Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[S:17][CH:18]=1)\[C:11]([OH:13])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:61]1([CH2:66][C@H:67]2[NH:70][C:69](=[O:71])[C@H:68]2[NH2:72])[CH:65]=[N:64][CH:63]=[N:62]1>C(Cl)Cl.CCOC(C)=O>[N:61]1([CH2:66][C@@H:67]2[C@H:68]([NH:72][C:11](=[O:13])/[C:10](=[N:9]\[O:8][CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:27])/[C:14]3[N:15]=[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[S:17][CH:18]=3)[C:69](=[O:71])[NH:70]2)[CH:65]=[N:64][CH:63]=[N:62]1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N[C@@H]1Cn1cncn1)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
To a solution of (Z)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (108 mg, 0.269 mmol) in DCM (2.7 mL) at 0° C. was added DIPEA (141 μL, 0.808 mmol) followed by HATU (113 mg, 0.296 mmol). To the resulting solution, after 20 min, was added a solution of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (50 mg, 0.299 mmol) in DCM. After 1 h of stirring it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford the title compound (106 mg, 72%). LCMS: R=0.78 min, m/z=551.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1](OC(=O)C1C=CC(CC)=CC=1)[CH3:2].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[CH:35][CH:34]=4)[N:27]=3)=[CH:24][NH:23][N:22]=2)=[CH:17][CH:16]=1>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:41][CH2:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]2[N:27]=[C:26]([C:25]3[C:21]([C:18]4[CH:19]=[CH:20][C:15]([CH2:1][CH3:2])=[CH:16][CH:17]=4)=[N:22][NH:23][CH:24]=3)[CH:31]=[CH:30][N:29]=2)=[CH:34][CH:35]=1)[CH3:44]
Reactant: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Reactant: CCOC(=O)c1ccc(CC)cc1
Product: CCc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(OCCN(CC)CC)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using 4-ethyl-benzoic acid ethyl ester (see Example 11) and 4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32]>>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCC1)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Yield: 33 %

Procedure:
The starting indole (C) was prepared according to the procedure of Example 1, starting with 5-(N-cyclopentylmethylcarbamoyl)indole (A) and methyl 4-bromomethyl-3-methoxybenzoate (B) to yield methyl 4-[5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]-3-methoxybenzoate (C) (1.14 g, 33%) as a tan foam; partial NMR (80 MHz, CDCl3): 3.45(dd, 2H, CH2N), 3.93(s, 3H, OCH3), 3.95(s, 3H, OCH3), 4.17(s, 2H, ArCH2), 6.17(t, 1H, NHCO), 7.01(d, 1H, H2 -indole), 7.16(d, 1H), 8.04(br s, 1H, H4 -indole), 8.45(br s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:16]=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].CC1C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([C:16]2[O:17][CH:30]=[N:29][CH:28]=2)=[CH:10]1)[CH3:15]
Reactant: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCn1cc(-c2cnco2)c2ccc(C(=O)OC)cc21
Yield: 22.9 %

Procedure:
1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K2CO3 (178 mg, 1.29 mmol), and MeOH (800 μL) were heated at 80° C. overnight. The reaction mixture was then partitioned between H2O and ether. After drying and concentrating the organic phase, the product was purified by silica gel chromatography (EtOAc/CH2Cl2, 10/90) to give methyl 1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (26 mg, 23%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:14]([O:16][CH2:17][CH3:18])=[O:15].F[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=1[N+:33]([O-:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[C:27]([O:26][C:24]([C:23]1[CH:31]=[CH:32][C:20]([O:12][C:11]2[C:10]([Cl:13])=[C:9]3[C:4]([CH:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[C:21]([N+:33]([O-:35])=[O:34])[CH:22]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(O)c2Cl
Reactant: CC(C)(C)OC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A mixture of ethyl 6,8-dichloro-7-hydroxychroman-4-carboxylate (2.50 g, 8.59 mmol), tert-butyl 4-fluoro-3-nitrobenzoate (2.20 g, 9.12 mmol) and potassium carbonate (1.8 g, 13 mmol) in 50 mL of NMP was degassed with argon for 10 minutes and was then heated at 80° C. overnight. After stirring overnight the reaction mixture was cooled to ambient temperature and diluted with 600 mL of water. The pH was adjusted to 1-2 with 1 N HCl and the resulting solids were collected by filtration. The solids were then dissolved in ethyl acetate and the solution was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 20% ethyl acetate in hexanes to give the desired product (2.74 g, 62.3% yield) as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl>[O:24]=[C:2]1[O:1][CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(OC(=O)C=Cc2ccccc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)OC1CCOC(=O)CC1
Reaction time: 24 h
Yield: 70 %

Procedure:
Product from step 2 (10.0 g, 38.5 mmol) was dissolved in 50 mL of dichloromethane and added dropwise into a solution of 3-chloroperoxybenzoic acid (99.3 g, 42.4 mmol) in dichloromethane (50 mL). The mixture was stirred for 24 h and then filtered. The solution obtained was washed twice with NaHCO3 (2 M) and once with brine. The extracted product was then purified by column chromatography (by silica gel using hexane/EtOAc gradient as eluent). The monomer was obtained as a white crystalline powder. Yield: 70%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=2)=[CH:2]1.[CH2:14]([Mg]Br)[CH3:15]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[CH:8][C:9]([CH:10]([OH:11])[CH2:14][CH3:15])=[CH:12][CH:13]=2)=[CH:2]1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(-c2ccoc2)nc1
Product: CCC(O)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 47b (194 mg, 1.12 mmol) and ethylmagnesium bromide (2.24 mL, 2.24 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Product was used directly in the next step without further characterization. White solid. Yield: 73 mg, 32%. MS (ESI): m/z=204.30 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.O>[C:16]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)(=[O:19])[CH:17]=[CH2:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Reaction time: 16 h
Yield: 84.2 %

Procedure:
A solution of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.6 g, 7.7 mmol) in dichloromethane (30 mL) was treated with acryloyl chloride (1.9 mL, 23 mmol, TCl), triethylamine (3.2 mL, 23 mmol, Aldrich), and catalytic 4-dimethylaminopyridine (50 mg 0.41 mmol, Aldrich). The mixture was stirred for 16 h, diluted with excess water, and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to provide 2-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.7 g, 84%). 1H NMR (400 MHz, DMSO-d6) is complicated due to amide rotomers δ ppm 2.86-2.95 (two triplets at 2.88 and 2.93, 2 H), 3.72-3.82 (two triplets at 3.74 and 3.80, 2 H), 3.89 (m, 3 H), 4.63-4.80 (two singlets at 4.65 and 4.77, 2 H), 5.73 (app d, J=10.3 Hz, 1 H), 6.16 (dd, J=16.7, 2.4 Hz, 1 H), 6.89 (dd, J=16.9, 10.3 Hz, 1 H), 7.21 (s, 1 H), 7.78-7.84 (two singlets at 7.79 and 7.83, 1 H); ESIMS (M+H)+=263.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:37][C:38]([F:45])([F:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][S:40]([CH2:39][C:38]([F:45])([F:44])[F:37])(=[O:42])=[O:41])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(CC(F)(F)F)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 96.4 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.0219 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (100 mg, 0.159 mmol, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:4][CH:3]=1.CN(C)[CH:25]=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:25]=[O:26])=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Product: Cc1cc(C#Cc2nc(C)n(-c3ccc(F)cc3)c2C=O)ccn1

Procedure:
3-(4-Fluoro-phenyl)-2-methyl-5-(2-methyl-pyridin-4-ylethynyl)-3H-imidazole-4-carbaldehyde (89) [MS: m/e=320.4 (M+)] was prepared in analogy to the method as above from 4-[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridine (1) and N,N-dimethyl-formamide.
Reaction SMILES: [C:1]([C:4]1[C:8](=[O:9])[NH:7][C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][C:5]=12)(=O)[CH3:2].Cl.C([BH3-])#N.[Na+]>CO.C(OCC)C.[Na+].[Cl-].O>[CH2:1]([C:4]1[C:8](=[O:9])[NH:7][C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][C:5]=12)[CH3:2]
Reactant: CC(=O)c1c2cccccc-2[nH]c1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CCc1c2cccccc-2[nH]c1=O

Procedure:
3-Acetyl-1,2-dihydrocyclohepta[b]pyrrol-2-one (5.6 g) was suspended in methanol (15 ml). A saturated solution of dry HCl in diethyl ether (10 ml) was added to the suspension. Sodium cyanoborohydride (11.3 g) was gradually added to the suspension which was maintained acidic by the simultaneous addition of more of the HCl solution. The reaction mixture was diluted with a saturated solution of NaCl in water and extracted with ethyl acetate. The extract was dried (Na2SO4) and evaporated to dryness. The residue was dissolved in chloroform and poured through a column of silica gel. Elution of the column with chloroform-methanol (98:2) gave 3-ethyl-1,2-dihydrocyclohepta[b]pyrrol-2-one; mp 166°-171° C.; nmr (CDCl3) δ1.2 (t, J=7 Hz, 3H), 2.65 (q, J=7 Hz, 2H), 7.1 (m, 5H), 12.0 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[C:10]([C:11]=1[C:12](=[O:16])[C:13]([NH2:15])=[O:14])=[C:9]([N+:17]([O-])=O)[CH:8]=[CH:7][CH:6]=2)[CH3:2].CCO>C1COCC1>[NH2:17][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([C:12](=[O:16])[C:13]([NH2:15])=[O:14])=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c([N+](=O)[O-])cccc2n1Cc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1c(C(=O)C(N)=O)c2c(N)cccc2n1Cc1ccccc1
Reaction time: 4 h
Yield: 30.2 %

Procedure:
A solution of 6.0 g (17.1 mmol) of 2-Ethyl-4-Nitro-α-oxo-1-(phenylmethyl)-1H-indole-3-acetamide in 140 ml of 1:1 THF:EtOH containing 1,0 g of 5% Pt/BaSO4 was hydrogenated at room temperature and 60 psi (4.22 Kg/cm2) for four hours. The catalyst was filtered and the filtrate evaporated in vacuo. The residue was chromatographed over silica gel eluting with Hexane/50 to 100% EtOAC to give 1.66 g (30%) of 4-Amino-2-Ethyl-α-oxo-1-(phenylmethyl)-1H-indole-3-Acetamide melting at 140°-144° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.[N:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24]>CN(C1C=CN=CC=1)C.C(O)C.O>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:19]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:20])[CH:3]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: Oc1cccnc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(Oc1cccnc1)N1CCCCC1
Temperature: 60 °C
Yield: 61.2 %

Procedure:
3-Hydroxypyridine (400 mg), TEA (1.17 ml) and DMAP (catalytic amount) were added in that order to a THF (10 ml) solution containing piperidine-1-carbonyl chloride (745 mg), and then heated at 60° C. for 5 hours. The reaction solution was cooled, then water (3 ml) was added thereto, and extracted with EtOAc. The extract was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain a colorless oil. The resulting oil was dissolved in ethanol, and an ethanol solution of oxalic acid (378 mg) added thereto to obtain a colorless powder. This was recrystallized from hexane/ethanol to obtain (pyridin-3-yl)piperidine-1-carboxylate oxalate (761 mg).
Reaction SMILES: N1C=CC(C2C=[N:10][NH:9][C:8]=2C2C=CC(CCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([C:49](=O)[CH2:50][C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([C:49]2[C:50]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[CH:8][NH:9][N:10]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1
Reactant: c1ccc2nc(CCc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Product: Clc1cc(-c2n[nH]cc2-c2ccncc2)ccc1OCc1ccc2ccccc2n1

Procedure:
Following the procedure for the preparation of 2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting 1-[3-Chloro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CD3OD) δ 8.37 (m, 4 H), 8.02 (d, J=8.7 Hz, 2 H), 7.93 (d, J=8.3 Hz, 2H), 7.78 (m, 2 H), 7.61 (t, J=7.1 Hz, 1 H), 7.31 (m, 2H), 7.21 (m, 1 H), 5.44 (s, 2H); MS: (M+H m/z=413.0).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.S(Cl)(Cl)=O.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][C:30](O)=[C:29]([NH2:34])[CH:28]=1.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:32]=[CH:31][C:30]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:34][C:29]=2[CH:28]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc2cc(-c3nc4cc(C(F)(F)F)ccc4o3)ccc2n1C1CCOCC1
Yield: 11.7 %

Procedure:
To 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (182 mg, 0.612 mmol) was added thionyl chloride (2 mL), and this was stirred at reflux for 3 hours. After the reaction was complete, concentration at reduced pressure gave a residue that was added to 4-trifluoromethyl-2-aminophenol (132 mg, 0.612 mmol), triethylamine (309 mg, 3.06 mmol) and tetrahydrofuran (5 mL), and this was stirred at room temperature for 14 hours. After the reaction was complete, this was concentrated, and to a dioxane (5 mL) solution of the residue obtained was added methanesulfonic acid (353 mg, 1.46 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water and saturated aqueous sodium hydrogen carbonate solution were added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (28.8 mg, 12% yield) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: Nc1ccccc1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(Nc2ccccc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with aniline following the procedure described for 4-[(butyl)-(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH:2]=1.[AlH](CC(C)C)CC(C)C>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH:13]([OH:15])[CH3:14])[CH:2]=1
Reactant: CC(=O)C=Cc1cnc2ccccc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(O)C=Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 22-1 (1.2 g, 6.1 mmol) in anhydrous THF (50 mL) was cooled to −78°, then treated dropwise with i-Bu2AlH (12.75 mL, 12.2 mmol). The resulting solution was stirred at −78° for 20 min, then quenched with ethyl acetate (20 mL), warmed to room temperature, treated with 1 M potassium sodium tartrate (25 mL) and stirred for 4 h. The mixture was extracted with ethyl acetate (2×150 mL) dried, filtered and evaporated to afford 22-2 as a yellow oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:35])([CH3:17])[C:15](=[O:36])[CH2:14][CH2:13]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:35][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:36])[C@H:11]2[C@H:20]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:25][C:26]=1[CH2:27][C@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(OC5CCCCO5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
7.4 g of 7α- (5-acetoxypentyl)-11β-fluoro-3-(tetrahydro-pyran-2-yloxy)oestra-1,3,5(10)-trien-17-one are stirred with 1.8 g of potassium carbonate at room temperature in 370 ml of methanol and 37 ml of water. After 3 h, the reaction mixture is added to ice-water. The precipitated product is filtered off with suction, dissolved in ethyl acetate, and the solution is washed with water until neutral, dried and concentrated in vacuo. 7.0 g of 11β-fluoro-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one are obtained as a foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][NH:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:27]([O:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:26]=1)=[O:24].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:21]([CH2:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])=[C:27]([O:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:26]=2)=[O:24])[CH3:20])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: CNCC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
3-(1-t-butyloxycarbonylpiperidin-4-yl)propionic acid (257 mg), di-t-butyl [[4-[(N-methylamino)acetyl]-o-phenylene]dioxy]diacetate hydrochloride (446 mg), N-methylmorpholine (101 mg), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 442 mg), and a catalytic amount of 4-dimethylaminopyridine were dissolved in 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 hours. After ethyl acetate (100 ml) was added to the reaction mixture, the resulting mixture was washed with water. The solvents were removed under reduced pressure. The residual mixture was purified by column chromatography on silica gel to give 285 mg of the title compound from the fraction eluted with n-hexan:ethyl acetate=3:1.