Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:27][O:28][NH2:29]>N1C=CC=CC=1>[CH3:27][O:28]/[N:29]=[C:12](\[C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:8][CH:9]=1)/[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: CON
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Agent: Cl
Solvent: c1ccncc1
Product: CO/N=C(/c1cc(OC)c(OC)c(OC)c1)c1csc(-c2ccccc2)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 1h (110 mg, 0.59 mmol) in 10 mL pyridine was added O-methylhydroxylamine hydrochloride (52 mg, 0.63 mmol) and the mixture was stirred at 60° C. for overnight. The reaction was quenched with 1 N HCl solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compounds 2f-cis (41 mg) and 2f-trans (33 mg). 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.96-7.94 (m, 2H), 7.45-7.44 (m, 3H), 6.94 (s, 2H), 4.13 (s, 3H), 3.91 (s, 6H), 3.88 (s, 3H). MS (ESI) m/z 407.2 (M+Na)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][N:9]2[CH:18]=1)([O:3]CC)=[O:2].[OH-].[K+]>CO.O>[OH2:2].[CH:7]1[C:6]([C:1]([OH:3])=[O:2])=[CH:18][N:9]2[C:8]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[CH:10]2.[CH:7]1[C:6]([C:1]([OH:3])=[O:2])=[CH:18][N:9]2[C:8]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[CH:10]2
Reactant: CCOC(=O)c1cc2c3ccccc3ncn2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c3ccccc3ncn2c1

Procedure:
A solution of the product of Example II (2.0 g, 0.008 m) and KOH (2.0 g, 0.036 m) in MeOH (20 ml) and H2O (20 ml) was refluxed for 1 hr. The methanol was removed under vacuum and the resulting aqueous solution was acidified with HCl (10% aqueous). When the solution became acidic, a white solid formed. It was filtered and washed well with H2O and dried, to yield 1.23 g of crude product. Crystallization from MeOH afforded the product as an off-white solid; m.p. 323°-325° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9]C(=O)OC(C)(C)C.[CH3:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[NH2:9][CH2:8][C@H:3]1[C@@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:23]([C:21]1[N:22]=[C:18]([CH3:17])[S:19][C:20]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:24]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: C[C@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccccc2)s1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using rac-cis-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate and 2-methyl-5-phenylthiazole-4-carboxylic acid. MS (ESI) 330.08 (M+H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=6[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1nn(C)c(C)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
A small screw cap test tube was charged with 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.2401 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (45.9 mg, 0.240 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (˜5 mL) and Hexane (˜40 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (10 mL) to afford the title compound in 59% yield (0.0835 g, 0.142 mmol).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:45])[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36](C)(C)[O:37][SiH2]C(C)(C)C)[CH:30]=1)[CH2:26][CH3:27])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:45])[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([CH2:36][OH:37])[CH:30]=1)[CH2:26][CH3:27])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCN(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(Cc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
TBAF (1M in THF, 3.03 mL, 3.03 mmol) was added dropwise to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-ethyl-carbamic acid tert-butyl ester (628 mg, 1.52 mmol) in THF (14.9 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc was added, and the mixture was washed with aq. sat. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 19:1) yielded the title compound (300 mg, 66%). LC-MS: tR=0.98 min; ES+: 300.28.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][OH:38].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:36][CH2:37][OH:38])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-bromoethanol (0.621 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 80 mg (yield 90%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[NH:3]1.CCN(C(C)C)C(C)C.[N:31]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[C:32]=[O:33]>C(Cl)Cl.O.CN(C=O)C>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=2)[N:3]1[C:32]([NH:31][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:33]
Reactant: O=C=Nc1cccnc1
Reactant: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1C(=O)Nc1cccnc1
Reaction time: 2 h

Procedure:
3-Methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.100 g, 0.343 mmol, semi-pure from the previous reaction) was dissolved in 3 mL DCM and DIEA (0.119 mL, 0.687 mmol) and 3-isocyanatopyridine (79 mg, 0.659 mmol) were added. Stirring was continued for 2 h and the mixture was hydrolyzed with 3 drops of water, diluted with 3 mL DMF and injected on the HPLC for purification. The title compound was obtained. No stereochemical assignment was performed.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([C:15]([NH2:17])=O)[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([CH2:15][NH2:17])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)[C@@H]1CCc2ccc(C(N)=O)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H]1CCc2ccc(CN)cc2C1

Procedure:
A solution of the (R)-7-(dipropylamino)-5,6,7,8-tetrahydro-2-naphthalenecarboxamide (8) (8.68 g) in dry tetrahydrofuran was stirred at room temperature and borane dimethylsulfide complex (10.0 M, 11.1 ml) was slowly added. When the initial reaction subsided, the mixture was heated at reflux for 2 days. The mixture was cooled in ice, and water was added dropwise. When the evolution of gas ceased, 10% hydrochloric acid (75 ml) was added, and the mixture was refluxed for 2 hours. The mixture was cooled in ice and basified with solid sodium hydroxide. The mixture was extracted with diethylether and then with 2:1 diethylether/tetrahydrofuran. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave the title compound a yellow oil (8.15 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2c(c1)Sc1sc3ccccc3c1C(=O)N2
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1ccc2c(c1)Sc1sc3ccccc3c1C(N1CCN(C)CC1)=N2

Procedure:
In the same manner as in Example 80 and using 8-methyl-1benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline, 1-methylpiperazine, 8-methyl-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.44) (0.18 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.055 g, 29%). MS (ISP) 374.1 [(M+H)+]; mp 228° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21]>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A solution of amorphous ibandronic acid (5 g) in water (30 ml) was stirred at room temperature. Aqueous sodium hydroxide (0.63 g NaOH in 20 mL water) was added, and the reaction mixture was stirred at room temperature for an additional 1 hour. The solution was evaporated until dry. Hexanes (100 ml) were added to the residue and stirred for 16 hours at room temperature. The precipitate was isolated by vacuum filtration, washed with hexanes (1×50 ml), and dried in a vacuum oven at 50° C. for 45 hours to obtain 5.1 g of amorphous ibandronate sodium.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[O:9]([CH2:16][CH2:17][OH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:18][CH2:17][CH2:16][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: OCCOc1ccccc1
Reactant: Clc1cncc(Cl)n1
Solvent: C1COCCO1
Product: Clc1cncc(OCCOc2ccccc2)n1
Reaction time: 0.08 h

Procedure:
K-t-BuO (1.61 g, 14.3 mmol) was added portionwise to a stirred mixture of 2,6-dichloropyrazine (2.03 g, 13.6 mmol) and 2-phenoxyethanol (2.54 g, 18.4 mmol) in dioxane (8 mL) at 0° C. (ice-bath). After 5 min of stirring, the ice-bath was removed and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ether, filtered and concentrated in vacuo. The oily residue was purified by silica gel chromatography (18×5 cm) using n-hexane/ethyl acetate (92:8) as eluent. This furnished 2.92 g (86%) of the title compound as a white solid. HRMS m/z calcd for C12H11ClN2O2 (M)+ 250.0509, found 250.0511. Anal. (C12H11ClN2O2) C, H, N.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[C:26]2[C:31]=1[O:30][CH2:29][CH2:28][O:27]2)CCC>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.CN(C)C=O>[O:27]1[CH2:28][CH2:29][O:30][C:31]2=[C:23]([C:2]3[C:10]4[C:6](=[N:7][N:8]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)[N:9]=4)[C:5]([C:25]4[S:24][CH:23]=[C:31]5[C:26]=4[O:27][CH2:28][CH2:29][O:30]5)=[CH:4][CH:3]=3)[S:24][CH:25]=[C:26]12
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: c1cc(-n2nc3c(-c4scc5c4OCCO5)ccc(-c4scc5c4OCCO5)c3n2)ccn1
Temperature: 100 °C

Procedure:
A mixture of Intermediate A (0.71 g, 2.0 mmol), tributyl(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)stannane (2.27 g, 5.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.20 g, 0.28 mmol), and anhydrous dimethylformamide (20 mL) was stirred under argon and heated at 100° C. for 4 hours. The volatiles were removed under reduced pressure, and the crude product was purified by column chromatography (silica gel, dichloromethane/ethyl acetate 75:25) and washing with ethanol (20 mL) to give 4,7-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 10) as orange crystals, 0.47 g (49%). 1H NMR (400 MHz, CDCl3): δ 8.82 (m, 2H, pyridine), 8.37 (m, 2H, pyridine), 8.20 (s, 2H, benzotriazole), 6.53 (s, 2H, thiophene), 4.39 (s, 4H, OCH2CH2O), 4.30 (s, 4H, OCH2CH2O). UV-vis spectrum (dichloromethane): λmax=448 nm. Fluorimetry (dichloromethane): λmax=559 nm.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])C=C.O.C(OCC)(=O)C.CN(C)[C:23]1[CH:28]=CC=C[CH:24]=1>>[CH2:28]([C:12]1[C:5]([OH:4])=[C:6]([CH:9]=[CH:10][C:11]=1[OH:13])[CH:7]=[O:8])[CH:23]=[CH2:24]
Reactant: C=CCOc1cc(O)ccc1C=O
Reactant: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(O)ccc(C=O)c1O

Procedure:
3.10 g of 2-allyloxy-4-hydroxybenzaldehyde was dissolved in 6 ml of N,N-dimethylaniline, and the reaction solution was heated to reflux under nitrogen atmosphere. Approximately 2.5 hours later, the reaction solution was stood to cool. Thereafter, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with 5 N hydrochloric acid, water, and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 0.88 g of the subject compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[N:28]1([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]3[CH:22]=[CH:23][C:24]4[NH:25][C:38]([C:37]5[CH:36]=[CH:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:41][CH:40]=5)=[N:1][C:4]=4[CH:5]=3)=[O:21])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 212 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholin-4-ylbenzoyl)aniline and 4-morpholinylbenzaldehyde. [M+H]+ calcd for C28H29N5O3: 484.23; found: 483.94.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([CH:18]=[CH:17][N:16]=2)[C:21]#[N:22])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C#N)ccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccnc(NC2CCNCC2)c1

Procedure:
A solution of 4-(4-cyano-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.30 g, 1.00 mmol) in 4 M HCl in dioxane (15 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 203.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1F
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example A5, 2.98 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-fluorophenyl)ethoxy]thiophene-2-carboxylate and 115 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[C:15]([NH2:16])=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[C:17](=S)=[S:18].CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]([SH:18])=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:6][CH:7]=1
Reactant: Nc1cncnc1NCc1ccc(F)cc1
Reactant: S=C=S
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2c(S)nc3cncnc32)cc1
Reaction time: 3 h
Yield: 78.9 %

Procedure:
A mixture of 8.72 parts of N4 -[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine, 63 parts of carbon disulfide and 45 parts of N,N-dimethylformamide was stirred for 3 hours at reflux temperature. After cooling, the reaction mixture was poured into water. The precipitated product was filtered off and dried, yielding 10.1 parts (78.9%) of 9-[(4-fluorophenyl)methyl]-9H-purine-8-thiol (interm. 24).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:12])C1C=CC=CC=1.CSC>C(O)(C(F)(F)F)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[N:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH:11]([NH2:10])[CH3:12]
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cnccn2c1-c1ccccn1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1nc2cnccn2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of [1-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-2-yl)-ethyl]-carbamic acid benzyl ester (450 mg, 1.2 mmol) and dimethylsulfide (1.0 mL) in TFA (4.0 mL) was stirred at rt overnight. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 1-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-2-yl)-ethylamine: LC-MS (ESI) m/z 240.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:26])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[Li]CCCC.[Cl:39][Si:40](Cl)([CH3:42])[CH3:41]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:26])[CH:8]2[Si:40]([Cl:39])([CH3:42])[CH3:41])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)CC(C)=C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
To a solution of 10.5 g (30.0 mmol) of 5-tert-butyl-7-(4-tert-butylphenyl)-6-methoxy-2-methyl-1H-indene in 200 ml of toluene 12.0 ml (30.0 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 10 h, and then 10 ml of THF was added. The formed mixture was stirred for 2 h at 60° C., then cooled to −20° C., and 19.4 g (150 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. The resulting solution was warmed to room temperature, refluxed for 1 h, and then filtered through glass frit (G3). The precipitate was additionally washed by 2×10 ml of toluene. The combined filtrate was evaporated to dryness to give 13.2 g (99%) of the title product as a yellowish oil which was further used without an additional purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:25]=[CH:24][C:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1.C(OCC)(=O)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[ClH:32].[CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:25]=[CH:24][C:11]2[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1
Reactant: C[C@@H]1COCCN1c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1COCCN1c1ccc2c(c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A mixture of tert-butyl 8-[(3R)-3-methylmorpholin-4-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (460 mg, 1.32 mmol), ethyl acetate (4 ml) and 4N hydrogen chloride-ethyl acetate solution (8 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (320 mg, 75.5%) as a solid.