Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][CH2:7][C:8](Br)=[O:9].[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>O>[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:8](=[O:9])[CH2:7][Br:6])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(Br)CBr
Reactant: CC(C)(CNc1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CN(C(=O)CBr)c1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
1.08 g of sodium bicarbonate (12.9 mmol) and 1.0 ml of bromoacetyl bromide (11.3 mmol) were added to a solution of 4.00 g of [2-(2-benzyloxyphenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (10a) (10.7 mmol) in a mixed solvent of ethyl acetate (50 ml) and water (50 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=2/1) to obtain 4.86 g of the title compound (yield: 92%).
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>COC(C)(C)C.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 86.2 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.816 g, 7.033 mmol) in t-butyl methyl ether (16 ml), lithium hydroxide monohydrate (0.271 g, 6.46 mmol) was added and the mixture was stirred for 2.25 hours at room temperature. A solution of methyl (Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (8) (1.554 g, 3.920 mmol) in t-butyl methyl ether (4.7 ml) and water (0.75 ml) were added thereto, and the mixed solution was heat refluxed for approximately 24 hours. After cooling to room temperature, water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 47 g, ethyl acetate:hexane=1:4), to give methyl(Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (9) (1.787 g; 3.380 mmol; yield: 86.2%) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]1(=[O:11])[CH2:10][CH2:9][CH:8]=[CH:7]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[N:1]1[N:2]([CH:8]2[CH2:9][CH2:10][C:6](=[O:11])[CH2:7]2)[N:3]=[CH:4][CH:5]=1
Reactant: O=C1C=CCC1
Reactant: c1c[nH]nn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CCC(n2nccn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,2,3-triazole (3.5 g.), cyclopent-2-enone (5.0 g.), benzyltrimethylammonium hydroxide (40% w/v solution in MeOH; 2.0 ml.) and dioxan (20 ml.) was stirred at room temperature overnight. The mixture was evaporated, treated with EtOAc, washed twice with water and once with brine, dried (MgSO4), and evaporated to give unpurified 3-(1,2,3-triazol-2-yl)cyclopentanone as a pale yellow oil. The n.m.r. spectrum of the product exhibited the following resonances: 7.62 (s, 2H); 5.3 (br quintet, 1H); 3.1-1.8 (m, 6H). (solvent CDCl3)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[Cl:21][C:15](=[O:17])[CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (3.84 g, 15.78 mmol) (prepared using M from ethyl 2-(piperidin-4-yl)acetate (Oakwood), Z) in DCM (79 mL) at ambient temperature were added oxalyl chloride (1.658 mL, 18.94 mmol) and DMF (0.115 g, 1.58 mmol). The reaction mixture was stirred at ambient temperature for about 3 h. The solvent was removed under reduced pressure to afford tert-butyl 4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (4.13 g, 100%) as a light yellow solid. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@@H:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([NH2:20])=[O:19])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: CC(=O)C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.57 mmol) and D-leucinamide HCl salt (104 mg, 0.625 mmol) in AcCN (2 mL) was added DIPEA (0.223 mL, 1.254 mmol). After stirring at room temperature for 4 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (150 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH3:11])[N:7]([CH:13]([CH3:14])[CH3:15])[C:6]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(C)n1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1c([C@H](C)Nc2ncnc3[nH]cnc23)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 90 °C
Yield: 9.2 %

Procedure:
(S)-1-(6-Fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.18 g, 0.6 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (145 mg, 0.60 mmol) and DIPEA (543 μL, 3.0 mmol) were added and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was loaded onto an SCX column to remove the THP group. The column was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The product fractions were collected, concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in DCM) to give 409 as a white solid (23 mg, 10%). LCMS (Method K): RT 2.94 min [M+H]+ 417. 1H NMR (DMSO-d6, 400 MHz): δ 12.69 (1H, br s), 8.69 (1H, d, J=4.4 Hz), 8.17 (1H, br s), 8.13 (1H, s), 7.93 (1H, td, J=7.8, 1.8 Hz), 7.66 (1H, dd, J=8.8, 5.0 Hz), 7.64 (1H, br s), 7.62 (1H, d, J=7.8 Hz), 7.47 (1H, ddd, J=7.7, 4.9, 1.1 Hz), 7.11 (1H, dd, J=10.2, 8.9 Hz), 5.90-5.78 (1H, m), 4.11-3.87 (1H, m), 1.62 (3H, d, J=6.6 Hz), 1.35-1.15 (6H, m)
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].I[C:17]1C=CC(C)=CC=1C(O)=O.FC1C=CC(I)=C(C=1)C(O)=O>>[CH3:17][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: O=C(O)c1cc(F)ccc1I
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 41, substituting for 2-iodo-5-methyl benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.87 (s 2H), 7.66 (d, J=1.3 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.53-7.46 (m, 1H), 2.45 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CCCCCCC.CCOC(C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2cc(F)ccc2N1
Yield: 93.1 %

Procedure:
2-Amino-5-fluorophenol (111MF10) (10.3 g, 81 mmol), 2-chloroacetyl chloride (10.1 g, 89 mmol) and K2CO3 (23.5 g, 170 mmol) were mixed according to GP1. CC (SiO2; Heptane/EtOAc 4:1-4) to give the title compound (111MF12) (12.6 g, 93%); 1H NMR (DMSO) δ 10.68 (s, 1H), 6.83-6.91 (m, 2H), 6.75-6.80 (m, 1H), 4.57 (s, 2H); 13C NMR (DMSO) δ 164.2, 157.8 (d, J=238.6 Hz), 144.0 (d, J=12.4 Hz), 123.9 (d, J=2.7 Hz), 116.3 (d, J=9.6 Hz), 108.6 (d, J=22.7 Hz), 104.0 (d, J=26.5 Hz), 66.7.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.CCCCCC.[F:18][C:19]1[CH:24]=[CH:23][C:22]([Si:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)(Cl)[CH2:26][Cl:27])=[CH:21][CH:20]=1>O1CCCC1>[Cl:27][CH2:26][Si:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)([C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=1)[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Fc1ccc([Si](Cl)(CCl)c2ccc(F)cc2)cc1
Reactant: C#CCCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC#C[Si](CCl)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.9 ml (0.024 mol) of 1-hexyne in 50 ml of tetrahydrofuran under nitrogen was cooled to -5° C. A solution of n-butyllithium in hexane (15 ml of 1.6 molar, 0.024 mol) was added dropwise, and the resulting solution was warmed to room temperature and stirred for 1.5 hours. The solution was then cooled to -65° C., and a solution of 6.0 g (0.0198 mol) of bis(4-fluorophenyl)chlorochloromethylsilane in 10 ml of THF was added dropwise. The reaction was warmed to room temperature and quenched by addition of saturated aqueous ammonium chloride. The solution was partitioned between water and ether, and the organic layer was separated, washed with brine and dried over magnesium sulfate. Removal of solvent gave the title compound as a clear colorless oil: nmr (CDCl3) 1.0 (3H, m), 1.5 (4H, m), 2.4 (2H, m), 3.2 (2H, s), 7.2 (4H, t, J= 9 Hz), 7.7 (4H, d of d, J=9, 6 Hz); ir (neat) 2180 cm-1.
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:19]([CH2:25][CH2:26][N:27]=4)[C:20]([NH2:24])=[N:21][C:22]=3[CH:23]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1>>[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:24][C:20]2[N:19]3[CH2:25][CH2:26][N:27]=[C:18]3[C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][S:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)(=[O:8])=[O:9])=[CH:23][C:22]=3[N:21]=2)=[O:34])=[CH:31][N:30]=1
Reactant: NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12
Reactant: Nc1ccc(C(=O)O)cn1
Product: Nc1ccc(C(=O)NC2=Nc3cc(OCCCS(=O)(=O)N4CCOCC4)ccc3C3=NCCN23)cn1

Procedure:
The procedure used for the preparation of Example 28, Step 2 was used to prepare the title compound from 8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 28, Step 1) and 6-aminonicotinic acid. Yield 50.0 mg (14%). TLC Rf=0.52 in 10% MeOH/CH2Cl2, HPLC MS RT=0.23 min, MH+=514.4; 1H NMR (MeOD) δ: 2.35 (2H, m), 3.20-3.33 (6H, m), 3.72 (4H, m), 4.26 (2H, t), 4.35 (2H, t), 4.63 (2H, t), 7.06 (1H, d), 7.19 (1H, dd), 7.36 (1H, s), 8.04 (1H, d), 8.56 (1H, dd), 8.74 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[N+:12]([O-])=O.C(=O)([O-])O.[Na+].[H][H]>[C].[Pd].O>[NH2:12][C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccnc(C(=O)O)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccnc(C(=O)O)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
4-Methoxy-3-nitropyridine-2-carboxylic acid (1.35 g, 6.81 mmol), sodium hydrogencarbonate (690 mg, 817 mmol), water (10 mL) and 10% palladium-carbon (135 mg) were stirred in a hydrogen atmosphere at room temperature for 24 hours. The reaction solution was filtered through Celite, the Celite was washed with water and methanol, and the mother liquid was concentrated. 2 N hydrochloric acid was added to the resulting residue, and the solution was controlled to have a pH of 1. The reaction solution was stirred at 0° C. for 1 hour, and the resulting pale gray solid was taken out through filtration and dried to obtain the intended compound (940 mg, 56%).
Reaction SMILES: [CH2:1]([C:3]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:23])[CH2:21][CH3:22])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)[CH3:2].C(OO)(=[O:26])C>>[O:26]1[C:20]([CH3:23])([CH2:21][CH3:22])[CH:19]1[CH2:18][CH2:17][C:3]([CH2:1][CH3:2])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: CCC(C)=CCCC(=CCOc1ccc2c(c1)OCCC2)CC
Reactant: CC(=O)OO
Product: CCC(=CCOc1ccc2c(c1)OCCC2)CCC1OC1(C)CC

Procedure:
Following the procedure of Example 17, 7-(3-ethyl-7-methyl-2,6-nonadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3-ethyl-7 -methyl-2-nonenyloxy)-chromane, nD20 = 1.5292.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[NH:28][N:27]=[C:26]([NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: CC(C)(C)c1cc(N)n[nH]1
Product: CCc1cc(-c2cncc(C(=O)Nc3cc(C(C)(C)C)[nH]n3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (5-tert-butyl-1H-pyrazol-3-yl)-amine to afford the title compound. MS: m/e=380 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11]C.Br.C(O)(=O)C>O>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])ccc1O

Procedure:
2-Methyl-4-nitroanisole (4.0 g)in 50 ml 1:1 hydrobromic acid:acetic acid is heated 12 hours at 120°. Solvent is stripped, the residue taken up in water and ethyl acetate, the mixture is filtered to remove insolubles, and the layers are separated. The organic phase is dried, filtered, and stripped to afford 2-methyl-4-nitrophenol. NMR (CDCl3): δ2.3 (3H,s), 6.8 (1H,d), 7.9 (1H,d of d), 8.0 (1H,d).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:29]([NH2:32])(=[O:31])=[O:30])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: NS(N)(=O)=O
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NS(N)(=O)=O)s2)cc1C#N
Temperature: 90 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
Prepared using General Procedure 18: To (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (25 mg, 0.06 mmol) in dioxane (1 mL) was added sulfamide (30 mg, 0.3 mmol) and the mixture was heated to 90° C. After 16 h, the solvent was evaporated and the residue was purified by column chromatography. Additional purification by recrystallization from MeOH provided 15.9 mg (26%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 47. LCMS-ESI (m/z) calculated for C21H21N5O3S2: 455.1; found 456.1 [M+H]+, tR=3.33 min. 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=2.3 Hz, 1H), 8.32 (dd, J=8.9, 2.4 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.56-7.38 (m, 2H), 7.23 (d, J=9.0 Hz, 1H), 6.75 (s, 2H), 4.95 (dt, J=12.2, 6.1 Hz, 1H), 4.87 (dd, J=16.6, 8.2 Hz, 1H), 3.42-3.26 (m, 1H), 3.07 (dt, J=16.4, 8.3 Hz, 1H), 2.61 (dtd, J=11.0, 7.9, 3.0 Hz, 1H), 2.00 (dq, J=12.7, 8.8 Hz, 1H), 1.38 (d, J=6.0 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 166.64, 165.62, 161.19, 146.08, 141.36, 133.89, 133.15, 127.97, 127.51, 127.27, 125.78, 122.22, 115.57, 114.95, 102.29, 72.17, 57.67, 33.41, 30.73, 21.52. Chiral HPLC: (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide was eluted in MeOH: 98.6% ee, tR=7.63 min (Chiral Method 2).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:8][NH:7][C:6](=[O:17])[NH:5]1.Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH3:3][CH:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:15]=2)=[N:8][NH:7][C:6](=[O:17])[NH:5]1
Reactant: CC1NC(=O)NN=C1c1ccc(O)cc1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1
Yield: 55.1 %

Procedure:
0.12 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to a solution of 0.55 g of 4,5-dihydro-5-methyl-6-(p-hydroxyphenyl)-1,2,4-triazin-3(2H)-one [prepared as described in step (a) above] dissolved in 6 ml of dimethylformamide, whilst ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, 0.33 g of ethyl chloroacetate was added. The mixture was then heated at 105° to 110° C. for 3 hours, whilst stirring. The dimethylformamide was then distilled off under reduced pressure, and the residue was diluted with water, after which the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and then subjected to column chromatography through silica gel eluted with a 1:50 by volume mixture of ethanol and methylene chloride to give a brown oil. This oil was triturated with ethyl acetate to give crystals, which were recrystallized from ethyl acetate, to give 0.43 g of the title compound as pale yellow needles melting at 152°-153° C.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:12]=C[C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])#N.Cl.O.[C:18]([OH:24])([C:20](F)(F)F)=[O:19]>CC#N>[C:18]([C:20]1[CH:12]=[C:5]([CH:4]=[CH:3][C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])([OH:24])=[O:19]
Reactant: N#Cc1cc(C[C@H](N)C(=O)O)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: O
Product: N[C@@H](Cc1ccc(O)c(C(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A 250 mL 3-necked flask equipped with a magnetic stirrer and a condenser was charged with 4.1 g of 3-cyano-L-tyrosine and 100 mL of 6N aqueous HCl. The mixture was heated to reflux with stirring. After 36 h, HPLC (C18, 90:10:0.1 H2O:MeCN:TFA) indicated no remaining starting material at k′=1.33 and a major new component at k′=1.69. The reaction mixture was cooled to RT, filtered to remove solids, and concentrated in vacuo to dryness. The residue was dissolved in 100 mL of 8:2 H2O:MeOH and the solution was passed through two C18 plugs (3.5×4.5 cm, EM separations LiChroprep RP-18) washing with 8:2 H2O:MeOH. The filtrate was concentrated in vacuo to dryness to afford 4.5 g of 3-carboxytyrosine as a brown solid. A portion of this material (1.30 g) was dissolved in 40 mL of 1,4dioxane with 2 mL of concentrated H2SO4 and the solution was added to 30 mL of isobutylene (condensed at −78° C.) in a 300 mL pressure bottle equipped with a magnetic stirrer. The vessel was stoppered, warmed to RT and stirred. After 48 h, the bottle was cooled to 0° C. in an ice water bath, opened, and the mixture was treated with 20 g of NaHCO3. After allowing the isobutylene to evaporate, the mixture was suspended in 300 mL of water and extracted with CH2Cl2 (4×100 mL). The combined CH2Cl2 extracts were washed with 5% aqueous NaHCO3 (2×50 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give a yellow-brown oil. Analysis by tlc (SiO2, 97:3 CH2Cl2:MeOH) indicated a major component at Rf=0.41 and three minor components at Rf=0.30, 0.25 and 0.0. The crude material was purified by flash chromatography on 75 g of silica gel (94:6 CH2Cl2:MeOH) to give 1.2 g of a light yellow oil. The oil was dissolved in 40 mL of ether and treated with 3.9 mL of 1M ethereal HCl. A precipitate formed which was collected by filtration and dried in vacuo to afford 1.14 g (53%) of tert-butyl 3-(tert-butoxycarbonyl)-L-tyrosinate HCl as a fluffy white solid. An analytical sample (26 mg) was prepared by recrystallization from MeOH-ether, m.p. 205° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.4 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (49.9 mg, 42%).