Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].Br[CH2:9][C:10]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=O>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(N)=S
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Solvent: C1CCOC1
Product: CC(C)Nc1nc(-c2cccc(C(=O)O)c2)cs1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Isopropyl-thiourea (2.47 mmol) and 3-(2-Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The volume was reduced to 5 mL and the mixture was then cooled to −20° C. and filtered. The solid was washed with a small amount of diethylether and dried. m/z=263.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([O:14]C)=[O:13].O[Li].O>CO.C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C1OCCc2c(Br)cccc21
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1OCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylate (12.1 g, 42.4 mmol) in 200 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (5.34 g, 0.127 mol), and the mixture was stirred at ambient temperature for 30 min. The solvents were removed under vacuum, and the residue was added 100 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=4˜5 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid.
Reaction SMILES: [F:1][C:2]([C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:21])[C:12]=3[N:22]=[C:9]2[CH2:8][O:7][CH2:6]1)([CH3:4])[CH3:3]>FC(F)(F)C(O)=O.[Pt]=O>[F:1][C:2]([C@@H:5]1[N:10]2[C:11]3[C:20]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[N:14]=[C:13]([NH2:21])[C:12]=3[N:22]=[C:9]2[CH2:8][O:7][CH2:6]1)([CH3:3])[CH3:4]
Reactant: CC(C)(F)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(F)[C@H]1COCc2nc3c(N)nc4c(c3n21)CCCC4
Reaction time: 20 h
Yield: 52.2 %

Procedure:
(11R)-11-(1-Fluoro-1-methylethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (300 mg, 1.00 mmol) was dissolved in 10 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (227 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 20 hours, an additional 200 mg of catalyst was added and the mixture was shaken under H2 at 50 PSI (3.4×105 Pa) for an additional 24 h. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with a mixture of 2-propanol and CH2Cl2 and the combined filtrates were concentrated under reduced pressure to give a syrup. The syrup was partitioned between H2O and CHCl3. The aqueous portion was made basic by addition of 10% NaOH solution until the pH was higher than 12. The layers were separated and the organic portion was washed successively with 10% NaOH (2×), H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a tan foam. Chromatography (SiO2, 25-33% CMA/CHCl3) followed by crystallization from ethyl acetate gave (11R)-11-(1-fluoro-1-methylethyl)-2,3,4,8,10,11-hexahydro-1H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (159 mg) as off-white crystals, mp 195.5-197.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:6][CH:5]=1
Reactant: O=C1OCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCN2CCOC2=O)cc1

Procedure:
Pd/C 10% (500 mg) is added to a solution of the compound obtained in Step B (16.6 mmoles) in MeOH (100 ml). The reaction mixture is stirred at 50° C. under 4.5 bars of hydrogen for 4 hours. The catalyst is filtered off and then washed with MeOH. The filtrate is evaporated to dryness and the product obtained is triturated in 10 ml of MeOH. The solid obtained is filtered off and dried in vacuo at 40° C. overnight to yield the title product in the form of a white solid, which is used directly in the next Step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([F:15])[F:14])[CH:10]=2)[C:5]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[CH:19][C:18]=2[Cl:24])=[N:4][N:3]=1.[OH2:25]>N1CCOCC1>[Cl:23][C:22]1[CH:21]=[N:20][CH:19]=[C:18]([Cl:24])[C:17]=1[CH2:16][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[CH:8][CH:7]=2)[C:2]([N:20]2[CH2:21][CH2:22][O:25][CH2:18][CH2:19]2)=[N:3][N:4]=1
Reactant: O
Reactant: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Solvent: C1COCCN1
Product: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCOCC3)c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A suspension under N2 of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-difluoromethoxy-phthalazine (5.5 g, 14.1 mmoles), prepared as described in example 99, in morpholine (11 ml) was heated at 100° C. for 1 hour, then cooled and poured into water (150 ml). A solid formed and was stirred for 15 minutes, then filtered, washed with water, dried over P2O5 at 50° C. under high vacuum. There were obtained 6 g of the title compound (yield: 96%). m.p.: 128.6-130.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[N:4][C:3]=1O.P(Br)(Br)([Br:15])=O.O.C(=O)([O-])O.[Na+]>ClCCl>[Br:15][C:3]1[N:4]=[N:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[Br:1]
Reactant: O=P(Br)(Br)Br
Reactant: Oc1nnc(C(F)(F)F)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(Br)c(Br)nn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 45.5 %

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-pyridazin-3-ol (D3) (4.0 g, 16.4 mmol) and phosphorus oxybromide (28.2 g, 98.4 mmol) was stirred at 60° C. for 4 h. After this period, the reaction mixture was poured into a mixture of ice and water, diluted with dichloromethane and neutralized with a saturated solution of sodium hydrogen carbonate. The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D5 (2.28 g, 46%) as a solid. C5HBr2F3N2 requires 305; Found 306 (MH+).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][S:10][CH2:11][C:12]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH3:13]>C(Cl)(Cl)(Cl)Cl>[CH3:9][S:10][CH:11]([Cl:1])[C:12]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH3:13]
Reactant: COc1ccc(Br)cc1C(C)(C)CSC
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)cc1C(C)(C)C(Cl)SC
Temperature: 40 °C
Yield: 98.9 %

Procedure:
N-Chlorosuccinimide (37.4 g, 0.28 mole) was added portionwise to 2-(2-methoxy-5-bromophenyl)-2-methyl-1-propyl methyl sulphide (79.3 g, 0.275 mole) in carbon tetrachloride (250 ml) at room temperature. An exothermic reaction ensued, the temperature being allowed to rise to 40° C. before control with an external cooling bath was applied. After addition, the reaction mixture was heated at about 40° C. for 4 hours, then cooled, filtered and run down yielding 88 g crude title product (99%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].CO[C:15](OC)([CH3:17])[CH3:16]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][C:15]1([CH3:17])[O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=2[CH2:9][O:10]1
Reactant: OCc1ccc(CO)c(CO)c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)OCc2ccc(CO)cc2CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14357.5 %

Procedure:
5 g of (3,4-bis-hydroxymethylphenyl)methanol (29.7 mmol), 25 ml of 2,2-dimethoxypropane (21.2 g; 0.2 mmol) and 0.29 g of p-toluenesulfonic acid (1.5 mmol) are introduced into a flask. After stirring for 1 hour 10 minutes at room temperature, the solvent is evaporated under vacuum at 30° C. and the crude product is chromatographed on silica gel (dichloromethane/methanol/aqueous ammonia=98/2/0.1). 5.98 g of (7,7-dimethyl-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl)methanol are obtained in the form of a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:41]([Si:44]([CH:62]([CH3:64])[CH3:63])([CH:59]([CH3:61])[CH3:60])[O:45][C:46]1[CH:55]=[C:54]2[C:49]([CH:50]=[CH:51][CH:52]=[C:53]2[C:56](O)=[O:57])=[CH:48][CH:47]=1)([CH3:43])[CH3:42].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:56]([C:53]1[C:54]2[C:49](=[CH:48][CH:47]=[C:46]([O:45][Si:44]([CH:59]([CH3:61])[CH3:60])([CH:62]([CH3:64])[CH3:63])[CH:41]([CH3:42])[CH3:43])[CH:55]=2)[CH:50]=[CH:51][CH:52]=1)=[O:57]
Reactant: COC(=O)CN
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cccc2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc12
Reaction time: 3 h

Procedure:
To glycine methyl ester hydrochloride (140 mg, 1.12 mmol) in dry DMF (1 mL) under argon were added PYBOP (233 g, 0.45 mmol), 7-(triisopropylsilyloxy)-1-naphthoic acid, as described in Example 30, Step D, (155 mg, 0.45 mmol), and N,N-diisopropylethylamine (0.31 mL, 1.78 mmol). The reaction mixture was stiffed for 3 hrs, then partitioned between CH2Cl2 (50 mL) and H2O (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CH2Cl2-5% EtOAc to yield the desired product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].[Na].Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:34]=[C:35]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[C:22]([NH:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH3:26])=[O:23]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][O:4][CH2:18][C:19]1[CH:20]=[C:21]([CH:34]=[C:35]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[C:22]([NH:24][C@@H:25]([C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[CH3:26])=[O:23]
Reactant: CCCCC(N)(CO)Cc1ccccc1
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCC(N)(COCc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-2-benzylhexane-1-ol intermediate II (0.100 mg, 0.48 mmol) in 1.1 mL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.48 mL, 0.48 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (0.040 g, 0.090 mmol) in 1.8 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h, and quenched by adding water. The aqueous layer was washed with EtOAc (3×), and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (20 g silica, 0->8% 0.1% NH4OH in i-PrOH/hexanes) afforded 3-{[(2-amino-2-benzylhexyl)oxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methyl sulfonyl)amino]benzamide. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.37-7.34 (m, 2H), 7.29-7.20 (m, 3H), 7.17-7.15 (m, 2H), 7.04 (m, 2H), 6.56 (br s, 1H), 5.30 (m, 1H), 4.56 (s, 2H), 3.34 (s, 3H), 3.20 (m, 2H), 1.59 (d, J=6.9 Hz, 3H), 1.60-1.39 (br m, 6H), 0.90 (t, J=7.0 Hz, 3H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>C(O)C>[CH3:15][O:16][CH2:17][CH2:18][NH:19][C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([NH:19][CH2:18][CH2:17][O:16][CH3:15])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COCCN
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Solvent: CCO
Product: COCCNC(=O)c1cnc(C(=O)NCCOC)cn1
Temperature: 20 °C

Procedure:
A solution of 500 mg of 2,5-dimethoxycarbonylpyrazine and 0.430 cm3 of 2-methoxyethylamine in 3 cm3 of ethanol is heated at a temperature in the region of the reflux temperature for 5 hours. The reaction mixture is cooled to a temperature of 20° C. and the white solid formed is then filtered off and washed with twice 5 cm3 of ethanol. 150 mg of N,N′-bis-(2-methoxyethyl)pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 165° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 3.29 (s, 6H: 2×OCH3); 3.51 (mt, 8H: 2×NCH2CH2O); 8.99 (mt, 2H: 2×CONH); 9.22 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>C(N(CC)CC)C>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1ccccc1C(Br)c1ccccc1
Reactant: Nc1cccc2cccnc12
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(Nc1cccc2cccnc12)c1ccccc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 4.75 g (33 mmol) of 8-aminoquinoline, 3.03 g (30 mmol) of triethylamine and 7.85 g (30 mmol) of 6 was stirred for 2 hr at 120° C. One more portion of 3.03 g of triethylamine as well as 7.85 g of 6 was added. The resulting mixture was stirred for additional 2 hr at 120° C. Next, one more portion of triethylamine and 6 were added, and the reaction mixture was stirred for 2 hr at 120° C. Finally, the product was isolated using flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol.). Yield 2.78 g (26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].O=[C:12]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13](OCC)=[O:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:13](=[O:14])[C:12]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[N:10]2
Reactant: CCOC(=O)C(=O)c1cccs1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1-c1cccs1
Temperature: 70 °C
Reaction time: 11 h

Procedure:
A mixture of 4,5-dichlorobenzene-1,2-diamine (1.0 g, 5.65 mmol), ethyl 2-oxo-2-(thiophen-2-yl)acetate (1.056 g, 5.73 mmol) and ethanol (8 ml) was stirred at 70° C. for 11 h, cooled to room temperature, filtered and washed with cold ethanol. The collected pale yellow solid was dried further (1.07 g) and used directly in next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](OC)=[O:11].ClCC1C=CC=C(C)N=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[O:11]
Reactant: COC(=O)c1nc2ccccc2o1
Agent: Cc1cccc(CCl)n1
Product: O=Cc1nc2ccccc2o1
Yield: 35 %

Procedure:
The title compound was prepared from methyl benzoxazole-2-carboxylate by the method of part (ii), above, on a 0.041 molar scale; yield 35% as a yellow oil. 1H--NMR(CDCl3)ppm(delta): 7.3-8.1 (m, 4H), 10.0 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C@@H:26]([OH:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@H:3]1[CH2:4][CH:5]=[C:6]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:31]([O:27][C@H:26]1[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@@H:3]([CH2:4][CH:5]=[C:6]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:2]1([CH3:1])[CH3:30])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
4,4-Dimethyl-5α-cholest-7-en-3β-ol [prepared according to J. Biol. Chem., 233:1343 (1958)]was converted to the title compound with benzoyl chloride in pyridine at ambient temperature for 18 hours. 3β-benzoyloxy-4,4-dimethyl-5α-cholest-7-ene had an mp of 160°-161° C. (from CH2Cl2/MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(F)cc3)[nH]2)cc1

Procedure:
5-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 5-(4-fluorophenyl)-2-(4-(2-dimethylaminoethyloxy)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:12](Cl)(=O)[C:13](Cl)=[O:14]>CCOCC>[OH:14][CH2:13][CH2:12][C:4]1[C:3]2[C:7](=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[CH3:1])[NH:6][CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)c2cc[nH]c2c1
Solvent: CCOCC
Product: Cc1cc(C)c2c(CCO)c[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
4,6-Dimethylindole (130 g) was dissolved in Et2O (130 ml), and oxalyl chloride (23.0 g) was dropwise added at 0° C. The mixture was stirred at room temperature for 5 hr, and Et2O was evaporated under reduced pressure. EtOH (200 ml) was added to the residue and the mixture was stirred at room temperature for 15 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in CHCl3 (200 ml). After washing with water, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The obtained residue was added to a suspension of LiAlH4 (17.0 g) in Et2O (200 ml), which was followed by refluxing for 2 hr. The reaction mixture was poured into ice water and extracted with AcOEt (200 ml). The AcOEt layer was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 13.0 g of 3-(2-hydroxyethyl)-4,6-dimethylindole.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1.Cl.[F:13][CH:14]1[CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>COCC(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH:14]([F:13])[CH2:15]2)[N:3]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:5]=1
Reactant: FC1CNC1
Reactant: Clc1cc(Cl)nc(C2CC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCC(C)O
Product: FC1CN(c2cc(Cl)nc(C3CC3)n2)C1
Temperature: 65 °C
Yield: 92.6 %

Procedure:
A mixture of 4,6-dichloro-2-cyclopropylpyrimidine 19 (1.05 g, 5.5 mmol), 3-fluoroazetidine hydrochloride 162 (0.68 g, 6 mmol) and potassium carbonate (2.48 g, 18 mmol) in 1-methoxy-2-propanol (10 ml) is heated at 65° C. for 2 hours. The mitre is cooled, concentrated in vacuo, diluted with dichloromethane and washed three times with water. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford 4-chloro-2-cyclopropyl-6-(3-fluoro-azetidin-1-yl)-pyrimidine 163 (1.16 g, 92%) as a yellow oil which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1c1ccc(F)cc1
Product: CN(C)C=C1CCCC(c2ccc(F)cc2)C1=O

Procedure:
2-(4-Fluoro-phenyl)-cyclohexanone (102 mg, 0.53 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (143 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 248.1 [(M+H)+].
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:19]=3)=[CH:13][C:12]=2[F:41])[CH:7]=[CH:6][N:5]=1)(=O)N.[ClH:42].[NH2:43]C1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC(F)=CC=3F)=O)=CC=2F)C=CN=1>>[ClH:42].[ClH:42].[ClH:42].[NH2:43][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:19]=3)=[CH:13][C:12]=2[F:41])[CH:7]=[CH:6][N:5]=1
Reactant: NC(=O)c1cc(Oc2ccc(Nc3nc(N4CCOCC4)ncc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Agent: Cl
Product: Nc1cc(Oc2ccc(Nc3nc(N4CCOCC4)ncc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Yield: 26 %

Procedure:
4-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-2-morpholinopyrimidine-5-carboxamide (55 mg, 0.01 mmol) was converted to the title compound (16 mg, 26%) in a manner similar to the preparation of 2-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (Step E of Example 3). 1H NMR (DMSO-d6) δ 11.24 (s, 1H), 10.20 (s, 1H), 8.85 (s, 1H), 7.92 (m, 2H), 7.82 (br s, 2H), 7.48-7.35 (m, 4H), 7.08 (m, 1H), 6.65 (dd, 1H, J=7.3, 2.5 Hz), 6.12 (d, 1H, J=2.4 Hz), 3.74 (m, 4H) 3.63 (m, 4H); MS(ESI+) m/z 538 (M+H)+.
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1(O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:5])C.C(O)(=[O:34])C>[Zn]>[CH2:27]([N:24]([CH2:25][CH3:26])[CH2:23][CH2:22][N:13]1[CH:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:4]([OH:5])=[O:34])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:21])[CH3:28]
Reactant: CC(=O)O
Reactant: CCN(CC)CCN1C(=O)c2ccccc2C1(O)c1ccccc1C(=O)N(CC)CC
Agent: [Zn]
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccccc1C(=O)O

Procedure:
To a solution of 2.18 g of Compound 29 in 25 ml of acetic acid was added 5 g of zinc powders activated by washing with 2N-hydrochloride. After heating at reflux for 3.5 hours, the mixture was filtered and concentrated under reduced pressure. To the residue was added 20 ml of water, and pH was adjusted to 7 with 10N-sodium chloride solution. Then, filtration was performed and the mother liquor was concentrated under reduced pressure. The residue was subjected to HP-10 high porous polymer column-column chromatography (eluting solvent, water:methyl alcohol=1:3). A major fraction was concentrated to dryness under reduced pressure to give 1.56 g of 2-[2-(2-diethylaminoethyl)isoindolin-1-on-3-yl]benzoic acid (Compound 27).