Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH:13]=[C:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[F:33][C:2]([F:1])([F:32])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=2)[CH:13]=[C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cc3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
A solution of tert-butyl 4-(3-(4-(2,2,2-trifluoroethoxy)phenoxy)benzylidene)piperidine-1-carboxylate (50 mg, 0.107 mmol) in dichloromethane (5 mL) was cooled to 0° C. and treated with trifluoroacetic acid (123 mg, 1.07 mmol) dropwise. The reaction mixture was then allowed to warm to room temperature and stirred at that temperature overnight. The reaction was concentrated, and the residue was dissolved in water (5 mL). The aqueous layer basified up to pH ˜8 with 1M sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (3×20 mL), and organic layers were washed with water (2×10 mL), dried over sodium sulfate, and concentrated to give the crude title compound (40 mg, quant.)
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=[NH:16])=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.[Br:29][CH:30]([Br:34])[C:31](O)=[O:32]>CN(C1C=CN=CC=1)C.ClCCl>[Br:29][CH:30]([Br:34])[C:31]([N:16]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]1[CH2:9][C:6]1[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=1)=[O:32]
Reactant: O=C(O)C(Br)Br
Reactant: N=c1ccccn1Cc1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(Br)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
200 mg (0.78 mmol) of the 1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-imine hydrochloride obtained by the method described in another method of Synthetic Example P1, 238 mg (1.95 mmol) of DMAP and 224 mg (1.17 mmol) of EDC-HCl were dissolved in 10 ml of anhydrous dichloromethane, 101 μl (202 mg, 1.17 mmol) of dibromoacetic acid was added thereto, and the resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with dichloromethane, washed once with water and twice with a 1% HCl aqueous solution, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the subject material. Amount obtained 50 mg (yield 15%)
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(C)=O)oc23)CC1

Procedure:
There was dissolved 1.3 g (0.005 mole) of 2-acetyl-7-(3-chloro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine in 10 ml of dioxane, and then the mixture was refluxed with heating for 6 hours. After completion of the reaction, 2N-NaOH solution was added to give the free base, which was extracted from chloroform. The extract was dried with magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resultant residue was crystallized from ethyl acetate.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.O1CCCC1>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][C:12]1[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=1
Reactant: Fc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c(F)c1
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1[nH]nc(CCc2ccc(F)cc2F)cc1O
Yield: 26 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2,4-difluorophenyl)ethynyl]pyridazine (Intermediate 21) except that the reaction was carried out in a mixture of ethanol and tetrahydrofuran (1:1). The crude material was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give a yellow solid. This was recrystallised from ethanol to give a white solid (yield=26%).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=2[CH3:38])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:28])=[O:29]
Reactant: Cc1c(C2=NN(Cc3cccc(Cl)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3cccc(Cl)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(3-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.18 (d, 1H), 7.92 (t, 1H), 7.84 (t, 1H), 7.45 (m, 6H), 6.90 (dt, 1H), 6.61 (dd, 1H), 5.10 (bs, 2H), 4.52 (s, 2H), 2.09 (s, 3H) ppm. MS calculated for C25H19FClN3O4S—H: 510, observed: 510.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1ccc(F)cc1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 4-fluoro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=215 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([NH:16]C(=O)OC(C)(C)C)([CH3:15])[CH3:14])=[N:10][C:9]=2[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])(=[O:33])=[O:32])[C:25]=2[F:42])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:44]>>[NH2:16][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:44])[N:7]=2)=[C:9]([C:24]2[C:25]([F:42])=[C:26]([NH:30][S:31]([C:34]3[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=3[F:40])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[N:10]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(N)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Yield: 45 %

Procedure:
Following a procedure analogous to the procedure described in Example 312 using 1,1-dimethylethyl {1-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate (100 mg, 0.156 mmol) and ammonium hydroxide (2 mL, 51.4 mmol) at 90° C. for 3 hours, the title compound was obtained as a solid (37 mg 45% yield). MS (ESI): 521.2 [M+H]+
Reaction SMILES: [ClH:1].CN.[CH3:4][O:5][C:6](=[O:17])[CH2:7][C:8](=[O:16])[N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[C:18]([BH3-])#[N:19].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[ClH:1].[CH3:4][O:5][C:6](=[O:17])[CH2:7][C:8]([N:9]1[CH2:14][CH2:13][CH:12]([NH:19][CH3:18])[CH2:11][CH2:10]1)=[O:16]
Reactant: [BH3-]C#N
Reactant: COC(=O)CC(=O)N1CCC(=O)CC1
Agent: CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: CNC1CCN(C(=O)CC(=O)OC)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
To a solution of methylamine hydrochloride (67.5 g, 10 eq) in methanol (520 mL) was added a solution of 3-oxo-3-(4-oxopiperidin-1-yl)propionic acid methyl ester (20 g; 0.1 mol) in methanol (170 mL) and stepwise sodium cyanoborohydride (powder; 5.03 g, 0.08 mol). The reaction mixture was stirred 24 hours at room temperature. After addition of a saturated water solution of sodium carbonate, the residue was evaporated and extracted with dichloromethane. The organic phase was dried and evaporated to yield the crude 3-(4-(methylamino)piperidin-1-yl)-3-oxopropionic acid methyl ester (11.6 g) which was converted to the hydrochloride with hydrogen chloride in ethyl acetate/methanol.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)c2ncccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1ccc(C(F)(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of tert-butyl 2-(8-(trifluoromethyl)quinolin-5-yl)acetate (400 mg, 1.28 mmol) in DCM (5 mL) was added TFA (10 mL) dropwise. The reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was removed and the residue was purified (silica gel chromatography) to give the final product 2-(8-(trifluoromethyl)quinolin-5-yl)acetic acid (180 mg, 54%). LC-MS (0.05% TFA): [M+1]+ 256.1. 1H-NMR (DMSO-d6, 400 MHz): δ 12.70 (s, 1H), 9.07 (m, 1H), 8.56 (m, 1H), 8.15 (d, 1H), 7.74 (m, 1H), 7.68 (m, 1H), 4.23 (s, 2H). 13C-NMR (DMSO-d6, 100 MHz): δ 171.9, 151.0, 144.0, 138.3, 133.5, 127.87, 127.83, 127.78, 125.3, 123.1, 122.2, 37.7.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:55]=2[F:61])=[CH:50][CH:49]=1)[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:60][C:58]1[CH:57]=[CH:56][C:55]([F:61])=[C:54]([C:51]2[CH:50]=[CH:49][C:48]([CH2:47][C@@H:38]([NH:37][C:10]([C:8]3[O:7][N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:9]=3)=[O:12])[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42])=[CH:53][CH:52]=2)[CH:59]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: CC(C)Cc1cc(C(=O)O)on1
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: CC(C)Cc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.1 %

Procedure:
3-Isobutylisoxazole-5-carboxylic acid (9 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (0.3 mg). MS m/z [M+H]+ calc'd for C27H30ClFN2O5, 517.18. found 517.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:22])([F:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19]O)=[N:17][CH:18]=2)=[CH:9][CH:8]=1>CN(C)C=O>[Cl:3][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([F:22])([F:21])[F:5])=[CH:8][CH:9]=2)=[CH:18][N:17]=1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccc(CCl)nc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 22.7 %

Procedure:
658 mg (0.40 ml, 5.53 mmol) thionyl chloride is added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 700 mg (2.76 mmol) [5-(4-Trifluoromethyl-phenyl)-pyridin-2-yl]-methanol, stirred for 5 min. at 0° C., and at room temperature (r.t.) for 1 h. The mixture is poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with ethyl acetate. The combined organic phases were washed with water, dried (sodium sulphate), and evaporated. Purification by chromatography on silica (eluent: ethyl acetate/n-heptane 1:4) gave 170 mg (23%) of 2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-pyridine as slightly pink crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:29](=S)=[S:30].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=4)[CH2:15][NH:16][C:29]3=[S:30])=[CH:9][CH:8]=2)=[CH:27][CH:28]=1
Reactant: NCC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(C(F)(F)F)c1
Reactant: S=C=S
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)c1cccc(C2CNC(=S)N2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Temperature: 80 °C
Yield: 68.5 %

Procedure:
To a solution of N1-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine (127 mg, 0.312 mmol) in EtOH (2.0 mL) are added CS2 (188 μL, 3.12 mmol) and iPr2NEt (272 μL, 1.56 mmol). The reaction mixture is heated at 80° C. overnight before removal of the solvent. The residue is purified by silica gel chromatography (0˜40% EtOAc/Hexanes) to provide the title compound (95.9 mg, 69% yield) as a white solid product; HPLC-MS calculated for C22H16ClF3N2OS (M+H+) 449.1, found 449.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]([CH3:12])[C:10]2[CH:13]=[CH:14][C:15](=[O:20])[C:16]([O:18][CH3:19])=[CH:17][C:9]=2[C:8](=[O:21])[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>>[O:21]=[C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[N:11]([CH3:12])[C:10]2[CH:13]=[CH:14][C:15](=[O:20])[C:16]([O:18][CH3:19])=[CH:17][C:9]1=2
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)c(=O)ccc2n1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(=O)cc(C(=O)O)n(C)c2ccc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-6-methoxy-1-methyl-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (2.89 g, described in Example 7) and 1N potassium hydroxide (11 ml) is stirred at room temperature for 16 hr. Hydrochloric acid (10%) is added until the solution is acidic. The precipitate is collected, washed with water and acetone and crystallized from acetic acid to obtain crystals of the title compound, mp > 250° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:4]=2[S:5](=[O:9])(=[O:8])[C:6]=1[CH3:7].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:3]2[CH:2]=[C:6]([CH2:7][N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[S:5](=[O:9])(=[O:8])[C:4]=2[CH:10]=1
Reactant: CC1=C(Cl)c2ccc(Cl)cc2S1(=O)=O
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)CC1=Cc2ccc(Cl)cc2S1(=O)=O

Procedure:
A mixture of 37.3 g (0.15 mol) 3,6-dichloro-2-methylbenzo[b]thiophene-1,1-dioxide, 200 ml methanol and 45 ml diethylamine is heated for 4 hours to reflux. Afterwards it is concentrated by evaporation, taken up in ethyl acetate, washed with water, dried, concentrated and chromatographed on silica gel (eluting agent ethyl acetate/isohexane 1:1). 29.5 g of the title compound (62% of the theoretical yield) having a melting point of 58°-59° C. is isolated.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1>C(O)C.[Pd]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12]
Reactant: CN(C)CCOc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCOc1cccc(N)c1
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a solution of 1-(2-dimethylaminoethoxy)-3-nitrobenzene (4.64 g, 22 mmol) in ethanol (200 ml) was added 10% palladium catalyst on charcoal (1 g). The reaction mixture was hydrogenated at atmospheric pressure for 2 hours, then filtered through kieselguhr and evaporated under reduced pressure to give the product as a yellow oil (4.0 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:18]=[N:19][CH:20]=[C:21](Cl)[CH:22]=1>CN(C)C=O>[Cl:16][C:17]1[N:18]=[N:19][CH:20]=[C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:22]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Clc1cnnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, is added Sodium hydride (100 mg) and the reaction mixture is allowed to stirred at 0 degree for 20 minutes. 3,5-dichloropyridazine (1.6 mmol) is added and the reaction mixture is warmed to room temperature. The reaction mixture is stirred at room temperature until formation of the desired compound. The reaction mixture is quenched with water and extracted with Ethyl acetate. The combined Ethyl acetate layers are dried over Sodium Sulfate and solvent is removed under reduced pressure. The residue can be purified by Prep-HPLC.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:17])[C@@H:5]([NH:9]C(OC(C)(C)C)=O)[CH:6]([CH3:8])[CH3:7].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:48])=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C@@H:32]([NH:39][C:40]([C:42]3[N:43]=[N:44][N:45]([OH:47])[CH:46]=3)=[O:41])[CH2:33][C@@H:34]([OH:38])[C:35]([OH:37])=[O:36])=[CH:27][CH:26]=2)[CH:24]=1.CC(C)=O.CCN(CC)CC.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:9][C@@H:5]([CH:6]([CH3:7])[CH3:8])[C:4]([O:3][CH2:2][O:47][N:45]1[CH:46]=[C:42]([C:40]([NH:39][C@H:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:23]3[CH:24]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=3[F:48])=[CH:26][CH:27]=2)[CH2:33][C@@H:34]([OH:38])[C:35]([OH:37])=[O:36])=[O:41])[N:43]=[N:44]1)=[O:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)OCOn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 10.4 %

Procedure:
(S)-2-t-Butoxycarbonylamino-3-methylbutyric acid chloromethyl ester (44.4 mg, 167 μmol) was added to a solution of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 mol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. 1:1 TFA/DCM (1.0 mL, 6.2 mmol) was added and the mixture was stirred at room temperature for 30 minutes, and then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (10 mg). MS m/z [M+H]+ calc'd for C26H29ClFN5O7, 578.17. found 578.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].C([P+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:32][C:33]1[CH:34]=[C:35]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=2[F:50])[C:36]([CH:39]2[CH2:41][CH2:40]2)=[CH:37][CH:38]=1>C1COCC1>[CH:39]1([C:36]2[C:35]([C:42]3[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=3[F:50])=[CH:34][C:33]([CH2:32][O:1][C:2]3[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=3)=[CH:38][CH:37]=2)[CH2:41][CH2:40]1
Reactant: COc1ccc(F)c(-c2cc(CCl)ccc2C2CC2)c1
Reactant: O=C(O)CCc1cccc(O)c1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(COc3cccc(CCC(=O)O)c3)ccc2C2CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To a solution of 3-(3-hydroxyphenyl)-propionic acid (0.031 g, 0.186 mmol) (commercially available from Alfa, CAS No. 621-54-5) in THF (1 mL) was added tetrabutylphosphonium hydroxide (40 wt % solution in water) (0.27 g, 0.39 mmol). The mixture was then cooled in an ice bath to 0° C. After 10 minutes, 13.5 (0.055 g, 0.191 mmol) was added at 0° C. Upon complete addition, the reaction was allowed to warm to room temperature. After 44 hours, the solvent was removed under vacuum. The residue was diluted with water and acidified with 2M HCl to pH 2. The mixture was extracted with EtOAc. The layers were separated and the solvent was removed under vacuum to yield an oil that was purified by flash chromatography (SiO2 gel 60, eluted with 0 to 65% EtOAc in hexanes) to yield a colorless film 13 (0.023 g, 28% yield.) 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (1H, dd, J=8.0, 1.8 Hz), 7.31 (1H, d, J=2.0 Hz), 7.23 (1H, t, J=8.0 Hz), 7.10 (1H, m), 6.99 (1H, d, J=7.8 Hz), 6.90 (5H, m), 5.04 (2H, s), 3.82 (3H, s), 2.95 (2H, t, J=7.8 Hz), 2.72 (2H, m), 1.85 (1H, m), 0.87 (2H, m), 0.68 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[N:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[N:27]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:36]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Cc2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N(c4cccc(Cc5ccccc5)n4)c4cccc(Cc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzyl-6-bromo-pyridine.
Reaction SMILES: [CH:1]([C:5]1[CH:19]=[CH:18][C:8]([NH:9][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)([CH2:3]C)[CH3:2].C(C1C=CC(N)=CC=1)(CC)C>>[CH:1]([C:5]1[CH:19]=[CH:18][C:8]([NH:9][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CCOC(CNc1ccc(C(C)CC)cc1)OCC
Agent: CCC(C)c1ccc(N)cc1
Product: CCOC(CNc1ccc(C(C)C)cc1)OCC

Procedure:
4-Sec-butyl-N-(2,2-diethoxyethyl)aniline; from 4-sec-butylaniline (56%).
Reaction SMILES: [N+:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:9]1[N:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(=O)[nH]c1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)nc1C(=O)OCC
Temperature: 80 °C
Yield: 73.9 %

Procedure:
Diethyl 1,6-dihydro-5-nitro-6-oxo-2,3-pyridinedicarboxylate (26.23 g, 0,092 mol) is partially dissolved under N2 atmosphere in 250 mL of phosphorous oxychloride and the mixture is heated to 80° C. for 15 hours. The mixture is cooled and concentrated and the resulting oil dissolved in ethyl acetate and washed with water, 10% K2CO3 and brine. The organic layer is dried over MgSO4, filtered and the solvent removed to yield a solid which is recrystallized from absolute ethanol/water to give 20.65 g of the produce as a brown solid in 73.9% yield, having a melting point of 84.5°-86° C.