Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([F:24])[CH:15]=3)=[CH:12][C:11]([C:25]([OH:27])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:52]3[CH2:56][C:55](=[O:57])[NH:54][CH2:53]3)=O)=N2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[C:16]([F:24])[CH:15]=3)=[CH:12][C:11]([C:25]([N:52]3[CH2:56][C:55](=[O:57])[NH:54][CH2:53]3)=[O:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2cc(F)cc(C(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(C(F)(F)F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 96A in analogy to the synthesis of the compound of Example 23. 17 mg (27% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][O:29][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=3)=[CH:26][CH:27]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a solution of [4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]phenyl]methanol (409 mg, 0.98 mmol), methyl 3-(4-hydroxyphenyl)propanoate (195 mg, 1.18 mmol) and tributylphosphine (297 mg, 1.47 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (371 mg, 1.47 mmol), and the mixture was stirred at room temperature for 16 hr. The insoluble materials were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (273 mg, yield 50%) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[NH:10][CH:9]=[C:8]1[C:19]#[N:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[O-2].[O-2].[Mn+4]>[CH:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:19]#[N:20])=[C:7]2[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:18]
Reactant: CCCCCCC1C(C#N)=CNc2ccc(CO)cc21
Agent: [Mn+4]
Agent: [O-2]
Product: CCCCCCc1c(C#N)cnc2ccc(C=O)cc12

Procedure:
Similar procedure as described in example 46f was used, starting from 4-hexyl-6-hydroxymethyl-1,4-dihydro-quinoline-3-carbonitrile (example 52b) and manganese dioxide to give 6-formyl-4-hexyl-quinoline-3-carbonitrile as a white solid. LC-MS m/e 267 (MH+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH3:15])(=O)=O)=CC=1.[F:21][C:22]([F:34])([F:33])[CH2:23][CH2:24][S:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:17][C:16]([F:19])([F:18])[CH:13]([CH2:14][CH3:15])[CH2:12][CH2:11][CH:28]([S:25]([CH2:24][CH2:23][C:22]([F:21])([F:33])[F:34])(=[O:26])=[O:27])[C:29]([O:31][CH3:32])=[O:30]
Reactant: CCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 96 h
Yield: 37.7 %

Procedure:
To a solution of 2.7 g of 3-(trifluoromethyl)pentyl p-toluenesulfonate and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide was added 1.2 g of potassium carbonate at room temperature. The reaction mixture was heated to 60° C., stirred at the same temperature for four days, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.20 g of methyl 5-trifluoromethyl-2-(3,3,3-trifluoropropylsulfonyl)heptanoate (hereinafter referred to as the present compound (4)).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:26]3[C:25]([Cl:28])=[CH:24][N:23]=[CH:22][C:21]=3[Cl:20])[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3c(Cl)cncc3Cl)CC2)cc1
Yield: 10.4 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 3,4,5-trichloropyridine (134 mg, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (16 mg), a white solid, in 10% yield.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl>C(=O)([O-])O.[Na+]>[CH:26]([Si:19]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[O:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:2]([C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[O:1])=[CH:16][CH:15]=1)([CH3:28])[CH3:27]
Reactant: CC(C)[Si](OCc1ccc(C(O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc(C(=O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Yield: 58.5 %

Procedure:
A solution of 3-[hydroxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile (2.06 g, 5.21 mmol), Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(H)-one) (2.7 g, 6.25 mmol), and dichloromethane (50 mL) is stirred at room temperature 24 hr. The mixture is diluted with aqueous saturated sodium hydrogen carbonate and extracted with dichloromethane (2×50 ml). The combined extracts are dried over magnesium sulfate, filtered, and concentrated. The residue is purified via silica chromatography eluting with hexanes to 8:2 hexanes:ethyl acetate to give the title compound (1.2 g, 60%) as a white solid. 1H NMR (CDCl3) δ 8.06-8.10 (m, 2H), 7.89-7.91 (m, 1H), 7.79-7.81 (m, 2H), 7.66 (t, 1H), 7.54-7.56 (m, 2H), 4.97 (s, 2H), 1.17-1.31 (m, 21H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][C:24]([NH:26][OH:27])=[NH:25])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:28](O)(=O)[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][C:24]3[N:25]=[C:28]([CH3:29])[O:27][N:26]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CC(=N)NO)CCC2c2ccc(F)cc2)cc1
Reactant: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N2C(Cc3noc(C)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale yellow oil, MS: m/e=416.3 (M+H+) was prepared in accordance with the general method of example 13 from (2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine and acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[N:22]=[C:21](SC)[NH:20][C:19](=[O:25])[CH:18]=1>N1C=CC=CC=1>[CH3:16][C:17]1[NH:22][C:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[N:20][C:19](=[O:25])[CH:18]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CSc1nc(C)cc(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1cc(=O)nc(Nc2ccc(C3=NNC(=O)CC3C)cc2)[nH]1
Yield: 34.9 %

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (2.6 g) and 6-methyl-2-methylthiopyrimidin-4-one (3 g) in dry pyridine (40 ml) was heated under reflux for 72 hours. The volume was reduced by evaporation and the crude product (3.16 g) was collected and washed with ethanol. Recrystallisation twice from dimethylformamide gave the title compound (1.39 g), m.p. 314°-318° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of 4-bromo-3-(trifluoromethyl)aniline (5.0 g, 20.8 mmol) and pyridine (16.9 mL, 208 mmol) in THF (60 mL) was treated slowly with methanesulfonyl chloride (2.10 mL, 27.1 mmol). The resulting yellow solution was stirred at room temperature for 2 hours, concentrated to dryness and then evaporated twice from toluene to afford syrup. The crude material was purified by silica gel chromatography eluting with 0% to 10% acetone in CH2Cl2 to afford Intermediate 52A (6.6 g, 100% yield) as a white solid. HPLC Ret timed: 3.32 min. MS: m/z=318, 320 [M+H]+; 1H NMR (500 MHz, CD3OD) δ ppm 7.80-7.75 (1 H, d), 7.63 (1 H, brs), 7.43-7.37 (1 H, d), 3.03 (3 H, s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:34])([F:33])[C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([CH2:31][NH2:32])=[CH:26][CH:25]=2.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:34][C:21]([F:20])([F:33])[C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([CH2:31][NH:32][C:7]([C:6]1[CH:5]=[N:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=1)=[O:9])=[CH:26][CH:25]=2
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
6-(Trifluoromethyl)nicotinic acid (Sigma-Aldrich; 178 mg, 0.934 mmol) was stirred in DCM (10 mL). Oxalyl chloride (0.131 mL, 1.494 mmol) then DMF (2.89 μl, 0.037 mmol) were added and the reaction mixture was left to stir at room temperature for 2 hrs under Argon. The reaction mixture was evaporated to dryness and the resulting residue was dissolved in DCM (10 mL). A solution of [(2-trifluoromethyl-1H-indol-5-yl)methyl]amine (Intermediate 4, 160 mg, 0.747 mmol) in DCM (10 mL) was added followed by triethylamine (0.208 mL, 1.494 mmol). The reaction mixture was left to stir at room temperature for 1 h. The reaction mixture was evaporated to dryness and the resulting residues where purified by MDAP to give the title compound (176 mg);
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.[C:16]([C:20]1[CH:36]=[CH:35][C:23]([CH2:24][NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.[Cl-].[Na+].O.O>[C:16]([C:20]1[CH:36]=[CH:35][C:23]([CH2:24][N:25]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[C:5](=[O:7])[C:4]2[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:2]([Cl:1])[C:3]=2[F:15])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
To a solution of 50 mg of 3-chloro-2-fluoro-5-trifluoromethyl-benzoic acid (0.206 mmol) and 68 mg (0.225 mmol) of (4-tert-butylbenzyl)-[2-(4-chlorophenyl)-ethyl]-amine in 3 ml of DMF were added 117 mg of HBTU (0.31 mmol) and 0.063 ml (0.62 mmol) of 4-methylmorpholine. After stirring the reaction mixture over night at RT it was poured on a mixture of 15 ml of brine and 15 ml of water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane/EtOAc 95:5) to give 76 mg (70%) of a light yellow amorphous material. MS (ISP) 526.0 (M+H)+. In analogy to example 1:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:13](O)[CH3:14]>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH3:14])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(F)cc1F
Yield: 100 %

Procedure:
A solution of 2,4-difluoro-benzoic acid (19.3 g) in dry ethanol (200 ml) was treated with gaseous hydrochloric acid for 0.25 hours, then heated to reflux for 4 hours. Evaporation gave a white solid (22.7 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1.[Cl:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1ccc(COc2nc(N)nc(-c3ccc(Cl)o3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-(5-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile and N-chlorosuccinimide in DMF. ES-MS m/e (%): 344 (M{37Cl}+H+, 35), 342 (M{35Cl}+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24]2)[CH:3]=1.[NH3:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:32])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24]2)[CH:3]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCN(S(C)(=O)=O)C3)c12
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCN(S(C)(=O)=O)C3)c12

Procedure:
Prepared analogously to example 1.4 from 4-[4-fluoro-2-((R)-1-methanesulfonyl-pyrrolidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and Ammonia in Methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>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:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[N:32][NH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:15][C:16]=1[F:21]
Reactant: Fc1cc(C2(c3ccc(Br)cc3)CCNCC2)ccc1Cl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Fc1cc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)ccc1Cl

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine)palladium (0) as the catalyst, to obtain the title compound. LCMS (PS-A3) Rt 7.11 min [M+H]+ 356. 1H NMR (Me-d3-OD) δ 2.62-2.80 (4H, m), 3.18-3.30 (partially overlaps with solvent, 4H, m), 7.23 (1H, t), 7.34-7.39 (1H, m), 7.22 (1H, dd), 7.30 (1H, dd), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2].S(=O)(=O)(O)O.[CH3:35]O>>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:18]3[C:22]([CH2:23][O:24][CH3:35])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: CO
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Agent: O=S(=O)(O)O
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1

Procedure:
A solution of 5.00 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole and 1.0 mL of conc. sulfuric acid in 200 mL of methanol was refluxed for 20 hours. After cooling, the solvent was removed in vacuo, and the residue was poured into saturated sodium bicarbonate solution. The resulting mixture was extracted with methylene chloride, and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) furnished 5.35 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole; NMR (200 MHz, CDCl3):δ8.26 (t, 1H); 8.03 (d of t, 1H); 7.76 (d of t, 1H); 7.51 (t, 1H); 7.33 (A2M2, 4H); 5.20 (s, 2H); 4.31 (s, 2H); 3.94 (s, 3H); 3.27 (s, 3H); 2.59 (t, 2H); 1.68 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: [NH+]1C=CC=CC=1.[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:29])[CH2:15][CH2:16][C@@H:17]2[CH:27]=[O:28])[CH2:9]1>ClCCl.C(OCC)C>[O:7]=[C:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:29])[CH2:15][CH2:16][C@@H:17]2[CH:27]=[O:28])[CH2:9]1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Yield: 60.4 %

Procedure:
To a suspension of 0.88 g of pyridinium dicromate in 2.20 ml of dichloromethane a solution of 0.50 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 2.5 ml of dichloromethane was added at room temperature. After 20 hrs the mixture was diluted with diethyl ether and filtered through celite; the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 6/4 eluant; the fractions containing the title compound were collected and evaporated to give 0.30 g of the title compound (II-f) as a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8](=[O:27])[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([O:24]CC)=[O:23])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[OH-].[Li+].Cl>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[O:27])[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([OH:24])=[O:23])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Mix 3-[(4-nitrophenacyl)amino]-2-carbethoxy-4,6-dichloroindole (161 mg, 0.381 mmol), tetrahydrofuan (20 ml) and water (20 mL). Add lithium hydroxide monohydrate (64 mg, 1.52 mmol) and stir overnight. Heat at reflux for 4 hours, cool to room temperature and pour onto 1N hydrochloric acid (100 mL). Collect the resulting solid by filtration and air dry to give the title compound (148 mg, 99%); mp 270°-72° C.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[N:50]=[CH:49][C:48]([C:54]([O:56][CH3:57])=[O:55])=[CH:47]2.[C:58](=[O:65])([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[NH2:59].C(=O)([O-])[O-].[Cs+].[Cs+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:61]([O:60][C:58]([NH:59][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[N:50]=[CH:49][C:48]([C:54]([O:56][CH3:57])=[O:55])=[CH:47]2)=[O:65])([CH3:64])([CH3:63])[CH3:62]
Reactant: COC(=O)c1cnc2ccc(Br)cc2c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc2ccc(NC(=O)OC(C)(C)C)cc2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
To a round bottom flask under dry nitrogen were added palladium(II) acetate (100 mg, 0.6 mmol), Xantphos (600 mg, 1 mmol), methyl 6-bromoquinoline-3-carboxylate (1.5 g, 5.64 mmol), t-butyl carbamate (0.99 g, 8.4 mmol) and cesium carbonate (3.67 g, 11.3 mmol). Dry 1,4-dioxane (30 mL) was added by syringe and the mixture was stirred at 100° C. under dry nitrogen for 4 h. The reaction mixture was cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (hexanes to 1:1 hexanes/ethyl acetate gradient) to afford methyl 6-(tert-butoxycarbonylamino)quinoline-3-carboxylate (Int-2, 1.29 g, 76%). LC-MS: (FA) ES+ 303; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.86 (s, 1H), 9.14 (d, J=2.1 Hz, 1H), 8.82 (d, J=1.9 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.00 (d, J=9.1 Hz, 1H), 7.87 (dd, J=9.1, 2.4 Hz, 1H), 3.93 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:15](=[O:17])[NH:14][N:13]=[CH:12][C:11]=2[N:10](COCC2C=CC=CC=2)[C:9]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH:38]2[CH2:40][CH2:39]2)[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>[Pd].C(O)C>[CH2:1]([C:8]1[C:16]2[C:15](=[O:17])[NH:14][N:13]=[CH:12][C:11]=2[NH:10][C:9]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH:38]2[CH2:40][CH2:39]2)[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc2c1c(Cc1ccccc1)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To 20 ml of ethanol solution containing 198 mg (0.364 mmol) of 3-benzyl-1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 19-(b), then, 28 mg of 5% palladium-active carbon and 0.36 ml of 1N hydrochloric acid were added thereto, and the mixture was stirred under 1 atm hydrogen atmosphere at 50° C. for 3.8 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, 8.6 ml of methanol and 4.3 ml of 28% aqueous ammonia were added to the obtained solid and the mixture was stirred at room temperature for 1 hour. Then, the solution was concentrated under reduced pressure, water was added to the obtained concentrate, and the precipitated solid was collected by filtration. The obtained solid was washed successively with water and then with diisopropyl ether and dried under reduced pressure to obtain 128 mg of the title compound as a white solid. (Yield: 84%)