Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([NH2:20])[NH:18][N:19]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.C(=O)(OC(C)(C)C)[O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>O.ClCCl>[NH2:20][C:17]1[N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[N:19]=[C:15]([O:14][CH2:13][C:7]2[CH:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=2)[CH:16]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
Potassium hydroxide (11.19 g, 199.4 mmol) dissolved in water (44.8 ml) was added to a solution of 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (7.121 g) dissolved in dichloromethane (40 ml). A solution of (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (6.8 g, 31.2 mmol) in DCM (35 ml) was added and the reaction mixture was stirred vigorously at room temperature for 4 h. The reaction mixture was separated and the organic layer was washed with water (2×15 ml) and brine (2×15 ml), dried over sodium sulphate, filtered, evaporated and dried in vacuo to give tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (8.70 g, 99%) as a cream solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[OH:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1>>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH2:18][O:17][C:10](=[O:11])[O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1
Reactant: OCc1cccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OCc1cccs1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with 2-hydroxy methyl thiophene.
Reaction SMILES: C[Mg]I.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.Br[C:14]1[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>C(OCC)C.C1C=CC=CC=1>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]2[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=2[C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[CH:5]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1NC(=O)C(c2ccc([N+](=O)[O-])cc2)=C1Br
Agent: C[Mg]I
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1ccc([N+](=O)[O-])cc1
Yield: 0.9 %

Procedure:
1.4 ml of a 3M solution of methylmagnesium iodide in diethyl ether was added to a solution of 360 mg indole in 20 ml of benzene under nitrogen. After stirring at room temperature for 10 minutes 300 mg of 3-bromo-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione were added and the resulting mixture was heated to reflux for 4 days. After cooling the solution was evaporated and the residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic phase was washed with water, dried and evaporated. The residue was purified on silica gel with dichloromethane and 1% methanol in dichloromethane and then with 20% methanol/water on Hypersil to give 3 mg of 3-(3-indolyl)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 125° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]=[C:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13].C(O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=C(C#N)CCC#N
Reactant: Sc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: CO
Product: N#CCCC(C#N)CSc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 3,4-dichlorobenzenethiol (3.00 ml), methyleneglutaronitrile (2.57 ml), ethanol (25 ml), and triton B (40% methanol solution, 10 drops) was refluxed for 4 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was recrystallized from diethyl ether-hexane to give 6.14 g of 2-(3,4-dichlorophenylthiomethyl)glutaronitrile.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1([N:12]2[C:16]([NH2:17])=[C:15]([C:18]#[N:19])[C:14]([CH3:20])=[N:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(O)(=O)C>[CH:6]1([N:12]2[C:16]([NH2:17])=[C:15]([C:18]([NH2:19])=[O:2])[C:14]([CH3:20])=[N:13]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(C2CCCCC2)c(N)c1C#N
Solvent: CC(=O)O
Product: Cc1nn(C2CCCCC2)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To concentrated sulfuric acid (50 ml) at 0° C. was added 1-cyclohexyl-3-methyl-4-cyano-5-amino-1H-pyrazole (2.2 g, 10.8 mmol). The reaction mixture was warmed to room temperature and stirred for 24 hours. The solution was poured into ice/concentrated ammonium hydroxide, the solution was then neutralized with acetic acid and extracted with dichloromethane (2×400 ml). The solvent was removed in vacuo, the residue was extracted with ethyl acetate (75 ml) and treated with DARCO. The solution was filtered, the solvent was removed in vacuo and the residue was dissolved in ether and cooled. A precipitate was obtained which was collected by filtration, washed with ether and dried at 50° C. in high vacuum for 60 hours to afford 1.83 g (76%) of 1-cyclohexyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide as yellow needles, m.p. 181°-182° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>CS(C)=O>[O:21]=[C:15]1[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:22][C@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]3)[CH:11]=[CH:10]4)[NH:20][C:19]=2[CH2:18][CH2:17][NH:16]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 249.5 %

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol) and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (Chem-Impex International, Wood Dale, Ill.; 168 mg, 0.840 mmol) in DMSO (0.5 mL) was stirred under argon at 100° C. for 19 h, then at 130° C. for 5 h, then at 150° C. for 17 h. The mixture was cooled to 25° C. and partitioned between DCM (30 mL) and water (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude (S)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)amino)piperidine-1-carboxylate (193.5 mg) as a brown solid (used without further purification in the subsequent transformation): m/z (ESI, +ve) 462.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:12])[NH:10][N:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:12])[N:10]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: COCCn1c(-c2ccc(Cl)s2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2ccc(Cl)s2)n(CCOC)c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 168A, 2.4 g (9.24 mmol) were suspended with 2.55 g (18.48 mmol) of potassium carbonate in 48 ml of acetonitrile. Then 1.08 ml (10.17 mmol) of ethyl chloroacetate were added and the mixture was heated under reflux at 80° C. for 4.5 h. A further 113 mg (0.92 mmol) of ethyl chloroacetate were added, with stirring at 80° C. for 2 h. The suspension was filtered through a layer of silica gel, which was washed with ethyl acetate, and the filtrate was concentrated on a rotary evaporator and dried in an HV. This gave 3.24 g (100% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:17]1[CH:18]=[C:19]([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)[CH2:24][C@@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:20]=[CH:21][CH:22]=1.C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:21]2[CH:20]=[C:19]([N:23]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:40])([F:41])[F:42])[CH:33]=3)[CH2:24][C@@H:25]([OH:30])[C:26]([F:27])([F:28])[F:29])[CH:18]=[CH:17][CH:22]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: O[C@H](CN(Cc1cccc(OC(F)(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Reactant: Cc1cc(O)ccc1F
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2cccc(N(Cc3cccc(OC(F)(F)F)c3)C[C@@H](O)C(F)(F)F)c2)ccc1F
Temperature: 105 °C
Reaction time: 0.08 h
Yield: 23 %

Procedure:
A suspension of 4-fluoro-3-methylphenol (98.0 μL, 0.88 mmol) and cesium carbonate (319.5 mg, 0.98 mmol) in 1 mL of N,N-dimethylacetamide was preheated at 60° C. for 5 minutes. To this solution was added 4 mL of a stock solution containing (2R)-3-[[(3-bromophenyl)][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.437 mmol) from EX-33B, 1-naphthoic acid (164 mg, 0.95 mmol), copper(I) trifluoromethansulfonate benzene complex (21.8 mg, 0.0434 mmol), 4 Å sieves (105 mg), and 4 mL of toluene. The reaction mixture was stirred at 105° C. for 3 weeks and 2 days. During that time, additional cesium carbonate and catalyst were added (a spatula tip of each) to the reaction three different times. The reaction was cooled to room temperature, filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 35% to 90% acetonitrile in water to afford 50.5 mg (23%) of the desired (2R)-3-[[3-(4-fluoro-3-methylphenoxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C24H20F7NO3: 504.1410 [M+H]+, found: 504.1389. 1H NMR (acetone-d6) δ 7.44 (t, 1H), 7.24 (d, 1H), 7.08-7.21 (m, 3H), 6.98 (t, 1H), 6.75-6.85 (m, 1H) 6.68-6.74 (m, 1H), 6.53 (d, 1H), 6.21-6.34 (m, 2H), 4.79 (t, 2H), 4.46-4.53 (m, 1H), 3.95 (dd, 1H), 2.61-2.72 (m, 1H), 2.20 (s, 3H).
Reaction SMILES: O[C@@H:2]1[C@H:6]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C@@H:5](/[CH:16]=[CH:17]/[C@@H:18]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:19]CC2C=CC=CC=2)[C@H:4]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:50](Cl)(=O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:51]1([CH2:50][CH2:19][C@H:18]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)/[CH:17]=[CH:16]/[C@@H:5]2[C@@H:6]3[C@@H:2]([O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7]3)[CH2:3][C@H:4]2[O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)CCCC=CC[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 7-((1R,2R,3R,5S)-5-hydroxy-2-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (32 g from example 48) in 320 mL dichloromethane was treated with N,N-diisopropyl-ethylamine (12.3 g, 94.8 mmol) and benzoyl chloride (7.9 g, 56.3 mmol. This mixture was then stirred for 10 minutes at room temperature under an atmosphere of nitrogen, followed by addition of 4-(dimethylamino)-pyridine (11.9 g, 97.7 mmol) at 0° C. while stirring for 10 minutes. The resulting mixture was quenched with a saturated sodium bicarbonate solution (300 mL) and extracted with dichloromethane (100 mL). The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to give 29.0 g of crude product. The crude product was purified by column chromatography providing 9.4 g of the title compound (58.6% yield, 3 steps).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH2:7]Cl.[C:9]1(C)[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1>[CH3:7][C:13]1[CH:14]=[CH:9][C:10]([S:15]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)(=[O:16])=[O:17])=[CH:11][CH:12]=1
Reactant: c1cn[nH]c1
Reactant: ClCCl
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of pyrazole (2 g, 29.0 mmol), dichloromethane (20 ml) and pyridine (5 ml) was added 4 toluene sulphonyl chloride (6.89 g, 36 mmol) and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between dichlormethane and an aqueous solution of sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue as purified by flash chromatography on silica eluting with a mixture of 70-100% dichloromethane in hexane and then 10% ethyl acetate in dichloromethane to give the product as a white solid (4.9 g, 76%). NMR Spectrum: (CDCl3) 2.43 (s, 3H), 6.39 (m, 1H), 7.34 (d, 2H), 7.72 (d, 1H), 7.89 (d, 2H), 8.10 (d, 1H). Mass Spectrum: M+H+ 223 and M+H− 221.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:22][C:23]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([CH:32]=[O:33])[CH:30]=[CH:31][C:23]=1[O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)N(Cc2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 36.5 %

Procedure:
N-Phenylbenzylamine (0.72 g, 3.9 mmol, 2 eq) was added to a solution of 2-benzyloxy-5-formylbenzoic acid (500 mg, 1.95 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (530 mg, 3.9 mmol, 2 eq), and N-methylmorpholine (0.58 mL, 5.3 mmol, 2.73 eq) in N,N-dimethylformamide (10 mL). To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (750 mg, 13.9 mmol, 2 eq) and the stirred reaction mixture was heated overnight at 50° C. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with 10% HCl (3×20 mL), brine (20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and brine (20 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica with petroleum ether:ethyl acetate (3:1) as eluent, to give the product as a white powder (300 mg, 37%). RF (petroleum ether:ethyl acetate 1:1) 0.55. 1H NMR (CDCl3) δ9.78 (s, 1H, O═C—H), 5.08 (s, 2H, OCH2Ph), 5.02 (s, 2H, NCH2Ph).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[S:33]([O-:35])=[O:34].[Na+]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:9][C:8]=2[C:4]2[C:3]([F:26])=[C:2]([NH:1][S:33]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][N:27]=3)(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S([O-])c1cnccn1
Reactant: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(N)c2F)n1
Agent: [Na+]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cnccn3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 278 using 4-[4-(3-amino-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.269 mmol) and sodium 2-pyrazinesulfinate (135 mg, 0.808 mmol), the title compound was obtained as a yellow solid (30 mg, 21% yield). MS (ESI): 514 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25]C(=O)OC(C)(C)C)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.Cl.CO>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=3[CH:18]=[N:17]2)([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: Cl
Solvent: CO
Product: CCC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of Step E (80 mg, 0.17 mmol) and 4 N HCl/MeOH (2 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dried in vacuo to give the title compound as colorless oil. LC/MS m/z=368.1[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:31][CH:30]([CH3:32])[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:13]([NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:21][CH2:20]2)[CH:23]=1)=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 4-methylbenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 534.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH2:14][OH:15].CCN(C(C)C)C(C)C>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:13][C:9]1[C:8]([CH2:14][OH:15])=[C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(Br)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1cccc(Br)c1CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloroacetyl chloride (380 mg, 3.37 mmol) in DCM (10 mL) was added (2-amino-6-bromophenyl)methanol (630 mg, 3.12 mmol) followed by DIPEA (1.253 mL, 7.17 mmol). The reaction was stirred at room temperature for 3 d. The mixture was diluted with a solution of saturated sodium bicarbonate (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated to give N-(3-bromo-2-(hydroxymethyl)phenyl)-2-chloroacetamide. The above product was dissolved in IPA (10 mL), and added 50% w/w aqueous NaOH (374 mg, 4.68 mmol). The mixture was stirred at room temperature for 3 h and concentrated. The residue was diluted with a solution of saturated sodium bicarbonate (15 mL) and extracted with DCM (80 mL). The organic layer was dried over sodium sulfate and concentrated to give 6-bromo-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one. The above intermediate was dissolved in THF (60 mL) and added 2.0 M borane dimethyl sulfide methyl sulfide complex in THF (6.24 mL, 12.47 mmol). The reaction was refluxed for 60 min, cooled to room temperature, and added MeOH (5.0 mL) dropwise. The mixture was refluxed for 30 min concentrated. The residue was diluted with a solution of saturated sodium bicarbonate (60 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (237 mg, 32% yield) as clear gum. LCMS, [M+H]+=229.9. 1H NMR (400 MHz, CDCl3) δ 7.13 (dd, J=7.9, 1.1 Hz, 1H), 6.94 (t, J=7.9 Hz, 1H), 6.74 (dd, J=7.9, 0.9 Hz, 1H), 4.92 (s, 2H), 4.06 (br. s., 1H), 3.89-3.81 (m, 2H), 3.24-3.17 (m, 2H).
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:17][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[C:19]=1[NH:27][C:28]([NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)=[O:29])[CH3:16]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1nnn[nH]1

Procedure:
5-Aminotetrazole hydrate (45 g, 0.44 mol) was refluxed in toluene (300 mL) in the presence of a Dean-Stark trap. After removal of the theoretical amount of water (7.9 mL) the mixture was allowed to cool, concentrated in vacuo, and the resulting solid stirred with acetonitrile (500 mL). Triethylamine (61 mL, 0.44 mol) and 2,6-diisopropyl phenylisocyanate (89.3 mL, 0.44 mol) were added sequentially and the mixture refluxed for 4 hours. The mixture was then allowed to cool, concentrated in vacuo to about 200 mL, and acidified with 1M citric acid. The solid was filtered, washed with water (1L), ethyl acetate (1L), and dried in vacuo to give the title compound (b), m.p. >240° C.
Reaction SMILES: C(=O)([O-])O.[Na+:5].[O:6]=[C:7]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][CH2:33][CH3:34])=[CH:16][C:11]=2[O:10][C:9]([C:35]([OH:37])=[O:36])=[CH:8]1>O>[O:6]=[C:7]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][CH2:33][CH3:34])=[CH:16][C:11]=2[O:10][C:9]([C:35]([O-:37])=[O:36])=[CH:8]1.[Na+:5]
Reactant: CCCc1ccccc1OCCCCCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1ccccc1OCCCCCCCOc1ccc2c(=O)cc(C(=O)[O-])oc2c1

Procedure:
A solution of 0.412 parts of sodium hydrogen carbonate in 20 parts of water was added to a suspension of 2.19 parts of 4-oxo-7-[7-(2-n-propyl phenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylic acid in 30 parts of water and the mixture heated until a clear solution was obtained. The filtrate was freeze dried to furnish 2.19 parts of sodium 4-oxo-7-[7-(2-n-propyl phenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(O)[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2>C(O)(C)C.Cl>[CH3:1][CH:2]1[CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[C:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2
Reactant: CC1Cc2sccc2C(O)(C2CCN(C)CC2)c2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: CC1Cc2sccc2C(=C2CCN(C)CC2)c2ccccc21

Procedure:
A solution of 12.0 g of 9,10-dihydro-9-methyl-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol in 180 ml of isopropanol and 180 ml of 7N hydrogen chloride in isopropanol was boiled for 3 hours, and concentrated to dryness. The residue was taken up in 100 ml of water. The mixture was made alkaline with concentrated aqueous sodium hydroxide and then extracted with methylene chloride. The extracts were washed with water, dried over potassium carbonate and concentrated. The title compound obtained as an oil was converted in ethanol into the hydrogen malate (M.Pt. of hydrogen malate: 193°-194° from ethanol).