Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.CCN(CC)CC.[O:16]=[C:17]([C:24]1[O:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][N:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:16]=[C:17]([C:24]1[O:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][N:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Clc1cccc(I)c1
Reactant: C#CCCCCC(=O)c1ncc(-c2ccccn2)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCC#Cc1cccc(Cl)c1)c1ncc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-chloro-3-iodobenzene (49 mg, 0.205 mmol) in anhydrous THF (0.5 mL) was treated with PdCl2(PPh3)2 (7 mg, 0.01 mmol). After stirring for 5 min at 25° C., Et3N (0.2 mL, 0.603 mmol) and CuI (10 mg, 0.053 mmol) were added. The suspension was stirred for 35 min and 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-hept-6-yne (3b, 30 mg, 0.067 mmol) was added. After stirring for 14 h at 25° C., the reaction mixture was filtered through Celite and concentrated. PTLC (SiO2, 50% EtOAc-hexanes) afforded 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-(3-chlorophenyl)hept-6-yne (4hh, 24 mg, 0.066 mmol, 56%) as a yellow solid: mp 50-51° C.; 1H NMR (CDCl3, 500 MHz) δ 8.68-8.66 (m, 1H), 7.89-7.86 (m, 2H), 7.82 (td, 1H, J=7.7, 1.8 Hz), 7.38 (m, 1H), 7.34-7.31 (m, 1H), 7.27-7.18 (m, 3H), 3.20 (t, 2H, J=7.4 Hz), 2.49 (t 2H, J=7.0 Hz), 2.00-1.95 (m, 2H), 1.77-1.71 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 187.9, 157.2, 153.3, 150.1, 146.2, 137.1, 133.9, 131.4, 129.6, 129.3, 127.8, 126.8, 125.5, 124.1, 120.3, 90.9, 79.8, 38.5, 27.8, 23.1, 19.1; IR (film) νmax 3061, 2932, 2865, 2230, 1703, 1592, 1575, 1558, 1505, 1471, 1426, 1385, 1283, 1243, 1152, 1081, 1065, 1023, 990, 962, 930, 880, 784, 740, 683 cm−1; ESI-TOF m/z 365.1058 (C21H17ClN2O4+H+ requires 365.1051).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Cl[CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][C:47]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[C:48]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:49]=2)[CH:44]=1.C(=O)([O-])[O-].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:12]=[C:13]([O:36][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[CH:49]=[C:48]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:47]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:46]3)[CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:16]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: ClCCCCc1ccc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCc2ccc3cc(OCc4ccccc4)c(OCc4ccccc4)cc3c2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 49.3 %

Procedure:
A mixture of 1.5 g (2.88 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 1.24 g (2.88 mmol) of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy) naphthalene, 0.8 g (5.75 mmol) ofpotassium carbonate and 0.43 g (2.88 mmol) of sodium iodide in 50 ml of acetone and 10 ml of DMF was stirred at reflux under argon for 40 hours. The acetone was removed by distillation and 50 ml of DMF, 1.24 g of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy)naphthalene, 0.8 g of potassium carbonate and 0.43 g of sodium iodide were added and the mixture was stirred and heated at 85° for 4 days. The DMF was removed using an oil pump at 55°. The residue was extracted with methylene chloride,the extract was concentrated and the product was purified by HPLC using 20%ethyl acetate-hexane to give 1.3 g (49% yield) of N-(2 -methoxy-2oxoethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycine methyl ester as a semisolid. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13]/[C:14](/[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)=[C:15](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)\[CH:16]=[O:17])=[O:11])([O-:3])=[O:2].CC(=CC)C.P(=O)(O)(O)[OH:40].[O-]Cl=O.[Na+]>CC(O)(C)C.C1COCC1>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24](/[C:14](/[CH2:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][N+:1]([O-:3])=[O:2])=[C:15](\[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)/[C:16]([OH:40])=[O:17])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)CCCCCO[N+](=O)[O-])=C(/C=O)c2ccccc2)cc1
Reactant: O=P(O)(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CS(=O)(=O)c1ccc(/C(COC(=O)CCCCCO[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4.3 g of (2Z)-2-[4-(methylsulfonyl)phenyl]-4-oxo-3-phenylbut-2-enyl 6-(nitrooxy)hexanoate in a solvent mixture of 50 mL of THF with 50 mL of t-BuOH, 5 mL of 2-methyl-2-butene was added followed by the addition of 20 mL of 2 M phosphoric acid and 20 mL of 1 M of NaClO2. The resulting mixture was stirred at rt for 15 min. The organic phases were separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over Na2SO4, filtered, and then evaporated. The crude was purified by flash chromatography over silica gel (5–100% EtOAc/hexane) to afford 3.8 g of the titled compound as white solid. 1H NMR (acetone-d6, 500 M Hz): δ 7.79 (d, 2H), 7.45 (d, 2 H), 7.22–7.15 (m, 3 H), 7.15–7.10 (m, 2 H), 5.31 (s, 2 H), 4.51 (t, 2 H), 3.07 (s, 3 H), 2.23 (t, 2 H), 1.72–1.65 (m, 2 H), 1.52–1.45 (m, 2 H), 1.37–1.29 (m, 2 H).
Reaction SMILES: C(O)(=O)C.FC(F)(F)C(O)=O.[BH4-].[Na+].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27](O)[C:28]#[CH:29])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1>C(Cl)Cl>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[CH:29])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: C#CC(O)c1ccc(N2CCN(C)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCc1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirred mixture of glacial acetic acid (72 ml) and trifluoroacetic acid (8 ml), NaBH4 (79.1 mmol) is added slowly under nitrogen at 15° C. The solution of 1-[4-(4-methyl-piperazin-1-yl)-phenyl]-prop-2-yn-1-ol (11.3 mmol) in CH2Cl2 (80 ml) is added dropwise over 0.5 h and the mixture is stirred at room temperature for 1 h. The solvents are removed under reduced pressure and the residue is added to saturated sodium bicarbonate. The aqueous solution is extracted with CH2Cl2. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to silica gel column chromatography, which is eluted with following solvents: CH2Cl2 and 5% MeOH in CH2Cl2. The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 86.8%, Rf=0.52 (CH2Cl2:MeOH=9:1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:15][CH2:16][CH2:17]O)[CH2:10]3)=[CH:5][CH:4]=1.[C:21]1([C:27]([N:29]2[C:34](=[O:35])[CH:33]=[CH:32][NH:31][C:30]2=[O:36])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[NH3:11].[C:21]1([C:27]([N:29]2[C:34](=[O:35])[CH:33]=[CH:32][N:31]([CH2:17][CH2:16][CH2:15][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:1])[F:19])=[CH:4][CH:5]=5)([CH2:14]4)[CH2:10]3)[C:30]2=[O:36])=[O:28])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=C(c1ccccc1)n1c(=O)cc[nH]c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N
Product: O=C(c1ccccc1)n1c(=O)ccn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c1=O

Procedure:
To a solution of 3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}-1-propanol (Prep5, 51 mg), 3-(phenylcarbonyl)-2,4(1H,3H)-pyrimidinedione (39 mg, prepared according to the procedure reported in J. Chem. Soc., Perkin Trans. 1, 2827 (1998)) and PPh3 (140 mg) in dry dioxane at 110° C., DEAD (40% solution in toluene, 0.243 mL) was added dropwise. After 3 hours the mixture was concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (10 g) eluting with DCM/MeOH from 100/0 to 95/5 followed by a SCX cartridge (eluting with MeOH and then NH3 0.3M in methanol) to give the title compound as a colourless oil (35 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>O1CCCC1>[CH3:25][S:26]([O:15][CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)[O:10][CH:11]=1)(=[O:28])=[O:27]
Reactant: OCc1coc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1coc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of {2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methan-1-ol (0.19 g, 0.78 mmol) in tetrahydrofuran (15 ml) was cooled to 0° C., and triethylamine (0.33 ml, 2,34 mmol) was added, followed by methanesulfonyl chloride (0. 12 ml, 1.56 mmol) dropwise. The mixture was stirred for 1 hour at 0° C., then water was added, and product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and solvent removed from the filtrate under reduced pressure, to yield {2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methyl methylsulfonate, the mesyl derivative of a compound of formula (15),
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)=[N+]=[N-].N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(OCC)(=O)C.[Pd]>[C:37]([NH:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of 14.92 g(35.5 mmol) of the azide 4 in 2000 mL of ethyl acetate was treated with 2 g of 10% palladium on carbon followed by hydrogenation at one atmosphere for 24 h. The flask was flushed with nitrogen, followed by sequential addition of 14.0 g(14.4 ml, 177.5 mmol) of pyridine and 9.1 g(8.4 mL, 88.8 mmol) of acetic anhydride. The mixture was stirred at ambient temperate for 72 h, followed by filtration through celite. The filtrate was extracted with water, 1N copper sulfate solution, dried and concentrated in vacuo to afford a tan solid. This material was purified by silica gel chromatography to afford 12.7 g(82%) of the product 5 as a powdery white solid, mp 153°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:21]1([CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:38][CH2:37][CH2:36][N:33]3[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[CH2:35][CH2:34]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Reactant: NCCN1CCC(CCCN2CCCCC2)CC1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CCCN3CCCCC3)CC2)c2cc(Cl)ccc21
Yield: 10 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(piperidin-l-yl)propyl]-piperidin-l-yl]ethanamine in a yield of 10% of theory. Colourless crystals, m.p. 176°-177° C. (acetonitrile).
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][CH2:10][CH:9]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:8]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:10][CH:9]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[C:8]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC1CNc2ccccc2N(c2ccccc2)C1=O)OCc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)N1CC(NC(=O)OCc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 84.7 %

Procedure:
1-Phenyl-2-oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (300 mg) was dissolved in methylene chloride (15 ml), isobutyryl chloride (107 mg), pyridine (79 mg) and 4-(N,N-dimethyl)aminopyridine (1 mg) were added, the mixture was refluxed for 2 hours. The reaction mixture was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 300 mg of the title compound (Yield: 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:38][C:39]1[N:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)[C:5]([NH:46][CH2:45][C:42]1[CH:43]=[N:44][C:39]([CH3:38])=[CH:40][CH:41]=1)=[O:7]
Reactant: CS(=O)(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: Cc1ccc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)c2cc(Br)cc(S(C)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-bromo-5-(methylsulfonyl)benzoic acid (630 mg, 2.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (860 mg, 4.5 mmol), 1-hydroxybenzotriazole hydrate (140 mg, 0.90 mmol), and CH2Cl2 (25 mL) were added (6-methylpyridin-3-yl)methanamine (550 mg, 4.5 mmol) and N,N-diisopropylethylamine (0.79 mL, 4.5 mmol). The mixture was stirred at room temperature overnight, and then diluted with CH2Cl2 (50 mL). The organic phase was washed with water and aq. Na2CO3 solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column (50-100% EtOAc/hexane) to afford a white solid. LC-MS: 385.2 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.51 (d, 1H, J=1.6 Hz), 8.28 (t, 1H, J=1.6 Hz), 8.23 (t, 1H, J=1.6 Hz), 8.19 (t, 1H, J=1.6 Hz), 7.66 (dd, 1H, J=8.0, 2.0 Hz), 7.19 (d, 1H, J=8.0 Hz), 6.93 (bs, 1H), 4.63 (d, 2H, J=5.6 Hz), 3.09 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[Cl:1])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A mixture of 2-chloro-4-nitroaniline (15.0 g, 86.9 mmol), triethylamine (13.3 ml, 95.6 mmol) and benzoyl chloride (11.1 ml, 95.6 mmol) were heated in toluene (200 ml) at reflux for 2 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature overnight, causing precipitation of a white solid. The solid was collected by suction filtration, washed with toluene (3×50 ml) and dried in vacuo. The crude product was taken up in dichloromethane (300 ml) and washed with 2.0 N aqueous hydrochloric acid (3×100 ml), water (100 ml), saturated aqueous sodium bicarbonate solution (3×100 ml) and water (100 ml). Drying of the organic layer over magnesium sulphate, followed by solvent evaporation in vacuo, yielded N-benzoyl 2-chloro-4-nitroaniline (6.83 g, 28% yield) as a yellow crystalline solid:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:52][C:51]4[CH:53]=[CH:54][C:48]([F:47])=[CH:49][CH:50]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(F)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2ccc(F)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-fluoroaniline (Aldrich) to give the title product. LC-MS (ES+) 758 [(M+H)+].
Reaction SMILES: [CH3:1]O.Cl.C1(C)C([S:10]([OH:12])=[O:11])=CC=CC=1.[Na].O.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:12][S:10]([C:19]1[CH:20]=[CH:21][C:16]([CH3:22])=[CH:17][CH:18]=1)=[O:11]
Reactant: CO
Reactant: Cc1ccccc1S(=O)O
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: COS(=O)c1ccc(C)cc1
Temperature: 22.5 °C
Reaction time: 2.5 h

Procedure:
To a 5-liter, 3-neck round bottom flask, was added 2845 mls of methanol (5 volumes) and was bubbled in 165.58 grams (1.4 equivalents, 4.47 gmoles) of anhydrous HCl. Heat evolved during addition of HCl to MeOH. The flask was maintained at a temperature range from 20 to 25° C. by cooling and adjusting addition rate. Sodium toluene sulfinic acid (1.0 equivalents, 569 grams, 3.19 gmoles) was added and stirred at room temperature for 1 to 4 hours. Water 2850 mls (5 volumes) was added, then and 2850 mls of toluene (5 volumes.) The mixture was stirred from 1 to 30 minutes and the layers were allowed to separate The layers were separated and the aqueous layer was back extracted twice using 1425 mls (2.5 volumes) of toluene for each back extraction. All toluene layers were combined and washed two times with 1425 mls (2.5 volumes) of 1 molar sodium bicarbonate solution for each wash. The layers were separated and the toluene layerers was concentrated under vacuum to approximately 3 volumes. The volumes were concentrated to a small alloquote to an oil on rotovap indicated a final weight yield of 476.78 grams of ester, 87.7% of theory weight.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[S:9]([CH2:12][C:13](OC)=[O:14])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18].O>O1CCCC1>[CH2:1]([N:8]([CH3:17])[S:9]([CH2:12][C:13]([NH2:18])=[O:14])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccccc1
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccccc1)S(=O)(=O)CC(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a stirred solution of methyl (N-benzyl-N-methylsulfamoyl)acetate (from step (a), 3.9 g, 15.2 mmol) in tetrahydrofuran (10 ml) at ambient temperature was added aqueous ammonia (10 ml, s.g.=0.88) in one portion. The orange solution was then stirred at ambient temperature for 18 hr, before being poured into water (50 ml) and extracted with ethyl acetate (3×25 ml). The organic extract was evaporated in vacuo to give the subtitle compound (2.8 g, 76%) as a white solid. m.p. 124-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[C:24]([O:25][C:26]2[N:31]=[C:30]3[S:32][C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])=[N:34][C:29]3=[CH:28][CH:27]=2)[CH:41]=[CH:42][C:43]=1[F:44])=[O:6]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (0.33 g, 1.5 mmol) produced in Example C61(v) in oxalyl chloride (1.5 mL) was added N,N-dimethylformamide (100 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1.5 mL) and tetrahydrofuran (1.5 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (0.345 g, 1.00 mmol) in N,N-dimethylacetamide (3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (430 mg, 78%) as colorless crystals.