Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:10][C@H:11]([OH:36])[C@@H:12]([NH:20][C:21](=[O:35])[C@H:22]([CH:32]([CH3:34])[CH3:33])[NH:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.[ClH:44]>O1CCOCC1>[ClH:44].[NH2:8][C@@H:9]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:10][C@H:11]([OH:36])[C@@H:12]([NH:20][C:21](=[O:35])[C@H:22]([CH:32]([CH3:34])[CH3:33])[NH:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)[C@H](NOCc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](NOCc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (2S,3S,5S)-5-amino-2-[N-(N-(2-pyridinyl-methoxy)valinyl)amino]-1,6-diphenyl-3-hydroxy hexane hydrochloride salt (LL-74A) was prepared from LL-74. The compound (2S,3S,5S)-5-[N-(tert-butyloxycarbonyl)amino]-2-[N-(N-(2-pyridinylmethoxy)valinyl)amino]-1,6-diphenyl-3-hydroxy hexane (LL-74, 108 mg, 0.183 mmol) was dissolved in 4.0M solution of HCl in dioxane (20 ml), and stirred at room temperature for 30 min. after which solvents were evaporated. The evaporation was repeated 3 times with ethyl ether (10 ml) and finally dried under vacuum. This compound (LL-74A) was used in next step without further purification. TLC [Rf =0.35 (chloroform:methanol, 8:2)]; HPLC (rt=12.6 min.); MS m/z 505 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=O)[N:6]=[C:7]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([O:23]C(=O)C)=[C:18]([CH3:27])[CH:17]=1)[N:8]2[CH3:15].[OH-].[Na+]>C(O)C>[OH:23][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([CH:7]2[N:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=3[O:2][CH3:1])[N:8]2[CH3:15])=[CH:17][C:18]=1[CH3:27]
Reactant: COc1cc(OC)c2c(=O)nc(-c3cc(C)c(OC(C)=O)c(C)c3)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c2c(c1)N(C)C(c1cc(C)c(O)c(C)c1)N=C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.8 %

Procedure:
A solution of 2,4-dimethoxy-6-methylamino-benzamide (0.28 g, 1.33 mmol) in pyridine (10 mL) was added to acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (1.1 eq.) and stirred at room temperature for 14 h. The solvent was removed and the reaction mixture was acidified with 1 N HCl and extracted with ethyl acetate. The solvent was removed and the crude was purified by silica gel column chromatography (40 g) employing 1% methanol in dichloromethane to give acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 67%). Acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 0.89 mmol) was dissolved in ethanol (5 mL), 5% aqueous NaOH solution (10 mL) was added dropwise and the mixture was stirred at room temperature for 1.5 h. The compound was extracted with ethyl acetate and washed with ether to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H-one (0.13 g, 43%). Selected data: MS (ES) m/z: 340.17; MP 188.5-189.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(O)(=O)C.[CH2:31]([O:33][C:34](=[O:37])[CH:35]=O)[CH3:32].C([BH3-])#N.[Na+]>CO>[CH2:31]([O:33][C:34](=[O:37])[CH2:35][N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[Cl:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]3)[CH2:15][CH2:16]1)[CH3:32]
Reactant: CCOC(=O)C=O
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)c(Cl)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)CN1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (5.38 mmol) of 7-Chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (7, free base) were dissolved in 100 mL of methanol. At room temperature, 1.09 g (10.8 mmol) of triethylamine, 3.23 g (53.8 mmol) of acetic acid, 7.63 g (33.6 mmol) of glyoxylic acid ethyl ester and molecular sieves (4 A) were added, followed by 253.6 mg (4.04 mmol) of sodium cyanoborohydride. After stirring for 2 h at room temperature, the reaction mixture was filtered and the filtrate was evaporated i. vac. The residue was dissolved in dichloromethane and washed with 1 N NaOH and sat. NaCl-solution. The organic layer was dried with MgSO4 and evaporated. The obtained crude product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:41](OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)([CH3:44])(C)[CH3:42].C1(B2OC(C)(C)C(C)(C)O2)CC1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([CH:44]5[CH2:41][CH2:42]5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Agent: CC1(C)OB(C2CC2)OC1(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C5CC5)cccc4c3=O)cc2)CCC1

Procedure:
Following the procedure used to prepare (1-{-4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with cyclopropyl boronic acid pinacol ester to give the title compound in a mixture containing 30% {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (65 mg). LCMS (Method A): RT=5.04 min, [M+H]+=508.
Reaction SMILES: [Br:1]Br.[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:1])[CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4]
Reactant: BrBr
Reactant: O=CNC1Cc2ccccc2NC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=CNC1Cc2cc(Br)ccc2NC1=O
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Bromine (16.0 g, 0.1 mol) was added to a stirred solution of 3-(formylamino)-3,4-dihydro-2(1H)quinolinone (19.0 g, 0.1 tool) and anhydrous sodium acetate (12.7 g, 0.2 tool) in acetic acid (500 mL). After 1 hour, water (1.5 L) was added and the precipitate was filtered off and air dried to give 17.8 g of 3-(formylamino)-6-bromo-3,4-dihydro-2(1H)quinolinone, mp 275°-282° C. This was dissolved in trifluoracetic acid (300 mL) and sodium nitrate (9.0 g) was added to the stirred solution. After I hour, water was added and the precipitate was filtered off and air dried to give 18.2 g of 3-(formylamino)-6-bromo-3,4-dihydro-8-nitro-2(1H) quinolinone, mp 232°-235° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:32])([CH2:11][C:12](=[O:31])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=O.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>ClCCl>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:8]([CH2:7][C:6]([CH3:32])([CH3:5])[CH2:11][C:12]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16][CH:15]=1)=[O:31])=[O:10]
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)CCNC(=O)CC(C)(C)CC(=O)Nc1ccc(OC(=O)N(C)c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 39 %

Procedure:
Thionylchloride (237 microL, 3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added N,N-dimethylethylenediamine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2), yielding the title compound (74 mg, 39% yield).
Reaction SMILES: [Cl:1][C:2]1([Cl:12])[CH2:4][CH:3]1[C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.C(O)(=[O:15])C.N([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:1][C:2]1([Cl:12])[CH2:4][CH:3]1[C:5]1[CH:11]=[CH:10][C:8]([OH:15])=[CH:7][CH:6]=1
Reactant: Nc1ccc(C2CC2(Cl)Cl)cc1
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C2CC2(Cl)Cl)cc1
Reaction time: 0.17 h

Procedure:
A solution of 50 g. (0.248 mole) of p-(2,2-dichlorocyclopropyl)aniline in 185 ml. of glacial acetic acid was cooled to about 10°C., and a solution of 18.9 g. (0.273 mole) of sodium nitrite in 185 ml. of water was added dropwise to the stirred solution. A thick slurry formed and this was added portionwise to a stirred solution of 160 ml. of concentrated sulfuric acid in 320 ml. of water held at 100°-105°C. The reaction mixture was stirred at 100 ± 5°C. for 10 minutes, then cooled and diluted with water. The resulting product was collected by filtration, dissolved in ether and washed with sodium bicarbonate solution. The ether solution was then extracted with sodium hydroxide solution, and the sodium hydroxide solution was acidified and extracted with ether. The ether solution was dried and concentrated in vacuo, and the residue (18 g.) was steam distilled affording 9 g. of a yellow gum which crystallized when triturated with ether. There was thus obtained 8 g. of p-(2,2-dichlorocyclopropyl)phenol, m.p. 54.5°-56°C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:41]([C:38]3[CH:39]=[CH:40][C:35]([Br:34])=[CH:36][CH:37]=3)(=[O:43])=[O:42])[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCNS(=O)(=O)c1ccc(Br)cc1
Yield: 72.4 %

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide was reacted with 166 mg 4-bromobenzenesulfonylchloride to give 106 mg 4-tert.-butyl-N-{6-[2-(4-bromobenzenesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.95 min, [M−1]−=691.41.
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[CH2:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>C1C=CC=CC=1>[CH:10]12[CH2:11][CH:12]([CH:8]=[CH:9]1)[CH:4]1[CH:5]2[C:1](=[O:7])[CH2:2][C:3]1=[O:6]
Reactant: C1=CCC=C1
Reactant: O=C1C=CC(=O)C1
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Solvent: c1ccccc1
Product: O=C1CC(=O)C2C3C=CC(C3)C12
Reaction time: 72 h

Procedure:
A solution of 4-cyclopentene-1,3-dione (5 84g; 0.06 mole) in anhydrous benzene (20ml) was treated with freshly distilled cyclopentadiene (7.3g; 0.122 mole) together with a few crystals of 2,5-di-t-butyl hydroquinone. An immediate reaction ensued with concommitant crystallisation of the product. After standing at room temperature for 3 days the title compound was filtered and recrystallised from methanol, m.p. 183° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)=[CH:15][C:14]([C:28](O)=[O:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.C(N=C=NCCCN(C)C)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:21][CH:22]=3)=[CH:15][C:14]([C:28]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[O:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(-c3ccco3)cc2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2nc(C(=O)N3CCOCC3)cc2-c2ccc(-c3ccco3)cc2)cc1F

Procedure:
A solution of 1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylic acid (0.2 g, 0.469 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC, 0.108 g, 0.563 mmol), and morpholine (0.04 mL, 0.492 mmol) in methylene chloride (10 mL) was stirred at room temperature for 3.5 hours. The mixture was diluted with methylene chloride (20 mL) and washed with saturated NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with methylene chloride/methanol (30/1). The resulting solid was recrystallized from methylene chloride-hexane to give the title compound to give the title compound (0.1 g, 43.1% yield).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:56])[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:52]([O:54][CH3:55])=[O:53])([C:22]3[CH:27]=[C:26]4[C:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:50][CH3:51])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([OH:47])[C@:33]3([CH2:48][CH3:49])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH2:4]1.[NH2:57][CH2:58][CH2:59][CH2:60][NH2:61]>CN(C=O)C>[CH3:1][CH2:2][C@@:3]1([OH:56])[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:52]([O:54][CH3:55])=[O:53])([C:22]3[CH:27]=[C:26]4[C:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:50][CH3:51])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([OH:47])[C@:33]3([CH2:48][CH3:49])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH2:4]1.[NH2:57][CH2:58][CH2:59][CH2:60][NH-:61]
Reactant: NCCCN
Agent: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](O)[C@]3(O)C(=O)OC)C2)C1
Solvent: CN(C)C=O
Product: [NH-]CCCN
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) a DMF solution (3 ml, 0.0624 mmol) of deacetylvinblastine acid azide (synthesis described in Example 9, Step C) was added 120 μl of 1,3-diaminopropane in DMF (2 ml). The reaction was stirred at -10° C. for 1 hr, filtered and concentrated to dryness to yield (11).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10](F)=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH:2]=[CH2:3].[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:39][N:40](C)C=O>O>[CH2:1]([O:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:39]#[N:40])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cn(C)c2cc(F)ccc2c1=O
Reactant: CN(C)C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: C=CCOc1cn(C)c2cc(C#N)ccc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-allyloxy-7-fluoro-1-methyl-4quinolone, obtained as described in Example 8a, (2.3 g), potassium cyanide (1.0 g), 18-crown-6 ether (5.0 g) and dimethylformamide (200 ml) was stirred at 95° for 2 days. After cooling to ambient temperature, the mixture was poured into water (600 ml) and extracted with dichloromethane (3×150 ml). The combined extracts were washed with water (2×200 ml), dried over magnesium sulphate and the solvent was removed by distillation. The residue was triturated with diethyl ether (50 ml) and the resultant solid added to a mixture of potassium cyanide (1.0 g), 18-crown-6 ether (5.0 g) and dimethylformamide (200 ml). The resultant solution was stirred at 140° for 16 hours and then allowed to cool to 60°. The solvent was removed under reduced pressure at 60° and the residue was partitioned between water (100 ml) and dichloromethane ( 200 ml). The dichloromethane solution was dried over magnesium sulphate and filtered through silica gel (30 g). The filter bed was washed with dichloromethane (5×100 ml) and the combined filtrate and washings were evaporated to give crude 3-allyloxy-7-cyano 1-methyl-4-quinolone.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)C.[F:21][C:22]([F:26])([F:25])[CH2:23]I.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:11]1[N:12]=[C:13]2[S:19][CH:18]=[CH:17][N:14]2[C:15](=[O:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:23][C:22]([F:26])([F:25])[F:21])=[CH:9][CH:8]=1
Reactant: FC(F)(F)CI
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To a solution of Step 1 intermediate from Intermediate 10 (400 mg, 2.712 mmol) in DMF (4 ml) was added 1,1,1-trifluoro-2-iodoethane (1.131 g, 5.413 mmol) at room temperature followed by Cs2CO3 (2.63 g, 8.120 mmol) and the reaction temperature was heated to 80° C. for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine and purified by column chromatography using 1% methanol in chloroform to afford the desired compound; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 4.79 (q, J=9.3 Hz, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 2H), 7.50 (d, J=4.8 Hz, 1H), 7.98 (d, J=4.5 Hz, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]=1)(=O)=O.Cl.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([C:34]2[S:44][C:43]3[N:45]4[C:36](=[CH:37][N:38]=[C:39]4[CH:40]=[CH:41][CH:42]=3)[CH:35]=2)=[O:33])[CH2:27][CH2:26]1.C(N(CC)CC)C.[I-].[Na+].N12CCCNC1CCCC=C2>C(#N)C>[C:19]([O:18][C:16]([NH:15][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:25]2[CH2:26][CH2:27][CH:28]([NH:31][C:32]([C:34]3[S:44][C:43]4[N:45]5[C:36](=[CH:37][N:38]=[C:39]5[CH:40]=[CH:41][CH:42]=4)[CH:35]=3)=[O:33])[CH2:29][CH2:30]2)[CH:14]=[CH:13][CH:12]=1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCCOS(C)(=O)=O)c1
Agent: C1=CN2CCCNC2CCC1
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(CCCN2CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC2)c1
Yield: 72.3 %

Procedure:
3-(3-tert-Butoxycarbonylaminophenyl)propyl methanesulfonate (423 mg, 1.28 mmol) was added to a stirred solution of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (400 mg, 1.07 mmol), triethylamine (539 mg, 5.33 mmol), sodium iodide (192 mg, 1.28 mmol) and 1,8-diazabicyclo[5.4.0]undecene (326 mg, 2.14 mmol) in acetonitrile (20 ml) at room temperature. After refluxing under nitrogen for 16 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (15 g) with Ethyl acetate-Methanol (3:1) to give N-[1-(3-(3-tert-butoxycarbonylaminophenyl)propan-1-yl]piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple amorphous powder(413 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[F:17][C:18]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28]Br)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>>[C:20]([C:19]1[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:25][C:18]=1[F:17])#[N:21]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: N#Cc1ccc(OCCBr)cc1F
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(C#N)c(F)c1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-fluoro-4-[(2-bromoethyl)oxy]benzonitrile: MS (ES) m/z 388 (M+1).
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[S-:15][C:16]#[N:17].[K+].O>CN(C)C=O>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([N:17]=[C:16]=[S:15])[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)c2cc(C#N)ccc2OC1N=C=S
Yield: 21.6 %

Procedure:
2-Chloro-5-cyano-2,3-dihydro-3,3-dimethylbenzofuran (5 g) from Example 15 and potassium thiocyanate (4.6 g) were heated in dimethylformamide (30 ml) at 110° C. for 7 hours. The mixture, after cooling, was added to water and the product extracted into diethyl ether. The ether solution was washed with water (twice), dried over magnesium sulphate and run down under vacuum yielding 4 g of crude product. Purification by silica gel chromatography in toluene yielded 1.2 g of title product, mp 52° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N2-butyl-8-methoxy-9-(tetrahydro-2H-pyran-2-ylmethyl)-9H-purine-2,6-diamine in dry methanol (5 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (1.5 ml) in one go. The reaction was left to stir at room temperature overnight. The reaction was concentrated in vacuo and the product purified by MDAP. This afforded the title compound 6 mg (slower-running on MDAP).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:22]1([S:28][CH2:29][CH2:30]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:30][CH2:29][S:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: ClCCSc1ccccc1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCSc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-phenylthioethylchloride analogously to Example 3.