Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:2]=1.Cl.[C:17](Cl)(Cl)=[S:18]>CCOCC.C(Cl)(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[CH:2]=[CH:1][C:6]([N:7]=[C:17]=[S:18])=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 77.9 %

Procedure:
Unless otherwise indicated, all thioureas, isothiocyanates, thioamides and amines were purchased from Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Transworld Chemical Co. (Rockville, Md.), or Aldrich Chemical Co., (Milwaukee, Wis.). (a) 4-Amino-4′-chlorodiphenylether (TCI America, Portland Oreg., 520 mg, 2.03 mmol) was slurried in 10 mL of ether and treated with ca. 1 mL of ether saturated with HCl gas. After 5 min. the solvent was removed in vacuo. To a stirring biphasic solution amine-HCl salt in 20 mL CHCl3-sat'd NaHCO3 (1:1, v/v) at ambient temperature was added thiophosgene (1.2 equiv, 2.4 mmol) in 5 mL of CHCl3 dropwise via an addition funnel. The reaction was vigorously stirred for 1 h (TLC, 50% ethyl acetate-hexanes indicates clean conversion to a higher Rf spot), at which time the layers were separated, the aqueous layer extracted with CHCl3 (1×20 mL), and the combined organic layers washed with brine (1×20 mL) and dried (Na2SO4). Concentration of the solvent in vacuo yielded the crude 4-(4-chlorophenoxy)-phenylisothiocyanate (414 mg). (b) The 4-(4-chlorophenoxy)-phenylisothiocyanate was transferred to an Ace Glass pressure tube equipped with a Teflon coated stir bar and treated with a 2.0 M solution of NH3 in 5 ml methanol (Aldrich Chemical Co., Milwaukee, Wis.)). The tube was sealed and immersed in a 80° C. oil bath. After 2 h, the reaction was cooled to 0° C. in an ice bath. The precipitates were filtered and dried under vacuum to yield amino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione (328 mg, 79%). 1H NMR (DMSO-d6, 300 MHz) 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C13H11ClN2OS, 278.8 (M+H), found 279.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:3]=1.[NH2:20][NH2:21]>O1CCOCC1>[NH:20]([C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:3]=1)[NH2:21]
Reactant: NN
Reactant: CC(C)(O)COc1cc(Cl)nc(N2CCOCC2)n1
Solvent: C1COCCO1
Product: CC(C)(O)COc1cc(NN)nc(N2CCOCC2)n1

Procedure:
1-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol (2.58 g) was dissolved in dioxane (50 mL) and hydrazine (3 mL) was added. The solution was heated to reflux for one hour, at which point the solvent was evaporated. The solid was dissolved in dichloromethane (200 mL) and washed with 10% sodium carbonate (10 mL). The organic layer was dried over magnesium sulfate and evaporated to give 1-(6-hydrazino-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol, which was used without purification in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([CH3:22])[C:17]=2[CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([S:23]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:12][CH3:13])(=[O:24])=[O:25])=[C:21]([CH3:22])[C:17]=2[CH:16]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(OC)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.4 %

Procedure:
Into 4 mL of pyridine were dissolved 120 mg of methyl 4-amino-3-methoxybenzoate and 150 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene, followed by 14 hours of stirring at room temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding water at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and then the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain 110 mg of the title compound as colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[N:17]=[C:7]3[C:8](=[O:16])[CH:9]2[CH2:13][CH2:14][Cl:15])[CH:4]=[N:3]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=1>C(Cl)(Cl)Cl>[ClH:15].[ClH:15].[CH3:27][C:2]1([CH3:1])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[N:17]=[C:7]3[C:8](=[O:16])[CH:9]2[CH2:13][CH2:14][N:29]([CH3:28])[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=2)[CH:4]=[N:3]1
Reactant: CC1(C)N=CC2=C3N=C(c4ccc(Cl)cc4)N=C3C(=O)C(CCCl)C2C1=O
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCN(C)CCC2C(=O)C3=NC(c4ccc(Cl)cc4)=NC3=C3C=NC(C)(C)C(=O)C32)cc1OC
Product: Cl
Temperature: 150 °C

Procedure:
A mixture consisting of 1.5 gm of 7,7-dimethyl-2-(4-chlorophenyl)-5-(2-chloro-ethyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 1.7 gm of N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amine was heated at 150° C. for 3 hours. After cooling the reaction mixture was dissolved in chloroform, and the solution was washed with water. The chloroform phase was evaporated, and the residue was chromatographed on a silicagel column (eluant: chloroform/acetone 19:1). The dihydrochloride was precipitated from acetone by addition of ethereal hydrochloric acid and recrystallized from methylene chloride/acetone.
Reaction SMILES: CN1CC[O:5][CH2:4]C1.[NH2:8][C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:16][N:15]([CH:31]3[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]3)[C:11]=2[N:12]=[CH:13][N:14]=1.[O:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][NH2:45])[CH2:39][CH2:38]1>ClCCl.C(OCC)(=O)C>[O:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][NH:45][C:4](=[O:5])[O:36][CH:33]2[CH2:34][CH2:35][CH:31]([N:15]3[C:11]4[N:12]=[CH:13][N:14]=[C:9]([NH2:8])[C:10]=4[C:17]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:22][CH:23]=4)=[CH:16]3)[CH2:32]2)[CH2:39][CH2:38]1
Reactant: NCCN1CCOCC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1
Reactant: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(OC(=O)NCCN2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4- Nitrochloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 mL) was cooled on an ice-water bath. 4-Methylmorpholine (7 uL, 0.062 mmol) was added slowly. After 20 minutes, the ice-water bath was removed and the reaction mixture was allowed to warm up to room temperature. 3-(4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-cyclopentanol (20 mg, 0.052 mmol) was added and the reaction mixture was stirred for 4days. The reaction mixture was diluted with dichloromethane. The organic layer was washed with water, saturated sodium bicarbonate, brine, dried over MgSO4, filtered and evaporated to give a yellow solid. A solution of the yellow solid in dichloromethane (1 mL) was added to 2-morpholino-1-ethanamine (0.2 mL). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (3 times), brine, dried over MgSO4, filtered and evaporated. The crude product was purified by HPLC to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl N-(2-morpholinoethyl)carbamate (17 mg, 0.031 mmol). 1H NMR (CDCl3-d) δ 2.08 (m, 4H), 2.43 (m, 7H), 2.73 (m, 1H), 3.29 (m, 2H), 3.67, (m, 4H), 5.28 (m, 5H), 7.09 (m, 6H), 7.40 (m, 4H), 8.30 (s, 1H). LC/MS: MH+=543, tr=2.13 min. (Pecospher, 3C-18, 3 um, 4.6×33 mm; 0-100% acetonitrile—0.1 M ammonium acetate over 5 min, 3.5 ml/min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2B1OC(C)(C)C(C)(C)O1.Cl[C:38]1[N:43]=[C:42]([O:44][C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:41]=[N:40][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C:38]1[N:43]=[C:42]([O:44][C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:41]=[N:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Cl)n2)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 110 °C
Yield: 88.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (2.75 g, 5.40 mmol) and (R)-tert-butyl 3-(6-chloropyrazin-2-yloxy)piperidine-1-carboxylate (1.694 g, 5.40 mmol) in p-dioxane/H2O (4:1, 16 mL) followed by A-Phos (0.191 g, 0.270 mmol) and potassium phosphate (2.92 g, 10.80 mmol). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 80 min. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-20% EtOAc in Hexanes) to give (R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (3.15 g, 4.77 mmol, 88% yield) as a solid. MS (ESI, pos. ion) m/z: 661 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH:17]4[CH2:19][CH:14]3[CH2:15][CH:16]4[O:20][CH2:21][CH2:22][OH:23])=[N:10][CH:9]=[N:8][C:7]=2[S:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][CH2:21][O:20][CH:16]1[CH2:15][CH:14]2[CH2:19][CH:17]1[CH2:18][N:13]2[C:11]1[C:12]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][S:6][C:7]=2[N:8]=[CH:9][N:10]=1)(=[O:34])=[O:33]
Reactant: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCO)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCOS(C)(=O)=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
2-[[2-(5-Isopropylthieno[2,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-yl]oxy]ethanol (0.56 g, 1.7 mmol) was stirred in DCM (13.25 g, 10 mL, 156.0 mmol) at 0° C. Triethylamine (0.52 g, 0.71 mL, 5.0 mmol) was added. Methanesulfonyl chloride (0.29 g, 0.20 mL, 2.5 mmol) was added dropwise and the reaction allowed to warm slowly to room temperature and stirred for 1 hour. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-[[2-(5-isopropylthieno[2,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-yl]oxy]ethyl methanesulfonate (0.747 g). LCMS RT=3.94 min. M+1=412.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27]C)=[O:26].O.[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate (7.56 g, 17.6 mmol) in a mixture of THF/water (2/1 v/v, 180 mL) was added lithium hydroxide monohydrate (1.48 g, 35.2 mmol). The resulting mixture was stirred at ambient temperature overnight and concentrated in vacuo followed by the addition of water (150 mL). The mixture was extracted with of ethyl acetate/hexanes, 1/3 v/v, 50.0 mL). The water layer was acidified with 1 N HCl solution until the pH value reached 2. The precipitate was filtered and dried to give the title compound (7.30 g, 100%) as a white solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 7.95 (dd, 1H), 7.49 (dt, 1H), 7.37 (t, 1H), 7.24-7.16 (m, 2H), 7.11-6.98 (m, 2H), 6.80 (d, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 5.91 (s, 2H), 5.37-5.19 (m, 2H), 4.88-4.68 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 168.8, 156.0, 148.8, 143.0, 142.3, 137.6, 133.1, 132.1, 131.5, 129.9, 129.4, 127.7, 126.5, 124.2, 123.6, 120.1, 109.8, 103.8, 101.9, 93.8, 80.5, 58.0, 42.6.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccccc2Cl)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(2-chlorophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 8, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [N+:1](O)([O-:3])=[O:2].[CH:5](=[O:7])[CH3:6].[N+:8]([CH:11]([CH3:13])[CH3:12])([O-:10])=[O:9].C(=O)C.C(O)C>C(O)C.[OH-].[Na+].O>[N+:1]([O-:3])([O:7][CH:5]([C:11]([CH3:13])([N+:8]([O-:10])=[O:9])[CH3:12])[CH3:6])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC=O
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(O[N+](=O)[O-])C(C)(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The precursor nitroalcohol compound 3-methyl-3-nitro-2-butanol can be prepared as follows: 88.10 grams of acetaldehyde mixed with 88.10 grams of ethanol (previously cooled in refrigerator) was added dropwise to 178.2 grams of 2-nitropropane in 100 ml of ethanol and 4 ml of NaOH. After about two-thirds of this acetaldehyde-ethanol addition charge was added, 4 ml of 10N NaOH and 15 ml of H2O were added to the reaction mixture. The remaining addition charge was then added dropwise to the reaction mixture as before. After being stirred one hour at room temperature, the reaction contents were transferred to a two liter distilling flask with magnetic stirring and c.w. condenser. A heating mantle was used, and the temperature adjusted to 35° C. At the end of a two-day period, the temperature had reached 39° C., and the heating mantle was shut off. Stirring of the reaction mixture continued. At the end of another two-day period, the temperature had fallen to 24° C. The pH of the reaction mixture was adjusted to 6.7 with 21 ml of a 9 gram 37% HCl in 68 ml H2O solution. The next day, the pH was found to still be at 6.7. Vacuum distillation with a hot water bath, vigoro tube, c.w. condenser, ice-chilled receiver, and dry ice trap was then begun. Heads came off from 50 mm pressure and 25° C. (pot temperature) through 3 mm pressure and 40° C. (pot temperature). The solution had turned blue-green, but nearly all of the color was removed with the heads in a first removed fraction of 265 ml. A second fraction of 27.53 grams was removed with a pot temperature of 66° C., a head temperature of 48° C., and 2 mm pressure. A third fraction of 86.11 grams of a slightly viscous liquid was removed at a pot temperature of 69° C., a head temperature of 55°-58° C., and 2 mm pressure. The second and third fractions were combined and found to be 85-86% pure 3-nitro-3-methyl-2-butanol by gas chromatography.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]1=[O:13].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1C(=O)N([I:41])C(=O)C1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH3:12])=[C:4]([I:41])[C:3]1=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(C(F)(F)F)n(C)c(=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C(F)(F)F)n(C)c(=O)c1I
Temperature: 77.5 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1,4-dimethyl-6-(trifluoromethyl)-1H-pyridin-2-one (1.44 g, 7.23 mmol), trifluoroacetic acid (9 mL) and trifluoroacetic anhydride (1.53 mL, 10.85 mmol) was added NIS (2.569 g, 10.85 mmol) at room temperature. Then, the mixture was heated to 70-85° C. and was stirred for 2 h. The reaction mixture was cooled to room temperature and saturated sodium carbonate solution was added slowly to neutralize the solution. Then, the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed successively with saturated sodium thiosulfate solution (100 mL) and brine solution (100 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the solvent gave a crude product, which was purified by silica gel chromatography on a Biotage (40 m) column to afford 1.02 g (45% yield) of 1,4-dimethyl-3-iodo-6-(trifluoromethyl)-1H-pyridin-2-one as an amorphous white solid. ES-LRMS: m/z 318.1 (M+H), 381.2 (M+Na+ CH3CN). f) Preparation of N-[(1,1-dimethylethoxyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]1([NH2:40])[CH2:39][CH2:38][CH2:37]1>>[CH:36]1([NH:40][CH2:24][C:21]2[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[O:23][N:22]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: NC1CCC1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCC2)no1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and cyclobutylamine (250 μl, 2.96 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:33][CH:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:33][CH:34]2[CH:39]3[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]3)[CH2:35]2)=[O:18])[C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1
Reactant: NC1CN2CCC1CC2
Reactant: CCN1CC(C)(C)Oc2c(C(=O)O)cc(Cl)cc21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1CC(C)(C)Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc21
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 1.5 g of 6-chloro-2,2-dimethyl-4-ethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.56 ml of triethylamine, and 0.67 g of pivaloyl chloride was added dropwise thereto at -10° to -5° C. under cooling. After stirring for 15 minutes at the same temperature, 0.70 g of 3-aminoquinuclidine was added at -10° to -5° C. and the mixture was stirred at room temperature for an hour. The resultant mixture was washed with water, dried over magnesium sulfate and concentrated. To the residue was added ethanolic hydrochloric acid and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 6-chloro-2,2-dimethyl-4-ethyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride as white crystals, melting at 273°-276° C.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1I
Reactant: NC(=O)c1ccccc1
Product: COc1ccccc1NC(=O)c1ccccc1
Yield: 20.7 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with 2-iodoanisole (135 μL, 1.04 mmol) at 40° C. for 18 h. The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 3:1; 15 mL fractions). Fractions 8-12 provided 49 mg (21% yield) of the product as a colorless oil. The 1H NMR spectrum was in accord with that reported by Narasaka et al. Tsutsi, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 1869.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2Cl)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(Cl)c2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCc2nc3ccccc3c(Oc3ccccc3)c2CC1
Reaction time: 40 h

Procedure:
A mixture of 15.0 gm (49.4 millimols) of 11-chloro-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and 28.2 gm (300 millimols) of phenol was melted at 150° C and held at that temperature for 40 hours. Then, the mixture was taken up in ethyl acetate, and the solution was extracted with dilute sodium hydroxide. The ethyl acetate phases were evaporated and chromatographed on a silicagel column with toluene/acetone (8:1) as the eluant. Subsequently, the crystals were triturated with ether/petroleum ether.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O.S(OC)(O[CH3:20])(=O)=O>C(OCC)C>[CH3:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Ethyl 4-hydroxybenzoate (15.0 g, 0.09 mol) is stirred into an initial mixture of KOH (6.3 g, 0.11 mol) in dist. water (60 ml) under protective gas. Dimethyl sulfate (8.8 ml, 0.09 mol) is added dropwise to the clear solution with stirring and ice-cooling such that the temperature does not exceed 15° C. After addition is complete, the cooling is removed, and to complete the reaction the reaction mixture is stirred at RT for 45 min and under reflux for 2 h, then cooled to RT. The deposited oil is taken up in diethyl ether (50 ml). The aqueous phase separated off is extracted with diethyl ether (150 ml), and the ethereal extracts obtained are combined, washed with sodium hydroxide solution (10% strength, 50 ml) and with saturated NaCl solution, dried over Na2SO4 sicc. and concentrated in vacuo: colorless oil, yield: 15.7 g (97%).