Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[K])(C)(C)C.CN(C)C=O.[OH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:23].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2c(O)cccc21
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2c(OCc3ccccc3)cccc21
Reaction time: 2 h

Procedure:
3.1 g of t-butoxypotassium was added under ice cooling and nitrogen replacement to a 50 mL dimethylformamide solution of 4.0 g of 5-hydroxytetralone, and the system was stirred for 15 minutes at the same temperature, after which 3.2 mL of benzyl bromide was added, and the system was stirred for 2 hours at the same temperature. After the reaction, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate, then subjected to reduced-pressure solvent distillation, and the residue was refined by silica gel column chromatography (20% ethyl acetate/hexane) to obtain 6.3 g of 5-benzyloxytetralone (compound 2-7 in Table 3-1) in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1>[Ir].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=C(C)c1ccc(OC)cc1
Agent: [Ir]
Solvent: ClCCl
Product: CCOC(=O)CC(C)c1ccc(OC)cc1
Yield: 100.4 %

Procedure:
According to the general procedure, a solution of ethyl 3-(4-methoxyphenyl)but-2-enoate (58 mg, 0.26 mmol) and iridium catalyst (S)-32 (8.4 mg, 0.0053 mmol, 2 mol %) in CH2Cl2 (3 mL) was hydrogenated. Removal of the solvent in vacuo and standard purification gave 35 (58 mg, 99%) as a colorless oil; [α]20D −26.7 (c 1.00, CHCl3); CSP HPLC analysis (Chiralcel OB-H; eluent: 99.5:0.5 hexanes/i-PrOH, 0.5 mL/min) determined a 96:4 er (92% ee) [tR(major) 21.73 min, tR(minor) 28.91 min]; 1H NMR (300 MHz, CDCl3) 7.14 (d, 2H, J=8.4 Hz), 6.84 (d, 2H, J=8.7 Hz), 4.07 (q, 2H, J=6.9 Hz), 3.78 (s, 3H), 3.24 (sextet, 1H, J=7.2 Hz), 2.61-2.46 (m, 2H), 1.27 (d, 3H, J=6.9 Hz), 1.18 (t, 3H, J=7.2 Hz) ppm; 13C NMR (75 MHz, CDCl3) 172.4, 158.0, 137.8, 131.4, 127.6, 113.8, 60.1, 55.1, 43.2, 35.7, 21.9, 14.1 ppm.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.CC(C)([O-])C.[K+]>O>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([NH:3][CH2:2][CH2:1][NH2:4])[CH:7]=1
Reactant: NCCN
Reactant: Clc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: NCCNc1cccnc1
Temperature: 118 °C

Procedure:
A mixture of 1.32 g of ethylenediamine, 250 mg of 3-chloropyridine, and 740 mg of potassium tert-butoxide was heated at 118° C. in a sealed tube for 18 hrs. The reaction was cooled to room temperature, diluted with water and extracted with chloroform. The organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title product as a red oil. MS (M+H)+=137.9.
Reaction SMILES: O[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:17]1[NH:16][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Oc1ncnc2ccsc12
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CC(Nc1ncnc3ccsc13)C2
Yield: 28.2 %

Procedure:
Using 4-hydroxythieno[3,2-d]pyrimidine (60 mg, 0.39 mmol), and phosphorus oxychloride (0.6 ml), and then 2-aminoindan (210 mg, 1.56 mmol), a similar procedure to Production Example 194 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:2) to obtain the title compound (30 mg, 0.11 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:14])[CH2:12][CH3:13])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:15](=O)([O:18]C)[O:16][CH3:17].[H-].[Na+].C(O)(=O)C>O>[CH3:13][CH:12]([C:11]([C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)=[O:14])[C:15]([O:16][CH3:17])=[O:18]
Reactant: COC(=O)OC
Reactant: CCC(=O)c1c(C)nn2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C)C(=O)c1c(C)nn2ccccc12

Procedure:
2-Methyl-3-propionylpyrazolo[1,5-a]pyridine (5.28 g) was dissolved into dimethyl carbonate (100 ml), and, after adding sodium hydride (3.37 g), the mixture was refluxed for 8 hours under heat. Under cooling in water bath, acetic acid was added, then, following dilution with water, the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure and the residue was purified by means of silica gel column chromatography (developing solvent, ethyl acetate:n-hexane=1:3˜1:1) to obtain aimed product (5.13 g) as a yellow oily product.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]2[C:25]3[C:20](=[CH:21][C:22]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[O:19][CH2:18][CH2:17]2)[CH2:10]1)C)(C)(C)C>Cl.CCO>[F:35][C:31]1[CH:30]=[C:29]([S:26]([C:22]2[CH:21]=[C:20]3[C:25]([CH:16]([CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][CH:9]([NH:7][CH3:6])[CH2:10]4)[CH2:17][CH2:18][O:19]3)=[CH:24][CH:23]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(CCC2CCOc3cc(S(=O)(=O)c4cccc(F)c4)ccc32)C1
Agent: Cl
Solvent: CCO
Product: CNC1CCN(CCC2CCOc3cc(S(=O)(=O)c4cccc(F)c4)ccc32)C1
Temperature: 60 °C

Procedure:
(1-{2-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-ethyl}-pyrrolidin-3-yl)-methyl-carbamic acid tert-butyl ester (0.9 g) was dissolved in 2N HCl in EtOH (2 ml) and the mixture was heated at 60° C. for 40 minutes. The reaction mixture was cooled to room temperature and was quenched with saturated NaHCO3, extracted with methylene chloride, dried with MgSO4, filtered, concentrated and purified with preparative TLC (10% MeOH in methylene chloride with 1% Et3N) to give (1-{2-[7-(3-fluoro-benzenesulfonyl)-chroman-4-yl]-ethyl}-pyrrolidin-3-yl)-methyl-amine, which was treated with a few drops of 2N HCl in EtOH and dried under vacuum to give (1-{2-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-ethyl}-pyrrolidin-3-yl)-methyl-amine HCl salt: 61.8 mg, MS: 419.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.Cl[C:21](Cl)([F:26])[C:22]([O:24][CH3:25])=[O:23]>[Zn].[Cu]Cl.O1CCCC1>[F:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=CC1(c2ccc(F)cc2)CC1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(F)cc2)CC1
Yield: 40.8 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.12 g) and molecular sieve 4A (1 g), tetrahydrofuran (18 ml), 1-(4-fluorophenyl)-1-formyl-cyclopropane (0.54 g), acetic anhydride (0.38 ml) and methyl dichlorofluoroacetate (0.69 g) to yield the title compound (0.32 g, 42%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].[S:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[N:24]=[CH:23]1>CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:27]([C:25]3[N:24]=[CH:23][S:22][CH:26]=3)=[O:28])[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: O=C(O)c1cscn1
Agent: Cl
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)c2cscn2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 42.2 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol) and 4-thiazolecarboxylic acid (39 mg, 0.30 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (138a) to obtain 51.6 mg of the title compound as a colorless solid (42%).
Reaction SMILES: C(OC(=O)N[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[N:13]=2)[CH2:9]1)(C)(C)C.Cl.N1CC([OH:25])C1>>[Cl:18][C:14]1[N:13]=[C:12]([N:10]2[CH2:11][CH:8]([OH:25])[CH2:9]2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccnc(Cl)n2)C1
Reactant: OC1CNC1
Agent: Cl
Product: OC1CN(c2ccnc(Cl)n2)C1

Procedure:
Prepared as [1-(2-chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester using azetidin-3-ol hydrochloride. MS: [M+H]+=186
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([N:22]([CH3:24])[CH3:23])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:32][C:31](=O)[CH:30]=[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH:44]=[CH:43][N:42]=[N:41]3)[CH:35]=2)[O:28]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[C:13]([NH:14][C:31](=[O:32])[CH2:30][C:29](=[O:28])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH:44]=[CH:43][N:42]=[N:41]3)[CH:35]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([N:22]([CH3:23])[CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnn3)c2)O1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1ccccc1F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1-c1ccccc1F

Procedure:
The title compound was prepared from (5-amino-2-dimethylamino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example J20) (691 mg, 2.0 mmol) and 2,2-dimethyl-6-(3-[1,2,3]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (Example L4) (543 mg, 2.0 mmol) according to the general procedure M. Obtained as a yellow solid (820 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1.O>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Br)ccc2OCC2CCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)nn1Cc1cc(Br)ccc1OCC1CCC1
Temperature: 100 °C

Procedure:
To a solution of -(5-bromo-2-cyclobutylmethoxy-benzyl)-5-methyl-1h-pyrazole-3-carboxylic acid ethyl ester, 24 (0.12 g, 0.29 mmol) in a mixture of MeOH (2 mL) and THF (4 ml) was added a solution of NaOH (0.061 g, 1.45 mmol) in 2 ml of H2O. The resulting mixture was heated at 100° C. in an Emrys microwave reactor for 20 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and the volatiles were removed in vacuum to yield 1-(5-bromo-2-cyclobutylmethoxy-benzyl)-5-methyl-1h-pyrazole-3-carboxylic acid, 25
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[NH:20][CH2:21][C:22]1[C:23]([NH:32][CH2:33][CH3:34])=[CH:24][C:25]([N:28]([O:30][CH3:31])[CH3:29])=[N:26][CH:27]=1.CCN(CC)CC>>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[N:20]1[CH2:21][C:22]2[CH:27]=[N:26][C:25]([N:28]([O:30][CH3:31])[CH3:29])=[CH:24][C:23]=2[N:32]([CH2:33][CH3:34])[C:2]1=[O:1]
Reactant: CCNc1cc(N(C)OC)ncc1CNc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1C(=O)N(c2cc([N+](=O)[O-])c(F)cc2Cl)Cc2cnc(N(C)OC)cc21
Yield: 50.3 %

Procedure:
Diphosgene (3.1 g, 15.66 mmol), 5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (4.3 g, 13.1 mmol) and Et3N (7 g, 65.2 mmol) were combined by the procedure of Example A4 to give 3-(2-chloro-4-fluoro-5-nitrophenyl)-1-ethyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.7 g, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, J=7.6 Hz, 1 H), 8.09 (d, J=11.2 Hz, 1 H), 8.00 (s, 1 H), 6.63 (s, 1 H), 4.91 (d, J=13.6 Hz, 1 H), 4.55 (d, J=13.6 Hz, 1 H), 3.93 (m, 2 H), 3.77 (s, 3 H), 3.20 (s, 3 H), 1.23 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 410.2 [M+H]+.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C>CN(C)C=O>[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][N:60]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:48])[CH:22]=[CH:21][N:20]=3)=[O:7])[CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: C1CN(CC2CCNCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC(CN2CCC2)CC1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(azetidin-1-ylmethyl)piperidine dihydrochloride (69 mg) and triethylamine (0.085 ml) at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the titled compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (42.0 mg, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:22])[C:11]2[C:16]([CH2:17]/1)=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[CH:12]=2.[CH2:23]([O:25]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:24].Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:22])[C:11]2[C:16]([CH2:17]/1)=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[CH:12]=2)(=[O:25])[CH3:24]
Reactant: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Br)C2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1C(C)=O)C2
Temperature: 110 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A toluene solution (3 mL) of compound 89 (0.4 g, 1.1 mmol), Pd(dba)2 (25.3 mg, 0.044 mmol) and PPh3 (23.1 mg, 0.088 mmol) was stirred at room temperature under argon for 15 min. Then, (1-ethoxyvinyl)tri(n-butyl)stannane (0.38 mL, 1.1 mmol) in toluene (3 mL) was added and the resulting mixture was stirred overnight at 110° C., cooled to room temperature and filtered on Celite, washed with EtOAc and concentrated under reduced pressure. Purification on silica gel (gradient of EtOAc in Petroleum ether) afford the product which was placed in presence of an aqueous solution of HCl 1M for 30 minutes at room temperature. After neutralization with a saturated aqueous solution of NaHCO3, aqueous phase was extracted with dichloromethane and the combined organic layers were dried over magnesium sulfate to afford the title compound 97 (Yield 288.1 mg, 81%) which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:13]([CH2:29][CH2:30][N:31]=3)[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[N:15][C:16]=2[C:17]=1[O:18][CH3:19].[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:19][O:18][C:17]1[C:16]2[N:15]=[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[N:13]3[CH2:29][CH2:30][N:31]=[C:12]3[C:11]=2[CH:10]=[CH:9][C:8]=1[O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: COc1c(OCCOCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1c(OCCOCCNS(=O)(=O)c2ccc(C)cc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 31, Step 5 was used to prepare the title compound from N-{8-[2-(2-aminoethoxy)-ethoxy]-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl}-nicotinamide (Example 31, Step 4) and (4-methylphenyl)sulfonyl chloride. HPLC MS RT=2.35 min, MH+=579.5.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH2:17][NH2:18])[OH:16].C(O)(=O)C(C)(C)C.CCCCCCC.O1CCCC1.C1(C)C=CC=CC=1>ClCCl.O>[OH:16][CH2:15][CH2:17][N:18]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)CCC(=O)c1ccccc1
Reactant: NCCO
Agent: CC(C)(C)C(=O)O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccccc2)n1CCO
Temperature: 115 °C

Procedure:
A mixture of 1-phenyl-hexane-1,4-dione (5 g), ethanol amine (1.6 g) and pivalic acid (2.15 g) in a solvent mixture containing n-heptane:tetrahydrofuran:toluene (4:1:1, 50 mL) was refluxed with stirring at 110-120° C. Water formed during the reaction was removed azeotropically during 3 to 4 hrs. The reaction mixture was cooled and the solvent was removed. The residue obtained was dissolved in dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (50 mL), water (50 mL), and then with brine (50 mL), dried (Na2SO4) and the solvent was evaporated. The crude compound obtained as an oily mass. The crude substance was used in the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[NH:7][C:8](=[O:25])[CH2:9][CH2:10][CH:11]1[CH2:24][C:15]2=[N:16][C:17]3[NH:18][CH2:19][CH2:20][CH2:21][C:22]=3[CH:23]=[C:14]2[CH2:13][CH2:12]1)C.[OH-].[Na+]>>[O:32]1[C:28]2[CH:27]=[C:26]([C@@H:6]([NH:7][C:8](=[O:25])[CH2:9][CH2:10][CH:11]3[CH2:24][C:15]4=[N:16][C:17]5[NH:18][CH2:19][CH2:20][CH2:21][C:22]=5[CH:23]=[C:14]4[CH2:13][CH2:12]3)[CH2:5][C:4]([OH:35])=[O:3])[CH:34]=[CH:33][C:29]=2[CH2:30][CH2:31]1
Reactant: CCOC(=O)C[C@H](NC(=O)CCC1CCc2cc3c(nc2C1)NCCC3)c1ccc2c(c1)OCC2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C[C@H](NC(=O)CCC1CCc2cc3c(nc2C1)NCCC3)c1ccc2c(c1)OCC2

Procedure:
A solution of 14-5 (0.050 g, 0.105 mmol) and aqueous 1N NaOH (0.210 mL, 0.210 mmol) was stirred at room temperature for 3 h. The solution was concentrated. The residue was triturated with Et2O and the white solid collected by to give 14-6.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][C@H:25]1[O:30][C@@H:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:18][CH2:19][CH:20]([N:27]5[CH2:26][C@H:25]([CH3:24])[O:30][C@H:29]([CH3:31])[CH2:28]5)[CH2:21][CH2:22]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H]1CN(C2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)C[C@H](C)O1
Yield: 59 %

Procedure:
Using a procedure similar to that described in Example 82, except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone and employing cis 2,6-dimethylmorpholine, the title compound was formed in 59% yield as a white solid, mp >300° C. (dec). free base: NMR (CDCl3, 250 MHz) 7.22 (m, 2H), 7.14 (m, 2H), 6.92 (m, 4H), 4.24 (s, 1H), 3.63 (m, 2H), 3.36 (s, 2H), 3.05 (br d, J=11.7 Hz, 2H), 2.71 (d, J=10.5 Hz, 2H), 2.56 (d, J=1.2 Hz, 2H), 2.18 (m, 3H), 1.87 (t, J=10.8 Hz, 2H), 1.73 (m, 2H), 1.52 (dt, J=3.6, 11.9 Hz, 2H), 1.14 (d, J=6.3 Hz, 6H) MS (CI, CH4) m/z 403 (M+1,100), 431 (M+29,21), 287 (45) hydrochloride salt:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([CH:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])[CH3:14].C(N(CC)CC)C.C1(C)C=CC=CC=1>CN(C)C1C=CN=CC=1.C(OCC)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:17][CH2:16][CH:15]([CH2:13][CH3:14])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCC(CC)CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added 4-nitrobenzoyl chloride (53.0 grams, 0.285 moles), 2-ethylhexanol (28.6 grams, 0.22 moles), triethyl amine (30.2 grams, 0.30 moles) and 4-dimethylaminopyridine (6.98 grams, 0.0.57 moles) and anhydrous toluene (420 ml). The contents of the flask were heated at reflux for 16 hours; cooled to room temperature. It was diluted with diethyl ether (300 ml). The ether extract was washed with diluted HCl(1wt %, 3×100 ml), followed with a saturated sodium bicarbonate solution (3×100 ml), brine (3×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 57.2 grams of crude product as a yellow oil. 1H NMR (CDCl3) δ 8.3(d, 2H), 8.2(d, 2H), 4.3(d, 2H), 1.75(heptet, 1H), 1.2-1.6(m, 8H), 0.8-1.0(m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].C(=O)([O-])[O-].[Li+].[Li+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.O>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][CH2:18][CH:20]([CH2:21][OH:22])[O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Yield: 14.7 %

Procedure:
4-Nitrocatechol (30 g, 0.19 mol), lithium carbonate (36 g, 0.49 mol), and epichlorohydrin (38 mL, 0.49 mol) in DMF (180 mL) were heated to 70-85° C. for 47 hours. Water was added and the mixture extracted with EtOAc (3×). Concentration of the combined EtOAc extracts and crystallization from MeOH gave the title compound, first crop, 5.98 g, 14.7% yield, mp 131.8-135° C. and second crop, 1.64 g, 4% yield, mp 133.1-136.7° C., (lit. mp 131-134° C.). 1H NMR (d6-DMSO) δ 7.78 (1H, dd, J=8.9, 2.7 Hz); 7.72 (1H, d, J=2.7 Hz); 7.11 (1H, d, J=8.9 Hz); 5.16 (1H, br s); 4.48 (1H, dd, J=11.4, 2.1 Hz); 4.32-4.23 (1H, m); 4.17 (1H, dd, J=11.4, 7.4 Hz); 3.66 (2H, br s).