Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2ccco2)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (99 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH2Cl2 was added 2-furoyl chloride (95%, 56.0 mg, 1.2 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 20 (80 mg, 61%). LRMS 286 (M-100)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.ClC1C=C(C=CC=1)C(OO)=[O:31].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11](=[O:31])[CH2:10][CH2:9]1
Reactant: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1N1CCSCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S1CCN(c2ccc(C3=NOC(COc4ccon4)C3)cc2F)CC1
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred solution of (5RS)-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (174 mg, 0.48 mM) in dichloromethane (5 ml) was added dropwise a solution of 3-chloroperoxybenzoic acid (80%, 124 mg, 0.57 mM) in dichloromethane (5 ml) at ambient temperature, and stirring continued for 1 hour. Aqueous sodium metabisulfite (5%, 5 ml) was added, and after stirring for 5 minutes the organic phase was separated. After further extraction with dichloromethane (2×10 ml), the combined extracts were washed with aqueous sodium bicarbonate solution (2×15 ml) and dried (magnesium sulfate). Crude product was chromatographed on a 10 g silica Mega Bond Elut® column, eluting first with a gradient from 0–50% ethyl acetate in dichloromethane (to remove sulfone, 10 mg), then with a gradient from 0–2.5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (128 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([Cl:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[C:9]([Cl:15])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Cl)cc(N)c1Cl
Temperature: 80 °C
Yield: 86.7 %

Procedure:
To stirred solution of methyl 2,5-dichloro-3-nitrobenzoate (3.3 g, 13.1 mmol) in ethanol (20 mL) was added ammonium chloride (3.5 g, 64.81 mmol) dissolved in water (20 mL) and iron powder (7 g, 82.35 mmol). The reaction mixture was heated at 80° C. for 3 h. On completion, water was added to the reaction mixture and the solids removed by filtration through celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with water, dried, and concentrated under reduced pressure to give methyl 3-amino-2,5-dichlorobenzoate (2.5 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].Cl>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(=O)c2ccc(F)cc2)c1
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C(=O)c2cc(CCNS(=O)(=O)c3ccc(Cl)cc3)cc(CCC(=O)O)c2)cc1
Reaction time: 20 h
Yield: 41 %

Procedure:
A solution of 3-[2-[(4-chlorophenyl)sulphonylamino]ethyl]-5-(4-fluorobenzoyl)benzenepropanoic acid (0.25 g) and sodium methanesulphinate (0.61 g) in dimethylsulphoxide (1.0 ml) was heated at 130° C. under dry nitrogen for 30 hours. Additional sodium methanesulphinate (1.2 g) was added and heating was continued for a further 20 hours. The solution was diluted with water, acidified with 2N hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (97:3) as eluent. The product fractions were combined and evaporated to give the title compound as a foam (0.115 g), Rf 0.25(SS 8). Found: C,54.96; H,4.53; N,2.18. C25H24CINO7S2 requires: C,54.59; H,4.40; N,2.55%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[C:9]([CH3:18])=[N:10][CH:11]=[C:12]([CH:16]=O)[C:13]=1[CH2:14][CH3:15])#[N:2].[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([NH:22][CH2:16][C:12]2[C:13]([CH2:14][CH3:15])=[C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([CH:21]=[CH:20][CH:19]=3)[C:1]#[N:2])[C:9]([CH3:18])=[N:10][CH:11]=2)=[CH:24][CH:25]=1)#[N:28]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCc1c(C=O)cnc(C)c1OCc1cccc(C#N)c1
Product: CCc1c(CNc2ccc(C#N)cc2)cnc(C)c1OCc1cccc(C#N)c1
Yield: 52.3 %

Procedure:
The reductive amination of 3-(3-cyano-benzyloxy)-4-ethyl-2-methyl-pyridine-5-carbaldehyde (101) (700 mg, 2.50 mmol) and 4-aminobenzonitrile (2.0 g, 16.9 mmol), as described in Example 21, gave 3-{5-[(4-cyano-phenylamino)-methyl]-4-ethyl-2-methyl-pyridin-3-yloxymethyl}-benzonitrile (102) (500 mg, 52% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9](O)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]2[CH:7]=[C:6]([C:18]([O:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)=[O:19])[CH:5]=[CH:4][C:3]1=2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]2[CH:7]=[C:6]([C:18]([O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(O)(C(=O)OCC)CCC3(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=CCC(C)(C)c2ccc(C(=O)Oc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (+/−) ethyl 4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate (Compound E54, 35.0 mg, 0.077 mmol) in 10 mL benzene was added a catalytic amount (approximately 2 mg) of p-toluenesulfonic acid monohydrate. The solution was heated to reflux under a Dean-Stark trap for 3 h, and then cooled to room temperature and stirred overnight. The solvent was removed under reduced pressure and the title compound isolated from the residue by column chromatography (10% EtOAc-hexanes).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc(O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(O)c1O
Temperature: 60 °C

Procedure:
A mixture of 2,3-dihydroxybenzoic acid (5 g), methanol (50 ml) and concentrated sulphuric acid (10 drops) was stirred and heated to 60° C. for 24 hours. The mixture was evaporated and the residue was taken up in ethyl acetate. The organic solution was washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate and evaporated to give methyl 2,3-dihydroxybenzoate (2.19 g); NMR Spectrum: (CDCl3) 3.95 (s, 3H), 5.7 (s, 1H), 6.8 (t, 1H), 7.15 (d, 1H), 7.35 (d, H).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH2:9])[CH2:3]1.Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][N:46]([C:11]([NH:9][CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8][CH:2]([OH:1])[CH2:3]4)=[O:12])[CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1
Reactant: NC1CCCCC(O)C1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, 3-hydroxycycloheptyl-amine, p-nitrophenyl chloroformate, diisopropylethyl amine and 7-chloro-4-piperazinylquinoline are reacted to afford the product. LC-MS: 403 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.96 (d, 1H), 7.45 (d, 1H), 6.84 (d, 1H), 4.50 (d, 1H), 4.10 (m, 2H), 3.65 (m, 4H), 3.20 (m, 4H), 2.38 (m, 1H), 2.0 (m, 3H), 1.80 (m, 4H), 1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[CH:9].C([Li])CCC.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH:21]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)[OH:22]
Reactant: O=Cc1cccnc1
Reactant: C#Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OC(C#Cc1ccccc1Cl)c1cccnc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 655 mg (4.8 mmol) of 2-chlorophenylacetylene in 10 mL of tetrahydrofuran (THF) cooled to −78° C. under a nitrogen atmosphere was added 3.0 mL (4.8 mmol) of 1.6M n-butyllithium in hexane. The solution was stirred at −78° C. for 2 hrs, and then a solution of 514 mg (4.8 mmol) of 3-pyridinecarboxaldehyde in 2.5 mL of tetrahydrofuran (THF) was added. After 3.5 hrs, the reaction mixture was poured into water. The organic product was extracted with ether several times. Combined ether extracts were washed with saturated sodium bicarbonate and dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation to give the oily 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-ol.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@@H:9]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:8]2[CH2:7]1)=O)C.[OH-].[Na+]>C(O)C>[C:13]1([C@@:9]23[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C@@H:8]2[CH2:7][NH:6][CH2:11][CH2:10]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)N1CC[C@@H]2Oc3ccccc3[C@@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Yield: 150.4 %

Procedure:
To a solution of 3.56 g of cis-2-ethoxycarbonyl-1,2,3,4,4a,9b-hexahydro-benzofuro[3,2-c]pyridine in 42 ml of absolute ethanol was added 28 ml of 20% aqueous NaOH solution. The resulting mixture was heated at reflux under nitrogen for 32 hours. Most of the ethanol was removed in vacuo. The residue was diluted with 50 ml of water and extracted with methylene chloride (2×100 ml). There were initially some problems with emulsions. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo to give 2.72 g (98.4%) of crystalline solid. Recrystallization from hexane afforded 1.98 g (71.6%) of crystals, m.p. s 91°, 95°-98°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[Al+3].[Cl-].[Cl-].[Cl-].C[Si]([C:29]#[N:30])(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:12][CH:13]2[C:29]#[N:30])=[O:8])=[CH:5][CH:4]=1
Reactant: c1ccc2scnc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)N2c3ccccc3SC2C#N)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-methoxybenzoylchloride (7.0 g, 41.0 mmol) was added dropwise to a stirring solution of benzothiazole (5.4 g, 40.0 mmol) in dichloromethane (40 mL) under argon atmosphere. A catalytic amount of AlCl3 and trimethylsilylcyanide (4.1 g, 42.0 mmol) were than added into the reaction mixture. After being stirred for 14 h at room temperature, the reaction mixture was evaporated to dryness in vacuo and the residue was triturated with ether to give 3-(4-methoxybenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile, 8.2 g (70%); mp 122-123° C. (Lit.21 122-123° C.). 1H NMR (DMSO-d6) δ 3.82 (3H, s, MeO), 6.72 (1H, brs, C2-H), 6.84 (1H, s, ArH), 7.01-7.14 (4H, m, 4×ArH), 7.52-7.55 (3H, m, 3×ArH).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][CH2:32][CH3:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.Cl[C:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:45].C(N(CC)CC)C.Cl>C(Cl)Cl.C(OCC)(=O)C>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:42])[F:41])[CH:36]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:32][CH3:33])[C:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:45])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reactant: CCOC(=O)CCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (164 mg) is dissolved in methylene chloride (5 ml), and thereto are added ethyl 6-(chloroformyl)hexanoate (67 mg) and triethylamine (26 μl), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=17:3→7:3) to give ethyl 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoate (147 mg). MS (m/z): 778 [M+H]+
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[N:7][C:6]=1[C:14]([O:16]C)=[O:15])=[O:4].[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[H-].[Na+].Cl>CN(C=O)C.CO>[CH2:10]([C:8]1[N:7]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([I:18])=[CH:20][CH:21]=2)[C:6]([C:14]([OH:16])=[O:15])=[C:5]([C:3]([OH:2])=[O:4])[N:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Reactant: BrCc1ccc(I)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nc(C(=O)O)c(C(=O)O)n1Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Dimethyl 2-butylimidazol-4,5-dicarboxylic acid (7.12 g, 29.6 mmol) and 4-iodobenzyl bromide (10.56 g, 35.5 mmol) were dissolved in DMF (50 ml), and 60% oily sodium hydride (1.3 g, 32.5 mmol) was added in small portions while stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours and methanol was added to treat excess sodium hydride. Then the reaction solution was neutralized with 2N HCl and the product was extracted with dichloromethane. The extracted solution was dried over sodium sulfate and concentrated in reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the titled compound (11.1 g, 82%) as a tan solid (mp:98-99° C., Rf:0.60 silica gel-ethyl acetate/hexane/=1/1). This has the following NMR spectrum.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[CH:13]=[O:14].O>C(O)C>[Cl:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[CH2:13][OH:14]
Reactant: O=Cc1sc2ccccc2c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1sc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium borohydride (231 mg, 6.1 mmol) in absolute ethanol (10 mL) was added a solution of 3-chloro-1-benzothiophen-2-carbaldehyde (1.0 g, 5.1 mmol) in absolute ethanol (5 mL) at 0° C. The mixture was stirred for 2 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (3-chloro-1-benzothiophen-2-yl)methanol was obtained as an orange pale solid (944 mg, 94% yield) and used for next step without further purification; 1H NMR (400 MHz, CDCl3): δ 2.17 (bs, 1H), 4.99 (s, 2H), 7.37-7.47 (m, 2H), 7.78-7.82 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[CH:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[NH2:23]OS(O)(=O)=O>C1COCC1.O>[NH2:23][N:9]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)=[CH:7][C:8]1=[O:10]
Reactant: NOS(=O)(=O)O
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nn1c(C2CC2)cc(-c2ccc(C(F)(F)F)cc2)cc1=O
Temperature: 23 °C
Reaction time: 20 h
Yield: 63.7 %

Procedure:
To a solution of 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (example C.28 step 2) (4.19 g, 15.0 mmol) in THF (225 mL) and 1M NaOH (90.0 mL, 90.0 mmol) was added dropwise a solution of hydroxylamine-O-sulfonic acid (HOSA) (95%, 5.36 g, 45.0 mmol) in H2O (60 mL) at 0° C. The reaction mixture was stirred at 23° C. for 20 h (76% conversion). Added again at 0° C. 3N NaOH (30 mL, 30.0 mmol) and then hydroxylamine-O-sulfonic acid (HOSA) (95%, 5.36 g, 45.0 mmol) and the reaction mixture was stirred at 23° C. for 3 days (88% conversion). Poured into ice water, extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4. Removal of the solvent in vacuum left a residue (5.17 g) which was purified by silica gel chromatography (400 g SiO2) to give the title compound as a light yellow solid (2.81 g, 64%). MS (ISP) 295.5 [(M+H)+]; mp 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([CH2:25][NH2:26])[OH:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:26][CH2:25][CH2:23][OH:24])=[O:14])=[O:7]
Reactant: NCCO
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCCO)c1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)acetylamino]-benzoic acid (150 mg, 0.44 mmol) and ethanolamine (0.04 ml, 0.66 mmol) in DMF 3.0 mL was added EDC (126.5 mg, 0.66 mmol), HOBt (89.2 mg, 0.66 mmol) and DIPEA (0.11 ml, 0.66 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=15:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-(2-hydroxy-ethyl)-benzamide as a white solid (135 mg, 80% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:15]1C=CC=C[CH:16]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a cold (0° C.) suspension of 4-acetamido-benzenesulphonyl chloride (4.0 g, 17 mmol) in CH2Cl2 (40 mL) was added pyridine (1.7 mL, 20 mmol) and DMAP (209 mg, 1.7 mmol). (A clear solution resulted). Anhydrous methylamine was bubbled into the solution for 1 hour at 0° C., and then the solution was allowed to stir at 25° C. for 2 hours. The solution was extracted with 1M NaOH (3×15 mL) and the combined extracts were adjusted to pH 6 at 0° C. with 3M HCl. The product, which precipitated as fluffy white crystals, was filtered and washed with cold water to afford 3.2 g (82%) of 4-acetamido-N-methylbenzenesulphonamide: 1H NMR (300 MHz, MeOH) δ 2.35 (s, 3H), 2.70 (s, 3H), 7.96 (s, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([N:11]3[C:15]([NH2:16])=[CH:14][CH:13]=[N:12]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:16][C:15]2[N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][CH:2]=[N:1]4)[N:12]=[CH:13][CH:14]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccnn1-c1cccc2ncccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccnn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 6.6 %

Procedure:
A stirred mixture of crude 1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.080 g, 0.38 mmol), 4-t-butylbenzenesulfonyl chloride (0.13 g, 0.57 mmol), and DMAP (0.068 g, 0.57 mmol) in pyridine (1.5 mL) was heated at 80° C. for 2 h. After cooling to room temperature, aqueous saturated sodium bicarbonate was added to the reaction mixture and extracted with 2:1 chloroform/iPrOH. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.010 g, 0.025 mmol, 7%). 1H NMR (400 MHz, CD3OD) δ 8.87 (dd, J=2.0, 4.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.76 (dd, J=7.2, 8.8 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.65-7.62 (m, 1H), 7.52-7.42 (m, 3H), 7.51 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.28 (dd, J=1.2, 7.2 Hz, 1H), 6.25 (s, 1H), 1.35 (s, 9H); MS: (ES) m/z calculated for C22H23N4O2S [M+H]+ 407.2. found 407.0.