Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][N:3]=[CH:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:34])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:33])[C@@H:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:7][CH2:6]1.[CH3:35]O[NH3+].[Cl-]>CN1CCCC1=O.CCOCC>[CH3:35][O:1][NH:2][N:3]=[CH:4][N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][NH:12][C:13](=[O:34])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:33])[C@@H:20]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:9][CH2:10]1
Reactant: CO[NH3+]
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC1CCN(C=NNO)CC1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CONN=CN1CCC(CNC(=O)[C@@H]2CCCN2C(=O)[C@@H](Cc2ccccc2)NS(C)(=O)=O)CC1
Temperature: 130 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a stirred solution of Example 3 Part D aminonitrile (0.34 g, 0.74 mmol) in 3.0 mL of 1-methyl-2-pyrrolidinone was added methoxyamine.HCl (0.18 g, 216 mmol). This reaction solution was immersed into a 85° C. oil bath. The bath temperature was slowly raised up no 130° C. in 80 min. The reaction solution was stirred at 130° C. for 2 h and cooled to room temperature. The solution was diluted with 30 mL of ether and the solution was decanted. The remaining oily residue was purified by preparative HPLC to give 250 mg (51%) of title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33][CH2:34][CH3:35])=[CH2:32])CCC>CN(C=O)C.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>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=[C:2]([C:31]([O:33][CH2:34][CH3:35])=[CH2:32])[N:7]2[N:8]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1nc(C)nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 100 °C
Yield: 48.5 %

Procedure:
To a mixture of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 100 mg, 0.257 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in DMF (0.8 ml) was added tributyl(1-ethoxyvinyl)tin (130 mg, 0.36 mmol) in DMF (1.5 ml). The reaction was degassed (3×) by pulling a vacuum and refilling with nitrogen. After heating at 100° C. for 1 hour under nitrogen, the reaction was cooled and then extracted from water with ethyl acetate. The organic layer was washed with ½ saturated brine and then brine. After drying (MgSO4), the mixture was concentrated, in vacuo, and purified on a Biotage™ Flash 12M column using 10% ethyl acetate in hexanes to afford product 14A-1 as a solid (53 mg, 49%): +APcI MS (M+1) 425.1; 1H NMR (400 MHz, CD3OD) δ 7.50-7.38 (m, 6H), 7.27 (d, J=8.7 Hz, 2H), 6.20 (d, J=3.3 Hz, 1H), 5.19 (d, J=3.3 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 2.75 (s, 3H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][C:20]=1[N+:31]([O-:33])=[O:32].C(N(CC)CC)C>CN(C)C=O>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][C:20]=3[N+:31]([O-:33])=[O:32])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1Br
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(-c4ccccc4)cc3[N+](=O)[O-])cc12
Temperature: 110 °C
Yield: 24 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-bromo-3-nitrobiphenyl were used. Triethylamine was used as base, N,N-dimethylformamide was used as solvent, and the reaction was heated at 110° C. for 12 hours. Column chromatography afforded the title compound (24%) as a red amorphous solid: 1H NMR (CDCl3) δ 9.63 (br s, NH), 8.97 (br s, NH), 8.42 (d, J=2.2 Hz, 1 H), 7.56-7.25 (m, 9H), 7.08 (d, J=9.0 Hz, 2H), 3.50-3.32 (m, 2H), 2.95-2.79 (m, 2H), 2.59-2.52 (m, 1H), 2.53 (s, 3H), 2.05-1.71 (m, 4H); 13C NMR (CDCl3) δ 144.4, 138.8, 134.9, 134.5, 132.4, 131.1, 130.2, 129.7, 129.0, 127.3, 126.2, 124.7, 124.1, 120.8, 116.7, 115.9, 112.7, 112.0, 67.9, 57.4, 40.6, 31.2, 28.6, 21.9; FAB HRMS calculated for [C26H26N4O2.H]427.2136, found 427.2099.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].[F-].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:12]1([C:11]2[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[N:3][C:4]3[C:9]([CH:10]=2)=[N:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc2cccnc2cc1-c1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3cccnc3cc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
2-Chloro-3-phenyl-1,5-naphthyridine (3-5; 103 mg, 0.43 mmole), 4-formylphenylboronic acid (77 mg, 0.51 mmole), KF (82 mg, 1.4 mmole), and Pd(PtBu3)2 (11 mg, 0.02 mmole) were combined in dry dioxane (2.5 mL). The mixture was degassed (3× pump/N2) then heated to reflux. After 18 hr the mixture was cooled to RT. 4-Formylphenylboronic acid (77 mg, 0.51 mmole), KF (82 mg, L 1.4 mmole), and Pd(PtBu3)2 (11 mg, 0.02 mmole) were added. The mixture was degassed (3× pump/N2) then heated to reflux. After 6 hr the mixture was cooled, diluted with saturated NaHCO3, and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (20% EtOAc/CHCl3) gave the title compound (3-6) as a pale yellow gum: 1H-NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), 9.05 (bs, 1H), 8.48 (m, 2H), 7.82 (dd, J=1.47 and 5.13 Hz, 2H), 7.71 (m, 1H), 7.63 (d, J=8.06 Hz, 2H), 7.36-7.27 (m, 5H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].N1C=CC=CC=1.ClCCl.[CH3:23][Si:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27]>O>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:27][CH2:26][CH2:25][Si:24]([CH3:29])([CH3:28])[CH3:23])=[O:9])(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 23.9 g of 3-(chlorosulfonyl)benzoyl chloride, 7.9 mL of pyridine, and 100 mL of dichloromethane was added dropwise 14 mL of 2-(trimethylsilyl)ethanol under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 29.4 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1CCCCC1.C(O)(=O)C.C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:9](=[CH:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)/C(=C/c1ccccc1)C(=O)c1ccccc1O
Yield: 83.9 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (618 mg, 2.6 mmol), benzaldehyde (265 μL, 2.6 mmol), 12.0 mL benzene, piperidine (13 μL, 0.13 mmol) and glacial acetic acid (7.5 μL, 0.13 mmol), refluxed for 2 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 708 mg (83%) of 5 as clear crystals. mp=109-110° C.; IR (film) 2978.4; 1737.4; 1692.4; 1643.3; 1145.8 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.92 (bs, 1H), 7.86 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.4 Hz), 1H, 7.37-7.28 (m, 5H), 7.04 (d, J=8.4 Hz. 1H), 6.83 (t, J=7.3 Hz, 1H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.6, 163.8, 162.8, 142.3, 137.2, 133.0, 131.9, 131.6, 130.7, 130.3, 129.1, 120.2, 119.6, 118.5, 82.8, 28.1; LRMS (electrospray): Mass calculated for C20H20O4, [M]+, 324.13. Found [M+23]+, 347.3. An NOE difference experiment was conducted for this compound and a positive NOE was seen for the alkene proton when the tert-butyl signal was irradiated and a positive NOE was seen for the tert-butyl signal upon irradiation of the alkene proton.
Reaction SMILES: [NH:1]([C:8]([C:11]1[N:12]([CH3:26])[C:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=2)=[N:14][N:15]=1)([CH3:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH2:28]>CO>[NH:1]([C:8]([C:11]1[N:12]([CH3:26])[C:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([NH2:28])=[O:21])=[CH:18][CH:17]=2)=[N:14][N:15]=1)([CH3:9])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nnc(C(C)(C)Nc3ccccc3)n2C)cc1
Reactant: CN
Solvent: CO
Product: Cn1c(-c2ccc(C(N)=O)cc2)nnc1C(C)(C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
Methyl 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}benzoate (300 mg) was dissolved in methanol (1 ml) and then methylamine (30% methanol solution, 886.3 mg) was added thereto, followed by stirring at room temperature overnight. The resulting precipitate was collected by filtration to obtain 349 mg of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}benzamide (white crystals).
Reaction SMILES: [F:1][C:2]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:3]=1[O:4][S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1C(OC(C)(C)C)=O)=[CH:13][CH:12]=[CH:11]2)(=[O:7])=[O:6].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][C:8]([S:5]([O:4][C:3]1[C:30]([F:37])=[C:31]([F:36])[C:32]([F:35])=[C:33]([F:34])[C:2]=1[F:1])(=[O:7])=[O:6])=[CH:9]2
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)cccc2c1
Reaction time: 4 h

Procedure:
A round-bottom flask was charged with tert-butyl 2-(6-((perfluorophenoxy)sulfonyl)naphthalen-1-yl)pyrrolidine-1-carboxylate (0.315 g, 0.580 mmol) and DCM (3.0 mL) to give a light yellow solution. TFA (1.786 ml, 23.18 mmol) was added in one portion to give a yellow solution. The reaction was stirred for four hours. The reaction was concentrated, dissolved in diethyl ether, and sonicated until a fine white solid triturated out of solution. The solids were filtered, washed with diethyl ether, and vacuum dried overnight to afford perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate as an off-white solid. m/z (ESI) 444.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](=O)([O:18]CC)[O:15]CC.CC[O-].[K+].Cl>O>[CH:1]1[C:13]2[CH:12]([C:14]([OH:18])=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)C1c2ccccc2-c2ccccc21
Temperature: 20 °C
Reaction time: 5 h
Yield: 70.1 %

Procedure:
A solution of 332 g (1.9 moles) of fluorene and 974 g (8.2 moles) of diethyl carbonate was added with cooling to keep the temperature no higher than 40° C. to a mixture of 584 g (4.6 moles) of diethyl carbonate and 186 g (2.2 moles) of potassium ethylate in a reaction vessel and the mixture was stirred at 65°-70° C. for 5 hours and was cooled to 20° C. The mixture was slowly poured into a solution of 220 g (2.2 moles) of hydrochloric acid and 500 g of water with cooling to keep the temperature at a maximum of 40° C. The product was then treated as in Example 1 to obtain 280 g of fluorene-9-carboxylic acid in the form of light-beige crystals melting at 227°-229° C. (72.7% yield based on fluorene).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cc(Cl)ccc1Cl

Procedure:
From 2,5-dichlorobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=417.1, tR (minutes, Method D)=0.76
Reaction SMILES: [C:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:8]=[CH:7][C:6]=1[C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34]C(C1C=NN(C3C=CC(Cl)=CC=3C)C=1C(C)(C)C)=O)[CH2:31]2>>[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34][C:21]([C:6]1[CH:7]=[N:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:11]=3)[C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[CH2:31]2
Reactant: CC(C)(C)c1c(C(=O)O)cnn1-c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(Cl)ccc1-n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1C(C)(C)C
Product: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]-5-tert-butyl-pyrazole-4-carboxamide was prepared from 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylic acid (Intermediate #119) by the same process used for Intermediate #114.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)COc1ccc(N)cc1
Reaction time: 3 h
Yield: 53.4 %

Procedure:
2-(4-Nitrophenoxy)propionic acid 2-[2-(4-nitrophenoxy)acetoxy]-ethyl ester 38 (20 g, 50 mmol) was dissolved in dry dimethylformamide (150 ml) in a pressure vessel. Palladium on carbon (5%, 5 g) was added and the mixture stirred under an atmosphere of hydrogen (4 kg) for 3 hrs. The catalyst was removed by filtration and ice water (1L) added to the filtrate. Crude 39 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using chloroform:ethyl acetate (8:2) to give pure 39 (10 g, 58%) as a dark brown syrup.
Reaction SMILES: [F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:26])([F:27])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:3][NH:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reaction time: 8 h

Procedure:
To a solution of 250 mg of tert-butyl 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate (Preparation 8) in 2 mL CH2Cl2 was added 1 mL of trifluoroacetic acid. The reaction was stirred overnight under a positive pressure of nitrogen. The reaction was concentrated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted 2× with EtOAc (20 mL). The combined organics were dried over Na2SO4 and condensed to yield 188 mg of a film. TLC shows much more polar spot. The crude product was carried on to the next reactions. MS calculated for (C19H13Cl3F4N2O), 466.00; found 467.9 M+H
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23](=[N-])(=[O:25])=[O:24].N1C=CC=CC=1.[ClH:33]>C(O)C.C(OCC)(=O)C>[ClH:33].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][NH:22][S:23]2(=[O:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: [N-]=S(=O)=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S1(=O)NCc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
In this reference example, 33.0 g (112.4 m.mols) of 1-benzyl-4-[N-(o-aminomethylphenyl)-amino]-piperidine, 21.6 g (224.8 m.mols) of sulfuryl amide and 250 ml of pyridine are mixed and refluxed with heating for 8 hours. The reaction solution is cooled to room temperature, concentrated to 70 ml and poured into 500 ml of ice water. The mixture is mixed with 300 ml of chloroform, stirred and adjusted to pH 9 with 2 N aqueous sodium hydroxide. The chloroform layer is separated with separating funnel and the remaining water layer is further extracted with chloroform (300 ml×3). The chloroform layers are combined, washed with water (300 ml×4), dried and concentrated to obtain an oily residue. This residue is dissolved in 150 ml of ethanol. To the solution, 50 ml of 5.7 N hydrogen chloride in ethyl acetate is added. The resultant solution is concentrated under reduced pressure. The crystalline residue is mixed with 50 ml of ethanol and filtered to obtain 29.0 g of the desired product. This compound is tested for NMR after it has been freed from hydrochloric acid, and it is tested for IR in its unaltered form of hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[CH:5][N:6]=1.[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:8]1([CH:4]2[S:3][CH:2]([NH2:1])[N:6]=[CH:5]2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: c1cn[nH]c1
Reactant: Nc1ncc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC1N=CC(n2cccn2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
A solution of 2-amino-5-bromothiazole (2.6 g, 14.68 mmol), pyrazole (1 g, 14.68 mmol) and cesium carbonate (11.92 g, 36.7 mmol) in DMF (29 mL) was heated at 55° C. for 1 hr under argon argon atmosphere. After 1 hr, 2-amino-5-bromothiazole (2.6 g, 14.68 mmol) was added and continued for next 1 hr. Reaction mixture was cooled to rt and poured over ice cold water (200 mL), extracted with ethylacetate (4×100 mL), washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude compound was purified by silica gel column chromatography using 60% ethyl acetate in hexane as eluent to afford pure 5-pyrazol-1-yl-5H-thiazol-2-amine (0.2 g).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)(O)=[O:2].C(Cl)(Cl)[Cl:21].S(Cl)(Cl)=O>CN(C)C=O>[Cl:21][C:1]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)=[O:2]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
A solution of 2.50 g. of 2-carboxy-5-oxo-5H-dibenzo[a,d]cycloheptene in 50 ml. of chloroform, 10 ml. of thionyl chloride and 0.3 ml. of dimethylformamide is stirred for 8 hours, then evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptene. This is dissolved in 50 ml. of chloroform and added to a 3-fold excess of ethereal diazomethane at 0°C. After 12 hours the solution is evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-diazoacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene. A solution of 1.37 g. of the latter compound in 50 ml. of tetrahydrofuran is added to 10 ml. of 0.1 N sulfuric acid containing 0.5 g. of copper powder. The mixture is refluxed for 3 hours and then cooled, filtered and poured into water. The solution is extracted with ethyl acetate and the extract washed, dried and evaporated to yield 2-hydroxyacetyl-5-oxo-5H-dibenzo[ a,d]cycloheptene which is recrystallized from chloroform/hexane. A solution of 0.05 g. of cupric acetate monohydrate in 5 ml. of acetic acid is heated to 100°C and 3.0 g. of granular zinc is added. The mixture is shaken for 3 minutes and the acetic acid is then decanted. The residual zinc-copper couple is washed three times with 5 ml. portions of acetic acid, then three times with 5 ml. portions of ether. It is then refluxed for four hours under nitrogen in 20 ml. of ether containing 2.5 ml. of methylene iodide, 1.32 g. of 2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene is added, and reflux is continued for a further four hours. The mixture is cooled and diluted with 50 ml. of benzene. The liquid phase is decanted and washed with water and aqueous sodium bisulfate, then dried and evaporated. The residue is chromatographed on 50 gm. of silica gel, eluting with ethyl acetate/hexane, to yield 2-(5-oxo-5H-dibenzo[a,d]-cyclohepten-2-yl)prop-1-en-3-ol.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: CS(=O)(=O)c1cccc(C(N)=NO)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cccc(S(C)(=O)=O)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was obtained following procedure described for example 54 step 1 but starting from Intermediate 28 (112 mg; 0.44 mmol) and Intermediate 64 (197 mg; 0.44 mmol). Purification by column chromatography (EtOAc:cHex from 10:90 to 50:50) yielded to a colorless oil. Trituration in ACN/pentane followed by filtration gave the title compound as an off-white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.59 (t, J=1.7 Hz, 1H), 8.47 (m, 1H), 8.35 (d, J=1.7 Hz, 1H), 8.21 (m, 2H), 7.93 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.33 (m, 3H), 7.15 (d, J=7.1 Hz, 1H), 4.23 (d, J=13.8 Hz, 1H), 4.17 (d, J=13.8 Hz, 1H), 3.35 (s, 3H), 3.26 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 435.3 (M+H)+. HPLC (Method A) Rt 5.35 min (Purity: 97.6%).