Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[Cl:25][C:26]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[F:2][C:3]([F:24])([F:23])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[C:17]([O:35][C:32]3[CH:33]=[CH:34][C:29]([O:28][C:27]4[CH:36]=[CH:37][C:38]([N+:40]([O-:42])=[O:41])=[CH:39][C:26]=4[Cl:25])=[CH:30][CH:31]=3)=[O:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)c(Cl)c1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Agent: Cl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2Cl)cc1

Procedure:
In Example 1-13, by using 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride hydrochloride instead of 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride hydrochloride, and 4-(2-chloro-4-nitrophenoxy)phenol instead of 4-(4-nitrophenoxy)phenol, 4-(2-chloro-4-nitrophenoxy)phenyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy)propionate was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH:22]12[O:27][CH:26]1[CH2:25][CH2:24][CH2:23]2>>[OH:27][CH:26]1[CH2:22][CH2:23][CH2:24][CH:25]1[N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: C1CC2OC2C1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C3CCCC3O)CC1)O2

Procedure:
Compound 161 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 6-oxabicyclo[3.1.0]hexane and conditions outlined in procedure X. M.p.=110-113° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.1 (m, 1H), 3.1 (d, 1H), 2.95 (s, 1H), 2.9 (d, 1H), 2.7-2.5 (m, 3H), 2.2-1.85 (m, 8H), 1.8-1.5 (m, 4H); LCMS: 386 [M+H].
Reaction SMILES: Cl.[F:2][CH:3]([CH2:13][O:14]C(=O)C)[CH2:4][N:5]1[CH:9]=[N:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1>>[F:2][CH:3]([CH2:13][OH:14])[CH2:4][N:5]1[CH:9]=[N:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1
Reactant: CC(=O)OCC(F)Cn1cnc([N+](=O)[O-])n1
Agent: Cl
Product: O=[N+]([O-])c1ncn(CC(F)CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
2N-HCl was added to 420 mg (1.81 mmol) of 1-(2'fluoro-3'-acetoxypropyl)-3-nitro-1,2,4-triazole and stirred overnight at room temperature. Then, the reaction solution was concentrated and subjected to isolation and purification by silica gel column chromatography to give 230 mg of 1-(2'-fluoro-3'-hydroxypropyl)-3-nitro-1,2,4-triazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[N:20]=[C:21]([CH3:24])[S:22][CH:23]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(Cn6cccn6)cc5)nc34)CC2)cs1
Temperature: 85 °C

Procedure:
To a mixture of 5-chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.060 g, 0.19 mmol), EtOH (3.3 mL) and DMF (0.44 mL), 4-(1H-pyrazol-1-ylmethyl)-benzaldehyde (0.039 g, 0.21 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.57 mL, 0.57 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a off-white solid (0.036 g, 37%); 1H-NMR (500 Mz, DMSO-d6): δ 2.62-2.69 (m, 7H), 3.63 (s, 2H, NCH2), 3.66-3.74 (m, 4H), 5.42 (s, 2H, NCH2), 6.30 (t, J=2.0 Hz, 1H), 7.31 (s, 1H, thiazole 5-H), 7.34 (d, J=8.0 Hz, 2H, ArH), 7.48-7.51 (m, 1H), 7.86 (m, 1H), 8.08-8.15 (m, 3H, 2ArH and imidazo[4,5-b]pyridine 5-H), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.16 min—505/507 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 505.1687, calculated for C25H26N8SCl (M+H)+: 505.1690.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(#N)C>[C:11]1([CH2:10][O:9][C:8]([NH:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][N:1]2[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NC[C@H]1CCCN1)OCc1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)N1CCC[C@@H]1CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a mixture of phenylmethyl [(2R)-2-pyrrolidinylmethyl]carbamate (D109, 1.26 g, 5.38 mmol) and K2CO3 (1.48 g, 10.76 mmol) in acetonitrile (20 ml), cooled to 0° C., was added dropwise diethyl bromomalonate (1.08 ml, 6.46 mmol) in a 2-3 mins time. Then the reaction mixture was allowed to warm-up to r.t. and it was stirred at this temperature for 2.5 hrs. Further diethyl bromomalonate (1.08 ml, 1.6 mmol) was added and the reaction mixture was stirred for one more hour.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:26]O>C(O)CC>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Reactant: OO
Solvent: CCCO
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Reaction time: 72 h

Procedure:
Following the general procedure of Example 12, to a solution of 50 grams (0.14 mol) of didodecylamine dissolved in 200 ml of n-propanol at 40° C. is added dropwise 9.62 grams (0.14 mol) of 50% aqueous hydrogen peroxide solution. After 72 hours at 40°-45° C., the reaction mixture is filtered to give a crude product which is subsequently recrystallized from 300 ml of hexane. The above-named product is obtained in a yield of 24.8 grams (48%) as white needles melting at 90°-92° C.
Reaction SMILES: [CH:1]([CH2:14][C:15](O)=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[CH:1]([CH2:14][C:15]([Cl:20])=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(=S)CC(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: S=C(Cl)CC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
19.5 g (0.076 mol) of benzhydrylthioacetic acid in 114 ml of benzene are placed in a three-necked flask provided with a condenser and a dropping funnel. The mixture is heated and 19 ml of thionyl chloride are added drop by drop. Once the addition is complete, the reflux is continued for about 1 hour, cooling and filtering are carried out and the benzene and the excess thionyl chloride and then evaporated. In this way, a clear orange oil is obtained.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2.C(N1C=CN=C1)(N1[CH:24]=[CH:23]N=C1)=O.C(O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:23][CH3:24])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Reaction time: 3 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic Acid (15 g., 0.06 mol) and 1,1' carbonyldiimidazole (9.8 g, 0.06 mol) in dimethylformamide (12 ml) and tetrahydrofuran (700 ml) is refluxed with stirring for 3 hours. Absolute ethanol (20 ml) is added and refluxing is continued for a further 3 hours. The solvents are removed under reduced pressure. The residue is shaken with hot 0.5 mol aqueous sodium bicarbonate (200 ml), cooled and filtered. The residue is washed several times with water and recrystallized from methanol to give the product (8.9 g.) mp 183°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:25]2[CH2:24][CH:23]3[CH:27]([C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21][C:22]3=[O:28])[CH2:26]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc(F)cc3)CC12
Reaction time: 1 h
Yield: 66.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(4-fluorophenyl)acetic acid (1.08 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 16 hours at 20° C. The reaction mixture is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized form acetonitrile (5 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(4-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2 g) melting at 210° C. is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br>>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:23])[CH:16]=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C2CCCN(CCc3ccccc3)C2)cc1OC
Agent: Br
Product: Oc1ccc(C2CCCN(CCc3ccccc3)C2)cc1O
Yield: 88.5 %

Procedure:
A mixture of 3.3 g of N-(β-phenylethyl)-3-(3',4'-dimethoxyphenyl)-piperidine and 33 ml of 66% hydrobromic acid was refluxed for an hour and was then distilled to dryness under reduced pressure. The residue was taken up in a water-methylene chloride mixture and was made alkaline with an aqueous solution saturated with sodium bicarbonate. The organic phase was decanted and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 2.67 g of N-(β-phenylethyl)-3-(3',4'-dihydroxyphenyl)-piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:13]([CH2:15][NH2:16])[OH:14]>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:16][CH2:15][CH2:13][OH:14])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NCCO
Reactant: Clc1c(Br)cnc2ccccc12
Solvent: O
Product: OCCNc1c(Br)cnc2ccccc12
Temperature: 150 °C

Procedure:
A mixture of 9.1 g of 3-bromo-4-chloro-quinoline and 2.0 g of ethanolamine was heated at 150° C. for 30 minutes. The reaction mixture was cooled, 60 ml of water was added and the precipitate was collected by filtration and recrystallized from isopropanol. The yield was 9.5 g, mp 163°-165° C.
Reaction SMILES: ClC1C=C(N[C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])C=CC=1SC1N(C)C=CN=1.N1(C2CCNCC2)CCCCC1>CN1CCCC1=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:29]#[N:30])=[CH:16]2
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Agent: C1CCN(C2CCNCC2)CC1
Solvent: CN1CCCC1=O
Product: COc1ccc2ncc(C#N)cc2c1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 220 mg (0.5 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 290 mg (1.72 mmol) of 4-piperidinopiperidine in 1.5 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 94:6 methylene chloride/methanol to 89:10:1 methylene chloride/methanol/ammonium hydroxide) gives 193 mg of 7-(1,4′-bipiperidin-1′-yl)-4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxyquinoline-3-carbonitrile as a beige solid, mp 221-223° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].[CH2:23]([O:25][CH2:26][CH2:27]Cl)[CH3:24].O>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:23][O:25][CH2:26][CH3:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccccc21
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
0.75 g of a60% suspension of sodium hydride in mineral oil were suspended in 20 mL of dry DMF and 4 g of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were added to the mixture. 1.91 g of 2-chloroethyl ethyl ether were added dropwise at room temperature and the mixture was stirred for 16 hours at 20-25° C. Water was carefully added and ethyl acetate was used as solvent extractor. The organic layer was separated and washed with water. The solvent was removed under reduced pressure affording 4.58 g of a colorless oil. The product was then crystallised from methyl-t-butyl ether/hexane giving a off white solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]1[C:21]([Cl:22])=[C:20]([F:23])[C:19]([Cl:24])=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:14][C:15]1[C:21]([Cl:22])=[C:20]([F:23])[C:19]([Cl:24])=[CH:18][C:16]=1[NH:17][C:7]([NH:6][C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=1[F:13])=[O:8]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(F)c(Cl)c1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Three grams (0.016 mol) of 2,6-difluoro-benzoyl isocyanate were added to a solution of 2.95 gm (0.015 mol) of 2,4-difluoro-3,5-dichloroaniline in 50 ml of toluene. The solution thus obtained was stirred for 15 hours at room temperature. Thereafter, the product which precipitated during that time was removed by suction filtration and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH2:31][O:32][CH3:33])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH2:31][O:32][CH3:33])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: COCCN(c1ccc(C(=O)O)c(Cl)c1)S(C)(=O)=O
Product: COCCN(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)S(C)(=O)=O

Procedure:
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55° C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485 μL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 μL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[C:7]([Cl:27])[CH:6]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:40])[CH:37]([CH3:39])[CH3:38]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]([C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:18]=2)=[C:7]([Cl:27])[CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)Cc1cc(Cl)c(Oc2ccc(NCc3ccccc3)cc2)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(Cl)c(Oc2ccc(N(Cc3ccccc3)C(=O)C(C)C)cc2)c(Cl)c1
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a stirred mixture of methyl[3,5-dichloro-4-(4-benzylaminophenoxy)phenyl]acetate (0.36 g), triethylamine (0.10 g) and dichloromethane (40 mL) was added isobutyryl chloride (0.15 g). After 16 hours at room temperature, the reaction mixture was concentrated, and the residue partioned between ethyl acetate and water. The organic phase was washed with hydrochloric acid (1 N), a saturated aqueous solution of sodium hydrogencarbonate and brine. After concentration, the residue was purified on column (silica gel, petrolium ether/ethyl acetate, 4:1) to give, to give 0.40 g of methyl[3,5-dichloro-4-(4-(2-methylpropanoyl-benzylamino)phenoxy)phenyl]acetate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCN=C=NCCCN(C)C.[CH:26]([NH:29]C(C)C)([CH3:28])[CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C.[Cl-].[NH4+].C(OCC)(=O)C>[CH:26]([NH:29][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)([CH3:28])[CH3:27]
Reactant: CC(C)NC(C)C
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of (4-methanesulfonyl-phenyl)-acetic acid (2.5 g, 11.7 mmol) in CH2Cl2 (20 mL) was added EDCI (2.46 g, 12.9 mmol) followed by diisopropyl amine (1.2 mL) and DMAP (140 mg, 1.2 mmol). After 18 h at 21° C., the resulting reaction mixture was diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate/THF, 35:60:5) provided the title compound as a white solid.
Reaction SMILES: OO.[NH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=[O:13]>C(O)(=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:13][N:3]=[C:4]3[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=23)=[CH:15][CH:16]=1
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Br)cc2)c1N
Agent: OO
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc2c(-c3ccc(Br)cc3)onc12
Temperature: 95 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution of 130 ml of 30% hydrogen peroxide in 350 ml of glacial acetic acid was heated on a steam bath for 1 hr and then cooled. To the cooled solution was added 31.0 g (0.0955 mole) of (2-amino-5-chloro-3-methylphenyl)(4-bromophenyl)methanone followed by 450 ml of glacial acetic acid. The reaction mixture was heated to 95° C. to dissolve all solids, heated at 65°-70° C. for 8 hr and then cooled. The reaction mixture was poured into 2.5 liters of ice water and let stand at ambient temperature for 3 hr and filtered. The filter cake was washed with 500 ml of 10% sodium bicarbonate solution and 500 ml of water and dried to give 22.5 g of solid. The solid was recrystallized from 2-propanol to give 20.5 g (67%) of fluffy yellow needles, m.p. 163°-165° C.
Reaction SMILES: O.O.O.O.O.[S:6]([O-])([O-])(=O)=S.[Na+].[Na+].O.Cl.[CH3:15][C:16]1[C:21]([OH:22])=[C:20]([CH2:23]Cl)[C:19]([CH:25]=[CH2:26])=[CH:18][N:17]=1>C(O)C>[CH3:15][C:16]1[C:21]([OH:22])=[C:20]([CH2:23][SH:6])[C:19]([CH:25]=[CH2:26])=[CH:18][N:17]=1
Reactant: O=S([O-])([O-])=S
Reactant: C=Cc1cnc(C)c(O)c1CCl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=Cc1cnc(C)c(O)c1CS
Temperature: 75 °C

Procedure:
A solution of 20 g. of sodium thiosulfate pentahydrate in 15 ml. of water is added to a solution of 18 g. of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride in 100 ml. of 50% ethanol. The mixture is heated 1 hour at 75° C., cooled and evaporated to dryness to give Bunte salt of 2-methyl-3hydroxy-4mercaptomethyl-5-vinylpyridine, m.p. 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.O.ON1C2C=CC=CC=2N=N1.[CH:26]1([N:32]=[C:33]=NC2CCCCC2)CCC[CH2:28][CH2:27]1.CNCCC>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:32]([CH3:33])[CH2:26][CH2:27][CH3:28])=[O:9])[CH:5]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CCCNC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 0 °C

Procedure:
Dissolve 5-iodo-isophthalic acid monomethyl ester (9.34 g, 30.5 mmol), 1-hydroxybenzotriazole hydrate (4.86 g, 36 mmol) and a solution of 1,3-dicyclohexylcarbodiimide (1 M in dichloromethane; 36 mL) in THF (70 mL). Cool to 0° C. for 15 min. Add methylpropylamine (3.69 mL, 36 mmol) and stir at room temperature for 12 h. Filter the solution though a filtering agent and wash with ethyl acetate, concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound.