Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@@H:22]5[CH2:25][N:26](C(OCC)=O)[CH2:27][C@H:21]45)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=[CH:3]1.C(O)(=O)C>Br.CO>[N:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:7]4[C:2](=[O:1])[CH:3]=[CH:4][CH:5]=[N:6]4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH2:24][CH2:23][C@@H:22]2[CH2:25][NH:26][CH2:27][C@H:21]12
Reactant: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Product: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Temperature: 67.5 °C
Yield: 116.1 %

Procedure:
A mixture of the product of Example 41E (7.50 g, 17.42 mmol) in 33% HBr in acetic acid (37 mL, 205.57 mmol, 11.8 equivalents) was heated to 65-70° C. for at least 6 hours while monitored by HPLC analysis for completion. When reaction is complete the mixture is cooled to not more than 45° C. and is diluted with methanol (111 mL). The mixture was cooled to 20-25° C., the product is collected by filtration and is washed with fresh methanol (50 mL). The wet cake is dried in the vacuum oven at not more than 55° C. to provide the title compound (7.25 g, 94.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1.CN(C=O)C.O>[CH2:35]([N:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1)[CH:34]=[CH2:33]
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2o1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(CCCc1ccc(F)cc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Temperature: 25 °C

Procedure:
To a stirred suspension of 6-{trans-4-[3-(4-fluorophenyl)-propylamino]-cyclohexyl}-3H-benzoxazol-2-one (400 mg, 0.99 mmol) in THF (40 mL) and DMF (3 mL) was added NaHCO3 (180 mg, 2.2 mmol) and allyl bromide (130 mg, 1.1 mmol). After refluxing overnight, additional DMF (1.5 mL), allyl bromide (30 mg, 29 mmoL), and NaHCO3 (21 mg, 0.25 mmol) were added. The reaction mixture was refluxed for 12 hours and then cooled to room temperature. The material was diluted with water and extracted with EtOAc (3×). The combined organics were washed with water, saturated NaCl solution (3×), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 90:10 CH2Cl2:MeOH), followed by formation of the HCl salt, gave 6-(trans-4-{allyl-[3-(4-fluorophenyl)propyl]-amino}cyclohexyl)-3H-benzoxazol-2-one (138 mg, 31%), as a white solid: mp 224-230° C.; IR (KBr): 2943, 1770, 1510 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.51 (s, 1H), 10.38 (br s, 1H), 7.31-7.28 (m, 2H), 7.17-7.11 (m, 3H), 7.00 (s, 2H), 6.11-6.04 (m, 1H), 5.55 (d, J=17 Hz, 1H), 5.45 (d, J=10 Hz, 1H), 3.87-3.71 (m, 2H), 3.38-3.31 (m, 1H), 3.19-3.13 (m, 1H), 3.05-2.92 (m, 1H), 2.70-2.51 (m, 3H), 2.18-2.12 (m, 2H), 2.07-1.99 (m, 2H), 1.92-1.87 (m, 2H), 1.72-1.50 (m, 4H); (ESI-MS (m/z): 409 [M+H]+; HPLC: method B, 11.34 minutes (98.1%); Anal. Calcd for C25H29FN2O2.HCl: C, 67.48; H, 6.80; N, 6.30. Found: C, 67.29; H, 6.93; N, 6.07.
Reaction SMILES: COC1C=CC(COC([N:11]2[CH2:15][C@@H:14]([S:16][C:17](=[O:19])[CH3:18])[CH2:13][C@H:12]2[C:20](=[O:29])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:22]([NH:21][C:20]([C@@H:12]1[CH2:13][C@H:14]([S:16][C:17](=[O:19])[CH3:18])[CH2:15][NH:11]1)=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(C)=O)C[C@H]2C(=O)NCc2ccccc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)S[C@@H]1CN[C@H](C(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
177 mg of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-benzylcarbamoyl-4-acetylthiopyrrolidine and 86 mg of anisole were dissolved in 0.5 ml of trifluoroacetic acid, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with an aqueous solution of sodium bicarbonate and water and dried over sodium sulfate. The solvent was removed by distillation, and the residue was subjected to silica gel thin layer chromatography to obtain (2S,4S)-2-benzylcarbamoyl-4-acetylthiopyrrolidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]1[CH3:35])([CH3:28])[CH3:27]>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:32]4[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[C@H:30]([CH3:35])[CH2:31]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CC(C)N1CCNC[C@H]1C
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C(C)C)[C@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-isopropyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (d, J=5.81 Hz, 4H) 1.30 (d, J=6.32 Hz, 5 H) 2.33 (d, J=2.27 Hz, 3 H) 2.85-3.65 (m, 5 H) 3.89 (br. s., 2 H) 4.20-4.83 (m, 1 H) 7.64 (br. s., 1 H) 7.70-7.79 (m, 1 H) 7.93-8.77 (m, 4 H) 9.36-10.10 (m, 1 H). ESI-MS m/z [M+H]+ 463.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[S:5][C:6]=1[Cl:7].O.NN>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[S:5][C:6]=1[Cl:7]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)c(Cl)s1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Cl)c(Cl)s1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a stirred suspension of 2-(4,5-Dichloro-thiophen-2-ylmethyl)-isoindole-1,3-dione (0.770 grams, 2.47 mmole) in methanol (30 ml) and tetrahydrofuran (10 ml) at room temperature was added hydrazine hydrate (0.395 grams, 12.3 mmole) and stirred at room temperature over night. A precipitate formed, and the mixture was concentrated to about 15 ml and filtered. The filtrate was poured into 100 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/methylene chloride as eluent to give an oil (0.341 g). MW 182.08; MS (m/e) 183 (M++1).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:28]([OH:30])=[O:29])[CH:20]([C:24]([F:27])([F:26])[F:25])[O:21]3)=[CH:16][C:15]=2[Cl:31])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.[O:35]1CCOCC1>O.CO>[F:25][C:24]([F:27])([F:26])[C:20]([OH:35])=[O:21].[NH2:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:28]([OH:30])=[O:29])[CH:20]([C:24]([F:27])([F:25])[F:26])[O:21]3)=[CH:16][C:15]=2[Cl:31])=[CH:11][CH:10]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(Cc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Product: O=C(O)C(F)(F)F
Reaction time: 8 h

Procedure:
The 7-{4-[(tert-butoxycarbonyl)amino]benzyl}-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (300 mg, 0.62 mmole) was stirred in 3 mL dioxane and 0.62 mL HCl (4M) in dioxane for 6 hrs. 1HNMR indicated that the reaction mixture was 1:1 ratio of starting material:product. Additional 0.3 mL 12 N HCl in 2 mL water was added to above mixture. After the mixture was stirred for overnight, 0.3 mL 12 N HCl was added. After another overnight stirring, the solution of 3 mL 12 N HCl in 3 mL MeOH and 3 mL water was added to above mixture and the mixture was stirred for 6 hrs. The mixture was purified by RPHPLC elute with 20 to 65% ACN in water with 0.1% TFA to give the desired product as a white solid with >95% purity: ESHRMS m/z 384.0594 (M+H, C18H14O3F3ClN, Calc'd 384.0609). 1H NMR (acetone-d6/400 MHz) 7.87 (s, 1H), 7.58(s, 1H), 7.39 (d, 1H, J=8.4 Hz), 7.22 (d, 1H, J=8.4 Hz), 6.02 (s, 1H), 5.82 (q, 1H, J=7.2 Hz), 4.15 (m, 2H).
Reaction SMILES: C1C2C3C=CC=CC=3CCCC=2C(CO)=CC=1.ClC(C(CF)(CF)CF)=C[C@@H]1[C@H](C(Cl)=O)C1(C)C.[Cl:36][C:37]([C:63]([CH2:68][F:69])([CH2:66][F:67])[CH2:64][F:65])=[CH:38][C@@H:39]1[C@H:41]([C:42]([O:44][CH2:45][C:46]2[C:51]3[CH2:52][CH2:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:50]=3[CH:49]=[CH:48][CH:47]=2)=[O:43])[C:40]1([CH3:62])[CH3:61]>>[Cl:36][C:37]([C:63]([CH2:68][F:69])([CH2:64][F:65])[CH2:66][F:67])=[CH:38][CH:39]1[CH:41]([C:42]([O:44][CH2:45][C:46]2[C:51]3[CH2:52][CH2:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:50]=3[CH:49]=[CH:48][CH:47]=2)=[O:43])[C:40]1([CH3:61])[CH3:62]
Reactant: CC1(C)[C@H](C=C(Cl)C(CF)(CF)CF)[C@@H]1C(=O)OCc1cccc2c1CCCc1ccccc1-2
Agent: CC1(C)[C@H](C=C(Cl)C(CF)(CF)CF)[C@@H]1C(=O)Cl
Agent: OCc1cccc2c1CCCc1ccccc1-2
Product: CC1(C)C(C=C(Cl)C(CF)(CF)CF)C1C(=O)OCc1cccc2c1CCCc1ccccc1-2

Procedure:
In the manner of Example I, but substituting 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-methanol and cis-3-(2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride, (6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate was prepared.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]I.[H-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2c(OCc3ccccc3)cccc21

Procedure:
Compounds of Formula I can be prepared as illustrated by exemplary reaction in Scheme 1. Reaction of 4-benzyloxy-indole with MeI in the presence of a base such as NaH produced 4-benzyloxy-1-methyl-indole. The benzyl protecting group was removed by hydrogenation to give the 4-hydroxy-1-methyl-indole. Reaction of 4-hydroxy-1-methyl-indole with an aryl-aldehyde such as 5-bromoveratraldehyde and malononitrile in the presence of a base such as piperidine produced the substituted 7-methyl-pyrrolo[2,3-h]chromene.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([CH:20]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]2[CH2:19][CH:18]([CH:20]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Reactant: Clc1ccc(C(Br)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1

Procedure:
A solution of 0.042 g (0.15 mmol) of 1-[bromo(phenyl)methyl]-4-chlorobenzene, 0.028 g (0.1 mmol) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate (Example 25, Step 1) and 0.298 g (0.3 mmol) of Cs2CO3 in 5 mL of acetonitrile was heated at 45° C. for 18 h. The solution was concentrated and the residue was dissolved in 5 mL of ethyl acetate. This solution was washed with 1 mL water and the aqueous layer was washed with a second aliquot of 3 mL ethyl acetate. The organic extracts were washed with brine, combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography on a Waters RCM column (5 micron silica gel, 20 mm×10 cm) using a 2:1 mixture of hexane and 5:4:1 hexane-methyl tert-butyl ether-acetonitrile. Homogenous fractions were pooled and concentrated to afford the title compound. 1NMR (CDCl3) δ 2.65-2.69 (m, 1H), 2.88-2.93 (m, 1H), 3.05-3.16 (m, 2H), 3.41-3.46 (m, 1H), 3.67 (s, 3H), 3.81-3.86 (m, 1H), 4.30 (s, 1H), 6.69-6.74 (m, 1H), 6.80-6.85 (m, 2H), 7.19-7.37 (m, 9H). Mass Spectrum: m/e=442 (M+1 35Cl) and 444 (M+1 37Cl).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][S:26][CH2:27][C:28](OCC)=[O:29])=[N:3]1.[CH3:33][NH2:34]>>[CH3:33][NH:34][C:28](=[O:29])[CH2:27][S:26][CH2:25][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CN
Reactant: CCOC(=O)CSCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Product: CNC(=O)CSCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1

Procedure:
A solution of ethyl [[[1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazol-3-yl]methyl]thio]acetate (0.4 g) in ethanolic methylamine (33%, 20 ml) under nitrogen, was heated under reflux for 30 h, cooled, evaporated in vacuo, the residue dissolved in 2N hydrochloric acid (20 ml), and washed with ethyl acetate. The acidic layer was basified with potassium carbonate extracted with ethyl acetate and the extract was dried and evaporated to give an oil (0.28 g) which was chromatographed using System E as eluent to give the title compound (0.13 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][CH2:12][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[OH:11]
Reactant: O=[N+]([O-])c1ccc(C2CO2)cc1
Reactant: NCCO
Product: O=[N+]([O-])c1ccc(C(O)CNCCO)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
The mixture of 2-(4-nitro-phenyl)-oxirane (24.1 g, 0.15 mol) in ethanolamine (500 mL) was stirred at 40° C. for 2 h, then room temperature for 18 h. The reaction was partitioned between ethyl acetate (200 mL) and water (200 mL) and the aqueous layer was extracted with ethyl acetate (4×100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was triturated with acetonitrile and collected to give the title compound (19.80 g, 0.09 mmol, 60%) as a white solid. ESMS m/z 227 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cccc(F)c1F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(F)c3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,3-difluorobenzoyl chloride (28 μL, 0.229 mmol) and mixing for 24 h, 43.5 mg (>100%) of the title compound were recovered.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][CH2:7][C:8]([NH:10][CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[NH:22][N:21]=[N:20][N:19]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]1=2)=[O:9].[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CO>C(Cl)Cl.O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=1)[CH2:6][CH2:7][C:8]([NH:10][CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]=[N:20][N:21]([CH3:37])[N:22]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]1=2)=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCN(c2nnn[nH]2)c2cc(Cl)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cn1nnc(N2CCCC(NC(=O)CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccc(Cl)cc32)n1
Temperature: 25 °C

Procedure:
To a solution of N-(3,5-Bis-trifluoromethyl-benzyl-N-[8-chloro-1-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (0.55 mmol, 0.29 g) in CH2Cl2 (5 mL) was added triphenyl phosphine (0.55 mmol, 0.14 g) and diethylazo dicarboxylate (0.55 mmol, 90.0 μL) at 0° C. To the above mixture, MeOH (2.75 mmol, 0.11 μL) was added and warmed to room temperature for 48 h. After completion, the reaction mixture was diluted with water (20 mL), extracted with EtOAC (3×25 mL) and the combined organic layers were washed with water and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by flash column chromatography to afford the title compound as colorless foam; Rf 0.60 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 547 (M+H+).
Reaction SMILES: O.[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH2:6][NH2:7].S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[ClH:13].[CH3:15][O:9][C:8](=[O:10])[C@H:3]([CH2:4][CH2:5][CH2:6][NH2:7])[NH2:2]
Reactant: O=S(Cl)Cl
Reactant: NCCC[C@H](N)C(=O)O
Reactant: CO
Solvent: O
Product: COC(=O)[C@@H](N)CCCN
Product: Cl

Procedure:
To a solution of L-ornithine monohydrate (25 g) in methanol (200 ml) was added dropwise thionyl chloride (32.6 ml) under cooling and stirring and the reaction mixture was refluxed. After 6 hours the solvent was removed in vacuum and the residue was then treated with isopropyl ether (300 ml) and the precipitated solid filtered off to give L-ornithine methyl ester dihydrochloride (33.09 g) as a colorless powder (hygroscopic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccco1
Yield: 90.5 %

Procedure:
The title compound was synthesized from 4-fluoro-3-nitro-phenylamine (2.00 g, 12.81 mmol) dissolved in THF (25 ml) and Hunig's base (3.312 g, 25.62 mmol) to which was added furan-2-carbonyl chloride (1.672 g, 12.81 mmol) drop wise over 10 minutes. Reaction mixture was stirred at room temperature for 1 hr at which time water was added and the title compound was collected by filtration providing the title compound (2.90 g, 90%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C@@H:26]([C:31](=[O:33])[NH2:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:15]([C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:31]([NH2:32])=[O:33])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 92, 2.6 grams, 5.2 mmol) in CH2Cl2 (25 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at rt for 1 h and then was concentrated to give a white solid (1.6 grams, 84%). MS (ESI), (M+H)+ 402.15; 1H NMR (DMSO-d6, 500 MHz), δ 7-87 (d, 2H, J=8.5), 7.66 (d, 2H, J=8.6), 7.41 (s, 1H), 7.04 (s, 1H), 4.17 (t, 1H, J=7.3), 3.40-3.50 (m, 1H), 3.20-3.25 (m, 1H), 3.03-3.10 (m, 1H), 2.65-2.80 (m, 2H), 1.85-2.00 (m, 1H), 1.20-1.85 (m, 2H), 1.45-1.60 (m, 1H), 1.30-1.40 (m, 1H), 1.10-1.30 (m, 4H), 0.75-0.90 (m, 1H), 0.82 (d, 3H, J=7.3), 0.80 (d, 3H, J=7.0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:11]2[NH:12][CH:13]=[CH:14][C:15](=O)[N:10]2[N:9]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:27].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:27][C:15]1[N:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:17]=[C:11]2[N:12]=[CH:13][CH:14]=1
Reactant: O=c1cc[nH]c2cc(-c3ccccc3Cl)nn12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Clc1ccccc1-c1cc2nccc(Cl)n2n1
Temperature: 95 °C
Yield: 54.3 %

Procedure:
To a slurry of 2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (I-1A-1b; 30.0 g, 122 mmol) and triethylamine (25.5 ml, 183 mmol) in toluene (1.3 liters) at room temperature was added POCl3 (58 ml, 0.62 mol), dropwise. The mixture was heated at 95° C. for 4 hours, cooled to room temperature, then slowly added to a stirred mixture of ice, sodium bicarbonate (300 g) and ethyl acetate (1 liter), keeping the temperature at 0° C. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were dried (MgSO4), and then concentrated, in vacuo, to afford an amber solid. This material was purified by silica gel chromatography using 2:1:0.1 methylene chloride/hexanes/methanol as eluant to afford I-1A-1c as a colorless solid (17.5 g, 54%): +APcI MS (M+1) 264.2; 1H NMR (400 MHz, CD2Cl2) δ 8.40 (d, J=4.6 Hz, 1H), 8.00–7.97 (m, 1H), 7.56–7.53 (m, 1H), 7.45–7.39 (m, 2H), 7.34 (s, 1), 7.03 (d, J=4.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])C)=C[CH:3]=1.N1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:17][C:18]([OH:22])(C#C)C.[Cl-].[NH4+]>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>[CH3:12][C:13]1[C:2]([CH3:3])=[C:7]([C:6]#[C:5][CH2:8][OH:10])[CH:16]=[CH:15][C:14]=1[C:18](=[O:22])[CH3:17]
Reactant: C#CC(C)(C)O
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)c1ccc(C#CCO)c(C)c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A 30 mL Schlenk tube was replaced with Ar, 1.59 g (8 mmol) of p-bromoacetophenone, 92.4 mg (0.08 mmol) of tetrakis(triphenylphosphine)palladium, 8 mL of piperidine and 853 μL (8.8 mmol) of 2-methyl-3-butyn-2-ol were added and the mixture was stirred at 100° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and then the mixture was extracted with diethyl ether. The extract was dried over magnesium sulfate, followed by distilling off of the solvent under reduced pressure by an evaporator. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=5/1) using silica gel to give dimethylhydroxymethyl-4-acetylphenylacetylene, i.e., the desired compound as a viscous yellow liquid. Yield: 1.5 g (yield: 93%).