Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:20][C:21]1[CH:28]=[C:27]([CH2:29][CH:30]=O)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[Br:20][C:21]1[CH:28]=[C:27]([CH2:29][CH2:30][N:5]2[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:13](=[CH:18][CH:19]=3)[C:14](=[O:17])[O:15][CH2:16]4)[CH2:3][CH2:4]2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: N#Cc1ccc(CC=O)cc1Br
Agent: Cl
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1Br

Procedure:
2-Bromo-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-bromo-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 456.0 [M+1]+. (0.099 μM)
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O>C(O)C>[CH3:17][N:16]([CH3:18])[C:14]1[CH:13]=[C:12]([N:19]([CH3:20])[CH3:21])[N:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[N:15]=1
Reactant: CC(=O)N1CCN(c2nc(N(C)C)cc(N(C)C)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1cc(N(C)C)nc(N2CCNCC2)n1
Yield: 80.9 %

Procedure:
A solution of 1-acetyl-4-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (1.3 g) and sodium hydroxide (0.5 g) in ethanol (15 ml)—water (15 ml) was refluxed under heating for 9.5 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (0.9 g) as a pale-brown oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:27]2[CH2:28][CH2:29][CH:24]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:25][CH2:26]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (1.3 mL, 12.3 mmol), triethylamine (6.0 mL; 43.0 mmol) and 4-(piperidin-1-yl)piperidine (2.36 g; 14.0 mmol) in dioxane (10 mL) was heated at reflux for 18 hr. After cooling to room temperature the mixture was concentrated under reduced pressure and the residue dissolved in DCM (150 mL). The DCM solution was washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate and concentrated under reduced pressure to produce a yellow solid. Hexanes were added and the suspension briefly sonicated. The solid was collected by filtration and washed with hexanes to give 1-(4-nitrophenyl)-4-(piperidin-1-yl)piperidine (3.05 g) as a yellow solid. A solution of 1-(4-nitrophenyl)-4-(piperidin-1-yl)piperidine (3.05 g; 10.5 mmol) in ethanol (20 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.251 g) at room temperature for 17 hr. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 4-[4-(piperidin-1-yl)piperidin-1-yl]benzenamine (2.01 g) as a purple/pink solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:19][C:20]1[CH:66]=[CH:65][C:23]([CH2:24][N:25]([CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH2:26][C:27]([C@:29]23[CH2:55][C:54](=[O:56])[C:53]([CH:57]([CH3:59])[CH3:58])=[C:30]2[C@@H:31]2[C@@:44]([CH3:47])([CH2:45][CH2:46]3)[C@@:43]3([CH3:48])[C@@H:34]([C@:35]4([CH3:52])[C@@H:40]([CH2:41][CH2:42]3)[C:39]([CH3:50])([CH3:49])[C@@H:38](O)[CH2:37][CH2:36]4)[CH2:33][CH2:32]2)=[O:28])=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:12][C:7]([CH3:13])([CH2:8][C:9]([O:11][C@H:38]1[CH2:37][CH2:36][C@@:35]2([CH3:52])[C@@H:40]([CH2:41][CH2:42][C@:43]3([CH3:48])[C@@H:34]2[CH2:33][CH2:32][C@H:31]2[C@@:44]3([CH3:47])[CH2:45][CH2:46][C@@:29]3([C:27](=[O:28])[CH2:26][N:25]([CH2:24][C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:66][CH:65]=4)[CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH2:55][C:54](=[O:56])[C:53]([CH:57]([CH3:59])[CH3:58])=[C:30]32)[C:39]1([CH3:49])[CH3:50])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14]
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (11.91 g, 58.9 mmol), N,N-dimethylpyridin-4-amine (4.50 g, 36.8 mmol) in DCM (20 mL) was added EDC (11.29 g, 58.9 mmol). The reaction mixture was stirred at rt for 1 h. Then, (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (52) (5 g, 7.36 mmol) was add. Upon completion, the mixture was washed with 2 M HCl, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The product was purified by a silica gel column using dichloromethane/methanol (20:1) to afford 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (53) (1.8 g, 1.917 mmol, 26.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.27 (s, 4H), 4.60-4.39 (m, 1H), 3.82 (d, J=13.8 Hz, 1H), 3.59 (d, J=13.8 Hz, 1H), 3.50-3.05 (m, 3H), 2.82-2.63 (m, 2H), 2.63-0.53 (m, 67H).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]1([CH3:31])[CH2:30][C:28](=O)[CH2:27][C:25](=[O:26])[CH2:24]1.C1(C)C=CC=CC=1>O>[NH2:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:28]3[CH2:30][C:23]([CH3:31])([CH3:22])[CH2:24][C:25](=[O:26])[CH:27]=3)[CH2:3][CH2:2]2)[N:16]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nc(N3CCN(C4=CC(=O)CC(C)(C)C4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 2.9 g (0.01 mol) of 2-piperazino-4-amino-6,7-dimethoxyquinazoline, 1.4 g (0.01 mol) of dimedone and 20 ml of toluene is heated at the boiling point under reflux for 4 hours, using a water separator. After cooling the solution, the reaction product precipitates. It is washed with petroleum ether and recrystallised from 220 ml of acetonitrile. 2.6 g of melting point 185°-187° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)=[C:4]([F:26])[C:3]=1[F:27].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:24])([S:20]([CH3:23])(=[O:21])=[O:22])[C:17]([NH:53][O:52][CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][O:46]3)=[O:18])[C:10](=[O:25])[CH:9]=2)=[C:4]([F:26])[C:3]=1[F:27]
Reactant: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Product: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (4500 mg, 10.7 mmol) in Me-THF (450 mL) was added N-methyl morpholine (1.80 mL, 16.1 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (2520 mg, 13.9 mmol). The reaction mixture was stirred at room temperature for 1 h. To the mixture was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1630 mg, 13.9 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was washed with water and passed through pad of sodium sulfate, celite and silica gel. The pad was washed with ethyl acetate. The combined organic solution was concentrated under reduced pressure to give the title compound as a solid in quantitative yield. LCMS m/z 519.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.57 (m, 3H) 1.59 (d, J=3.90 Hz, 3H) 1.64-1.74 (m, 3H) 2.15-2.26 (m, 1H) 2.39-2.49 (m, 1H) 3.10 (d, J=6.44 Hz, 3H) 3.46-3.58 (m, 1H) 3.70-3.83 (m, 1H) 4.03 (d, J=7.02 Hz, 1H) 4.07-4.21 (m, 1H) 4.95-5.01 (m, 1H) 6.48-6.53 (m, 1H) 6.61-6.64 (m, 1H) 7.42-7.49 (m, 1H) 7.51-7.59 (m, 1H) 7.79 (dd, J=10.83, 7.12 Hz, 1H), H—N wasn't observed. 19F NMR (376 MHz, DMSO-d6) ppm −138.09 (dd, J=22.56, 7.52 Hz)-139.10 (dd, J=22.56, 7.52 Hz)
Reaction SMILES: COC1C=C2C(=CC=1)CC(=O)CC2.C1([PH2](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41]([CH:45]([CH3:51])[C:46]([O:48]CC)=[O:47])=[CH:40][CH:39]=[CH:38]2>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41]([CH:45]([CH3:51])[C:46]([OH:48])=[O:47])=[CH:40][CH:39]=[CH:38]2
Reactant: CCOC(=O)C(C)c1cccc2cc(OC)ccc12
Agent: COc1ccc2c(c1)CCC(=O)C2
Agent: c1ccc([PH2](c2ccccc2)c2ccccc2)cc1
Product: COc1ccc2c(C(C)C(=O)O)cccc2c1

Procedure:
Thus, for example, by reacting 6-methoxy-2-tetralone with the triphenylphosphorane derived from ethyl 2-halopropionate, 2,2-(1'-carbethoxyeth-1',1'-ylidene)-6-methoxytetralin is prepared. Dehydrogenation thereof provides ethyl 6-methoxynaphthyl-α-methylacetate which upon hydrolysis affords 6-methoxynaphthyl-α-methylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:21]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:26])[F:25])=[CH:24][CH:23]=3)=[O:22])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc2cnccc2c1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1ccc2cnccc2c1

Procedure:
Prepared from 6-aminoisoquinoline (Description 51) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 362 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CCO[C:14]([S-:16])=[S:15].[K+].Cl>CN(C)C=O.O>[Cl:9][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:14]([SH:16])[S:15][C:3]=2[C:2]=1[Cl:1]
Reactant: Nc1ccc(Cl)c(Cl)c1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc2ccc(Cl)c(Cl)c2s1
Temperature: 95 °C
Yield: 91.5 %

Procedure:
A mixture of 1.5 g (8.33 mmol) 3.4-dichloro-2-fluoroaniline and 1.64 g (10.00 mmol) potassium ethylxanthogenate in 8 mL dry N,N-dimethylformamide was heated in a 95° C. oil bath for 5 h. The reaction mixture was cooled to room temperature and diluted with water (25 mL). The mixture was acidified with aqueous HCl 2N. The precipitate was collected by filtration, washed with water and dried to provide 1.8 g (92%) of the title compound as a white solid. MS(m/e): 233.8 (M−H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[F:14][C:15]1[CH:16]=[C:17](Br)[CH:18]=[C:19]([F:22])[C:20]=1[F:21].C(N(CC)CC)C>C(OC)(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:14][C:15]1[CH:16]=[C:17]([C:13]#[C:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: C#Cc1ccc(OCCCC)cc1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCCCOc1ccc(C#Cc2cc(F)c(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.4 mmol of bis(triphenylphosphine)palladium(II) chloride and 0.2 mmol of CuI are added at room temperature to a mixture of 0.02 m of 4-butoxyphenylacetylene, 0.02 m of 3,4,5-trifluorobromobenzene and 50 ml of triethylamine. The reaction mixture is stirred at room temperature for 2 hours, diluted with methyl tert.-butyl ether and filtered with suction, and the solution is evaporated. Purification by chromatography and/or crystallization gives 3,4,5-trifluoro-4'-butoxytolan.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](I)[CH:27]=1>CO>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[C:30]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:31]=1
Reactant: OB(O)c1c(O)cccc1Cl
Reactant: Cc1ccc(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(Br)cc1-c1c(O)cccc1Cl
Temperature: 105 °C
Yield: 80 %

Procedure:
(2-Chloro-6-hydroxyphenyl)boronic acid (250 mg, 1.450 mmol, 1 equiv), Pd(PPPh3)4 (168 mg, 0.145 mmol, 0.1 equiv) and aqueous Na2CO3 (2 M, 1.8 ml, 3.63 mmol, 2.5 equiv) were mixed with toluene (2 mL) in a sealed microwave tube. 4-Bromo-2-iodo-1-methylbenzene (431 mg, 1.450 mmol, 1.0 equiv) in MeOH (1.00 mL) was to the above mixture. The mixture was heated at 105° C. overnight. Then, the crude reaction mixture was loaded on 12 g column and purified at 30% EtOAc/hexane to afford 5′-bromo-6-chloro-2′-methyl-[1,1′-biphenyl]-2-ol (345 mg, 80%). LCMS (M+1)=299.0.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.ClC(Cl)(Cl)[C:37]([N:39]=C=O)=[O:38]>N1C=CC=CC=1.CO>[C:37]([N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:34])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:29][CH2:30]1)(=[O:38])[NH2:39]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(N)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (240 mg, 0.52 mmol), (prepared as described for the starting material in Example 15), was dissolved in pyridine (5 ml) and cooled to 0° C. Trichloroacetyl isocyanate (61 μl, 0.52 mmol) was added and the mixture stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at 45° C. for 2.5 hours. Aqueous ammonia (1 ml) was added and the mixture was stirred at 60° C. for 1.5 hours and then at ambient temperature overnight. The solvent was removed under reduced pressure. Column chromatography of the residue using methylne chloride/methanol (90/10) followed by methylene chloride/methanol (saturated with ammonia) (90/10) gave a solid which was suspended in methanol and filtered to give 7-(3-[4-carbamoylpiperazin-1-yl]propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (120 mg, 46%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.CN(C=O)C>O>[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(OCc2cccc(Br)c2)c1
Temperature: 60 °C

Procedure:
To tert-butyl 3-hydroxyphenylcarbamate (0.245 g, 1.17 mmol), K2CO3 (404 mg, 2.93 mmol), and 3-bromobenzyl bromide (322 mg, 1.29 mmol) was added anhydrous DMF (5 mL). The reaction mixture was heated to 60° C. for 18 hours. The reaction mixture was cooled to rt, poured into water and the resulting precipitate was collected by filtration and washed with water to provide the desired product tert-butyl 3-(3-bromobenzyloxy)phenylcarbamate (34A) with sufficient purity for subsequent use.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1([C@@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:7]1[C:2]([NH:26][C@H:23]2[CH2:22][CH2:21][C@@H:20]([C:14]3([CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:25][CH2:24]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:10][O:11][CH3:12]
Reactant: COCc1ncnc(Cl)c1OC
Reactant: CC1([C@H]2CC[C@@H](N)CC2)CCCCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCc1ncnc(N[C@H]2CC[C@@H](C3(C)CCCCC3)CC2)c1OC

Procedure:
2.83 g (15 mmol) of 4-chloro-5-methoxy-6-methoxymethylpyrimidine [Collection Czechoslov. Chem. Commun. 33 (1968) 2266], 2.93 g (15 mmol) of cis-4-(1-methylcyclohexyl)cyclohexylamine and 3.03 g (30 mmol) of triethylamine are heated under reflux in 10 ml of toluene for 6 hours. After cooling, the mixture was subjected to extraction by stirring with water, and the organic phase was dried and concentrated. For purification it was chromatographed on silica gel (eluent: ethyl acetate). 1.2 g (23% of theory) of pure cis isomer were obtained as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][CH2:19][C@@H:20]([N:30]2[CH:34]=[C:33]([C:35]([NH2:37])=[O:36])[N:32]=[CH:31]2)[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:11][CH:10]=1)C1C=CC=CC=1>C1CCCCC=1.C(O)C.[OH-].[OH-].[Pd+2]>[Si:23]([O:22][CH2:21][C@H:20]([N:30]1[CH:34]=[C:33]([C:35]([NH2:37])=[O:36])[N:32]=[CH:31]1)[CH2:19][CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:17]=2)[CH:13]=[CH:14]1)([C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(OCc3ccccc3)cc21)n1cnc(C(N)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(O)cc21)n1cnc(C(N)=O)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 1-[(R)-4-(6-Benzyloxyindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (975 mg, 1.88 mmol) in cyclohexene (10 ml) and ethanol (20 ml) was added 20% palladium hydroxide on carbon (488 mg). The resulting mixture was stirred at reflux for 1 hour. After cooling to room temperature, the mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated in vacuo and then the residue was purified by silica gel (20 g) chromatography eluted with chloroform/methanol (100:1 to 50:1) to give 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-hydroxyindol-1-yl)-2-butyl]imidazole-4-carboxamide (772 mg, 95.8%) as a colorless solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:10]1([N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>O1CCCC1>[C:10]1([N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C(=NN(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 500 parts of tetrahydrofuran were dissolved 23.8 parts of 4- 5-(5H-dibenzo b,f!azepinyl)!benzaldehyde and 26.5 parts of N,N-diphenylhydrazine hydrochloride. This solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2,000 parts of water, and the crystals precipitated were taken out by filtration. The crystals obtained were washed with ethyl alcohol and then dried at reduced pressure. The crystals dried were dissolved in 100 parts of ethyl acetate, and this solution was poured into 1,000 parts of methyl alcohol to recrystallize the reaction product. Thus, 28.9 parts (yield, 77.9%) of 4- 5-(5H-dibenzo b,f!azepinyl)!benzaldehyde N,N-diphenylhydrazone was obtained. This compound had a melting point of 178.0° to 179.0° C. The results of elemental analysis are shown in Table 4 below, together with calculated values for C33H25N3.
Reaction SMILES: O.NN.[CH3:4][N:5]([CH3:39])[C:6](=S)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([C:24]4[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[N:27][N:26]5[CH2:35][CH2:36][CH2:37][C:25]=45)=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=1>CO.[Ni]>[CH3:4][N:5]([CH3:39])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([C:24]4[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[N:27][N:26]5[CH2:35][CH2:36][CH2:37][C:25]=45)=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=1
Reactant: CN(C)C(=S)c1cccc(Oc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C)Cc1cccc(Oc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a refluxing mixture of Raney-nickel and hydrazine-monohydrate (0.5 mL, 10.17 mmol) in methanol (5 mL) is added N,N-dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-thiobenzamide (311.0 mg, 0.63 mmol) in methanol (20 mL). The mixture is stirred 10 min and cooled to room temperature, filtered, and concentrated in vacuo. The residue is chromatographed by HPLC (C18 column) to yield the title compound, 60.2 mg (20%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[NH:6][S:5]1(=[O:17])=[O:16])[CH3:3].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:3][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[N:6]([CH2:22][CH:21]=[CH2:20])[S:5]1(=[O:17])=[O:16])[CH3:1]
Reactant: C=CCBr
Reactant: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1c2ccc(SC)cc2CN(C(C)C)S1(=O)=O

Procedure:
3,4-Dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide (10 g, 0.0367 mol) was added to a suspension of sodium hydride (1.61 g, 60% dispersion) in dry dimethylformamide (200 ml) at room temperature under a nitrogen atmosphere. The pale grey suspension was stirred for ten mins, and then allyl bromide (3.49 ml, 0.0404 mol) was added in one portion. The reaction mixture was stirred at 80° C. for 3 hr. The mixture was then concentrated in vacuo to yield a brown residue. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was then dried (MgSO4) and concentrated in vacuo to afford 3,4-dihydro-3-(1-methylethyl)-6-methylthio-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. δ(1H NMR, DMSO, ppm): 1.1 (6H, d), 2.5 (3H, s), 4.1 (1H, m), 4.5 (2H, d), 4.7 (2H, s), 5.3 (1H, dd), 5.4 (1H, dd), 6.0 (1H, m), 7.0 (1H, d), 7.3 (2H, m).