Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)=[CH:4][CH:3]=1.[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:28])[CH3:29]
Reactant: O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(4-fluorophenyl)methyl]-1-indanol (96% trans, 4% cis) and 0.93 (0.004 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.42 g of trans-3-[(4-fluorophenyl)methyl]-1-indanyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[O:24])[CH2:20][CH2:19][C:17]=2[N:18]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.ClCCl>CN(C)C=O.O>[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)=[O:24])[CH2:20][CH2:19][C:17]=2[N:18]=1
Reactant: O=C(OCCCCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCCCn1ccnc1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 18 h
Yield: 32.7 %

Procedure:
Add sodium hydride (0.050 g; 2.2 equiv; 1.25 mmoles) to a solution of 3-chloropropyl 2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (0.22 g; 1.0 equiv; 0.57 mmoles) and 1H-imidazole (0.082 g; 2.1 equiv; 1.20 mmoles) in dimethylformamide (2 mL) and stir for 18 hours. Dilute the reaction with dichloromethane and water. Separate the layers and further extract the aqueous layer with dichloromethane (2×). Dry the combined organic extracts with sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford the desired 3-(1H-imidazol-1-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.078 g; 33%) as a white solid: MS (m/z): 419 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][C:64]([O:92][CH3:93])=[C:65]([O:87][CH2:88][CH2:89][O:90][CH3:91])[CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH3:93][O:92][C:64]1[CH:63]=[C:62]2[C:67]([C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)=[N:69][C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([NH:53][C:8](=[O:10])[CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:55]=3)=[N:61]2)=[CH:66][C:65]=1[O:87][CH2:88][CH2:89][O:90][CH3:91]
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(N)c3)nc2cc1OC
Reactant: O=C(O)CN1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-morpholinoacetic acid (0.034 g, 0.24 mmol), DIEA (0.165 mL, 0.94 mmol) and PyBOP® (0.125 g, 0.24 mmol) in CH2Cl2 (1 mL) was stirred at RT for 10 minutes, upon which it was added to a solution of tert-Butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.260 g, 0.47 mmol) in CH2Cl2 (10 mL). the subsequent was stirred at RT for 1 hr upon which further aliquots of 2-morpholinoacetic acid (0.034 g, 0.24 mmol) and PyBOP® (0.125 g, 0.24 mmol) were added. The resulting mixture was stirred at RT overnight upon which the mixture was concentrated in vacuo and taken directly to the next step. HPLC retention time 5.35 mins.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[CH:20]1([C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:29]([OH:31])=[O:30].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([CH:20]4[CH2:22][CH2:21]4)=[CH:28][N:27]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: O=C(O)c1ccc(C2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C4CC4)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A9B) and 5-cyclopropyl-pyridine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as an amorphous light yellow material. MS (ISP): m/z=419.2 [M+H]+.
Reaction SMILES: [I:1][CH3:2].[CH:3]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:27])=[C:13]([N:16]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[CH2:17]4)[CH:14]=3)[C:9](=[O:28])[C:8]([C:29]([OH:31])=[O:30])=[CH:7]2)[CH2:5][CH2:4]1>C(#N)C>[I-:1].[C:29]([C:8]1[C:9](=[O:28])[C:10]2[C:15](=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:22]=[N+:23]([CH3:2])[CH:24]=[CH:25][CH:26]=4)[CH2:17]3)=[C:12]([F:27])[CH:11]=2)[N:6]([CH:3]2[CH2:4][CH2:5]2)[CH:7]=1)([OH:31])=[O:30]
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCC(c4cccnc4)C3)c(F)cc2c1=O
Reactant: CI
Solvent: CC#N
Product: C[n+]1cccc(C2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)c1
Product: [I-]
Yield: 88.7 %

Procedure:
Iodomethane (1.62 g, 11.4 mmol) was added dropwise to a stirred suspension of 1-cyclopropyl 6-fluoro-1,4-dihydro-4-oxo-7-[3-(3-pyridinyl)-1-pyrrolidinyl]-3-quinolinecarboxylic acid (0.30 g, 0.8 mmol) in acetonitrile (30 mL). The resulting mixture was heated at reflux for 2 hours. The suspension was then filtered, the solids were washed with acetonitrile and ether, and dried in vacuo at 40° C. to give the title compound (0.38 g, 88%) as a light yellow solid, mp 278°-280° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[F:27])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7](C1CCCCO1)[CH:6]=2.CO.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27]
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2Br)c(F)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Temperature: 50 °C
Yield: 96.9 %

Procedure:
To a 3000 mL flask is added 6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (250 g, 573.1 mmol) followed by MeOH (1000 mL) and MeSO3H (1 12.71 mL,1.72 mol) and heated to 50° C. for 14 hours. Solid crystallizes out of solution. The mixture is then cooled to RT. The reaction mixture is concentrated under vacuum at 45° C. to dryness to get solid. The solid is diluted with DCM (2000 mL) and treated with water (1000 mL) and 5N NaOH (about 350 mL) until the pH is 8-9. The organic layer is separated and the solvent is removed followed by azeotrope with toluene to give 195.6 g of the yellow solid material. MS (m/z): 354.0 (M+H).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[OH:25][CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:10]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: OCCOCCCl
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
82 g of 4,4-diphenylpiperidine, 50 g of diethylene glycol monochlorohydrin, 250 g of finely powdered potassium carbonate and 1 g of potassium iodide are heated at the boiling point under reflux, with vigorous stirring, in 1.2 l of a 1:1 mixture of dioxane and 1-butanol for 50 h. After cooling, the mixture is filtered and the filtrate is concentrated. The oily residue is taken up in ethyl acetate and the solution is filtered again. After the filtrate has been concentrated to constant weight (high vacuum), the title compound is obtained as a waxy viscous residue. Yield: 106 g. The hydrochloride is obtained with ethereal hydrochloric acid and is recrystallized from 2-propanol. M.p.: 120°-121° C.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([CH2:48][NH:49][S:50]([CH2:53][CH:54]([CH3:56])[CH3:55])(=[O:52])=[O:51])=[N:33][C:34]=2[NH:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO>[CH2:27]([NH:26][C:24]([C@@H:13]1[C@@H:14]([OH:15])[C@@H:10]([OH:9])[C@H:11]([N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][C:32]([CH2:48][NH:49][S:50]([CH2:53][CH:54]([CH3:55])[CH3:56])(=[O:52])=[O:51])=[N:33][C:34]=3[NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[O:12]1)=[O:25])[CH3:28]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4ccc(OC)cc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4ccc(OC)cc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
A solution of (2R,3R,4S,5S)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-2-{2-{[(isobutylsulfonyl)amino]methyl}-6-[(4-methoxybenzyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl benzoate (Preparation 22) (40 mg, 0.05 mmol) in methanol (2 ml) was treated with potassium carbonate (28 mg, 0.20 mmol). The mixture was stirred at room temperature for 20 minutes after which time a precipitate had formed. Dichloromethane (10 ml) was added to the mixture to dissolve the precipitate. The mixture was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) to afford the title compound as a white solid (21 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[NH2:1][C:2]1[N:3]=[C:4]([C:8]([O:10][CH2:15][CH3:16])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Nc1cccc(C(=O)O)n1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccc(N)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 2-amino-6-pyridinecarboxylic acid 77 (6.0 g, 43.5 mmol) in ethanol (150 mL) was added thionyl chloride (12.0 g, 101 mmol) at 0° C. The resulting reaction mixture was stirred at reflux for 12 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Saturated aqueous Na2CO3 solution was added until the pH of the solution reached 9. The mixture was concentrated under reduced pressure and dichloromethane (150 mL) was added to the resulting residue. The mixture was stirred vigorously at room temperature for 30 min and then filtered. The filtrate was concentrated under reduced pressure to afford 78 (5.5 g, 76% yield).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:26]=[O:27]>C(Cl)Cl>[F:36][C:35]([F:37])([F:38])[O:34][C:31]1[CH:30]=[CH:29][C:28]([NH:25][C:26](=[O:27])[NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:2])=[O:24])[CH2:6][CH2:7]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 25 °C

Procedure:
To 150 mg (0.5 mmol) {4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester in 5 mL DCM, 102 mg (0.5 mmol) 1-Isocyanato-4-trifluoromethoxy-benzene was added and the resulting mixture was stirred at room temperature over night. Dilution of reaction mixture with hexanes caused desired product to precipitate which was collected by filtration to afford [4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-acetic acid methyl ester: M+1=528.2. 1H NMR (400 MHz, DMSO-D6) ppm 1.09-1.20 (m, 2 H) 1.50 (td, J=12.63, 10.11 Hz, 2 H) 1.80 (s, 3 H)1.83 (d, J=3.28 Hz, 2 H) 2.25 (d, J=6.82 Hz, 2 H) 2.51-2.54 (m, 1 H) 3.61 (s, 3 H) 7.31 (dd, J=8.72, 3.16 Hz, 4 H) 7.55-7.61 (m, 2 H) 7.86 (d, J=8.59 Hz, 1 H) 7.94 (d, J=8.34 Hz, 2 H) 8.02 (dd, J=8.72, 2.65 Hz, 1H) 8.66 (d, J=2.78 Hz, 1 H) 8.99 (s, 1 H) 9.05 (s, 1 H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5](=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2].[NH3:13]>>[NH2:13][C:5]([CH2:4][CH2:3][C:1]#[N:2])=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)CCC#N
Reactant: N
Product: CCOC(=O)C=C(N)CCC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
3.80 g (22.4 mmol) of ethyl 5-cyano-3-oxopentanoate were taken up in 5 ml of a saturated ethanolic ammonia solution and stirred at room temperature for 24 h. The volatile components were distilled off using a rotary evaporator, giving 3.60 g (95%) of ethyl 3-amino-5-cyano-2-pentenoate. 1H-NMR (300 MHz, DMSO) 1.16 (t, 3H), 2.37 (t, 2H), 2.75 (t, 2H), 3.99 (q, 2H), 4.41 (s, 1H), 6.96 (s, broad, 1H), 7.69 (s, broad, 1H). MS (DCI/NH3): 169 (M+H)+, 186 (M+NH4)+, 337 (2M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.[ClH:13].[Cl:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.[OH-].[Na+].Cl>COCCOCCOC.C(OCC)(=O)C.CCOCC>[ClH:14].[ClH:13].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1N
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Br)ccc1N1CCNCC1
Temperature: 170 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
A suspension of 4-bromo-2-tert-butylaniline (Reference Example 8, 25.0 g, 110 mmol) and bis(2-chloroethyl)amine hydrochloride (21.5 g, 120 mmol) in diethylene glycol dimethyl ether (157 mL) was stirred for 3 days at 170° C. It was cooled to room temperature, added 1 M sodium hydroxide solution (50 mL), and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude product. It was diluted with ethyl acetate and ether (50:50) and added 1 M hydrochloric acid solution to provide 1-(4-bromo-2-tert-butylphenyl)piperazine dihydrochloride (16.2 g, 40%) as a gray solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH:7]([CH2:28][N:29](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].C(OCC)C>[C:1]([O:5][C:6](=[O:44])[CH:7]([CH2:28][NH2:29])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN(Cc3ccccc3)Cc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
The product from step (c) above (4.6 g, 7.62 mmole) in ethanol (75 ml) was hydrogenated in an atmosphere of hydrogen (50 p.s.i., 3.46 bar) over palladium on charcoal (200 mg), at room temperature overnight. The reaction mixture was filtered through a Solkaflok pad, and the filtrate evaporated to dryness to yield the crude product as an oil. This was dissolved in diethyl ether, and extracted into dilute hydrochloric acid (pH 2) (2×). The combined aqueous layers were washed with diethyl ether, then neutralised with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×). The combined organic phases were dried (Na2SO4) and evaporated to yield the title amine as an oil (2.91 g, 90%). Found: C,64.80; H,9.28; N,6.76. C23H40N2O5 requires C,65.06; H,9.50; N,6.60%.
Reaction SMILES: [CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1>CC(C)=O>[CH3:1][C@H:2]1[C:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]2[C:11]([CH2:24][O:25][C:27]([CH3:32])([CH3:28])[O:23]2)=[CH:10][CH:9]([C:15]3=[O:16])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]2(O)[C@H]1O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Solvent: CC(C)=O
Solvent: O
Product: CC1=CC23C(=O)C(C=C4COC(C)(C)O[C@H]4[C@]2(O)[C@H]1O)C1C(C[C@H]3C)C1(C)C

Procedure:
Ingenol is reacted with p-toluenesulphonic acid hydrate and acetone to give ingenol-5,20-acetonide according to the procedure of Opferkuch et al. (1981). Ingenol-5,20-acetonide is converted to the ingenol 3-acylate by treatment with the appropriate acyl chloride and 4-(N,N-dimethylamino)pyridine or pyridine in toluene or benzene, or treatment with the appropriate acid, an alkylpyridinium salt and tributylamine in toluene then treatment with methanolic perchloric acid according to the procedure of Sorg et al. (1982). The ingenol 3-acylate could be converted to the 20-chloro-20-deoxyingenol 3-acylate 5-benzoate by the method of Example 15.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C:28]1=[O:36]>C1(C)C=CC=CC=1.C1COCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([CH3:26])[C:28]1=[O:36]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CN1C(=O)Cc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(C3C(=O)N(C)c4ccccc43)c2cc1OC
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (5 ml of a 0.5M solution in toluene, 2.5 mmol) was rapidly added at ambient temperature to a solution of 4-chloro-6,7-dimethoxyquinazoline (337 mg, 1.5 mmol) and 1-methyloxindole (368 mg, 2.5 mmol), (prepared according to the method described in J. Am. Chem. Soc 1945, 67, 1656), in THF (30ml). After 30 minutes, the precipitate was collected by filtration and washed with ether. A second precipitate was isolated from the filtrate. The two solids were mixed and purified by column flash chromatography using methylene chloride/methanol (96/4 and 94/6) as eluent. During the evaporation of the solvents, the compound crystallised. The solid was filtered off, washed with ether and dried under vacuum to give 6,7-dimethoxy-4-(1-methyloxindol-3-yl)quinazoline (103 mg, 20%) as red orange needles.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32].C(=O)([O-])O.[Na+]>C1COCC1>[OH:32][CH2:31][CH2:30][N:29]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1)[CH2:33][CH2:34][OH:35]
Reactant: OCCNCCO
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(CCO)CCO)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (10 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added diethanolamine (222 μl). The mixture was refluxed for 34 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/triethylamine=10/1) and recrystallized from ethyl acetate-hexane to give N-[4-[N,N-bis(2-hydroxyethyl)aminomethy]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 51) (148 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[C:7]2[C:8](N[C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1)=[O:9])#[N:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1.[Cl-].[NH4+]>ClCCl>[OH:9][CH2:8][C:7]1[CH:13]=[C:3]([CH:4]=[CH:5][C:6]=1[C:11](=[O:12])[C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:1]#[N:2]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccc2c(c1)C(=O)NC2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(C#N)cc2CO)cc1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
20.0 g (125.6 mmol) of 5-cyanophthalimide was dissolved in 200 ml of anhydrous dichloromethane. The solution was cooled to −78° C., and 188 ml of 4-methoxyphenylmagnesium bromide (1 M in THF, 188 mmol) was added dropwise. The mixture was raised to room temperature and stirred for 16 hrs, followed by addition of a saturated ammonium chloride solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, thereby yielding a yellow compound, represented by Formula 3. The compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:16]=1
Reactant: Nc1ccccn1
Reactant: CC(Br)C(=O)c1ccc2c(c1)N(C)C(=O)CS2
Product: Cc1c(-c2ccc3c(c2)N(C)C(=O)CS3)nc2ccccn12
Yield: 67.9 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (2.1 g) was prepared in the substantially same manner as that of Example 4 from 6-(2-bromopropionyl)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (3.14 g) and 2-aminopyridine (2.85 g).