Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:1]([OH:3])(=[O:5])=[O:2])[CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccncc1
Product: O=S(=O)(O)c1cccnc1
Yield: 50 %

Procedure:
Fischer (Ber., Vol. 15, 62 (1882) described already in 1882 the sulfonation of pyridine with concentrated sulfuric acid at 300° to 350° C. and after a reaction time of 24 hours, pyridine-3-sulfonic acid could be isolated with a yield of 50%. Subsequent investigations had the goal to produce the acid under milder reaction conditions in a shorter reaction time with a higher yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:38])([F:37])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([O:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1.[CH3:39][NH:40][CH2:41][CH2:42][OH:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:43][CH2:42][CH2:41][N:40]([CH3:39])[C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([C:11]([F:37])([F:10])[F:38])=[N:13][N:14]=4)[N:17]=3)[CH2:26][CH2:25]2)=[CH:36][CH:35]=1
Reactant: CNCCO
Reactant: O=C(O)c1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)C(=O)c1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
DIPEA (0.087 mL, 0.5 mmol) was added to 4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]benzoic acid (100 mg, 0.25 mmol), 2-(methylamino)ethanol (20.28 mg, 0.27 mmol) and HATU (114 mg, 0.3 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 24 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(2-hydroxyethyl)-N-methyl-4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]benzamide (64 mg, 55%).
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H:40]([O:43]CCC)[CH2:39][CH2:38]2)CCCCC1.C1(N([C@H]2CC[C@H](OC)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)CCCC1.O[C@H]1CC[C@H](C2C=CC=C3C=2C(=O)NC3=O)CC1.BrCCC.C1(=O)CCCCC1.C(OC(=O)CNS(C1SC(N)=NC=1)(=O)=O)C>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([O:43][CH2:40][CH2:39][CH3:38])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCCO[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Agent: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: O=C1NC(=O)c2c1cccc2[C@H]1CC[C@H](O)CC1
Solvent: CCCBr
Solvent: O=C1CCCCC1
Product: CCCO[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-propoxy-cyclohexyl)-amine (prepared according to the procedure described for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Step 1) using (trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione, 1-bromopropane and cyclohexanone) and (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Clc1ccc2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1cccc(-c2ccc3ccccc3n2)c1
Yield: 77.5 %

Procedure:
2-chloroquinoline (9.25 g, 56.5 mmol), (3-chlorophenyl)boronic acid (9.28 g, 59.4 mmol), Pd(PPh3)4 (1.634 g, 1.413 mmol) were charged into the reaction flask with 300 mL of 1,2-dimethoxyethane. Sodium carbonate (14.98 g, 141 mmol) was dissolved in 50 mL of water and was charged into the reaction flask. The reaction flask was then evacuated and back-filled with nitrogen then was heated to reflux for 20 hours. The organic layer was separated and dried over magnesium sulfate. The organics were filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 5-25% ethyl acetate/hexanes yielding 2-(3-chlorophenyl)quinoline (10.5 g, 77% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])P(OC)(OC)=O.C1CCN2C(=NCCC2)CC1.[CH3:34][O:35][C:36]1[N:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][CH:40]=[C:39]2[CH:46]=O.CC(=O)OCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])/[C:4](/[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[CH:46]/[C:39]1[C:38]2[C:43](=[CH:44][CH:45]=[C:36]([O:35][CH3:34])[N:37]=2)[N:42]=[CH:41][CH:40]=1
Reactant: COc1ccc2nccc(C=O)c2n1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccnc2ccc(OC)nc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A solution of benzyloxycarbonylamino-(dimethoxy-phosphoryl)-acetic acid methyl ester (2.07 g, 6.25 mmol) in DCM (10 mL) was cooled to 0° C. and DBU (0.95 g, 6.25 mmol) was added dropwise. The mixture was stirred at 0° C. for 15 min and then added via syringe dropwise to a suspension of 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (0.94 g, 5 mmol) in DCM (15 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, diluted with DCM, washed with water, dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 1:1) gave the product (25:1 Z/E mixture) as a colourless foam (1.92 g, 98% yield).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16](N)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)CCC.N([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>[Cu](Cl)Cl.[Cl-].[NH4+]>[C:28]([O:27][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:5])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCCCOC(=O)N1CCC(c2cc(C(=O)OCC)c(N)s2)CC1
Reactant: CC(C)(C)ON=O
Agent: Cl[Cu]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
4-(5-Amino-4-ethoxycarbonyl-thiophen-2-yl)-piperidine-1-carboxylic acid butyl ester (13.4 g, 38 mmol) was added to t-butyl nitrite (56.4 mmol) and copper(II)chloride (38 mmol) in IMS (500 mL). The reaction was stirred for 1 hour then saturated aqueous ammonium chloride (70 mL) was added and the resulting mixture stirred for a further 15 minutes. The solution was filtered and the filtrate was evaporated under vacuum. The residue was then partitioned between DCM and water. The organic layer was separated and dried over magnesium sulphate, filtered and the solvent evaporated. The product was purified by column chromatography on silica, eluting with 0%-40% ethyl acetate in cyclohexane to give a clear oil (11.7 g). 1H NMR (400 MHz, CHCl3-d): δ 7.9 (s, 1H), 7.2 (s, 1H), 4.3 (q, 2H), 4.2 (m, 2H), 2.9-2.7 (m, 3H), 2.0 (m, 2H), 1.7 (m, 2H), 1.5 (s, 9H), 1.4 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1C(I)=C(C(O)=O)C(I)=C(C(O)=O)[C:7]=1I.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N:1]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:7][CH:2]=1
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Reactant: Cc1ccccc1
Product: c1ccc2ncccc2c1
Yield: 92.3 %

Procedure:
According to the procedure described in Example 1, the reaction is carried out with the same amounts of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid using toluene instead of meta-xylene, with quinoline, giving a yield of 92.3%.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[N:12]=1)=[N+:8]=[N-:9].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Br:17][C:13]1[N:12]=[C:11]([CH2:10][N:7]2[CH:3]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[N:9]=[N:8]2)[CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1cccc(Br)n1
Reactant: C#CC(=O)OC
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cn(Cc2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl propiolate (641 μL, 7.63 mmol) and 2-(azidomethyl)-6-bromopyridine (1.25 g, 5.87 mmol) were combined in t-BuOH (9.0 mL) and water (5.0 mL). A solution of CuSO4.5H2O (73 mg, 0.29 mmol) in water (2.0 mL) was added, followed by sodium ascorbate (232 mg, 1.17 mmol) in water (2.0 mL). The reaction was stirred at room temperature for 18 h, during which time it became a yellow suspension. The suspension was diluted with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude solid was purified by flash chromatography (40-100% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:6]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[N:7][CH:8]=1
Reactant: COC(=O)Cc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1CC(=O)O
Reaction time: 4 h
Yield: 45.2 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-acetic acid methyl ester (0.14 g, 0.3 mmol) in tetrahydrofuran (3.0 mL) and water (0.6 mL) was added lithium hydroxide monohydrate (0.031 g, 0.75 mmol) at ambient temperature. After stirring for 4 hours the reaction mixture was filtered through a pad of silica gel eluting with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo to provide the title compound (0.061 g).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].C[Si](C)(C)N[Si](C)(C)C.C(O[CH2:25][O:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=O)C.O>CC(C)=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[C:30]([O:29][CH2:28][CH2:27][O:26][CH2:25][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)OCCOCOC(C)=O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 130 °C
Yield: 57.3 %

Procedure:
A mixture of 10 gms (66 mmoles) of guanine, 50 ml of hexamethyldisilazane, and 0.4 gms (3 mmmol) of ammonium sulfate was heated to 115°-118° C. for 18 hours. The ammonia gas was removed as it was formed. After 18 hours of heating, a solution was formed indicating the completion of silylation. To this solution was added 15 gms (85 mmol) of 2-oxa-1,4-butanediol diacetate and 0.1 ml of trimethylsilyl triftriflate. The mixture was heated to 130° C. for a period of 4.5 hours. The solution was cooled to 50° C. and 10 ml of water dissolved in 100 ml of acetone was added. The mixture was heated to reflux and a precipitate was formed immediately. The mixture was cooled and the solid was collected by filtration to yield 10.1 g (58% yield) of 9-(2-acetoxyethoxy)methylguanine, with a 13:1 ratio of N-9 to N-7 isomer. Characteristic analytical data are as follows: 1H NMR (DMSO-d6) δ1.90 (3H, singlet, --OAc) , 3.58 (2H, multiplet, --OCH2 --) , 4.0 (2H, multiplet, --CH2OAc) , 5.25 (2H, singlet, --NCH2O--), 6.5 (2H, br singlet, --NH2), 7.75 (1H, singlet, --N=CH--N--).
Reaction SMILES: [CH2:1]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1Cc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1ccccc1Cc1ccccc1)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
Methyl 2-[N-(2-(benzyl)benzyl)-N-ethylamino]-5-pyridinecarboxylate (0.9 g, 2.5 mmol) in THF (6 ml) and methanol (6 ml) were treated with 1N aqueous sodium hydroxide (7 ml), and stirred at ambient temperature overnight. The clear solution was evaporated to low bulk, treated with water and glacial acetic acid to pH4. The resultant white precipitate was stirred for 15 minutes, filtered, washed well with water, then sucked dry to yield the title product as a white solid (0.8 g, 92%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[C:22]([C:27]([F:30])([F:29])[F:28])=[N:23][CH:24]=[CH:25][CH:26]=4)[N:19]=[C:18]([C:31]([OH:34])([CH3:33])[CH3:32])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Cl:35]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>CC#N.C(Cl)Cl>[Cl:35][C:17]1[C:18]([C:31]([OH:34])([CH3:32])[CH3:33])=[N:19][N:20]([C:21]2[C:22]([C:27]([F:30])([F:29])[F:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[C:16]=1[C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2cccnc2C(F)(F)F)n1
Agent: O=C1CCC(=O)N1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(O)c1nn(-c2cccnc2C(F)(F)F)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1Cl
Temperature: 75 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 2-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1-(2-(trifluoromethyl)-pyridin-3-yl)-1H-pyrazol-3-yl)propan-2-ol (10.6 g, 21 mmol) in MeCN (200 mL) was added N-chlorosuccinimide. The resulting solution was heated to 75° C. in a heating mantle. After stirring for 3 hours at 75° C. heating was discontinued and the solution was concentrated under reduced pressure to afford a yellow foam. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane. Fractions that Were pure by TLC analysis were combined and concentrated under reduced pressure to afford a white sticky foam that was contaminated with succinimide as evidenced by NMR analysis. This material was taken up in CH2Cl2 and washed with saturated aqueous Na2CO3 (2×). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(4-chloro-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrazol-3-yl)propan-2-ol (6.7 g, 60% yield) as an off-white foam. 1H NMR (400 MHz CDCl3): δ 8.85 (1H, m), 8.06 (1H, t), 7.86 (1H, m), 7.82-7.73 (2H, m), 7.67-7.62 (1H, m), 7.58 (1H, t), 7.28 (1H, d), 7.01 (1H, d), 3.08 (3H, s), 2.93 (1H, s), 1.73 (6H, s). MS(ES): 542 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+].[NH2:21][C:22]1[C:37]([CH2:38][N:39]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:40][CH3:41])=[CH:36][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH3:35])[CH2:32][CH2:33]Cl)=[O:27])=[CH:24][C:23]=1[Br:48]>>[NH2:21][C:22]1[C:37]([CH2:38][N:39]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:40][CH3:41])=[CH:36][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH3:35])[CH2:32][CH2:33][O:18][C:17](=[O:19])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[O:27])=[CH:24][C:23]=1[Br:48]
Reactant: CCN(Cc1cc(C(=O)OCCN(C)CCCl)cc(Br)c1N)C1CCCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)OCCN(C)CCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from sodium 2-[(2,6-dichlorophenyl)-amino]-phenyl-acetate and N-{2-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyloxy]-ethyl}-N-(2-chloroethyl)-methylamine analogous to Example 8. Oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[N:12]1([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C)P(=O)(N(C)C)N(C)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][N:15]2[CH2:14][CH2:13][N:12]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:29][CH:30]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCOC(=O)c1ccc(N2CCN(CC=Cc3ccc(Cl)cc3)CC2)cc1
Reaction time: 5 h
Yield: 48 %

Procedure:
A mixture of 9.4 g. (50 mmole) 4-chlorocinnamyl chloride and 13.1 g. (50 mmole) n-butyl 4-(piperazin-1-yl)-benzoate in 40 ml. hexamethylphosphoric acid triamide is heated for 10 hours to 60° C., 6.9 g. (50 mmole) potassium carbonate are added thereto and stirring continued for 5 hours at 60° C. After cooling, the reaction mixture is diluted with the tenfold amount of water, the organic components are taken up in ethyl acetate and the dried ethyl acetate solution is evaporated. The residue is recrystallised from methanol to give 10.0 g. (48%) of desired product; m.p. 115°-117° C. The hydrochloride melts at 166°-168° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]2[CH2:11][O:12][CH:13](C3C=CC=CC=3)[O:14][C:8]2=[CH:7][CH:6]=1)[OH:4].C(N(C(C)C)CC)(C)C.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[C:44]([S:48]([NH2:51])(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>CN(C)C=O>[CH:13]([OH:14])=[O:12].[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH2:11][OH:12])[N:10]=1)[CH2:2][NH:1][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[C:44]([S:48]([NH2:51])(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCBr)c1
Reactant: NCC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNCC(O)c2ccc(O)c(CO)n2)c1
Product: O=CO
Yield: 22.1 %

Procedure:
A stirred solution of 2-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (100 mg) (EP220054A2), diisopropylethylamine (0.08 ml) and 3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (120 mg) in N,N-dimethylformamide (2 ml) under nitrogen was heated to 50° for 18 h. The mixture was cooled to 20° and the solvent evaporated in vacuo. The residue was dissolved in acetic acid (4 ml) and water (2 ml) and was heated to 70° for 18 h. The mixture was cooled to 20°, the solvent evaporated in vacuo and the residue purified by mass-directed autopreparative HPLC to give the title compound (22 mg). LCMS RT=2.23 min, ES+ve 496 (MH)+.
Reaction SMILES: CS(O[CH:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:18]1([NH:17][CH:6]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(OS(C)(=O)=O)c1cccs1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccccc1)c1cccs1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
Ethyl 2-(methylsulfonyloxy)-2-(thiophen-2-yl)acetate (I27) (5.7 g, 21.6 mmol), aniline (2.16 ml, 23.7 mmol) and DIPEA (4.52 ml, 25.9 mmol) were dissolved in acetonitrile (20 ml) to give a yellow solution which was heated under microwave irradiation into a sealed vial at 100° C. for 15 minutes. Conversion complete by UPLC/MS-UV. The solvent was evaporated, and the residue was dissolved in DCM and washed with water and brine, dried (Na2SO4), filtered and evaporated to dryness. The resulting crude was purified by flash chromatography (Petroleum ether/EtOAc=85/15) to get desired compound as a solid (4.33 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([Cl:24])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Sc2ccc(Cl)cc2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(Oc1ccc(Sc2ccc(Cl)cc2)cc1)C(=O)Cl

Procedure:
A mixture of 15 g (0.0465 mol) of p-(p-chlorophenylthio)-phenoxy-isobutyric acid (CRL 40,201) and of 16.75 ml (0.232 mol) of thionyl chloride is heated to the reflux temperature for 10 minutes. After having taken up the reaction mixture in benzene, filtered the solution in the presence of charcoal and evaporated the solvent, 16 g of an orange-coloured oil are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Li]CCCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CCOCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)c1cc(I)ccc1Br
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccc(Br)c(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of 1-bromo-4-iodo-2-(trifluoromethyl)benzene (246 mg, 0.701 mmol) in 1.4 mL of Et2O (C=0.5M) was added dropwise a 1.6M solution of BuLi in hexane (460 μL, 1.05 eq) at −78° C. After 15 min of stirring, benzaldehyde (86 μL, 1.2 eq) was slowly added. The mixture was stirred for 4 h at −75° C. and then, hydrolyzed with water and with a 1M HCl solution to acidify. The layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organics were washed with brine, dried over MgSO4, filtered and solvents were removed in vacuo. The crude residue was purified by silica gel flash chromatography (cyclohexane/AcOEt 93:7 to 90:10) to afford the desired product in 76% yield (176 mg) as an uncoloured oil. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=2.2 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.41-7.27 (m, 6H), 5.81 (s, 1H), 2.36 (s, OH); 13C NMR (75 MHz, CDCl3) δ 143.5 (C), 142.8 (C), 135.1 (d, J=2.0 Hz, CH), 131.0 (CH), 130.2 (q, J=31.3 Hz, C), 129.0 (CH), 128.5 (CH), 126.7 (CH), 125.9 (q, J=5.4 Hz, CH), 123.0 (q, J=273.6 Hz, C), 118.9 (q, J=2.0 Hz, C), 75.4 (CH); MS (ESI) m/z: 313.0, 315.0 [M-OH, 79Br, 81Br]+; 348.0, 350.0 [M+NH4, 79Br, 81Br]+; 680.0 [2M+NH4, 79Br, 81Br]+.