Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Br[CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[O:12][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]([OH:6])[C:4]=2[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)c(O)c1Cl
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(C(=O)OCC)Oc2c(ccc(OC)c2Cl)C1O
Yield: 79.6 %

Procedure:
To a solution of (14h) (69.91 g., 0.375 mol) and diethyl bromomalonate (79.9 ml., 0.468 mol) in 2-butanone (400 ml.) was added freshly powdered anhydrous potassium carbonate (51.78 g.). The suspension was stirred vigorously and heated at reflux for 4.5 hours, then filtered and evaporated to dryness. The oil obtained was redissolved in carbon tetrachloride and filtered, then evaporated and recrystallized from chloroform with hexane to yield 79.6% of (15h), m.p. 115.5°-117° C. Analysis (C15H17ClO7) C,H.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:12][CH2:13][C:14](Cl)=C)=[CH:9][CH:10]=2)[O:5][C:4](=[O:18])[CH:3]=1.[CH2:19](N(CC)C1C=CC=CC=1)C>CCOCC>[CH3:1][C:2]1[C:11]2[CH:10]=[C:9]3[C:8](=[C:7]([CH3:17])[C:6]=2[O:5][C:4](=[O:18])[CH:3]=1)[O:12][C:13]([CH3:14])=[CH:19]3
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1C
Reactant: CCN(CC)c1ccccc1
Solvent: CCOCC
Product: Cc1cc2cc3c(C)cc(=O)oc3c(C)c2o1
Yield: 41.6 %

Procedure:
A mixture of 4,8-dimethyl-7-(2'-chloroallyloxy)coumarin (500 mg., 1.89 m mole) and N,N-diethylaniline (5.0 ml) was protected by an "Aquasorb" (TM), brand of phosphorous pentoxide drying tube, while being heated under reflux for twenty-four hours at an oil bath temperature of 220°-225° C. Treatment of the reaction mixture as described in part 1-B gave some black, ether-insoluble material which was discarded. The desired 4,5',8-trimethylpsoralene was obtained as a tan solid (154 mg., 41.6% yield), which was recrystallized from 95% ethanol to obtain light tan needles (53 mg., 14% yield) of m.p. 233° C. (rptd: m.p. 234° C.). Its infrared spectrum was identical to that of a commercial sample.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:23][CH3:24])[CH2:20][CH2:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=O)[CH2:11][CH2:10]4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH2:4]1.[O:25]([NH2:27])[CH3:26].Cl.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO.O>[CH3:26][O:25][N:27]=[C:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH2:19][CH2:20][C:3]([O:23][CH3:24])([O:2][CH3:1])[CH2:4][C:5]=1[CH2:6][C@H:7]3[CH3:22]
Reactant: CON
Reactant: COC1(OC)CCC2=C(C[C@@H](C)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: CON=C1CC[C@H]2[C@@H]3[C@H](C)CC4=C(CCC(OC)(OC)C4)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(7α)-3,3-Dimethoxy-7-methylestr-5(10)-en-17-one (100 mg, 0.3 mmol) was added to a solution of methoxylamine.HCl (100 mg, 1.2 mmol) and sodium acetate (123 mg, 1.5 mmol) in 6 mL MeOH. The reaction mixture was stirred for 3 days at room temperature. Water and a solution of saturated sodium hydrogen carbonate was added and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated to dryness to give the crude (7α)-3,3-dimethoxy-7-methylestr-5(10)-en-17-one O-methyloxime, which was converted into (7α)-3-methylene-7-methylestr-5(10)-en-17-one O-methyloxime according to the methods described above, [α]D +149° (c 0.11 in ethanol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:26])=[C:8]([C:10]2[NH:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[N:11]=2)[CH:9]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:30]([CH:27]2[CH2:29][CH2:28]2)=[O:31])=[CH:9][C:8]=1[C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[N:11]=1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1
Yield: 93.7 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using methyl 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate hydrochloride (0.250 g, 0.5 mmol), cyclopropane carbonyl chloride (0.108 g, 1.0 mmol), DIPEA (2.0 mL), THF (10 mL) to afford 0.200 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.05 (s, 2H), 1.60 (m, 2H), 3.14 (m, 1H), 3.87 (s, 3H), 4.33 (d, J=5.7 Hz, 2H), 7.41-7.61 (m, 4H), 8.11-8.17 (m, 3H), 8.69 (m, 1H), 12.65 (br s, 1H); MS (m/z): 427.14 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]I)[CH:5]=[CH:6][C:7]=1[Cl:8].[C-:21]#[N:22].[Na+].O>CS(C)=O>[C:21]([CH2:11][CH2:10][C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@H](CCI)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCC#N)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a stirred solution of 366 (810 mg, 1.88 mmol) in DMSO (4 mL) at RT was added NaCN (102 mg, 2.07 mmol) and the resulting mixture was stirred at 80° C. overnight. The mixture was poured into water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated. The product was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 534 mgs (86%) of (R)-tert-butyl 3-cyano-1-(3,4-dichlorophenyl)propylcarbamate (368).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@@H:32]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[C@@H:34]([F:39])[CH2:33]1)=[N+:30]=[N-:31]>>[N:29]([C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[C@H:34]([F:39])[CH2:33]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=N[C@@H]1CC[C@@H](N)[C@@H](F)C1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N=[N+]=[N-])C[C@H]1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1R*,2S*,4R*)-4-azido-2-fluorocyclohexanamine hydrochloride (example C56) the title compound is obtained as pale yellow foam.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[NH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH2:2]([N:9]1[CH2:10][CH:11]=[C:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[NH:17][CH:16]=2)[CH2:13][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1[nH]cc(-c2cc[n+](Cc3ccccc3)cc2)c2ccccc12
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]cc(C2=CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 25 °C
Yield: 89.8 %

Procedure:
1-Benzyl-4-(1-oxo-2H-isoquinolin-4-yl)pyridinium bromide (9.0 g) was dissolved in methanol (100 mL), and sodium borohydride (3.7 g) was added in small portions with stirring at room temperature. After the completion of the reaction, the solvent was evaporated. Water was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. Ethyl acetate was added to the obtained residue, and the precipitated crystals were collected by filtration to give 4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one (6.5 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=O)=[C:4]([NH:15][CH3:16])[CH:3]=1.CC(C)([O-])C.[K+].O.[CH3:24][S:25]([CH3:27])=[O:26]>>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:8])[CH2:24][S:25]([CH3:27])=[O:26])=[C:4]([NH:15][CH3:16])[CH:3]=1
Reactant: CS(C)=O
Reactant: CNc1cc(F)ccc1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CNc1cc(F)ccc1C(=O)CS(C)=O
Temperature: 25 °C

Procedure:
A solution of t-butyl 4-fluoro-2-methylaminobenzoate (28.9 g) in dimethylsulphoxide (133 ml) was added to a solution of potassium t-butoxide (72.2 g) in dimethylsulphoxide (300 ml) at ambient temperature under nitrogen. The stirred mixture was heated at 50° for eight hours and then cooled to ambient temperature. Water (1300 ml) was added to the mixture whilst maintaining the temperature below 35°. Extraction with trichloromethane and evaporation of the extract in vacuo gave 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone, m.p. 129°-134°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[O:11][C:10]2=[O:17])=[CH:5][CH:4]=1.[OH-].[Na+].[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)#[N:21].Cl>C1COCC1>[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[O:11][C:10]3=[O:17])=[CH:7][CH:8]=2)=[O:27])=[CH:24][CH:23]=1)#[N:21]
Reactant: NCc1ccc(N2CC(C(=O)O)OC2=O)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)NCc2ccc(N3CC(C(=O)O)OC3=O)cc2)cc1

Procedure:
5.4 g of 3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinecarboxylic acid are suspended in 70 ml of THF. 35 ml of 1N NaOH are added dropwise with stirring. Subsequently, a solution of 6.6 g of 4-cyanobenzoyl chloride in 60 ml of THF is added dropwise. The pH of the solution is maintained at between 9 and 10.5 by addition of 1N NaOH. After reaction has taken place, the mixture is acidified at a pH of 1 with 2N HCl. The solvent is removed and the residue is filtered off with suction and washed with water. 3-[4-(4-cyanobenzamidomethyl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid is obtained, m.p. 234°.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCO[CH2:18][CH3:19]>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH2:1][NH2:8])=[CH:3][CH:4]=2)[CH2:19][CH2:18][CH2:3][CH2:2][CH2:1]1
Reactant: N#Cc1ccccc1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Benzonitrile 18m (1.2 g, 6.48 mmol) dissolved in 10 ml of ether was added dropwise at 0° C. to LiAlH4 (2 equiv., 493 mg) suspended in diethyl ether (40 ml). The mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and filtrated and the salts were washed with ether. The organic phase was separated, anhydrified and evaporated giving 1 g of an orange oil. Yield=82%. 1HNMR (DMSO, 200 MHz) δ 1.57 (6H, m), 3.06 (4H, m), 3.58 (2H, s), 6.84 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=8.4 Hz), 7.33 (2H, bs).
Reaction SMILES: [Br-].C[O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][C:7]=1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[CH3:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1>>[CH3:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][CH2:21][C:7]2[O:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=3)=[CH:10][C:6]=2[CH2:4][OH:3])=[CH:44][CH:43]=1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Br-]
Product: Cc1ccc(CCc2oc(-c3ccc(C(F)(F)F)cc3)cc2CO)cc1

Procedure:
prepare from intermediate 62 and 4-methylbenzaldehyde
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[I:13])[NH:4][C:3]1=O.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([CH2:23][N+:24]#[C-:25])[N:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[N:24]=[CH:25][N:4]4[C:5]5[C:10](=[C:9]([I:13])[CH:8]=[CH:7][CH:6]=5)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=34)[N:19]=2)[CH2:17][CH2:16]1
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Reactant: Cn1c(=O)[nH]c2cccc(I)c2c1=O
Product: Cn1c(=O)c2c(I)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
M.p. 217°-220° C. by reaction between 3-methyl-5-iodo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][N:23]([CH3:22])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CNCCO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CN(CCO)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 71 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-methylamino-ethanol according to the GPA affording 25 mg (71%) of an orange-dark powder. Rt=2.98 min.
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([SH:12])[CH:9]=[C:8]([O:13][CH3:14])[N:7]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C>[NH2:5][C:6]1[N:11]=[C:10]([S:12][CH:2]([F:4])[F:1])[CH:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: FC(F)Cl
Reactant: COc1cc(S)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(SC(F)F)nc(N)n1

Procedure:
Gaseous difluorochloromethane is introduced for 11/2 hours at 60° to 65° C. into a suspension of 7.8 g of 2-amino-4-mercapto-6-methoxy-pyrimidine and 30 ml of concentrated sodium hydroxide solution in 100 ml of dioxane. By the addition of water, extraction with ethyl acetate, concentration of the organic phase by evaporation and crystalisation from methanol at -78° C., there are obtained 6.4 g of 2-amino-4-difluoromethylthio-6-methoxy-pyrimidine, m.p. 83° to 84° C. (compound No. 1.13).
Reaction SMILES: ClC1C(Cl)=C(O)C=C2C=1C1C(CC)(C2)CCC(=O)C=1.BrCC(OCC)=O.[Cl:27][C:28]1[C:40]([Cl:41])=[C:39]([OH:42])[CH:38]=[C:37]2[C:29]=1[C:30]1[C:35]([CH3:43])([CH2:36]2)[CH2:34][CH2:33][C:32](=[O:44])[CH:31]=1.Br[C:46]1([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]1>>[Cl:27][C:28]1[C:40]([Cl:41])=[C:39]([O:42][C:46]2([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:38]=[C:37]2[C:29]=1[C:30]1[C:35]([CH3:43])([CH2:36]2)[CH2:34][CH2:33][C:32](=[O:44])[CH:31]=1
Reactant: CC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Reactant: CCOC(=O)C1(Br)CCCC1
Agent: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Agent: CCOC(=O)CBr
Product: CCOC(=O)C1(Oc2cc3c(c(Cl)c2Cl)C2=CC(=O)CCC2(C)C3)CCCC1

Procedure:
Carrying out a reaction as described in Example 1, Step D, except that the 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one and ethyl bromoacetate are replaced by equimolar quantities of 5,6-dichloro-7-hydroxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one and ethyl 1-bromocyclopentane-1-carboxylate, there is obtained ethyl 1-[(5,6-dichloro-9a-methyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]cyclopentane-1-carboxylate.
Reaction SMILES: Cl.[C@@H:2]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.C[Si](Cl)(C)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.ClCCl>N1C=CC=CC=1>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([NH:15][C:14]2[CH:16]=[CH:17][N:10]([C@@H:2]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]3)[C:11](=[O:12])[N:13]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)n2)cc1
Reaction time: 8 h

Procedure:
2'-deoxycytidine hydrochloride (1.32 g, 5 mmol) is allowed to react for 1 hour with trimethylsilyl chloride (2.5 ml, 20 mmol) in anhydrous pyridine (20 ml) while stirring. The reaction mixture is then concentrated by evaporation to a volume of ca. 15 ml while excluding moisture and p-toluenesulfonyl chloride (1.9 g, 10 mmol) is added. The well-sealed reaction vessel is stored overnight at 60° C. in a drying cupboard. Examination of the mixture by thin-layer chromatography shows a complete conversion of the starting materials. The reaction volume is increased by addition of dichloromethane (50 ml) and the organic phase is extracted by shaking with a saturated aqueous sodium bicarbonate solution (60 ml). The aqueous layer is extracted twice with dichloromethane (20 ml). The combined extracts are concentrated in a water jet vacuum and made up to a volume of ca. 15 ml with pyridine. Concentrated aqueous ammonia solution (15 ml) is added to this and the progress of the desilylation is monitored by thin layer chromatography. The reaction is quantitative after 4 hours. The reaction mixture is then concentrated under reduced pressure and the crude product, 4-N-p-toluenesulfonyl-2'-deoxycytidine obtained is concentrated by coevaporation with anhydrous pyridine (3×20 ml) and subsequently dissolved again in absolute pyridine (20 ml). 4,4'-dimethoxytrityl chloride (1.70 g, 5 mmol) is added. The tritylation reaction is observed by thin layer chromatography and is completed within 2 hours. The reaction mixture is partitioned between dichloromethane (50 ml) and 0.5M aqueous sodium bicarbonate solution (50 ml). The aqueous layer is additionally extracted with dichloromethane (2×50 ml) and the organic extracts are dried over anhydrous sodium sulfate and concentrated. Pure 5'-O-dimethoxytrityl-4-N-p-toluenesulfonyl-2'-deoxycytidine is obtained after chromatographic purification on a silica gel column with dichloromethane/methanol as the eluting agent. The product is dissolved in benzene (20 ml), frozen and lyophilized in an oil-pump vacuum. The pure product is isolated as a white solid substance. 2.520 g, 73.7% yield
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCN(C)CC3)ccc2S(C)(=O)=O)c1OC
Yield: 7.5 %

Procedure:
N-(1-(5-Chloro-2,3-dimethoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (0.50 g, 1.29 mmol), 1-methylpiperazine (0.60 g, 6.40 mmol), N,N-diisopropylethylamine (0.66 g, 5.15 mmol) were stirred at 110° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (45.1 mg, 7.5% yield). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H), 6.87 (d, 1H), 6.76 (d, 1H), 6.52 (d, 1H), 6.22 (dd, 1H), 5.91 (d, 1H), 4.85 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.19 (m, 4H), 3.04 (s, 3H), 2.43 (m, 4H), 1.54 (d, 3H); MS (ESI) m/z: 468.0 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(OC)c(OC)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate (28 mg, 0.091 mmol) and 1-(3-methoxy phenyl) piperazine (27 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (27 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:2) mixture and concentration gave 26 mg of the titled compound (yield, 64%). 1H NMR (300 MHz, CDCl3) δ 3.27-3.29 (m, 4H), 3.78-3.81 (m, 7H), 3.94 (s, 3H), 3.97-3.98 (m, 1H), 4.00 (s, 3H), 4.15 (s, 3H), 6.47-6.49 (m, 2H), 6.56-6.58 (m, 1H), 7.11 (s, 1H), 7.14-7.27 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[NH:6][C:7](=[O:13])[N:8]([CH2:10][O:11][CH3:12])[CH:9]=1)([O-:3])=[O:2].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[N+:1]([C:4]1[C:5](=[O:14])[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:13])[N:8]([CH2:10][O:11][CH3:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: COCn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c([N+](=O)[O-])cn(COC)c1=O
Temperature: 25 °C

Procedure:
The compound of example 41 (10.0 g, 50 mmole) is dissolved in tetrabutylammonium flouride (120 mL of a 1.0M solution in tetrahydrofuran, 0.124 mole). Ethyl bromoacetate (8.3 mL, 75 mmole) is added. The reaction is stirred at room temperature. The reaction mixture is concentrated, then partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent is removed under vacuum to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C(=O)O)c1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-(5-bromopyridin-2-yl)-2-methylpropanoate (514 mg, 2 mmol) was dissolved in dry DCM (10 mL) and cooled to −10° C. BBr3 (20 mL of 1M solution in DCM) was added drop-wise under argon to the solution. The reaction mixture was stirred 30 min at −10° C. and then at room temperature for 72 h and evaporated to give 2-(5-Bromopyridin-2-yl)-2-methylpropanoic acid used in the next step without further purification. MS+H (244, 246).