Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][C:23]([C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:24]
Reactant: O=C(Cl)Cc1cccc(F)c1F
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To 7-azaindole (1 g, 8.5 mmol) and AlCl3 (1.2 g, 9.0 mmol) in methlene chloride at 0° C. was added (2,3-difluorophenyl)-acetyl chloride [prepared by treating (2,3-difluoro-phenyl)-acetic acid (1.5 mg, 8.72 mmol) with oxalyl chloride (0.90 mL)] in methlene chloride. After stirring at room temperature for 2 hours, the solution was poured into ice water and extracted with methlene chloride, dried (Na2SO4), and concentrated to give 300 mg (13% yield) of title compound used without purification. LCMS Rt=3.00 minutes, MH+ 273.1, M− 271.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[CH2:12][CH3:13].Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:16][OH:17])[CH2:12][CH3:13]
Reactant: NO
Reactant: CCC(=O)c1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CCC(=NO)c1ccc2ccccc2c1
Yield: 89.7 %

Procedure:
A mixture of 2.1 g (11.41 mmol) of 1-(2-naphthyl)-1-propanone and 2.1 g (30.22 mmol) of hydroxylamine hydrochloride was heated under reflux in 30 ml of pyridine for 1 hour. The solution was evaporated to dryness and the residue was partitioned between water and diethyl ether. The organic layer was washed twice with 2M hydrochloric acid, dried over magnesium sulphate, filtered and evaporated to dryness to give 2.04 g of 1-(2-naphthyl)-1-propanone oxime as a pink solid, 1H NMR (400 MHz, CDCL3) δ: 1.2-1.3 (t,3H), 2.9-3.0 (q,2H), 7.45-7.55 (m,2H), 7.8-7.9 (m,4H), 8.02 (s,1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([S:37][C:38]2[CH:43]=[C:42]([C:44](C)(C)C)[C:41]([OH:48])=[C:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:39]=2)[CH2:18][CH:19]([S:21][C:22]2[CH:27]=[C:26]([C:28](C)(C)C)[C:25]([OH:32])=[C:24]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:23]=2)[CH3:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])(C)(C)C.C(C1C=C(SC(C)CC=O)C=C(C)C=1O)(C)(C)C.C(C1C=C(S)C=C(C)C=1O)(C)(C)C>>[C:49]([C:40]1[CH:39]=[C:38]([S:37][CH:17]([S:16][C:7]2[CH:6]=[C:5]([CH3:1])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=2)[CH2:18][CH:19]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([OH:32])=[C:24]([C:33]([CH3:34])([CH3:35])[CH3:36])[CH:23]=2)[CH3:20])[CH:43]=[C:42]([CH3:44])[C:41]=1[OH:48])([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cc1cc(S)cc(C(C)(C)C)c1O
Agent: Cc1cc(SC(C)CC=O)cc(C(C)(C)C)c1O
Product: Cc1cc(SC(C)CC(Sc2cc(C)c(O)c(C(C)(C)C)c2)Sc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
The instant compound named above is made in an analogous manner to the compound of Example 3 by reacting a one molar proportion of reactant (a) with two molar proportions of 2-tert-butyl-6-methyl-4-mercaptophenol. After recrystallization from a solvent mixture of 12:1 heptane: toluene, the compound is isolated as white crystals melting at 65°-69° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:35]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[S:35])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cccnc2c(-c2cccc(Cl)c2)nn1Cc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=c1c2cccnc2c(-c2cccc(Cl)c2)nn1Cc1ccccc1
Yield: 38.6 %

Procedure:
To a solution of 6-benzyl-8-(3-chlorophenyl)pyrido-[2,3-d]pyridazin-5-one (0.96 g, 2.76 mmoles) in toluene (100 mL) at room temperature under a nitrogen atmosphere was added solid 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) (0.67 g, 1.66 mmoles). The reaction mixture was heated under reflux for 18 hours, and then cooled and concentrated. Chromatography on silica gel using ethyl acetate/hexane (1:4) gave 0.233 g of 6-benzyl-8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-thione (23.2%), mp 132° C.
Reaction SMILES: CS[C:3]([N:7]1[N:11]=[CH:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8]1)=[N:4][CH2:5][CH3:6].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>C(#N)C>[CH2:8]1[C:9]2([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:10]=[N:11][N:7]1[C:3](=[N:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:27])=[O:28])[NH:4][CH2:5][CH3:6]
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCN=C(SC)N1CC2(C=N1)CCCC2
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC2(C=N1)CCCC2
Yield: 0.1 %

Procedure:
157 mg (1 mol equiv.) N-Ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboximidothioic acid methyl ester and 157 mg (1.05 mol equiv.) 4-acetamidobenzenesulfonamide were taken up in 5 mL acetonitrile. The reaction mixture was refluxed overnight under magnetic stirring and volatiles were removed in vacuo. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (ethyl acetate) afforded 236 mg (87%) of N-(4-{[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)-acetamide. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.2 Hz, 3H), 1.62-1.83 (m, 8H), 2.20 (s, 3H), 3.43-3.51 (m, 2H), 3.80 (s, 2H), 6.80 (s, 1H), 6.87 (br.s., 1H), 7.56 (d, J=8.8 Hz, 2H), 7.77 (br.s., 1H), 7.83 (d, J=8.8 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([F:8])[CH2:4][PH:5](=[O:7])[OH:6].[CH3:9][Si](N[Si](C)(C)C)(C)C.CCN(C(C)C)C(C)C.CI>C(Cl)Cl.COCCOCCOC>[NH2:1][CH2:2][C@@H:3]([F:8])[CH2:4][P:5]([CH3:9])(=[O:6])[OH:7]
Reactant: NC[C@@H](F)C[PH](=O)O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CP(=O)(O)C[C@H](F)CN
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 65.4 %

Procedure:
A suspension of compound (2R)-(3-amino-2-fluoropropyl)phosphinic acid (1.0 g, 7.1 mmol) in HMDS (7.47 mL, 35.4 mmol) was heated to reflux for 16 h. The reaction was cooled to room temperature, treated with diglyme (8.0 mL) and heated to reflux for 6 h. After the mixture was cooled to room temperature , Hünig's base (1.23 mL, 7.1 mmol) was added followed by dropwise addition of methyl iodide (1.32 mL, 21.2 mmol). The reaction was stirred for 23.5 h then it was diluted with methylene chloride and extracted with 2 N HCl solution. The aqueous layer was washed with methylene chloride and diethyl ether and then evaporated under reduced pressure. The crude product was passed through a Dowex 50WX8-200 mesh H+ form column eluting, with 1:1 methanol/water until no further material was detected by TLC analysis. The product was then eluted with 1:3 concentrated ammonium hydroxide solution/methanol. Further purification by column chromatography on silica gel eluting with methylene chloride, methanol, concentrated ammonium hydroxide solution (6:3:1) afforded (2R)-(3-amino-2-fluoropropyl)(methyl)phosphinic acid as a white solid (720 mg, 65%). 1H NMR (300 MHz, D2O) δ5.20 (m, 0.5H), 5.03 (m, 0.5H), 3.20-3.42 (m, 2H), 1.80-2.22 (m, 2H), 1.30 (d, J=14.0 Hz, 3H).
Reaction SMILES: FC(F)(F)C[O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19].[OH-].[Na+]>C(O)C.O>[F:19][C:18]([F:20])([F:21])[CH2:17][O:16][C:7]1[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=1[C:5]([OH:22])=[O:4]
Reactant: O=C(OCC(F)(F)F)c1ccc(C(F)(F)F)cc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1OCC(F)(F)F
Yield: 71.7 %

Procedure:
1.48 g 2-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-benzoic acid 2,2,2-trifluoro-ethyl ester were dissolved in 10 ml ethanol. 0.34 g sodium hydroxide dissolved in 10 ml water were added and the reaction mixture stirred under reflux overnight. Then the ethanol was removed in vacuo. The residue was diluted by the addition of 30 ml water. Then concentrated hydrochloride acid was added to acidify the solution. Thereby 2-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-benzoic acid precipitated as white solid. The solid was collected by filtration dissolved in 50 ml ethyl acetate and dried over MgSO4. The solvent was removed in vacuo to obtain 826 mg 2-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-benzoic acid as a white solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[C:29]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(OC(C)(C)C)=O>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:38][CH:39]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1

Procedure:
Compound 48a was prepared from compound 15a and 2-(BOC-amino)pyridine-5-boronic acid pinacol ester according to procedure described in Example 13, Step A. Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H31N7O4: 453.3 (M+H-BOC). Found 554.2.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=O)[N:14]=2)[CH:11]=1.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=3)=[O:17])[N:14]=2)[CH:11]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Me3Al (2.0M solution in toluene) (2.78 ml, 5.57 mmol) was added to a solution of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (500 mg, 1.85 mmol) in methylene chloride (10 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. (4-(trifluoromethoxy)phenyl)methanamine (0.42 ml, 2.78 mmol) was added to the above mixture at room temperature. The reaction mixture was stirred at 50° C. for 20 hours. After cooling to room temperature, the reaction was quenched by 1N HCl solution (2-3 mL). The reaction mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with methylene chloride. The combined organic layer was washed with brine, then dried over anhydrous magnesium sulfate. After concentration, the residue was purified by flash chromatography (ethyl acetate:hexane=1:1) to give the title compound, 6-bromo-N-(4-(trifluoromethoxy)-benzyl)imidazo[1,2-a]pyridine-2-carboxamide, as a solid (440 mg, 57% yield).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:25])[CH2:6][NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][N:11]=1)=[O:9])[CH3:3].O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>O>[CH2:2]([O:4][C:5](=[O:25])[CH2:6][NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([F:40])[CH:46]=2)=[CH:12][N:11]=1)=[O:9])[CH3:3]
Reactant: CCOC(=O)CNC(=O)c1ncc(OS(=O)(=O)C(F)(F)F)cc1O
Reactant: OB(O)c1cccc(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1ncc(-c2cccc(F)c2)cc1O
Temperature: 80 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a 5 L round-bottomed flask was charged [(3-hydroxy-5-trifluoromethanesulfonyloxypyridine-2-carbonyl)-amino]-acetic acid ethyl ester sodium salt, 4, (310 g, 0.78 mol), 1,4-dioxane (3 L) and water (150 mL). The solution was subjected to a vacuum-nitrogen purge cycle, followed by the addition of potassium phosphate (50 g, 0.234 mol) and 3-fluorophenylboronic acid (163 g, 1.17 mol). After addition, the vacuum-nitrogen purge cycle was repeated once. 1,1-Bis(diphenyl-phosphino)ferrocenepalladium (II) chloride CH2Cl2 complex (72 g, 0.088 mol, 0.11 eq.) was then added. After another vacuum-nitrogen purge cycle, the reaction mixture was then heated to 75 to 85° C. The progress of the reaction was monitored by TLC. The reaction was complete after 14-16 hours. The reaction was cooled to 15 to 25° C. and concentrated by rotary evaporation at up to 45° C. bath temperature until solvent collection had ceased. The residue was treated with an aqueous solution of HCl (1M, 1.5 L) and ethyl acetate (1.5 L) and stirred for 30 minutes at room temperature. The layers were then separated. The organic layer was washed with water (1.5 L), brine (1.5 L), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethylacetate/acetic acid: 3:1:0.01 by vol/vol) to afford 226 g (90% yield) of the desired product. MS (ESI+): m/z 319 (M+1); 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H), 8.44 (s, 1H), 8.32-0.31 (d, J=1.5 Hz, 1H), 7.51-7.44 (m, 2H), 7.40-7.37 (m, 1H), 7.32-7.27 (m, 1H), 7.17-7.13 (t, J=6.6 Hz, 1H), 4.33-4.25 (m, 4H), 1.36-1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12]O)[S:7][C:6]=2[C:14]=1[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:37]I.O>C1C=CC=CC=1.N1C=CC=CC=1>[OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][I:37])[S:7][C:6]=2[C:14]=1[CH3:15]
Reactant: II
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2
Reaction time: 0.5 h

Procedure:
3.0 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71) were dissolved in a mixture of 40 ml of benzene and 4 ml of pyridine, after which 6.2 g of triphenylphosphine were dissolved in the mixture. After the dissolution, 6.0 g of iodine was added to the solution all at once. The reaction temperatures of the mixture rose to 45° C. The reaction was allowed to continue for another 30 minutes at room temperature, and then the reaction mixture was poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude reaction product was subjected to silica gel Lobar column chromatography, and the title compound, melting at 72°-75° C. was obtained from the fraction eluted with benzene.
Reaction SMILES: C[O:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH3:16])=[O:14])=O.C(C1C=CC=CC=1C)C1C=CC=CC=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C[N+]1C=CNC=1.CCCS([O-])(=O)=O>>[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH3:16])=[O:14])=[C:3]=[O:2]
Reactant: COC(=O)NCCCCCCNC(=O)OC
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: CCCS(=O)(=O)[O-]
Product: COC(=O)NCCCCCCN=C=O
Temperature: 240 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
500 mL 3-necked flask equipped with a reflux apparatus, cooler, thermometer and sampling device was charged with 1,6-bis(methoxycarbonylamino)hexane (HDC, 50 g), benzyltoluene (250 g), di-n-butyltin dilaurate (0.05 g), and 1-methylimidazolium-3-propanesulfonate (0.1 g) as a zwitterionic compound, which were heated to 240° C. under 20 mmHg pressure. The reaction time was 2 hours, and the temperature of the reflux and cooling condenser was kept at 60° C. or more to prevent the reverse reaction. The resulting 1,6-diisocyanatohexane (HDI) and methanol were separately collected into a flask and dry ice-acetone trap. After the completion of the reaction, the product collected in the flask was analyzed with gas chromatography, which showed 94.1% yield of HDI, 5.2% yield of 1-isocyanato-6-methoxycarbonylaminohexane (HMI), and only 1.3 g of high-boiling polymer precipitates.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[F:10].C([N-]C(C)C)(C)C.[Li+].[C:19](=[O:21])=[O:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])=[C:6]([CH:7]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: Fc1ccc(Br)c(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 1-bromo-2,3,4-trifluorobenzene (13.64 g, 64.6 mmol) in THF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 33.9 mL, 67.8 mmol) at −78° C. under nitrogen atmosphere. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl (300 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 5% sodium hydroxide (300 mL). The aqueous layer was acidized to pH 1 and extracted with ethyl acetate (200 mL×3). The combined organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (white solid, 13.51 g, 82% yield). 1H NMR (400 MHz, CDCl3): δ 13.94 (s, 1H), 7.95 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)N>CO>[Cl:23][C:24]1[CH:30]=[C:29]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C:3]=23)[CH:28]=[CH:26][CH:25]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cccc(Nc2n[nH]c(N=CN(C)C)c2C#N)c1
Agent: Cl
Solvent: CO
Product: COc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
A mixture of 1.38 g (4.85 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(3-methoxy-phenylamino)-pyrazole, 0.915 g (5.58 mmol) of 3-chloro-aniline hydrochloride and 20 ml of methanol is heated under reflux for 16 hours. Concentration of the reaction mixture by evaporation in vacuo and recrystallization of the residue from methanol/water yield the title compound; m.p. 202-203° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH2:21])[CH2:13]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.Cl[S:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:8][CH2:9][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH:21][S:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:33])=[O:32])[CH2:13]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CS(=O)(=O)NC1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21

Procedure:
A sample of 1'-(1,1-dimethylethyloxycarbonyl)-3-amino-2,3-dihydrospiro(1H-indene-1,4'-piperidine), prepared by hydrogenation of 500 mg of oxime (1.58 mmole) as in Example 135, in 2 mL methylene chloride containing 475 mg of DMAP (2.46×1.58 mmole), and 550λ of triethylamine (2.51×1.58 mmole), was stirred under nitrogen in an ice bath while adding a solution of 400λ of 8.4M methyl chlorosulfonylacetate (2.13×1.58 mmole) in 2 mL methylene chloride dropwise over 2-3 minutes. The suspension was stored over night in the refrigerator. It was then washed twice with water, then with 5% citric acid. Atypically, solid material was still present in suspension; this was s removed by filtration, the filtrate dried with magnesium sulfate and concentrated under reduced pressure. Again, solid formed and was removed by filtration. Finally, preparative TLC on four 8"×8"×1,000μ GF silica gel plates using 2:1 ethyl acetate:hexane afforded 389 mg of the title compound
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12]C)[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:14](Cl)(=O)[C:15](Cl)=O.CN(C=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([Cl:11])=[C:6]([C:7]([C:15]2[CH:14]=[CH:6][CH:10]=[CH:2][CH:3]=2)=[O:9])[CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Br)cc(O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 208.2 %

Procedure:
To a suspension of compound 56 (6.0 g, 22.6 mmol) in CH2Cl2 (100 mL) were added oxalyl chloride (2.4 mL, 27.1 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with benzene (100 mL) and cooled to 0° C. To the reaction mixture was added AlCl3 (6.9 g, 52.0 mmol) portionwise at 0° C. The mixture was stirred at 90° C. for 15 hours. The mixture was cooled to rt and evaporated in vacuo. The residue was cooled to 0° C. and aq. 1N HCl solution was added. The mixture was extracted with EtOAc (150 mL×1). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 166 (7.33 g, quantitative yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:28][CH2:29][CH2:30][NH:31][C:32]1[N:33]([CH3:42])[C:34](=[O:41])[N:35]([CH3:40])[C:36](=[O:39])[C:37]=1[CH3:38]>>[CH2:21]([O:20][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:28][CH2:29][CH2:30][NH:31][C:32]1[N:33]([CH3:42])[C:34](=[O:41])[N:35]([CH3:40])[C:36](=[O:39])[C:37]=1[CH3:38])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2OCc2ccccc2)cc1
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Product: Cc1c(NCCNCC(O)COc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)n(C)c(=O)n(C)c1=O
Yield: 32 %

Procedure:
Yield 32% of theory; colorless oil from 3,4-dibenzyloxyphenyl glycidyl ether and 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].N1C=CC=CC=1C.[Cl-].[NH4+]>CS(C)=O>[CH3:18][CH:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH:21]=1)[CH3:19]
Reactant: CC(C)c1ccc(O)cc1
Reactant: Nc1ncccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccn1
Solvent: CS(C)=O
Product: CC(C)c1ccc(Oc2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
A mixture of 3-bromopyridin-2-amine (1200 mg), tripotassium phosphate (2945 mg), 4-isopropylphenol (1134 mg), copper iodide(I) (132 mg) and picoline acid (171 mg) in DMSO (40 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to saturated aqueous ammonium chloride solution, filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (180.4 mg) as a pale-brown solid.