Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3](=[O:11])O1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1>C(Cl)Cl>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:3](=[O:11])[CH2:4][C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:1]2=[O:12])[CH2:19][CH2:20]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: ClCCl
Product: O=C1Cc2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of 2-benzopyran-1,3(4H)dione and 0.02 mol of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine are heated at 160°-170° C. for 1 hours under an atmosphere of N2, with stirring. The mixture is then allowed to cool and the substance is dissolved in methylene chloride. The substance is purified over a silica gel column (mobile phase: CH2Cl2 /iprOH (10:0.5)).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:4](=[O:31])[C:3]=1[Cl:32].CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>>[Cl:32][C:3]1[C:4](=[O:31])[N:5]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:6]2[C:11]([C:2]=1[N:1]=[CH:35][N:36]([CH3:38])[CH3:37])=[CH:10][C:9]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[N:7]=2
Reactant: CC(C)Cn1c(=O)c(Cl)c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Reactant: COC(OC)N(C)C
Product: CC(C)Cn1c(=O)c(Cl)c(N=CN(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
The product of EXAMPLE 61 (50 mg) was combined with N,N-dimethylformamide dimethylacetal (4 mL). The reaction was heated to 95° C. and stirred for 90 minutes at which the solution was concentrated in vacuo. Purification by flash chromatography on silica eluted with 0-30% EtOAc in hexane afforded the title compound (E/Z mixture of isomers). HPLC/MS: 560.9 (M+1), 562.9 (M+3); Rt=4.48 min.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[NH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+].[C:18]([C:24]([O:26][CH3:27])=[O:25])#[C:19][C:20]([O:22][CH3:23])=[O:21]>CO.O.C(OCC)(=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]1([C:24]([O:26][CH3:27])=[O:25])[O:11][N:10]2[C:6]([C:5]([CH3:9])([CH3:8])[O:4][CH2:3][CH2:2]2)=[N:7]1
Reactant: NO
Reactant: CC(C)(C#N)OCCCl
Reactant: COC(=O)C#CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)CC1(C(=O)OC)N=C2N(CCOC2(C)C)O1
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Alternate procedure. To a solution of 2-(2-chloroethoxy)-2-methylpropanenitrile (5.00 g, 33.87 mmol) in methanol (30 mL) was added at 20–22° C. a 50% aqueous solution of hydroxylamine (2.21 mL, 40.58 mmol). Sodium carbonate (1.44 g, 13.59 mmol) and finally water (5 mL) were added. The suspension was stirred at 20–25° C. for 18 h. The reaction mixture was heated at reflux (65–66° C.) for 3 h. The resulting solution was cooled to 20–25° C. The pH (7.5) required no adjustment. The mixture was cooled to −5° C. and dimethyl acetylenedicarboxylate (3.75 mL, 30.56 mmoles) was added slowly over about 18 min keeping the temperature between −5° C. to 0° C. The mixture was stirred for 60 min. Additional dimethyl acetylenedicarboxylate (0.4 mL, 3.26 mmoles) was added and mixture was stirred another 10 min at 0° C. to complete the reaction as confirmed by HPLC. Ethyl acetate (50 mL) and water (25 mL) were added to the reaction mixture. The phases were separated and the aqueous phase was extracted again with ethyl acetate (25 mL). The combined ethyl acetate extracts were washed with about 14% aq. NaCl (2×25 mL). The solvent was removed under vacuum to afford methyl 2-(2-methoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate as a crude oil (9.4 g, 96.9% yield) with a purity of 71% by HPLC. A sample (0.80 g) was purified by reverse-phase chromatography giving an oil (0.48 g) of 97% purity by HPLC, which crystallized on standing; mp 68–69° C.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1>[CH2:1]([N:6]1[C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]2[C:28]1=[O:29])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCNc1nc[nH]c1-c1nc(-c2ccccc2)n[nH]1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2nc(-c3ccccc3)nc2c2[nH]cnc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
N-pentyl-5-(3-phenyl-1H-1,2,4-triazol-5-yl)-1H-imidazol-4-amine (50 mg, 0.17 mmol) and N,N-carbonyldiimidazole (50 mg, 0.3 mmol) were dissolved in THF (10 mL) and stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative LCMS (method B) to yield the desired product (25 mg, 45% yield). LCMS calculated for C17H19N6O (M+H): 323.2; found 323.1.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH:39]1[C:52]2[C:51](=[O:53])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[O:44][C:43]=2[CH:42]=[CH:41][CH:40]=1>>[OH:53][C:51]1([C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:52]1=[CH:39][CH:40]=[CH:41][CH:42]=2
Reactant: O=c1c2ccccc2oc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C3(O)c4ccccc4Oc4ccccc43)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-(9-Hydroxyxanthen-9-yl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using xanthone instead of benzophenone) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O>[F:9][C:5]1[CH:4]=[CH:3][C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C@H:11]2[CH3:10])=[N:7][C:6]=1[CH3:8]
Reactant: Cc1nc(Br)ccc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)ccc1F
Temperature: 110 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a mixture of 500 mg of 6-bromo-3-fluoro-2-methylpyridine, 580 mg of tert-butyl (3R)-3-methylpiperazine-1-carboxylate, 506 mg of sodium tert-butoxide, and 61 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 7.5 mL of toluene was added 48 mg of tris(dibenzylidenacetone)dipalladium (0), followed by stirring at 110° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 780 mg of tert-butyl (3R)-4-(5-fluoro-6-methylpyridin-2-yl)-3-methylpiperazine-1-carboxylate.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:7]=1O)([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:18]([OH:22])(=[O:21])[CH:19]=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)CCl>[C:1]([C:6]1[CH:7]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:9]2[O:22][C:18](=[O:21])[CH:19]([OH:20])[C:10]=2[CH:11]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CCC(C)(C)c1cccc(C(C)(C)CC)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: CCC(C)(C)c1cc2c(c(C(C)(C)CC)c1)OC(=O)C2O
Temperature: 25 °C

Procedure:
2,6-Di-tert-pentylphenol (161.4 g), glyoxylic acid (122.3 g of the 50% b.w. solution in water) and 1.3 g of p-toluene sulphonic acid are heated in 500 ml of ethylenechloride under nitrogen at reflux temperature in an apparatus designed for the removal of water. After 3.5 hours the reaction mixture is cooled to room temperature, washed 3 times with 25 ml water, dried over magnesium sulphite and evaporated under reduced pressure to give 214.3 g of: 5,7-di-tert-pentyl-3-hydroxy-3H-benzofuran-2-one as an orange coloured oil.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH:5]([CH3:32])[CH:6]([NH:19][C:20]([CH:22]1[CH2:26][CH:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][NH:23]1)=[O:21])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([CH2:16][CH2:17][CH3:18])[O:8]1>CO.CCOCC>[CH3:32][CH:5]([CH3:4])[CH:6]([NH:19][C:20]([CH:22]1[CH2:26][CH:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][N:23]1[CH2:1][CH2:2][OH:3])=[O:21])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([CH2:16][CH2:17][CH3:18])[O:8]1
Reactant: C1CO1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(CCC)C(O)C(O)C2O)C1
Solvent: CO
Solvent: CCOCC
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(CCC)C(O)C(O)C2O)N(CCO)C1
Reaction time: 48 h
Yield: 34 %

Procedure:
The title compound was prepared according to the process illustrated in Scheme 19. Ethylene oxide was used as the alkylating agent. To a stirred solution of 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide (example 103) (12.0 mg 0.029 mmol, 1 equiv) and TEA (100 μL) in MeOH (2 mL) at 0° C. was added condensed ethylene oxide (200 μL) was added and the reaction mixture stirred 48 h. The reaction mixture evaporated to dryness, and the resulting residue was purified by column chromatography on silica 20% 0.25M NH3 in MeOH/DCM to give the crude N alkylated product. The crude product was taken up in Et2O, filtered and the filtrate treated with 2M HCl in Et2O, the precipitated HCl salt was collected washed with Et2O and lyophilized to give the title compound as a colorless powder (4.4 mg 34%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[N:13]=[N:12][C:11]([NH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])([CH3:17])[CH3:16])=[N:10][CH:9]=2)[CH:7]=1.[CH3:26][N:27](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:5]1[CH:4]=[CH:3][C:2]([C:26]#[N:27])=[CH:7][C:6]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])([CH3:17])[CH3:16])=[N:10][CH:9]=1
Reactant: CC(C)(Nc1ncc(-c2cc(Br)ccc2F)nn1)c1ccccc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(Nc1ncc(-c2cc(C#N)ccc2F)nn1)c1ccccc1F
Temperature: 100 °C

Procedure:
6-(5-Bromo-2-fluorophenyl)-N-(2-(2-fluorophenyl)propan-2-yl)-1,2,4-triazin-3-amine (2.2 g, 5.6 mmol), zinc cyanide (0.72 g, 6.2 mmol), Pd(PPh3)4 (2.9 g, 2.8 mmol), and DMF (20 mL) were combined and heated in a round bottom flask at 100° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated and purified using silica gel chromatography to provide a yellow solid (1.7 g), m/z=352.1 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:7])[C:4]([OH:6])=[O:5].O=S(Cl)[Cl:10].[CH3:12]O>>[ClH:10].[NH2:1][CH2:2][C@H:3]([OH:7])[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: NC[C@H](O)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H](O)CN
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled suspension of (S)-3-amino-2-hydroxypropanoic acid (0.904 g) in MeOH (15 mL) was added SOCl2 (2.0 mL, 27 mmol) over ˜2.5 minutes. After the addition the reaction was allowed to warm to room temperature. After stirring overnight, the reaction was evaporated in vacuo. MeOH was added and the mixture evaporated in vacuo a second time to yield the product (S)-methyl 3-amino-2-hydroxypropanoate hydrochloride as a colorless oil. 1H NMR (400 MHz, DMSO-d6): 8.16 (3H, s), 6.36 (1H, s), 4.38 (1H, br d, J=8.3 Hz), 3.68 (3H, s), 3.10 (1H, dd, J=12.9 Hz, 3.7 Hz), 2.90 (1H, dd, J=12.9 Hz, 8.6 Hz).
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].[Br:18]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([Br:18])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: N#CN1c2ccccc2CCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CN1c2ccccc2CC(Br)c2ccccc21
Temperature: 2.5 °C
Reaction time: 0.92 h
Yield: 91.4 %

Procedure:
6.60 g (0.030 mols) of 5-cyano-10,11-dihydro-5H-dibenz[b,f]-azepine (I) are stirred at 50° C. with 50 ml of CCl4. The fluid suspension is added under stirring with 5.6 g (0.0315 mols) of N-bromosuccinimide of purity above 98%, then with 0.37 g (0.0015 mols) of dibenzoylperoxide. Temperature is raised to mild reflux and the mixture is stirred for a further 55 minutes controlling the formed foam, then cooled and solvent is evaporated off. The residue is suspended in toluene (15 ml) at 80° C. for 20 minutes, filtered, the solution is cooled at 0-5° C. for 1 hour, to obtain 8.2 g (83%) of 5-cyano-10-bromo-10,11-dihydro-5H-dibenz[b,f]azepine (II), m.p. 132-9 (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc(OC)cc1
Yield: 87 %

Procedure:
The compound prepared in Example 3 was reacted with 4-methoxy-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[C:4]=1[O:13][CH3:14].[CH3:15]N(CCN(C)C)C.[Li]CCCC.CCCCCC.CI>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([O:13][CH3:14])=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][C:8]=1[CH3:15]
Reactant: COc1ccc(OC)c(OC)c1OC
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: COc1cc(C)c(OC)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Syper, L. et al., Tetrahedron 36:123 (1980). To a solution of 1,2,3,4-tetramethoxybenzene 12 (4.0 g, 20.2 mmol) and TMEDA (6 mL, 38.0 mmol) in hexanes (44 mL) and THF (80 mL) at 0° C. under Ar, n-BuLi in hexane (1.6 M, 25.6 mmol) was added dropwise over a 10 min period and the reaction stirred for 30 min at 0° C. under Ar. Subsequent to dropwise addition of CH3I (20 mL, 160 mmol) over an 8 min period, the reaction was stirred for 3 h at 0° C. under Ar and then quenched by addition of aqueous NH4Cl and ether (20 mL). The organic layer was sequentially washed with concentrated NH4OH, water, and brine. Drying and concentration of the organic layer was followed by purification of the residue by flash chromatography (hexanes, hexanes/EtOAc, 19:1, v/v) to afford 13 as a clear oil (3.6 g, 83%). 1H NMR (CDCl3): δ6.45 (s, 1 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 2.23 (s, 3 H). 13C NMR (CDCl3): δ149.0, 146.9, 145.3, 140.7, 125.7, 108.2, 61.0, 60.9, 60.5, 55.9, 15.7.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[N:16]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:15]1=[O:39].[C:40](=[O:42])=[O:41].[OH-].[Na+]>O1CCCC1>[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[C:21]([C:40]([OH:42])=[O:41])=[C:22]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[N:16]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:15]1=[O:39]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc4ccccc34)sc21
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3cccc4ccccc34)sc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (2.0M solution in hexanes, 1.90 ml) was added dropwise to a solution of diisopropylamine (0.069 ml) in anhydrous tetrahydrofuran (30 ml ) at 0° C., under nitrogen. The solution was stirred for 5 minutes then cooled to −78° C. and a solution of 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.50 g) in anhydrous tetrahydrofuran (15 ml) was added dropwise. After 15 minutes, the flask was transferred to a sealed bomb containing carbon dioxide pellets (2 g) and heated to 50° C. for 18 hours. The reaction mixture was cooled to room temperature then added to aqueous sodium hydroxide solution (0.25M, 75 ml) and washed with ether (2×75 ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ether (2×75 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with isohexane:ethyl acetate (3:1) containing 1% acetic acid, to give the subtitle compound (0.337 g) as a solid.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2CCC2C=CC(OCC(O)=O)=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]([C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1)#[CH:37]>>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:37]#[C:36][C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: O=C(O)COc1ccc(CCc2ccccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Product: N#Cc1ccc(C#Cc2ccccc2-c2nc3ccccc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-cyclohexylmethyl-1H-benzoimidazole (Example 79, intermediate e) and 4-ethynyl-benzonitrile (CAS Reg. No. 3032-92-6). Yellow solid (22%). MS (Turbo Spray): m/z=416.6 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[N:28][CH:29]=1.O>O1CCCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:8]2([C:11]#[N:12])[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:28][CH:29]=1
Reactant: N#CC1CCC2(CC1)OCCO2
Reactant: Fc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
After 1,4-dioxaspiro[4,5]decane-8-carbonitrile (2.5 g) was dissolved in tetrahydrofuran (8 ml), 1M tetrahydrofuran-solution of lithium bis(trimethylsilyl)amide (15 ml) was added at 0° C. and stirred for 30 minutes. 5-Bromo-2-fluoropyridine (2.64 g) was further added and stirred at room temperature for two hours. Water was added to the reaction solution, extracted with ethyl acetate and concentrated in vacuo. The residue was purified with silica gel chromatography (n-hexane/ethyl acetate) and the resulting solid was washed with n-hexane to give the titled compound (3.32 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13]>>[C:11]1(=[O:15])[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[CH:8]2)[CH:4]=[CH:3][CH2:2][N:1]3[C:12]1=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1=Cc2ccccc2NC1
Product: O=C1C(=O)N2CC=Cc3cccc1c32

Procedure:
Generally speaking, the reaction of a 1,2-dihydroquinoline (II) with oxalyl chloride (III) to give a 4-H-pyrrolo[3,2,1-ij]quinolin-1,2-dione (I) is carried out in a dry aprotic solvent by the dropwise addition of a solution of the 1,2-dihydroquinoline in the same solvent to the stirred solution of oxalyl chloride in an inert atmosphere at or near room temperature. Subsequent to the addition the reaction mixture is briefly stirred at ambient temperature and then at gentle reflux to complete the reaction. The solvent is stripped from the reaction mixture at reduced pressure to give a solid residue which on crystallization from a selected solvent or solvent system furnishes the 4-pyrrolo[3,2,1-ij]quinoline-1,2-dione I.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=[O:13])[CH3:12])[CH:6]=1.CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([C:7]1[CH:6]=[C:5]([CH2:4][O:3][S:21]([CH3:24])(=[O:23])=[O:22])[CH:10]=[CH:9][N:8]=1)(=[O:13])[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(CO)ccn1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(COS(C)(=O)=O)ccn1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-hydroxymethyl-pyridin-2-yl)-ethanone (165 mg, 1.09 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.20 mL, 1.43 mmol) followed by DMAP (13 mg, 0.10 mmol) and Ms-Cl (0.11 mL, 1.39 mmol). After stirring at 0° C. for 1 h30, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude methanesulfonic acid 2-acetyl-pyridin-4-ylmethyl ester as a brown oil. The crude material (250 mg) was dissolved in acetone (8 mL) under inert atmosphere (N2). 4-Nitro-1H-pyrazole (139 mg, 1.09 mmol) was added followed by K2CO3 (761 mg, 5.45 mmol) and TBA bromide (70 mg, 0.22 mmol). The reaction mixture was stirred at rt for 2 h and concentrated to dryness. The residue was partitioned between water (5 mL) and EA (10 mL). The layers were separated and the aq. layer extracted with EA (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.41. LC-MS-conditions 02: tR=0.84 min, [M+H]+=247.33.
Reaction SMILES: [ClH:1].N[CH2:3][CH:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[NH2:10][CH2:11][CH:12]1CC(C(O)=O)C1>>[ClH:1].[NH2:10][CH2:11][CH:12]1[CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3]1
Reactant: NCC1CC(C(=O)O)C1
Reactant: COC(=O)C(C)CN
Agent: Cl
Product: COC(=O)C1CC(CN)C1

Procedure:
Compound 81-B was prepared in analogy to compound W in Example 20 by using 3-(aminomethyl)cyclobutanecarboxylic acid (PharmaBlock (Nanjing) R&D Co. Ltd, CAS: 1310729-95-3) instead of DL-3-aminoisobutyric acid.