Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[O:15])=[N:2]1.[C:25](P(=O)(OCC)OCC)#[N:26].CN.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:26][CH3:25])=[O:22])=[CH:18][N:17]=2)=[O:15])=[N:2]1
Reactant: CCOP(=O)(C#N)OCC
Reactant: O=C(O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Agent: CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)nicotinic acid (62 mg, 0.13 mmol), diethyl cyanophosphonate (21 μL, 0.14 mmol), methylamine (2.0M soln in THF, 15 μL, 0.14 mmol) and triethylamine (20 μL, 0.14 mmol) in dichloromethane (5 mL) was allowed to stir at room temperature overnight. The solution was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 30% ethyl acetate in hexanes, and selected fractions were combined and concentrated under reduced pressure to yield N2-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-N5-methylpyridine-2,5-dicarboxamide as a white solid, (50 mg). 1H NMR (300 MHz, DMSO-d6): 9.16 (broad s, 1H), 8.99 (s, 1H), 8.79 (m, 1H), 8.37 (d, 1H), 8.23 (t, 2H), 7.91 (d, 1H), 7.58 (s, 1H), 7.49 (t, 1H), 7.39 (t, 1H), 3.61 (m, 3H), 3.34 ppm (m, 4H). MW=355 confirmed by LC-MS, tr=2.98 min (Method B) MH+=356.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH:12]([OH:14])[CH2:11]1)(C(C)(C)C)(C)C.[CH3:23]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.C[O+](C)C>C(Cl)Cl.[Cl-].[Na+].O>[OH:8][CH2:9][C:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH:12]([O:14][CH3:23])[CH2:11]1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CC(C)(C)OC(=O)NC1(CO[Si](C)(C)C(C)(C)C)CC(O)C1
Agent: C[O+](C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC1CC(CO)(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
500 mg (1.51 mmol) of tert-butyl 1-((tert-butyldimethylsilyloxy)methyl)-3-hydroxycyclobutylcarbamate (prepared by reduction of ethyl-1[[(tert-butyloxy)carbonyl]amino]-3-hydroxycyclobutane-1-carboxylate as described in J. Med. Chem., 1990 33(10) 2905-2915) and proton sponge (N,N,N′,N′ tetramethylnapthalene-1,8 diamine) (1.63 g, 6.04 mmol) were dissolved in DCM (18 mL), cooled down to 0° C., and 447 mg (3.02 mmol) of trimethyloxonium borontetrafluoride was added in one portion as a solid under vigorous stirring. The reaction mixture was stirred for 3 h and diluted with DCM (50 mL) and brine (20 mL), added under vigorous stirring. The organic phase was washed with sodium bicarbonate, brine, dried over sodium sulphate, evaporated and purified on short silica column (DCM as an eluent). The resulting product was dissolved in THF (5 mL), and a solution of tetrabutylammonium fluoride in THF (1M, 4.5 mL) was added, and the reaction was stirred at room temperature for 4.5 h. The reaction was monitored by TLC and once deemed to have reached completion, it was absorbed onto silica and purified on silica (EtOAc-hexane 1:1 to neat EtOAc) to give the title compound (251 mg, 72%). LC/MS 232 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.[BH4-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])=[CH:19][CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)CCNC2C1(c2ccc(Cl)cc2)CCC1
Product: Cl
Temperature: 25 °C

Procedure:
N-[2-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-yl}oxy)ethyl]propane-1-sulfonamide (320 mg, 0.62 mmol) was dissolved in methanol (5 mL) and water (0.1 mL) and sodiumborohydride (47 mg, 1.25 mmol) was added at 4° C. in small portions. The reaction mixture was allowed to warm to room temperature and stirring was continued over night. The solvent was evaporated in vacuo, the residue was treated with dichloromethane and water. The aqueous layer was extracted several times with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (RP, acetonitrile, water). The purified amine was then converted into the corresponding hydrochloric acid salt by adding 5M isoporpanolic hydrochloric acid followed by concentration in vacuo. Yield: 35 mg (0.07 mmol, 11%, colorless solid).
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[CH2:11][NH:12][C:13]2[C:18](=[O:19])[N:17]([CH2:20][C:21]([OH:23])=O)[C:16]([CH3:24])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][NH2:36])[CH:33]=2)[NH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O>[NH3:6].[CH:2]1([CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[CH2:11][NH:12][C:13]2[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:36][CH2:35][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[C:26]4[CH3:25])=[O:23])[C:16]([CH3:24])=[CH:15][N:14]=2)[CH2:3][CH2:4]1
Reactant: Cc1cnc(NC[C@@H]2CCCN2CC2CC2)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NC[C@@H]4CCCN4CC4CC4)c3=O)cc12
Product: N
Yield: 58.6 %

Procedure:
A mixture of 2-[5-({[(2S)-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetic acid hydrochloride (preparation 76) (380 mg, 1.07 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (171 mg, 1.07 mmol), HOBT (216 mg, 1.60 mmol), WSCDI.HCl (255 mg, 1.33 mmol) and N-methylmorpholine (0.38 ml, 3.46 mmol) in N,N-dimethylformamide (4 ml), was stirred at room temperature for 24 hrs under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as eluant. This product was further purified using a Biotage™ (KP-Sil|™ 60 Å silica gel) cartridge and dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as eluant to give the title compound as a white solid, (145 mg, 29%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH:5]=[C:6](Br)[CH:7]=1.[C:27]1([CH3:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:31]1[C:32]2[C:27](=[CH:33][C:3]3[C:4]([C:9]=2[C:2]2[CH:3]=[C:4]([C:9]4[N:10]=[C:11]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:12]=[C:13]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:14]=4)[CH:5]=[C:6]([C:49]4[CH:50]=[CH:51][C:46]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=5)=[CH:47][CH:48]=4)[CH:7]=2)=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH:28]=[CH:29][CH:30]=1
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Reactant: Cc1ccccc1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4ccc(-c5ccccn5)cc4)cc(-c4c5ccccc5cc5ccccc45)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a stream of argon, 0.98 g (3.21 mmol) of 9-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)anthracene, 1.50 g (3.21 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 37.1 mg (0.032 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 100 mL of toluene and 20 mL of ethanol, and the resultant suspension was heated to 60° C. To the suspension, 9.63 mL (9.63 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 3 hours. Then the mixture was cooled to room temperature, and 0.96 g (4.82 mmol) of 4-(2-pyridyl)phenylboronic acid and 6.42 mL (6.42 mmol) of an aqueous 1M K2CO3 solution were added. Then the mixture was heated to 60° C. and maintained at that temperature for 17 hours while being stirred. Then the reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 0.68 g of the target 2-[5-(9-anthryl)-4′-(2-pyridyl)biphenyl-3-yl]-4,6-diphenyl-1,3,5-triazine as a white solid (yield: 330).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][N:16]([CH3:26])[C:17]([C:19]1[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18].O>CN(C)C=O>[CH3:15][N:16]([CH3:26])[C:17]([C:19]1[C:20]([S:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: SCc1ccccc1
Reactant: CN(C)C(=O)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
A solution of 25.0 g (223 mmol) of potassium t-butoxide in 100 ml of dimethylformamide was cooled to 0° C. and 22 ml (186 mmol) of benzyl mercaptan added dropwise at 0° C. After addition was complete, the reaction mixture was allowed to warm to 25° C. and stirred at this temperature for 15 minutes. The reaction mixture was then re-cooled to O° C. and 34.0 g (186 mmol) of N,N-dimethyl-2-(chloro)-3-pyridinecarboxamide added in one portion. After an exotherm to 50° C., the mixture was heated at 80° C. for 1.5 hour. The mixture was cooled, poured into 100 ml of water and extracted with ether. The combined organic extracts were washed twice with water, then brine and dried over sodium sulfate. Concentration gave 19.2 g of a viscous yellow oil. IR (Nujol) 1640 (CONMe2) cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>[Pt](=O)=O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[NH2:14]
Reactant: [H][H]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(F)cc1Br
Yield: 106 %

Procedure:
To an ethanol solution (300 ml) of 2-fluoro-4-bromo-5-methoxycarbonyloxy nitrobenzene (30.4 g, 0.1 mol) was added platinum dioxide (1.0 g) and the mixture was stirred under a hydrogen atmosphere until no hydrogen was absorbed. After the removal of the catalyst by filtration, the solvent of the filtrate was evaporated under reduced pressure to give a brown solid (28.0 g) of 2-fluoro-4-bromo-5-methoxycarbonyloxy aniline.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])([C:6]1[S:7][C:8](F)=[C:9]([F:12])[C:10]=1[F:11])[OH:5].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:3][C:4]([C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])([C:6]1[S:7][C:8]([Br:1])=[C:9]([F:12])[C:10]=1[F:11])[OH:5]
Reactant: OC(F)(c1sc(F)c(F)c1F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OC(F)(c1sc(Br)c(F)c1F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (0.698 g, 4.37 mmol) was added to a solution of 1 (1.80 g, 4.16 mmol) in CH2Cl2 (15 mL). After stirring overnight at room temperature, the mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3×20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo (1.90 g, 89%). 1H NMR (CDCl3): δ 7.02 (d, 1H, 2J=3.7 Hz), 6.97 (d, 1H, 2J=3.8 Hz), 5.46-5.38 (m, 1H), 2.64 (d, 1H, 2J=5.2 Hz); HRMS (EI, 70 eV) m/z: calcd (M+) for C11H4F13BrOS, 509.90; found, 509.8945.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:35][N:34]=[N:33][N:32]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[N:35]([CH3:36])[N:34]=[N:33][N:32]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5nnn[nH]5)c4)cc3C2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnnc1-c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
A suspension of N-(3-tert-butylphenyl)-7-{[2-(1H-tetrazol-5-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.075 g, 0.16 mmol), potassium carbonate (0.11 g, 0.80 mmol), and methyl iodide (0.019 mL, 0.30 mmol) in acetone (8 mL) was allowed to stir at 0° C. for 10 min. The reaction mixture was allowed to warm to rt, diluted with water, and extracted with EtOAc. The organic solution were combined and concentrated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-{[2-(1-methyl-1H-tetrazol-5-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (9.3 mg) I-321 [1H NMR (400 MHz, d6-DMSO, HCOOH salt) δ: 9.94 (s, 1H), 8.67 (d, 1H), 7.63 (t, 1H), 7.57 (d, 1H), 7.49 (d, 1H), 7.27 (d, 1H), 7.18-7.22 (m, 2H), 7.04-7.07 (m, 2H), 6.99-7.02 (m, 1H), 3.31 (s, 3H), 2.73-2.96 (m, 5H), 2.08-2.12 (m, 1H), 1.79-1.83 (m, 1H), and 1.25 (s, 9H), LCMS: (FA) ES+ 484.0, ES− 482.0] and N-(3-tert-butylphenyl)-7-{[2-(2-methyl-2H-tetrazol-5-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (10.6 mg) I-334. [1H NMR (400 MHz, d6-DMSO, HCOOH salt) δ: 9.95 (s, 1H), 8.60 (d, 1H), 7.63 (t, 1H), 7.47-7.50 (m, 2H), 7.18-7.20 (m, 2H), 7.10 (dd, 1H), 7.05-7.07 (m, 2H), 6.98 (d, 1H), 3.31 (s, 3H), 2.74-2.95 (m, 5H), 2.07-2.12 (m, 1H), 1.77-1.82 (m, 1H), and 1.25 (s, 9H), LCMS: (FA) ES+ 484.0, ES− 482.0].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:21])[N:11]([NH:13]C(=O)OC(C)(C)C)[CH:12]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:21])[N:11]([NH2:13])[CH:12]=1
Reactant: Cc1nc(-c2ccccc2F)cn1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2F)cn1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound C2 (17.4 g, 59.7 mmol) in dichloromethane (120 mL) was treated with trifluoroacetic acid (23.0 mL, 299 mmol) and allowed to stir for 18 hours at room temperature. Excess 1 N aqueous sodium hydroxide solution was added, and the mixture was stirred vigorously for 15 minutes. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a brown solid. Yield: 9.95 g, 52.0 mmol, 87%. LCMS m/z 192.3 [M+H]+.
Reaction SMILES: CCN(CC)CC.C(OC([N:15]1[CH2:19][C:18]([F:21])([F:20])[C:17]([CH3:23])([CH3:22])[C@H:16]1[C:24]([OH:26])=O)=O)(C)(C)C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:24]([C@@H:16]1[C:17]([CH3:22])([CH3:23])[C:18]([F:20])([F:21])[CH2:19][NH:15]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C(C)(C)[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)[C@@H](C(=O)NCC(F)(F)F)NCC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 107 %

Procedure:
NEt3 (75.2 g, 743 mmol) was slowly added to a 10° C. solution of (2S)-4,4-difluoro-3,3-dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (98.3 g, 352 mmol), chlorodiphenylphosphate (101 g, 376 mmol), and ethyl acetate (1.0 L). The mixture was warmed to ambient temperature for 45 min., and was then cooled to 10° C. 2,2,2-Trifluoroethylamine (39.5 g, 399 mmol) was slowly added and the resultant mixture was stirred at ambient temperature for 2.75 h. 20% Aqueous citric acid (1.0 L) was added and the resulting layers were separated. The aqueous fraction was extracted with ethyl acetate (2×300 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (2×500 mL), and then with saturated aqueous NaCl (300 mL). The resulting organic fraction was concentrated to a weight of 900 g using a rotary evaporator. A 3 N HCl/ethyl acetate solution (500 mL) was added to the concentrate, and the mixture was stirred at ambient temperature for 24 h. The resulting solid was filtered, washed with ethyl acetate (100 mL), and was then dried in a vacuum oven at 55° C. to provide 98.0 g (93.9%) of (2S)-4,4-difluoro-3,3-dimethyl-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide; hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.46 (br s, 2H), 9.50 (t, J=6.2Hz, 1H), 4.17–4.33 (m, 2H), 3.68–4.02 (m, 3H), 1.23 (app d, J=2.1 Hz, 3H), 0.97 (app d, J=2.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 165.6, 127.9 (dd, JCF=250.2, 257.2 Hz), 125.6 (q, JCF=279.0 Hz), 64.8, 48.2 (t, JCF=33.4 Hz), 45.7 (t, JCF=21.2 Hz), 18.2 (d, JCF=7.5Hz), 17.2 (app dd, JCF=2.3, 5.8 Hz); MS (CI) m/z 261.1015 (261.1026 calcd for C9H14N2OF5, M−HCl+H+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=[C:5]2[CH2:4]1)[CH3:2].[Li][CH2:18][CH2:19]CC.C(I)C>CC#N>[CH2:18]([C:9]1[S:8][C:7]([C:10]([OH:12])=[O:11])=[C:6]2[CH2:13][CH2:14][C:3]([CH2:1][CH3:2])([CH2:15][CH3:16])[CH2:4][C:5]=12)[CH3:19]
Reactant: CCC1(CC)CCc2c(csc2C(=O)O)C1
Reactant: [Li]CCCC
Solvent: CC#N
Solvent: CCI
Product: CCc1sc(C(=O)O)c2c1CC(CC)(CC)CC2

Procedure:
3,5,5-Triethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid is prepared from 5,5-diethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid by treatment with tert.-BuLi followed by ethyliodide in analogy to Example C; LC-MS: tR=1.07 min, [M+1+CH3CN]=308.14.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][O:17][C:18]([C:20]1[C:21]2[CH:22]=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[O:19].C([O-])(=O)C.[Na+]>C(Cl)CCl>[CH3:16][O:17][C:18]([C:20]1[C:21]2[C:22]([CH:9]=[O:10])=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of N-methylformanilide (15.6 g) and phosphorus oxychloride (17.7 g) is added ethylene dichloride (75 g ) followed by 4-indolecarboxylic acid methyl ester (17.5 g). The reaction mixture is stirred at room temperature for 1 1/2 hr., then at 45°-50°C for 30 minutes more. The mixture is now poured into a solution of 75 g of sodium acetate in 150 ml of ice-water. More ethylene dichloride is added. The layers are separated and the organic phase is washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residual brown oil is passed through a silica gel column using 3% methanol in chloroform. Concentration of the eluate affords a solid which on recrystallization from benzene affords the pure title compound, mp 135°C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH:13]1([C:16](=[O:23])[CH2:17][C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH2:15][CH2:14]1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:17]([C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:23])[C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1

Procedure:
A mixture containing 1.6 g 4-acetamidobenzaldehyde, 1.5 g 1,3-dicyclopropyl-1,3-propanedione, 0.2 ml of piperidine and 0.4 ml of acetic acid in 50 ml of toluene was refluxed for 3 h by using a Dean-Stark separator. After standing over night at room temperature the crystals were filtered and washed with toluene. The product was recrystallized from ethanol. Yield 2.0 g, mp 166°-167° C.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([CH:5]1[O:7][CH2:6]1)[Cl:4].[CH3:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=O)=[CH:13][CH:12]=1)[CH3:10].[OH2:20]>CN(C)C=O>[Cl:4][CH2:3][CH:5]1[O:7][C:6](=[O:20])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]([CH3:10])[CH3:8])=[CH:12][CH:13]=2)[CH2:18]1
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: ClCC1CO1
Reactant: O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N2CC(CCl)OC2=O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
0.2-0.3 grams of lithium chloride was added to a solution of 7 grams (0.076 mole) epichlorohydrin in 30 ml dimethylformamide at 90° C. Heating was discontinued, and a solution of 12.25 grams (0.076 mole) 4(1-methylethyl)phenylisocyanate in 10 ml dimethylformamide was added dropwise at such a rate that the reaction temperature did not exceed 110° C. When the addition was complete heat was reapplied and the reaction solution was stirred at 90° C. for 3 hours. The solution was then added in a slow stream to a vigorously stirred mixture of ice and water, about 200 ml total volume. The reaction product solidified and was recovered by filtration. Recrystallization from methanol afforded an 85% yield of white crystalline material (mp 77°-79° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=1)#N.[CH3:14][O:15][C:16]1C=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([CH:31]2[NH:13][C:6]3[CH:5]=[CH:4][C:3]([C:1]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[O:15][CH3:14])=[CH:8][C:7]=3[S:9](=[O:11])(=[O:10])[NH:12]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=CC1CCCCC1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
5-Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H (using 2-methoxyphenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M.p. 219-222° C.