:4]([C:8]1[S:9][C:10]([Sn:19]([CH3:21])([CH3:20])[CH3:18])=[CH:11][CH:12]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCC(CCC)c1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(CCC)c1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(1-propylbutyl)thiophene (3.4 g, 18.7 mmol) in dry THF (60 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 11.1 mL, 27.8 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 10 minutes, and then allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 28 mL, 28.0 mmol) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water. The resulting mixture was diluted with hexane, washed with water, dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (6.27 g, 97.5%), which was directly used in the next step without further purification.
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH3:24])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:4]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccncc3)nc(NN)nc21
Product: Cc1cc(C)n(-c2nc(Nc3ccncc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-pyridin-4-yl-amine and 2,4-pentanedione.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]3[CH:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1.Cl.[CH3:30][NH:31][CH2:32][CH2:33][SH:34]>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[C:13]3[CH:14]=[N:15][C:16]([S:34][CH2:33][CH2:32][NH:31][CH3:30])=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CNCCS
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2oc(Cl)cc2c1
Agent: Cl
Product: CCC(=C(c1ccc(O)cc1)c1ccc(SCCNC)nc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 16, step C described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70 mg, 1.0 eq) was reacted with 2-(methylamino)ethanethiol hydrochloride (217 mg, 10 eq) to give the desired product (Z/E=1/1). m/z=465[M+1]+.
Reaction SMILES: Cl.[C:2](OCC)(=O)C.[CH:8]1([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]3[CH2:17][CH:18]([C:20]4[N:25]=[CH:24][C:23]([O:26][CH2:27][C@@H:28]([NH:30][C:31](=O)[O:32]C(C)(C)C)[CH3:29])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[CH2:10][CH2:9]1>C(OCC)(=O)C>[CH:8]1([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]3[CH2:17][CH:18]([C:20]4[N:25]=[CH:24][C:23]([O:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:32])[CH3:2])[CH3:29])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[CH2:10][CH2:9]1
Reactant: C[C@@H](COc1ccc(C2Cc3ccc(OCC4CC4)cc3O2)nc1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc(C2Cc3ccc(OCC4CC4)cc3O2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4M Hydrogen chloride/ethyl acetate (10 mL) was added dropwise to a solution of tert-butyl [(1S)-2-({6-[6-(cyclopropylmethoxy)-2,3-dihydro-1-benzofuran-2-yl]pyridin-3-yl}oxy)-1-methylethyl]carbamate (80 mg) in ethyl acetate (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 6 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in pyridine (10 mL), and acetic anhydride (0.026 mL) was added thereto at room temperature. The reaction mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (49.3 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19]([C:21]([NH2:23])=O)=[N:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>O1CCOCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19]([C:21](=[S:25])[NH2:23])=[N:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(C)c1cc(-c2nnc(C(N)=O)s2)cc(C(C)(C)C)c1O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(-c2nnc(C(N)=S)s2)cc(C(C)(C)C)c1O
Yield: 58.5 %

Procedure:
A mixture of 1.5 g (4.5 mmol) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxamide and 1.0 g (2.2 mmol) of P2S5 in 20 ml of dioxane is warmed at reflux for one hour under a nitrogen atmosphere. The reaction is poured through a plug of SiO2, washing with t-butylmethylether. Recrystallization from toluene gives 0.45 g (1.6 g theor., 28%) of the thioamide as a yellow solid, mp 215°-216° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[BH4-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: COC(=O)c1cc(C=O)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(CO)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a mixture of 907 mg (2.0 mmol) of the product of Example 268 in 50 ml of MeOH:THF (4:1) was added sodium borohydride. The reaction was then stilred at room temperature for 30 min and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with 5% HCl and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 872 mg (96%) of the desired product as a white crystalline solid. Electrospray Mass Spec 456 (M+H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]([NH2:12])=[S:11].C(=O)([O-])O.[Na+]>C(O)C>[NH2:12][C:10]1[S:11][CH:2]=[C:3]([C:4]([CH3:7])([CH3:6])[CH3:5])[N:9]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1csc(N)n1
Yield: 90.9 %

Procedure:
A mixture of 1-bromo-3,3-dimethyl-2-butanone (5.03 g, 28.1 mmol), thiourea (2.35 g, 30.9 mmol) and ethanol (30 mL) was refluxed for 1.5 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (3.99 g, 90.9%) as an yellowish white powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[NH:6][C:5]2=[O:17])[CH2:3][CH2:2]1.[H-].[Na+].[N+:20](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>O1CCOCC1.CN(C)C=O>[NH2:20][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:17]
Reactant: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nn1c(=O)c2cc(F)c(F)cc2n(C2CC2)c1=O
Temperature: 60 °C
Yield: 63.8 %

Procedure:
To a solution of 1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 23a, 2.0 g, 8.92 mmol) in dioxane (7.5 mL) and dimethylformamide (7.5 mL) is added NaH (60% dispersion in oil, 428 mg, 10.7 mmol). The solution is heated to 60° C. for 10 minutes and cooled to room temperature. To the cooled solution is added O-(2,4-dinitrophenyl)hydroxylamine (1.77 g, 8.92 mmol), and the solution is heated to 80° C. for 30 minutes. The resulting red solution is cooled to room temperature, poured over crushed ice, and extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered, and the solvent removed under reduced pressure. The resulting solid is triturated with Et2O and air dried to afford 1.44 g of the title compound. MS CI: m/z 254 (MH+).
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:34])[N:18]([CH3:33])[C:19]2[CH:20]=[N:21][C:22]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)=[CH:9]1)=O)(C)(C)C.[H-].[Na+].CI>C1COCC1>[CH3:33][N:18]([C:19]1[CH:20]=[N:21][C:22]([O:25][C:26]2[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:24]=1)[C:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH3:6])[CH:9]=1)=[O:34]
Reactant: Cc1ncccc1Oc1ccc(N(C)C(=O)c2cn(C(=O)OC(C)(C)C)c3ccccc23)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ncccc1Oc1ccc(N(C)C(=O)c2cn(C)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.7 %

Procedure:
The tert-butyl-3-(methyl(6-(2-methylpyridine-3-yloxy)pyridine-3-yl)carbamoyl)-1H-indole-1-carboxylate (40 mg, 0.087 mmol) in Example 12 was dissolved in THF (10 ml), and NaH (21 mg, 0.54 mmol) and methyl iodide (0.95 g, 0.67 mmol) were added to the solution. The reaction solution was stirred at room temperature for 5 hours, and then the product was washed and filtered to yield a target compound as a brown solid (20 mg, 12%) by chromatography (methanol:dichloromethane=1:20).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:22])=[N:11][C:12]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[NH2:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([O:16][CH:17]([CH3:21])[C:18]([N:33]([CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[CH2:32][CH2:31]2)[CH3:34])=[O:20])=[N:11][C:10]=1[CH3:22]
Reactant: Cc1nc(OC(C)C(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(CC2CC2)CC1
Product: Cc1nc(OC(C)C(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1N

Procedure:
The title compound was synthesized from Compound 12 and 1-(cyclopropylmethyl)-N-methyl-piperidine-4-amine in the same manner as in Example 64.