Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[Cl:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=2)[NH:22][N:21]=1.N=C=N>CN(C=O)C>[Cl:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:16]([C:9]3[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][C:12](=[O:14])[NH:11][C:10]=3[CH3:15])=[O:18])[CH:27]=2)[NH:22][N:21]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)cc2)CC(=O)N1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(F)cc2)CC(=O)N1
Yield: 16.6 %

Procedure:
The product from Example 2, Step 2 (170 mg, 0.68 mmol, 1.0 equiv) was combined with 3-chloro-1H-indazol-5-amine (172 mg, 1.02 mmol, 1.5 equiv) and PS-carbodiimide resin (0.994 mmol/g loading, 1.085 g, 1.02 mmol, 1.5 equiv) in 10 mL of DMF and reacted overnight at room temperature. The reaction mixture was filtered and washed alternately with MeOH and CH2Cl2 (twice), then with diethyl ether. The filtrate was concentrated en vacuo and redissolved in ethyl acetate. The solution was washed with 0.5 N HCl, 0.5 N NaOH, and satd. NaCl. The organic layer was concentrated en vacuo. Purification by flash chromatography (0-50% EtOAc in CH2Cl2) followed by trituration with CH2Cl2 provided 45 mg (16.5%) of the title compound as light pink crystals. MS (ES+) m/e 399 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][N:18](S(C(F)(F)F)(=O)=O)[N:19]=3)[CH2:15]2)[C:10]1=[O:30].[CH3:40][N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.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.C(Cl)Cl.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:44]2[CH:43]=[N:42][N:41]([CH3:40])[CH:45]=2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][NH:18][N:19]=3)[CH2:15]2)[C:10]1=[O:30]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCc2nn(S(=O)(=O)C(F)(F)F)cc2C1
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: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cc(Cl)c(CC3CCN(C4CCc5n[nH]cc5C4)C3=O)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Combine trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-3-ylmethyl]phenyl ester (Preparation 33) (0.5, 0.77 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.484 g, 2.3 mmol), sodium carbonate (2.7 ml of 2.0 M, 5.4 mmol) in DME (12 mL) and degas with a stream of nitrogen. Add (Ph3P)4Pd (0.089 g, 0.07 mmol), and stir at 80° C. for 4 hour under nitrogen atmosphere. Cool to ambient temperature and add ethyl acetate (20 mL) and water (10 mL). Extract the aqueous phase with ethyl acetate (2×20 mL), dry (sodium sulfate) and condense under reduced pressure. Chromatography (silica, 95:5 CH2Cl2/MeOH) yields 0.144 g (42%) as a white solid MS (m/z): 445 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][S:15]([C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:13]=1.[CH2:30](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[C:4]([NH:14][S:15]([C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)(=[O:16])=[O:17])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:30])[CH2:9][CH2:8][C:7]=2[CH:13]=1
Reactant: CCN(CC)CC
Reactant: COc1cc2c(cc1NS(=O)(=O)c1ccc(-c3ccc(Cl)cc3)s1)CCNCC2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc2c(cc1NS(=O)(=O)c1ccc(-c3ccc(Cl)cc3)s1)CCN(C)CC2
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a suspension of the amine hydrochloride salt D9 (0.96 g, 0.00198 moles) in 1,2-dichloroethane (50 ml) at room temperature was added triethylamine (5 ml, excess) followed by 37% aqueous formaldehyde (5 ml, excess). After vigorous stirring for 5 minutes, sodium triacetoxyborohydride (5 g, excess) was added portionwise over 5 minutes and the resultant solution stirred for a further 2 hours. The reaction was partitioned between water and dichloromethane and the organic phase washed with water, brine and dried over anhydrous MgSO4. The solution was evaporated to dryness affording the title compound E1 as a pale yellow solid (0.993 g, 100%). M-H 461. 1H NMR: δ CDCl3 2.67–2.88 (6H, m), 3.60–3.95 (8H, m), 6.58 (1H, s), 7.07 (1H, S), 7.13 (1H, d), 7.33–7.50 (6H, m).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[N:8]=[C:7]([S:11][CH3:12])[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[Na].[CH3:15]I>C(#N)C>[CH3:15][N:8]1[C:7]([S:11][CH3:12])=[N:6][C:5](=[O:13])[N:4]([CH:1]([CH3:3])[CH3:2])[C:9]1=[O:10]
Reactant: CSc1nc(=O)n(C(C)C)c(=O)[nH]1
Reactant: CI
Agent: [Na]
Solvent: CC#N
Product: CSc1nc(=O)n(C(C)C)c(=O)n1C

Procedure:
Eighty parts of sodium 3-isopropyl-6-methylthio-s-triazine-2,4(1H,3H)-dione and 49 parts of methyl iodide are refluxed overnight in 700 parts of acetonitrile. The solvent is evaporated and the residue dissolved in methylene chloride. The methylene chloride solution is washed with water, dried, and evaporated to afford after recrystallization from 1-chlorobutane: hexane 54 parts of 1-methyl-3-isopropyl-6-methylthio-s-triazine-2,4(1H,3H)-dione, m.p. 74°-77°.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:13](OCC)=[O:14]>C1COCC1>[CH:13]([CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]([O:10][CH2:11][CH3:12])=[O:9])=[O:14]
Reactant: CCOC=O
Reactant: CCCCCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C=O)C(=O)OCC
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
First, 60 g of 60% NaH was suspended in 600 ml of THF and 72.1 g of ethyl hexanoate was added dropwise to the suspension solution thus prepared at room temperature. After the suspension solution was raised in temperature to 40° C. and stirred for 15 minutes, 185.2 g of ethyl formate was added dropwise for 6 hours. Furthermore, 30 g of 60% NaH and 92.6 g of ethyl formate were divided into four parts and each part was added separately. Afterward, the solution mixture was stirred at 40° C. for 3 hours.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([O:6]C)=[O:5].[OH-].[Li+].C(O)(C)(C)C.O.Cl>>[CH3:1][CH:2]([CH3:22])[C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)[C@H](C(=O)O)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
(R)-Methyl 3-methyl-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)butanoate (0.6 g, 0.002 mol) was stirred with lithium hydroxide (0.09 g, 0.004 mol) in tert-butyl alcohol (4 mL, 0.04 mol) and water (2 mL, 0.1 mol) at 0° C. for 3 hours. 1 N HCl was added until pH<7 and then reaction mixture was extracted with CH2Cl2 (40 mL×3). The organic layers were dried over MgSO4, filtered, purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) and the product was recovered as a yellow oil. MS m/z 291.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15]I>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:14][C:13]([F:18])([F:17])[F:12])[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: FC(F)(F)CCI
Product: Fc1ccc2c(c1)c(I)nn2CCC(F)(F)F
Yield: 46 %

Procedure:
The title compound was prepared in 46% yield from 5-fluoro-3-iodo-indazole and 1,1,1-trifluoro-3-iodopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.75-2.83 (2H, m), 4.60 (2H, t, J=7.2 Hz), 7.14 (1H, dd, J=2.0, 8.0 Hz), 7.26 (1H, td, J=2.4, 9.2 Hz), 7.34 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([N:20]([CH3:19])[CH3:30])=[N:22][CH:23]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CN(C)c1ccc(C(=O)O)cn1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(N(C)C)nc3)CC2)ccc1Cl
Yield: 26 %

Procedure:
The title compound (11 mg, 26%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 6-dimethylamino nicotinic acid (J. Org. Chem. 1999, 9, 2293). MS: 417.4 (MH+)
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:14][C:12]([CH3:15])([OH:13])[CH2:11][CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(OCc2ccccc2)cc1
Yield: 79 %

Procedure:
Reaction of epoxide 140 (see Example 2JJ) with 4-(benzyloxy)phenol as in Example 2AA at 82° C. for 10 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 2% EtOAc/CH2Cl2, gave 1-[4-(benzyloxy)phenoxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methyl-2-butanol (142) (79%) as an oil; 1H NMR (CDCl3) δ 7.79 (s, 1H), 7.44-7.29 (m, 5H), 6.92 (dt, J=9.2, 3.0 Hz, 2H), 6.83 (dt, J=9.2, 3.0 Hz, 2H), 4.28 (ddd, J=14.0, 9.7, 6.1 Hz, 1H), 4.23 (ddd, J=14.0, 9.7, 6.3 Hz, 1H), 3.81 (d, J=9.1 Hz, 1H), 3.77 (d, J=9.0 Hz, 1H), 2.29 (s, 1H), 2.22 (ddd, J=13.8, 9.6, 6.2 Hz, 1H), 2.02 (ddd, J=13.6, 9.7, 6.5 Hz, 1H), 1.38 (s, 3H); HRESIMS calcd for C21H23ClN3O5 m/z [M+H]+ 434.1293, 432.1321. found 434.1298, 432.1319.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][CH2:13][C:15]3[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: COC(=O)CCc1ccc(OCc2ccc(C=O)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)CCc1ccc(OCc2ccc(CNc3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.3 %

Procedure:
To a solution of 4-phenyl-1,3-thiazol-2-amine (0.25 g, 1.4 mmol), methyl 3-[4-[(4-formylbenzyl)oxy]phenyl]propionate (0.58 g, 2.0 mmol) and acetic acid (0.25 g, 4.2 mmol) in 1,2-dichloroethane (15 mL) was added triacetoxysodium borohydride (0.83 g, 3.9 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (0.31 g, yield 49%) as an oil.
Reaction SMILES: [CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16](C3N=CC(O)=CN=3)[CH:17]=2)C1)[CH2:2]CCCCCCCC.C(C1C=CC(C2SC(C3C=CC(O)=CC=3)=CN=2)=CC=1)CCCCC.[C:51]1([CH3:70])[CH:56]=[CH:55][C:54]([S:57]([O:60]CCCC2C=CC=CC=2)(=[O:59])=[O:58])=[CH:53][CH:52]=1>>[C:51]1([CH3:70])[CH:52]=[CH:53][C:54]([S:57]([O:60][CH2:2][CH2:1][CH2:11][CH2:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:58])=[O:59])=[CH:55][CH:56]=1
Reactant: CCCCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2)cc1
Agent: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccccc2)cc1
Yield: 71.1 %

Procedure:
An objective product was prepared in the same manner as in Example 2 except that 2-(2-decylindan-5-yl)pyrimidine-5-ol was changed to 4-{2-(4-hexylphenyl)thiazole-5-yl}phenol and 3-phenylpropyl p-toluenesulfonate was changed to 4-phenylbutyl p-toluenesulfonate (Yield: 71.1%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:14][C:15]1[C:24](F)=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2>CN(C=O)C>[Cl:14][C:15]1[C:24]([O:11][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2
Reactant: Fc1ccc2cnccc2c1Cl
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c(OC2CCC3(CC2)OCCO3)ccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
887 mg (5.61 mmol) 1,4-Dioxa-spiro[4.5]decan-8-ol were dissolved in 50 ml DMF and 224 mg (5.61 mmol) sodium hydride (60%) were added. After stirring for 30 minutes at room temperature, a solution of 815 mg (4.49 mmol) 5-chloro-6-fluoro-isoquinoline (8) in 10 ml DMF was added and the mixture was heated to 100° C. After 4 h one additional equivalent of 1,4-dioxa-spiro[4.5]decan-8-ol and sodium hydride were added and stirring was continued at 100° C. After 1.5 h complete conversion could be detected. For working up, the solvent was removed under reduced pressure, the residue was taken up in H2O and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The obtained orange oil (2.17 g) was stirred in diisopropyl ether and the insoluble white precipitate was filtered off. After drying of the precipitate, 549 mg of the title compound could be isolated. Rt=1.15 min (Method #1). Detected mass: 320.1/322.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]1[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:19]([Cl:28])=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:17][C:16]1[CH:18]=[C:19]([Cl:28])[C:20]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:21][C:15]=1[F:14])=[O:8])=[O:5]
Reactant: Nc1cc(Cl)c(OCC(F)(F)F)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OCC(F)(F)F)cc1F
Reaction time: 10 h

Procedure:
A solution of 3.0 g of 2,6-difluorobenzoylisocyanate in 10 ml of dry toluene is added at room temperature to a solution of 4 g of 2-fluoro-4-(2,2,2-trifluoroethoxy)-5-chloroaniline in 50 ml of dry toluene, and the batch is stirred for 10 hours. Subsequently, about 75% of the solvent is removed by rotary evaporation. The resultant precipitate is isolated by suction filtration, washed with a small amount of cold toluene and hexane and dried in vacuo, affording the title compound of the formula ##STR15## in the form of a white, crystalline powder; m.p.: 201°-202° C.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[C:16]([N:17]4[N:21]=[CH:20][CH:19]=[N:18]4)=[CH:15][CH:14]=[CH:13][C:12]=3F)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[F:23]C1C=CC=C(N2N=CC=N2)C=1C(O)=O>>[C@H:1]12[N:8]([C:9]([C:11]3[CH:12]=[C:13]([F:23])[CH:14]=[CH:15][C:16]=3[N:17]3[N:21]=[CH:20][CH:19]=[N:18]3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: O=C(c1c(F)cccc1-n1nccn1)N1C[C@H]2CCNC[C@H]21
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Product: O=C(c1cc(F)ccc1-n1nccn1)N1C[C@H]2CCNC[C@H]21

Procedure:
The title compound was prepared in a manner analogous to Intermediate 28, substituting 5-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid for 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. C15H16FN5O, 301.32; m/z found 302.0 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:3][CH:2]=1.[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:14][C:10]1[CH:9]=[C:8]([N:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:15]([Cl:17])=[O:16])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1cccc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1cccc(Cl)c1
Yield: 58 %

Procedure:
Following the procedure of Example 15, Step A, 20.4 g (100 mmole) of 3-chlorodiphenylamine i.e., N-(3-chlorophenyl)aniline] and phosgene in toluene gave 15.4 g (58%) of N-(3-chlorophenyl)-N-phenylcarbamoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][CH:11]=[C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[K+].Cl>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=[C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1
Reactant: CC(C)Cc1nn(C)c(=O)c2c[nH]cc12
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)Cc1nn(C)c(=O)c2cn(Cc3ccccc3)cc12

Procedure:
A solution of 2,6-dihydro-2-methyl-4-(2-methylpropyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (0.65 g) in dry dimethyl formamide (3 ml) was added dropwise to sodium hydride (0.15 g of a 60% dispersion in oil) in dimethyl formamide (10 ml) with stirring. After 20 minutes benzyl bromide (0.45 ml) and a crystal of potassium iodide were added. The mixture was stirred for 11 days and then poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The organic phase was washed with water, dried, and evaporated to give an oil, which was purified by chromatography on silica (ethyl acetate/isohexane 3:1) to afford, after crystallisation from cyclohexane, 2,6-dihydro-2-methyl-4-(2-methylpropyl)-6-phenylmethyl-1H-pyrrolo[3,4-d]pyridazin-1-one (0.3 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].O>CN(C)C=O.C(OCC)(=O)C>[C:41]([O:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2nccc(Oc3ccc(C(O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(C(OC(C)=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(4-Tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]-methanol (51 mg) was dissolved in N,N-dimethylformamide (10 ml). Triethylamine (1 ml) and acetic anhydride (0.5 ml) were then added to the solution, and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by thin-layer chromatography on silica gel using chloroform/acetone for development to give the title compound (35 mg, yield 63%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine (9.2 g, 0.028 mol) in THF (100 ml) was added a solution of K2CO3 (7.91 g, 0.057 mol) in H2O (35 ml). After 10 minutes, ethyl chloroformate (2.86 ml, 0.030 mol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (100 ml) and a solution of borane in THF (1M) was added (114.5 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (100 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (100 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 7.31 g (76%) of the title compound as a colorless oil. ES-MS m/e: 335.3 (M+H+).
Reaction SMILES: CC12CC(CC1)CC2=O.C([C:14]1[CH:19]=[C:18](C)[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])C)N=1)(C)(C)C.[F:25][C:26]([F:39])([F:38])[S:27]([O:30]S(C(F)(F)F)(=O)=O)(=[O:29])=[O:28].O>C(Cl)Cl>[F:25][C:26]([F:39])([F:38])[S:27]([O:30][C:16]12[CH2:17][CH:18]([CH2:19][CH2:14]1)[CH2:24][C:21]2=[CH2:23])(=[O:29])=[O:28]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: CC12CCC(CC1=O)C2
Solvent: ClCCl
Solvent: O
Product: C=C1CC2CCC1(OS(=O)(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of methylbicyclo[2.2.1]heptan-2-one (26 g, 0.209 mol) and 2,6-di-tert-butyl-4-methyl-pyridine (64 g, 0.315 mol) in DCM (300 mL) was added dropwise trifluoromethanesulfonic anhydride (88 g, 0.315 mol) in DCM (50 mL) at 0° C. The reaction mixture was stirred at room temperature for 24 h. The mixture was poured into water, and extracted with DCM (2×100 mL). The combined extracts were washed with a 10% hydrochloric acid solution (3×100 mL), saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL) and dried over sodium sulfate. Concentration under reduced pressure gave the crude product, which was purified by silica gel column chromatography (100% n-pentane) to give the desired product (7.6 g, 0.03 mol, 14%). 1H NMR (400 MHz, CDCl3): δ ppm 5.15 (brs, 1H), 4.89 (brs, 1H), 2.51-2.39 (m, 2H), 2.26-2.17 (m, 2H), 2.12-2.05 (m, 2H), 1.99-1.85 (m, 2H), 1.53-1.50 (m, 1H).