Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[CH:10]=1.[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33](Cl)=[O:34])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33](=[O:34])[NH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:14]=[C:13]([CH3:15])[N:12]=2)[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccccc1-c1cc(N)nc(C)n1
Reactant: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)nc(C)n1
Reaction time: 3 h
Yield: 114.5 %

Procedure:
6-(2-Methoxy-phenyl)-2-methyl-pyrimidin-4-ylamine (XXXVI) (0.111 g, 0.512 mmol) was taken in 3 ml of dry dichloromethane, DMAP (0.075 g, 0.614 mmol) and a solution of 3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXV) (0.155 g, 0.563 mmol) in dichloromethane (1 ml) were added dropwise at room temperature and the reaction mixture was stirred for 3 hours. Then water was added to the reaction mixture followed by extraction with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.270 g of 3-[6-(2-methoxy-phenyl)-2-methyl-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXXVII).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](O)[CH2:9][C:10]#[CH:11]>>[C:1]1([O:7][CH2:11][CH2:10][C:9]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C#CCCO
Product: C#CCCOc1ccccc1

Procedure:
The title compound was synthesized using phenol and 3-butyn-1-ol by conducting a reaction similar to that mentioned in Reference example 35.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]=[N:17]O)(=O)C>CC(O)=O.[Zn]>[NH2:17][CH2:16][C:9]1[C:10]([Cl:15])=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[O:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: NCc1c(Cl)cc(Cl)cc1OCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(3,5-dichloro-2-((hydroxyimino)methyl)phenoxy)ethyl acetate (1.15 mmol) in 2 mL AcOH was cooled to 0° C. and zinc dust (4.36 mmol) was added. The reaction mixture was stirred at RT for 1 h. It was filtered over a pad of celite and washed with EtOAc and MeOH. The filtrate was conc. and redissolved in water (pH 4 with 2N HCl solution). It was washed once with EtOAc, the ageous phase was basified with 1M NaOH solution, extracted 3 times with EtOAc and DCM. The comb. org. layers were dried over MgSO4 and concentrated in vacuo to give the desired product as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>CO>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][N:21]=[CH:4][C:3]2[C:2]([Br:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=2[Br:11])=[CH:16][CH:15]=1
Reactant: NNc1ccc(F)cc1
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(C=NNc2ccc(F)cc2)c(Br)c1
Yield: 97 %

Procedure:
2,6-Dibromo-4-methylbenzaldehyde (600 g, 2.16 mmol) (which may be prepared according to the method of Lulinski and Serwatowski, Journal of Organic Chemistry, 68, (2003), 5384), (4-fluorophenyl)hydrazine hydrochloride (351 mg, 2.16 mmol) and sodium acetate (180 mg, 2.19 mmol) were heated in methanol (15 ml) under reflux for 2 hours in a nitrogen atmosphere. The methanol was evaporated and the residue partitioned between dichloromethane (30 ml) and aqueous brine (30 ml). The organic phase was separated, combined with additional dichloromethane extracts (2×15 ml), washed with aqueous sodium bicarbonate (2×15 ml), passed through a hydrophobic frit and evaporated to give the title compound (809 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[S:9]2(=[O:25])=[O:24])=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30]>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([CH2:7][C:6]2[CH:26]=[CH:27][C:3]([CH2:2][N:29]([CH3:30])[CH3:28])=[CH:4][CH:5]=2)[S:9]1(=[O:24])=[O:25]
Reactant: CNC
Reactant: O=S1(=O)N(Cc2ccc(CBr)cc2)c2ccccc2N1c1ccccc1F
Product: CN(C)Cc1ccc(CN2c3ccccc3N(c3ccccc3F)S2(=O)=O)cc1
Yield: 92 %

Procedure:
In an analogous manner to general procedure V, 1-[4-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.11 g, 0.24 mmol) was treated with dimethylamine (10 mL) to provide 0.09 g, (92%) of 1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N,N-dimethylmethanamine. MS (ES) m/z 411.0. HPLC purity 97.3% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:10]=1
Reactant: N=C(N)c1ccccc1F
Reactant: SC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Fc1ccccc1-c1nsc(Cl)n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a solution of 2-fluorobenzenecarboximidamide (1.38 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.88 g (87.4%) of the desired product as an oil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:12]=2[CH:11]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: C#Cc1ccccc1
Product: Brc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-bromo-2-iodophenol to the title product. Purification by flash chromatography (20% CH2Cl2 in hexanes as the eluent) gave the analytically pure product as a white solid (468 mg, 86% yield). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=6.97, 2H), 7.69-7.67 (m, 1H), 7.46-7.35 (m, 5H), 6.91 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 157.18, 153.56, 131.17, 129.85, 128.97, 128.82, 127.04, 125.02, 123.43, 115.95, 112.56, 100.58. Anal. Calcd. for C14H9BrO: C, 61.57; H, 3.32; Br, 29.26. Found C, 61.46; H, 3.26; Br, 29.50. m.p.: 157° C. (lit.,9, 158-159° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC=C)=[CH:9][CH:8]=1)[CH3:2].CN(C)[C:28]1[CH:33]=CC=C[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:33][CH:28]=[CH2:29])[CH:8]=1)[CH3:2]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Product: C=CCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 3-(4-allyloxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (475 mg, 1.39 mmol) in dimethylaniline (1.5 mL) was heated at reflux for 18 h. After cooling to ambient temperature, the reaction mixture was partitioned between EtOAc and 1N H2SO4. The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (100 mL SiO2, hexanes to 30% EtOAc/hexanes) to provide the desired product (343 mg, 72%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.23 (t, J=8.4 Hz, 2H), 7.02-6.96 (m, 3H), 6.83 (d, J=8.8 Hz, 2H), 6.72 (d, J=7.6 Hz, 1H), 6.05 (m, 1H), 5.16-5.09 (m, 2H), 4.21 (q, J=6.8 Hz, 2H), 3.38 (d, J=6.4 Hz, 2H), 3.25 (A of AB, J=13.6 Hz, 1H), 3.10 (B of AB, J=13.6 Hz, 1H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]2[N:4]([C:5]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][S:11][C:6]=3[C:7]2=[O:10])[CH:3]=1.[OH-].[K+].[N+:24](C)([O-:26])=[O:25]>>[N+:24]([C:2]1[CH:9]=[C:8]2[N:4]([C:5]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][S:11][C:6]=3[C:7]2=[O:10])[CH:3]=1)([O-:26])=[O:25]
Reactant: COc1ccc(-c2csc3c2-n2cc(Br)cc2C3=O)cc1
Reactant: C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(-c2csc3c2-n2cc([N+](=O)[O-])cc2C3=O)cc1

Procedure:
A solution of 1 mmol of the compound obtained in Example 12 in 50 ml of nitromethane is stirred for 12 hours at ambient temperature and the reaction mixture is then poured into a 1M potassium hydroxide solution. After extracting with dichloromethane, the organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. Chromatography on silica gel (chloroform) allows the expected product to be isolated.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+]>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)O)cc1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of L-lysine dihydrochloride (1 mmol) in a mixture of THF and 1M K2CO3 (3 mL/3 mL) was added 4-methylbenzenesulfonyl chloride (381 mg, 2.00 mmol). The reaction mixture was stirred for 2 h and then quenched with 1N HCl and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated. The crude was purified by flash chromatography using hexane/EtOAc/AcOH (30:69.4/0.6) to give 75% of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH:19]=1)[C:7]([O:9]CC1C=CC(F)=CC=1F)=[O:8].[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccc(F)cc1F)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Temperature: 50 °C

Procedure:
To a solution of (2,4-difluorophenyl)methyl 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoate (may be prepared as described in Description 21; 833 mg, 1.466 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (211 mg, 8.79 mmol) and water (1 ml). The mixture was heated at 50° C. for 4 hours, cooled and neutralised with 2M hydrochloric acid (3.66 ml, 7.33 mmol). The solvent was removed in vacuo to yield the title compound as a white solid. 648 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH2:20])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH:20][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)N(CCN)C(C)C
Product: CC(C)N(CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
p-Nitrobenzenesulfonyl chloride was reacted with N,N-diisopropyl ethylene diamine to give N-[2-[bis(1-methylethyl)amino]ethyl]-4-nitrobenzene sulfonamide as the free base, m.r. 86°-88° C.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=O.Cl.[CH2:25]([NH2:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O>[CH2:25]([NH:27][C:9](=[O:11])/[CH:8]=[C:7](/[CH3:12])\[CH2:6][CH2:5]/[CH:4]=[C:3](/[CH2:2][OH:1])\[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:26]
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C\C(=O)O)CO
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)/C=C(/C)CC/C=C(/CO)CC/C=C(\C)CCC=C(C)C

Procedure:
Following the same manner as in Example 9, the reaction and after-treatment were conducted by using 1.1 g of (E,Z,E), (E,E,E), (Z,Z,E) and (Z,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid, 350 mg of ethylamine hydrochloride, 0.80 ml of diphenylphosphoric acid azide and 1.0 ml of triethylamine in 6.0 ml of N,N-dimethylformamide to afford 780 mg of the end product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32](OCC)=[O:33])[CH2:31][CH2:30][CH2:29]3)[N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH3:44]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32](=[O:33])[NH2:44])[CH2:29][CH2:30][CH2:31]3)[N:24]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Reactant: N
Solvent: CO
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(N)=O)CCC3)n(-c3ccccc3)n2)CC1

Procedure:
50 mg of 4-((S)-4-Carboxy-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester were dissolved in 1 ml of a 8 M solution of ammonia in methanol. After 16 h at RT the solvents were evaporated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(N=C=O)cc1C(F)(F)F
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc1C(F)(F)F

Procedure:
61 mg of pale yellow solid 3-{4-[3-(4-methyl-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-methyl-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([NH2:22])=[O:21].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=2)[C:20]([NH2:22])=[O:21])=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: NC(=O)c1ccnc(N)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(OCC(=O)Nc2cc(C(N)=O)ccn2)cc1
Yield: 56.5 %

Procedure:
A solution of 4-tert-butylphenoxy acetic acid (60.1 mg, 0.29 mmol), 2-amino isonicotinamide (60.3 mg, 0.44 mmol), DIPEA (0.1 ml, 0.58 mmol) and PyBOP (301.8 mg, 0.58 mmol) in DMF 4.0 mL was stirred, then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC (n-Hexane:EtoAc:MeOH=6:3:1) to give 2-[2-(4-tert-butyl-phenoxy)-acetylamino]-isonicotinamide as a white solid (53.6 mg, 56.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH3:28][O:29][CH2:30][CH:31]([NH2:34])[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:34][CH:31]([CH2:30][O:29][CH3:28])[CH2:32][CH3:33])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Reactant: CCC(N)COC
Agent: Cl
Product: CCC(COC)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 28.2 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.40 g, 0.97 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (0.27 g, 1.94 mmol) were treated substantially as described in Part C of Example 19a to produce 0.10 g (28%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 365.8 [(M+H)+, 100].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=1)[OH:11]
Reactant: CO
Reactant: O=C(O)c1cc(Br)ccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 70 °C

Procedure:
To a solution of 5-bromosalicylic acid (200 g, 0.92 mol) in methanol (2 L) was added thionylchloride (440 g, 3.7 mol) at 0° C. with stirring and then allowed to reflux at 70° C. for 40 h. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10% cold aqueous NaHCO3 solution (2×1 L), brine and dried. The solvent was removed under vacuum to give the title compound as a low melting point solid (190 g, 89%). TLC: PetEther/EtOAc, 7:3, Rf: 0.6
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCN(C[C@@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 220 was synthesized using 9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=77-79° C.; 400 MHz 1H NMR (CDCl3) δ: 8.08 (dd, J=8.6, 5.9 Hz, 1H), 7.37 (dd, J=9.4, 2.7 Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 3H), 7.14 (td, J=8.2, 2.7 Hz, 1H), 4.04-3.95 (m, 1H), 2.98-2.82 (m, 2H), 2.93 (s, 2H), 2.79-2.66 (m, 3H), 2.54-2.37 (m, 3H), 2.16-2.08 (m, 2H), 1.97-1.80 (m, 2H); LCMS: 454 [M+H].
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]=[N:11]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=O)C>>[CH:1]1([CH2:6][CH2:7][CH:8]([CH3:13])[CH2:9][C:10]#[N:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CC=NO)CCC1CCCC1
Solvent: CC(=O)OC(C)=O
Product: CC(CC#N)CCC1CCCC1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
5-cyclopentyl-3-methylpentanal oxime (3.7 g; 20 mmol) and acetic anhydride (4.5 g; 40 mmol) were heated at 110° C. during 1.5 hours, poured into ice-water (100 ml), and extracted with MTBE (150 ml). The organic phase was washed with brine (4×150 ml), dried (MgSO4), concentrated in, vacuo, and purified by flash chromatography (MTBE/hexane 1:15) to give 1.9 g (57% yield) of 5-cyclopentyl-3-methylpentanenitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[O:5][C:6]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][C:25]=3[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH2:19][CH2:18]2)[CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:42][O:43][CH2:44]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]2[CH2:26][C:27]([CH3:30])([CH3:31])[CH2:28][CH2:29][C:24]=2[CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:15]3[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:5][C:4]4[CH:39]=[CH:40][CH:41]=[C:2]([O:1][CH2:42][O:43][CH3:44])[CH:3]=4)[CH:16]=3)[CH2:22][CH2:21]2)=[CH:37][CH:36]=1
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc(OCOC)c1

Procedure:
A suspension of EXAMPLE 176B (0.295 g), methoxymethyl chloride (0.117 mL) and cesium carbonate (0.334 g) in N,N-dimethylformamide (3 mL) was stirred at 60° C. for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The water layer was extracted with dichloromethane. The combined organic extracts were washed with water (2×), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromotography (silica gel, 5%-20% ethyl acetate/hexanes) providing the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12].ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C(OCC)(=O)C>[C:31]([C:16]1[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([F:1])[CH:3]=2)[NH:9][C:8](=[O:11])[C:7]3([CH3:13])[CH3:12])=[CH:18][CH:17]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
To a stirred solution of tert-butyl 2-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate (1.0 g, 2.9 mmol) was added chlorosulfonylisocyanate (0.28 mL, 3.2 mmol). The mixture was stirred at 25° C. for 2 h then DMF (0.21 mL, 2.9 mmol) was added and the mixture was stirred for an additional 1 h. The mixture was diluted with ethyl acetate and washed with NaHCO3, water, saturated aqueous NaCl, dried over MgSO4, and concentrated. Flash chromatography (2% MeOH/CH2Cl2) afforded 0.23 g (21%) of the title compound as a white solid.