Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[CH3:23][C:24](=[CH2:28])[C:25](O)=[O:26].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[F:22][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[C:24]([CH3:28])=[CH2:23])=[CH:7][C:6]=1[C:8]1[C:9]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: C=C(C)C(=O)O
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cc(N)ccc3F)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccc(F)c(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To crude ethyl 4-(5-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (133 mg, 0.443 mmol) was added THF (4.43 mL), TEA (93 μL, 0.66 mmol), methylacrylic acid (57 mg, 0.66 mmol) and 1-propanephosphonic acid cyclic anhydride (3.26 mL, 0.443 mmol). The reaction was stirred at 25° C. overnight. The reaction was quenched by pouring into a separatory funnel containing aqueous sodium hydrogen carbonate (5%) and was extracted with ethyl acetate (×3). The organic layers were combined and dried with Na2SO4, filtered, and evaporated in vacuo. The crude reaction was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The products were collected and lyophilized to afford a colorless solid. LRMS (ESI) calc'd for C19H18N4O3F [M+H]+: 369, found 369.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.O[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:27]=[C:18]1[C:19]2[C:20](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:22])[N:17]1[O:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
An ice-cold mixture of tert-butyl (cis-3-hydroxycyclopentyl)methylcarbamate 114 (0.19 g, 0.88 mmol), N-hydroxyphthalimide (0.29 g, 1.78 mmol), and triphenylphosphine (0.46 g, 1.75 mmoL) in tetrahydrofuran (10 mL) was treated with diisopropylazodicarboxylate (0.40 g, 1.98 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo to a yellow foam which was purified by chromatography to give 115 (0.19 g, containing DIAD byproduct) as a yellow oil. The mixture was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N-:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:29]([C:26]1[CH:25]=[CH:24][C:23]([Br:22])=[CH:28][CH:27]=1)[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(C[N-]c2ccc(Br)cc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CN(C)c1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(Br)cc2)cc1
Yield: 99.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57 g) and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]amide (0.61 g) as starting materials, 5-benzyloxy-N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.14 g) was obtained. By the reaction and treatment in the same manner as in Example 133 using this compound, N-(4-bromophenyl)-N-[(dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.23 g) was obtained. melting point: 218-220° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]([C:10](=[O:24])[NH:11][C@:12]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@H:13]2[CH:15]=[CH2:16])[CH2:8][CH:7]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=2)[CH:6]=1)=[O:4].[Li+].[OH-]>O1CCOCC1.O>[C:20]([O:19][C:17]([C@@:12]1([NH:11][C:10]([CH:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=4)[N:29]=[C:28]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:27]=3)[CH2:8]2)=[O:24])[CH2:14][C@H:13]1[CH:15]=[CH2:16])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)OC)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)O)C(=O)OC(C)(C)C
Yield: 1 %

Procedure:
The methyl ester 30 (35 mg, 59 mmol) was dissolved in dioxane/water (1:1, 4 mL) and LiOH (1.2 mmol) was added. The reaction was stirred over night and then co-concentrated. This gave the title compound (0.32 g, 90%) as a yellow salt.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a mixture of 4-bromobutyric acid (1 g), benzyl alcohol (0.65 g) and triphenyl phosphine (1.57 g) in tetrahydrofuran (12 mL) was added diethyl azodicarboxylate (40% toluene solution, 2.88 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.69 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][C:16]([C:15]1[CH:19]=[CH:20][C:12]([O:11][C@@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C

Procedure:
0.350 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid (1.26 mmol, 1 eq.) is placed in 13 mL of dichloromethane with stirring, at room temperature, under a nitrogen atmosphere. 0.16 mL of oxalyl chloride (1.89 mmol, 1.5 eq.) and 2 drops of dimethylformamide are successively added. The reaction medium is stirred for 1.5 hours and concentrated under vacuum. The methyl cis-4-(4-chlorocarbonylphenoxy)cyclohexanecarboxylate formed is dissolved in 13 mL of acetonitrile and placed under nitrogen. 0.255 g N-cyclopentyl[1.3.4]thiadiazole-2,5-diamine (1.39 mmol, 1.1 eq.) and 0.12 mL of pyridine (1.51 mmol, 1.2 eq.) are successively added. After 3 days, the medium is filtered and rinsed with acetonitrile to give 0.33 g of methyl cis-4-[4-(5-cyclopentylamino[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[NH2:10][C@H:11]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:10][C@H:11]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:21]=2)[CH2:16][CH2:15]1)=[O:8]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1sccc1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3sccc3Cl)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 3-chloro-2-thiophenecarbonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 524.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=1>C1(C)C=CC=CC=1.C(O)(=O)C.[Fe]>[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1nc2ccccc2[nH]1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(N)cc1-c1nc2ccccc2[nH]1
Temperature: 125 °C
Yield: 71.6 %

Procedure:
Iron powder (3.0 g, 50.9 mmol) was added to a solution of nitrobenzimidazole 7 (4.30 g, 16.9 mmol) in toluene (30 ml) and acetic acid (30 ml), and the reaction mixture was heated at 125° C. for about 1 h (completion of the reaction was monitored by TLC). The resulting crude mixture was filtered through a cotton wool plug (to remove iron particles). The crude solution was evaporated to dryness, diluted with EtOAc, washed with saturated NaHCO3 (until the pH=7), and the aqueous phase was back-extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated at reduced pressure to give 8 (2.70 g, 73%) a brown solid: 1H NMR(C2D6SO) δ 12.55 (s, 1H), 7.73 (d, 1H), 7.57 (d, 1H), 7.16 (broad m, 2H), 7.09 (d, 1H), 7.01 (app d, 1H), 6.70 (dd, 1H) 5.15 (broad s, 2H), 2.39 (s, 3H); MS (ES, positive mode): 224 [M++1].
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[NH:21][CH:20]([C:22]([OH:24])=[O:23])[C:19]([CH3:26])([CH3:25])[S:18]2)[CH:12]=1>C1COCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[N:21]([CH:1]=[O:2])[CH:20]([C:22]([OH:24])=[O:23])[C:19]([CH3:26])([CH3:25])[S:18]2)[CH:12]=1
Reactant: CC1(C)SC(c2cccnc2)NC1C(=O)O
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC1(C)SC(c2cccnc2)N(C=O)C1C(=O)O
Reaction time: 17 h
Yield: 89.4 %

Procedure:
Formic acid (17 g, 378 mmol) and acetic anhydride (13 g, 126 mmol) where combined at 10° C. A slurry of 2-(3-pyridinyl)-5,5-dimethyl-4-thiazolidinecarboxylic acid (10 g, 42 mmol), Prepared as in step 1, in THF (250 mL) was added over five minutes. The resulting clear-yellow solution was wanted slowly to ambient temperature and stirred for 17 hours, during which time it became a white suspension. The THF was removed in vacuo, and the resulting slurry was filtered to yield a white solid. The solid was rinsed with ether to give 2-(3-pyridinyl)-3-formyl-5,5-dimethyl-4-thiazolidinecarboxylic acid (10 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9][CH2:10][CH2:11]Br>CC#N>[Br:9][CH2:10][CH2:11][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: BrCCBr
Solvent: CC#N
Product: Clc1cccc(NCCBr)c1
Temperature: 80 °C
Yield: 9.8 %

Procedure:
A mixture of 3-chloroaniline (50 g, 0.39 mol) and 1,2-dibromoethane (73 g, 0.39 mol) in MeCN (500 mL) was heated at 80° C. for 2 days. The reaction mixture was concentrated on rotavap and subjected to silica flash column chromatography using 0 to 30% EtOAc in PE to isolate N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 10%) as a yellow solid. To a solution of N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 38.46 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (7.74 g, 38.46 mmol) in THF (100 mL) was added DIEA (14.88 g, 115.38 mmol). The resulting mixture was stirred at 70° C. for 2 days. It was partitioned in EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous was extracted with EtOAC (50 mL×3). The combined organic layer was washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 5% MeOH in DCM to isolated (R)-tert-butyl 3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398) (10.1 g, 74.4%) as a white solid.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.C[Si]([N:37]=[C:38]=[O:39])(C)C>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:38]([NH2:37])=[O:39])=[CH:25][CH:24]=1
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a stirred suspension of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (2.8 g, 6.8 mmol) and Et3N (9.1 mL, 68.5 mmol) in CH2Cl2 (50 mL) was added trimethylsilylisocyanate (3.8 mL, 27.4 mmol), and the resulting solution was stirred at rt for 1.5 h. The solution was then partitioned between CH2Cl2 (500 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (5% to 10% CH3OH in CH2Cl2) afforded the title compound as a white solid (2.2 g, 85%).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[CH3:2].CN(C=O)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CCCCOc1ccc2c(c1)CCCN2
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1ccc2c(c1)CCCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 39 %

Procedure:
To 70 mg (0.25 mmol) Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine in 1.4 ml DMF 87 μl (0.5 mmol) Huenig's base and 54 μl (0.38 mmol) benzyl chloroformate were added. The solution was stirred at RT over night, was concentrated and the residue was dissolved in ether and 0.1M NaOH. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2MeOH 5:1 yielded 40 mg (38%) 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester as light yellow oil, MS: 411 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[S:37]1[CH:41]=[N:40][N:39]=[C:38]1[NH2:42].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:42][C:38]4[S:37][CH:41]=[N:40][N:39]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE VVVV, 145.2 mg, 0.268 mmol). 1,3,4-thiadiazol-2-amine (32.6 mg, 0.322 mmol), and cesium carbonate (262 mg, 0.805 mmol). Acetonitrile (1342 μl) was added, and the mixture was stirred for 2 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with 10% MeOH/EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from MeOH, then the mixture was filtered through a membrane filter. The collected solid was washed with MeOH (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (65.89 mg, 0.144 mmol, 53.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.51 (br. s., 1H), 8.80 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.98 (s, 1H), 7.89-7.82 (m, 1H), 7.80-7.72 (m, 1H), 7.65 (s, 1H), 3.78 (s, 3H). m/z (ESI) 458.2 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[CH:12]=[N:13][OH:14]>CN(C=O)C>[Cl:1][O:14][N:13]=[CH:12][C:11]1[C:10]([Cl:9])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:19]
Reactant: ON=Cc1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ClON=Cc1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
N-Chlorosuccinimide (1162 g, 8.53 mol) in DMF (4.5 L) is added dropwise over a solution of 2,6-dichloro-benzaldehyde oxime (1621.78 g, 8.53 mol) in DMF (5.3 L) heated at 40° C. (addition is complete in about 6 hours). The mixture is stirred for 1 h at that temperature. The reaction is cooled at room temperature, poured onto H2O (30 L) at 0° C., and extracted with MTBE (36 L). The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated to dryness (at 30° C.). The crude, as a solid-oil, is triturated in 1 L of hexane and the solid formed is filtered and dried under vacuum to obtain the desired compound (1440.9 g, 75% yield). MS (m/e): 224 (M+1)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]([NH2:19])([CH2:17][CH3:18])([CH3:16])[CH3:15]>C(#N)C>[CH3:15][C:14]([NH:19][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:16])[CH2:17][CH3:18]
Reactant: CCC(C)(C)N
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)CC
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.152 mmol, Example 8D) in acetonitrile (3 mL ) at room temperature under nitrogen was added tert-amylamine (0.027 g, 0.228 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 5% MeOH/CH2Cl2 to provide the titled compound. MS (DCI) m/z 248 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>COCCOC>[CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([O:5][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)(CO)C(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: COCCOC
Product: COc1ccc(COC(=O)C(C)(C)CO)cc1

Procedure:
A solution of 1.03 g (8.7 mmol) of 2,2-dimethyl-3-hydroxypropionic acid, 1.8 mL (12.9 mmol), of TEA and 1.3 mL (9.5 mmol) of para-methoxybenzyl chloride in 8 mL of DME was stirred at rt for 24 h. The mixture was partitioned between 200 mL Et2O and 100 mL of H2O. After separating layers, the organic phase was washed with 100 mL of 1 N NaHCO3, 100 mL of 2 N HCl, 2×100 mL of H2O, 100 mL of brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography using a gradient of 3:1 v/v to 3:2 v/v of hexanes/EtOAc as the eluant to afford the title compound: RF: 0.17 (4:1 v/v hexanes/EtOAc); 1H-NMR (500 MHz) δ 1.21 (s, 6H), 3.57 (s, 2H), 3.82 (s, 3H), 5.09 (s, 2H), 6.90 (d, J=8.8, 2H), 7.28 (d, J=8.8, 2H).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([CH3:24])[CH:14]=[CH:13][C:12]([O:15][C:16]([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])=[O:17])=[CH:11][CH:10]=1.O=O>C(OCC)C>[C:21]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:22])[CH2:20][CH2:19][CH2:18][C:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:24])=[CH:14][CH:13]=1)=[O:17]
Reactant: CC(C)(C)OO
Reactant: Cc1ccc(OC(=O)CCCC(=O)Cl)cc1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(OC(=O)CCCC(=O)OOC(C)(C)C)cc1
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
To a vigorously stirred solution of 4.9 g. (0.045 mole) of 82.0% t-butyl hydroperoxide and 18.0 g. (0.045 mole) of aqueous 10% sodium hydroxide at 10°-14° C was slowly added 8.2 g. (0.034 mole) of 4-(p-tolyloxycarbonyl)butyryl chloride (prepared from p-tolyl 4-carboxybutyrate and thionyl chloride) in 25 ml. of diethyl ether. The reaction mixture was then stirred for 3.5 hours at 8°-10° C. After a work-up simular to that in Example I 8.2 g. (theory, 10.0 g.) of white solid, m.p. 50°-55° C, was obtained. The assay according to "active oxygen" content was 93.6% and the corrected yield was 76.7%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[CH2:30]([N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1)[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:37]4[CH:36]=[N:35][N:34]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH:38]=4)=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)Cn1cc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cn1

Procedure:
Using the method of Example 81 and using 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.459 g, 3.07 mmol), 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.3 g, 9.23 mmol) tetrakis(triphenylphosphine)palladium (0.355 g, 0.307 mmol), dimethoxyethane (15 mL) and sodium carbonate (2M, 5.4 mL) gives the title compound. Purify the crude material over silica gel (1/1 hexane in ethyl acetate) to yield 1.047 g (76%) of the title compound: mass spectrum (m/z): 450(M+2).
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[Cl:5][C:6]1[C:12](Cl)=[CH:11][C:9]([NH2:10])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1.O>CN(C=O)C>[Cl:5][C:6]1[C:12]([S:2][CH3:1])=[CH:11][C:9]([NH2:10])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: CS
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(N)c([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h

Procedure:
Methyl mercaptan gas was passed into a stirred suspension of 1.16 g (30 mmol) of 60% oil-dispersed NaH in 45 mL of DMF until evolution of H2 gas ceased. 5 g (24 mmol) of 4,5-dichloro-2-nitroaniline (Aldrich) was then added portionwise. After 30 min of stirring, the reaction mixture was poured into 200 mL of water. Yellow precipitate formed was collected by filtration and dried. This gave 3.8 g (72%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ2.5 (s, 3H, CH3), 6.9 (s, 1H, aromatic), 7.6 (br s, 2H, NH2), 8.0 (s, 1H, aromatic)