Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 4-iodophenylsulphonyl chloride (3.64 g, 12 mmol) in DCM (30 ml) was added dropwise to a solution of 2-methoxyethylamine (1.3 ml, 15 mmol) and triethylamine (2 ml, 15 mmol) in DCM (60 ml) cooled by an ice bath to 0° C. The mixture was then allowed to warm to ambient temperature and stirred for 1 hour. The solvent was removed by evaporation and the resulting oil dissolved EtOAc (100 ml) and washed with 1N aqueous citric acid solution (2×100 ml), brine (100 ml) and dried. The volatiles were removed by evaporation to give the title compound (4.1 g, 100%) as a clear oil. NMR 3.12 (2H, q), 3.28 (3H, s), 3.44 (2H, t), 4.90 (1H, t), 7.57 (2H, d), 7.81 (2H, d); m/z: 342.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([NH:13][NH2:14])=[O:12])[N:10]=2)[CH:7]=1.[C:16](OCC)(OCC)(OCC)[CH3:17]>CC(O)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]3[O:12][C:16]([CH3:17])=[N:14][N:13]=3)[N:10]=2)[CH:7]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1c(C(=O)NN)nc2ccc(I)cn12
Solvent: CC(=O)O
Product: Cc1nnc(-c2nc3ccc(I)cn3c2C)o1
Temperature: 25 °C

Procedure:
To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbohydrazide (200 mg) in AcOH (0.5 ml) was added triethyl orthoacetate (2 ml) at room temperature, and the reaction mixture was heated at reflux for 4 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, and the EtOAc layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (100 mg) as a light yellow solid.
Reaction SMILES: OC1C=CC(CC(NC2C=CC=C(C#CC3C=CC=CC=3)C=2)=O)=CC=1OC.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]#[C:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:37])=[CH:31][C:30]=1[O:53][CH3:54]>>[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:37])=[CH:31][C:30]=1[O:53][CH3:54]
Reactant: COc1cc(CC(=O)Nc2ccccc2C#Cc2ccccc2)ccc1O
Agent: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3)c2)ccc1O
Product: COc1cc(CC(=O)Nc2ccccc2CCc2ccccc2)ccc1O

Procedure:
Instead of 4-hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]-phenylacetamide (the compound of Example 36) in Example 54, 4-hydroxy-3-methoxy-N-[2-(2-phenylethynyl)phenyl]phenylacetamide (the compound of Example 107) is treated in a similar manner to Example 54 to give the desired compound.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25].O>CN(C)C=O>[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([N:8]1[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])=[O:26]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)c(C)c1
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 523 mg) at room temperature, and the mixture was stirred for 1 hr. Mesitylsulfonyl chloride (2.42 g) was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3→3:2) to give the title compound as a pale-yellow oil (yield 1.76 g, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:23][C:22](=[O:24])[C:21]3[C:16](=[C:17]([CH3:28])[CH:18]=[C:19]4[CH:27]=[N:26][NH:25][C:20]4=3)[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C(#N)C.O>[CH:29]([NH:32][C:22]([C:21]1[C:16]([NH:15][C:14]([C:4]2[N:5]([C:7]3[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]([Br:1])[CH:3]=2)=[O:23])=[C:17]([CH3:28])[CH:18]=[C:19]2[C:20]=1[NH:25][N:26]=[CH:27]2)=[O:24])([CH3:31])[CH3:30]
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: CC#N
Solvent: O
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a suspension of 600 mg of the above 7-[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v) is added 1.11 mL (13.1 mmol) of isopropylamine. The reaction mixture is stirred for 9 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 1:2) affords 110 mg (16% over two steps) of the product as a white solid; LC/MS:518/520 (M+H)+, m.p.: 163-166° C.
Reaction SMILES: CO[CH:3]([O:27][CH3:28])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:18]=3[CH3:19])=[CH:10][C:9]=2[CH:26]=1.C[Si]([C:33]#[N:34])(C)C.B(F)(F)F.CCOCC>ClCCl>[CH3:28][O:27][CH:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:18]=3[CH3:19])=[CH:10][C:9]=2[CH:26]=1)[C:33]#[N:34]
Reactant: COC(Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)OC
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(C#N)Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Yield: 85.9 %

Procedure:
To a solution of 5-(2,2-dimethoxyethyl)-2-[(5-methyl-2-phenyl-4-oxazolyl)methyl]benzofuran (0.75 g, 2.0 mmol) in dichloromethane (15 ml) were added trimethylsilyl cyanide (0.80 ml, 6.0 mmol) and boron trifluoride etherate (50 μl, 0.5 mmol). After 1 hour the solution was diluted with dichloromethane, washed with 5% sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (hexanes/ethyl acetate, 2:1) and isolated as a solid (0.64 g, mp 107°-109° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7]2[N:8]=[CH:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[Cl:18][C:19]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:18][C:19]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:3]1[CH2:4][CH2:5][C:6]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:8][C:7]=2[C:2]1([CH3:17])[CH3:1])=[O:22]
Reactant: CC1(C)NCCc2c1ncn2-c1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C)c2ncn(-c3ccccc3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of the product of Example 53, Step B (59 mg, 0.26 mmol) in DCM (2 mL) was added Intermediate 12 (63 mg, 0.26 mmol) and K2CO3 (89 mg, 0.65 mmol). The resulting suspension was stirred at room temperature for 2 h. The crude reaction mixture was filtered and concentrated and then purified on 12 g SiO2 column with 0-4% NH3/MeOH CH2Cl2 to give the desired compound (55 mg, 48%). MS (ESI): mass calcd. for C22H19ClF3N3O, 433.1. m/z found, 434.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J=7.8, 1.4 Hz, 1H), 7.67 (s, 1H), 7.54-7.37 (m, 5H), 7.30 (dd, J=5.3, 3.3 Hz, 2H), 3.53-3.38 (m, 2H), 2.72-2.54 (m, 2H), 2.01 (d, J=6.3 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:21])=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:13]=1)=[O:11].Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[C:15]([O:21][S:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=2)(=[O:34])=[O:33])=[C:14]([CH:22]([CH3:23])[CH3:24])[CH:13]=1)=[O:11]
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 46.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197 g, 0.831 mmol). Purification on Dynamax C18 (90% CH3CN/H2O) gave 0.20 g (47%) of the title compound as a yellow solid, mp 90-95” C. 1H NMR (DMSO-d6) δ 1.06 (d, 12H), 1.85 (s, 3H), 2.19 (s, 3H), 3.07 (septet, 2H), 3.91 (s, 2H), 7.14-7.16 (m, 2H), 7.29 (dt, 1H), 7.44 (d, 1H), 7.47-7.52 (m, 4H), 8.05 (d, 1H). IR (KBr) 3400, 2950, 1690, 1380 and 1190 cm−1. mass spectrum (−ESI) m/z 667/669 (M−H). Anal. Calcd. for C33H33BrO8S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.82; H, 5.13; N, 0.13.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:17]=2)(=[O:15])=[O:14])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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:29][C:24]1[CH:23]=[C:22]([C:18]2[CH:17]=[C:16]([S:13]([NH:12][C:5]3[CH:4]=[CH:3][C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:6]=3[S:8]([NH2:11])(=[O:10])=[O:9])(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: NS(=O)(=O)c1cc(Br)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Reactant: OB(O)c1ccccc1
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: CN(C)C=O
Product: NS(=O)(=O)c1cc(-c2ccccc2)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
5-Bromo-2-[[3-(3,4-dichlorophenyl)phenyl]sulfonylamino]benzenesulfonamide (70 mg, 0.13 mmol) was dissolved in DMF (700 μl), then phenylboronic acid (20 mg, 0.16 mmol) was added followed by the addition of 2M sodium carbonate solution (260 μl). The mixture was subjected to vacuum/argon (×3), tetrakis(triphenylphosphine)palladium (8 mg, 0.05 mol %) was added and the reaction was allowed to stir at 80° C. overnight. The cooled reaction mixture was filtered and was then purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (23 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[OH-].[Na+]>O.CO>[CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1C)SCCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1SCCC2(C)C

Procedure:
62.9 g of methyl 4,4,8-trimethylthiochroman-7-carboxylate were initially charged in 600 ml of a 1:1 mixture of water/methanol, and 15.1 g (0.377 mol) of sodium hydroxide were added. The solution was then heated under reflux for three hours, the organic solvent was removed, 200 ml of water were added and the mixture was made acidic using conc. hydrochloric acid with cooling. The precipitate was filtered off with suction, washed with water and dried.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[NH:35][CH:36]=[CH:37][C:30]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[NH:35]1[C:31]2=[N:32][CH:33]=[CH:34][C:29]([NH:1][C@H:2]([C:5]3[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=4)[C:13](=[O:26])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[F:27])[N:6]=3)[CH2:3][CH3:4])=[C:30]2[CH:37]=[CH:36]1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Reactant: Clc1ccnc2[nH]ccc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ccnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 4-chloro-1H-pyrrolo[2,3-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 9A).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Sodium hydride (0.20 g, 60% dispersion in mineral oil) was added to a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.92 g) in anhydrous 1-methyl-2-pyrrolidinone (5 ml), precooled in ice. After stirring for 30 minutes under nitrogen, 2,5-dibromopyridine (1.0 g) was added. The reaction mixture was then stirred for two hours at room temperature before heating to 70° C. for four hours. The resultant dark mixture was poured onto ice (200 ml) containing 2% citric acid (20 ml), and was extracted with diethyl ether (3×15 ml). The aqueous phase was then basified to pH 13 with solid sodium hydroxide, and extracted with diethyl ether (2×15 ml). The combined organics were washed water (3×20 ml), saturated brine (20 ml) and dried over anhydrous sodium sulfate and evaporated to give the title compound as a light brown oil (0.87 g, 58%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1ccc(F)cc1F
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 48 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,4-difluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 8.05–7.98 (3H, m), 7.44 (2H, d, J=8.6 Hz), 7.35–7.27 (1H, m), 7.06–6.93 (2H, m), 5.442–5.32 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 447 (M+H)+, 445 (M−H)−.
Reaction SMILES: ClC1C=CC(C2C3CN([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])CC3ON=2)=CC=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[F:53][C:54]([F:70])([F:69])[C:55]1[N:60]=[CH:59][C:58]([C:61]2[C@@H:65]3[CH2:66][NH:67][CH2:68][C@@H:64]3[O:63][N:62]=2)=[CH:57][CH:56]=1>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:67]3[CH2:68][CH:64]4[CH:65]([C:61]([C:58]5[CH:59]=[N:60][C:55]([C:54]([F:69])([F:53])[F:70])=[CH:56][CH:57]=5)=[N:62][O:63]4)[CH2:66]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: FC(F)(F)c1ccc(C2=NO[C@H]3CNC[C@@H]23)cn1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(C(F)(F)F)nc5)C4C3)c(F)cc2c1=O

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using a suitably substituted TFA salt 4d. Acid 103 was isolated as a gold solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]([CH2:17][CH2:18]O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:33]([NH2:36])[CH:34]=[CH2:35].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][CH2:18][N:36]2[CH2:33][CH:34]=[CH2:35])=[CH:4][CH:3]=1
Reactant: C=CCN
Reactant: OCCN(C[C@H](O)c1ccc(Cl)cc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCN1CCN(c2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)(phenyl)amino]-1-ethanol (1.68 g, 4.94 mmol) produced in Example 11, ethyl acetate (10 mL) and triethylamine (1.75 g, 3.5 equivalents) were added. The mixture was cooled to 5° C. Methanesulfonyl chloride (1.81 g, 3.2 equivalents) was added dropwise thereto, and then allylamine (1.69 g, 6.0 equivalents) was added dropwise thereto. The mixture was stirred at 5° C. for 1 hour and then at 25° C. for 2 hours. The reaction mixture was transferred in an autoclave, and stirred at 50° C. for 18 hours. The mixture was cooled to room temperature, and then 10 wt % aqueous solution of sodium carbonate (8.38 g) was added to the mixture. After the organic layer and aqueous layer were separated, the organic layer was washed twice with distilled water (10 mL). The obtained organic layer was concentrated to give 1.11 g of a concentrate as yellow oil (chemical purity: 30.2 area %). The concentrate was purified by column chromatography (gel: silica gel, solvent: ethyl acetate/hexane=1/9), and the obtained fractions were concentrated and dried under vacuum, to obtain 307 mg of the title compound as colorless oil (yield: 19%, chemical purity: 98.1 area %). The retention time in the chemical purity analysis method was 56.6 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:35])[C:10](=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.O.[OH:37]OS([O-])=O.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:35])[C:10](=[O:37])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)C(C(=O)c1ccc(OC)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(4-methoxyphenyl)-3-oxo-2-(triphenylphosphoranylidene)propionate. (0.510 g, 1.1 mmol) in THF (10 ml) was added water (10 ml) followed by oxone (0.974 g, 1.6 mmol) in portions and the resulting mixture was stirred at room temperature overnight. The solid was removed by filtration and filtrate concentrated in vacuo and extracted with DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford crude ethyl 3-(4-methoxyphenyl)-2,3-dioxopropanoate as a yellow oil (0.500 g) as a mixture with triphenylphosphine oxide which was used without further purification. LCMS (2) 2.38 min; m/z 237.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([C:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[O:24][N:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:61][CH2:62][CH2:63][S:64]([OH:67])(=[O:66])=[O:65]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([C:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[C:29]([C:33]4[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=4)[CH:30]=[CH:31][CH:32]=3)[O:24][N:23]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:61][CH2:62][CH2:63][S:64]([OH:67])(=[O:66])=[O:65])=[O:18])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc([C@H](Cc2ccc(C(=O)O)cc2)c2cc(-c3cccc(-c4ccc(Cl)cc4)c3)on2)cc1
Reactant: NCCS(=O)(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc([C@H](Cc2ccc(C(=O)NCCS(=O)(=O)O)cc2)c2cc(-c3cccc(-c4ccc(Cl)cc4)c3)on2)cc1
Reaction time: 14 h

Procedure:
To a mixture of (S)-4-{2-(4-tert-Butyl-phenyl)-2-[5-(4′-chloro-biphenyl-3-yl)-isoxazol-3-yl]-ethyl}-benzoic acid (0.25 g, 0.46 mmol), EDCI (133 mg, 0.69 mmol), HOBt (107 mg, 0.69 mmol), N,N-diispropylethylamine (0.25 mL, 1.95 mmol) in DMF (10 mL), and followed by taurine (116 mg, 0.093 mmol) was added. The resulting mixture was stirred for 14 h and monitored by LCMS after completion of the reaction the solvent was removed under reduced pressure. The resulting mixture was purified by column chromatography on C-18, eluting with H2O/Acetonitrile 40% to afford (4-{2-(4-tert-Butyl-phenyl)-2-[5-(4′-chloro-biphenyl-3-yl)-isoxazol-3-yl]-ethyl}-benzoylamino)ethane sulfonic acid (29) as a white solid. (125 mg, 42%): 1H NMR (300 MHz, MeOD): 8.01 (s, 1H), 7.78 (d, J=6.9 Hz, 2H), 7.70-7.47 (m, 6H), 7.35 (d, J=9.0 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 6.86 (s, 1H), 4.47 (t, J=6.9 Hz, 1H), 3.85-3.70 (m, 2H), 3.75 (dd, J=4.9, 13.2 Hz, 1H), 3.25-3.05 (m, 2H), 1.31 (s, 9H); LC-MS m/z=643 [C36H35ClN2O5S]+; HPLC conditions: Waters Atlantis C-18 OBD 4.6×150 mm; mobile phase=ACN/(H2O:0.1 TFA) flow rate=1.0 mL/min; detection=UV @ 254 and 220 nm retention time in min: 21.20; Anal Calcd: (MF:C36H35ClN2O5S+1.5H2O+0.2 CH2Cl2) Calcd: C, 63.27; H, 5.63; N, 4.08. Found: C, 63.24; H, 5.75; N, 3.96. αD[25] MeOH (4.66 mg in 1.0 mL)=+13.487.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].O>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[C:8](=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nn1
Reactant: CC(C)(C)S(N)=O
Solvent: O
Solvent: C1CCOC1
Product: C/C(=N\S(=O)C(C)(C)C)c1ccc(Cl)nn1
Temperature: 60 °C

Procedure:
To a solution of 1-(6-chloro-pyridazin-3-yl)-ethanone (34 mg, 0.22 mmol) in dry THF (1.0 mL) was added 2-methyl-propane-2-sulfinic acid amide (29 mg, 0.24 mmol). Ti(OEt)4 (0.090 mL, 0.43 mmol) was added in one portion and the reaction was heated to 60° C. for 1 h. Water was added to the reaction mixture and the resulting slurry was filtered through a pad of diatomaceous earth. The filtrate was dried over Na2SO4 and was concentrated to provide 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-eth-(E)-ylidene]-amide as a crude residue that was used without purification, m/z 260.5 [M+H]+.