Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:17][CH2:18][CH2:19][CH3:20])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[N:7][CH:8]=1)#[CH:2].[C:21]([Si:25]([CH3:34])([CH3:33])[O:26][CH2:27][CH2:28][CH2:29][N+:30]([O-])=[O:31])([CH3:24])([CH3:23])[CH3:22].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Si:25]([O:26][CH2:27][CH2:28][C:29]1[CH:2]=[C:1]([C:3]2[C:4]([NH:17][CH2:18][CH2:19][CH3:20])=[N:5][C:6]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[N:7][CH:8]=2)[O:31][N:30]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:34])[CH3:33]
Reactant: C#Cc1cnc(Nc2cccc(F)c2)nc1NCCC
Reactant: CC(C)(C)[Si](C)(C)OCCC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCO[Si](C)(C)C(C)(C)C)no1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 42 %

Procedure:
To a solution of 5-ethynyl-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (S2, 30 mg) and tert-butyldimethyl(3-nitropropyloxy)silane (S3, 146 mg) synthesized according to the method described in Journal of Medicinal Chemistry, 2011, 54, pp. 7280-7288 in toluene (1 mL), phenyl isocyanate (36 μL) and triethylamine (46 μL) were added at room temperature, and the mixture was stirred at 60° C. for 4 hours and 40 minutes. To the reaction mixture, phenyl isocyanate (36 μL) and triethylamine (46 μL) were added, and the mixture was further stirred at 60° C. for 6 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 5-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)isoxazol-5-yl)-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (S4, 22 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(Br)cc3Cl)c3c(F)c4nnsc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (40 mg, 0.10 mmol) in DCM (5 mL) was added triethylamine (21 mg, 0.20 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (27 mg, 0.15 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (50 mg, 87.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.78-7.76 (d, 2H), 7.33 (m, 1H), 5.76-5.58 (m, 1H), 5.08 (m, 2H), 2.93-2.86 (m, 1H), 2.13-2.0 (m, 1H), 1.97-1.87 (m, 2H), 1.28-1.16 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32](#[N:34])C.O.CN>[Cl-].[Na+].O>[CH3:32][NH:34][C:25]([C:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16][C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([C:28]([F:30])([F:31])[F:29])[CH:11]=1)=[O:26])=[O:27]
Reactant: CC#N
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3ncccc3c12
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2ncccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a suspension of 150 mg (0.30 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,8-diaza-phenanthren-4-one in 6 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 79 μL (0.91 mmol) of methylamine (solution 40% in water). The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:1) affords 110 mg (76%) of a white solid; LC/MS:475/477 (M+H)+, m.p.: 210-211° C.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[CH:3]=1.[CH2:12](C([Sn])=C(CCCC)CCCC)[CH2:13]CC.[Li+].[Cl-]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:12]([C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[CH:3]=1)=[CH2:13]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Brc1cnc2nccnc2c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1cnc2nccnc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
7-Bromo-pyrido[2,3-b]pyrazine (560 mg, 2.7 mmol) was suspended in toluene (25 ml) with tributylvinyltin (2.30 ml, 8.1 mmol), tetrakis(triphenylphosphine) palladium (106 mg, 106 mmol) and LiCl (336 mg, 8.06 mmol). The mixture was heated to 100° C. under a nitrogen atmosphere. After 2 h, the reaction was complete and the toluene was removed under vacuum. The crude was taken up in ethyl acetate and washed three times with a 1 N HCl solution. The combined acid washings were washed twice with ethyl acetate. The acidic water was made basic with the addition of solid sodium carbonate, and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried using MgSO4, and concentrated under vacuum to yield the title product (250 mg, 59%) as a tan solid.1H NMR (DMSO-d6): δ=9.40 (d, 1H, J=2.5Hz), 9.08 (dd, 2H, J=12.3 Hz, 1.8 Hz), 8.60 (d, 1H, J=2.5 Hz), 7.11(m,1H), 6.40 (d, 1H, J=17.8 Hz,), 5.64 (d, 1H, J=11.3 Hz). Calculated mass=157.18, [M+H]+=158. HPLC Method D: 99.3% @ 210-370 nm; 99.7% @ 240 nm; RT=4.5 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][NH2:41])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][NH:41][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and 3-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:36])=[O:17])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COC(=O)CCCCc1ccccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2ccccc2CCCCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 4, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(5-bromopentyl)oxy]benzenepentanoic acid methyl ester from the preceding example, followed by saponification, in 46.5% overall yield. The product was an off-white solid, mp 75°-76° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([NH:8][CH:9]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])[CH3:4].C(O)C.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[CH2:32]>C1C=CC=CC=1>[CH2:3]([O:5][C:6]([N:8]1[CH2:32][CH:31]([C:30]([O:34][CH2:35][CH3:36])=[O:33])[C:10](=[O:11])[CH:9]1[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)NC(C(=O)OC)C(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)C1CN(C(=O)OCC)C(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
To a suspension of 80% sodium hydride (2.48 g, 83 mmol) in benzene (50 ml) was slowly added a solution of methyl 2- ethoxycarbonylamino- 3,3-diphenylpropanoate (Example 1b, 27.0 g, 83 mmol) in benzene (200 ml) and the mixture then heated at reflux for 1 h. Ethanol (1.0 ml) followed by ethyl acrylate (8.95 ml, 83 mmol) were added and the reaction heated at reflux for 2 h, the solvent was then distilled off and the residue allowed to cool to room temperature. A solution of the residue in water was added to a concentrated sulphuric acid/ice mixture and the product extracted into ethyl acetate. The organic phase was washed with saturated brine and dried (MgSO4). The residue was chromatographed on silica gel in dichloromethane/methanol (97:3) to give 1,4-bis(ethoxycarbonyl)-2-(diphenylmethyl)-pyrrolidin-3-one, m/z (CI+) 396(MH). A solution of this oil in 1.0M oxalic acid was heated at reflux for 8 h, cooled and the product extracted into chloroform. After separation the chloroform was removed in vacuo and the residue chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluant to give 2-(diphenylmethyl)-1-ethoxycarbonylpyrrolidin-3 -one. 1H NMR (250 MHz, CDCl3) δ7.14-7.52 (10H, m), 4.80 (1H, br s), 4.68 (1H, vbr s), 4.18 (2H, br q), 3.94 (1H, vbs), 3.06 (1H, m), 2.34 (1H, m), 1.76 (1H, m), 1.22 (3H, t, J=7.0 Hz). m/z (CI+) 324(MH).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([N:14]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[C:11]([F:13])=[CH:12][C:7]=3[N:6]3[C:27](=[O:32])[NH:28][C:29](=[O:31])[CH:30]=[C:5]23)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]([F:13])=[CH:12][C:7]=3[N:6]3[C:27](=[O:32])[NH:28][C:29](=[O:31])[CH:30]=[C:5]23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)[nH]c(=O)cc2n3C2CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc2n(C3CC3)c3cc(N4CCNCC4)c(F)cc3n2c(=O)[nH]1
Reaction time: 2 h
Yield: 60.6 %

Procedure:
tert-Butyl 4-[5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate (471 mg, 1 mmol) is dissolved in trifluoroacetic acid (2 ml). After 1 hour at 25° the trifluoroacetic acid is distilled off. The residue is taken up in water (10 ml), treated with sodium hydrogen carbonate (168 mg, 2 mmol) and stirred at 25° for 2 hours. The suspension is cooled to 0°. The crystals are filtered off, washed in succession with in each case 5 ml of cold water and ethanol and recrystallized from ethanol/water (95/5). There are obtained 208 mg (60.6%) of 5-cyclopropyl-8-fluoro-7-(1-piperazinyl)-pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione trifluoroacetate.
Reaction SMILES: [ClH:1].[CH2:2]([N+:9]1(C)[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([O:18][CH3:19])[CH:15]=2)[CH2:10]1)C1C=CC=CC=1.Cl.[H][H]>CO.[C].[Pd]>[ClH:1].[CH3:19][O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:20][CH3:21])[CH2:10][N:9]([CH3:2])[CH2:17]2
Reactant: COc1cc2c(cc1OC)C[N+](C)(Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1OC)CN(C)C2

Procedure:
1.0 g (3.12 mmol) of N-benzyl-5,6-dimethoxy-N-methylisoindolinium hydrochloride was dissolved in 20 ml of methanol, and 0.5 ml of 6N hydrochloric acid and 100 mg of a 10% palladium carbon catalyst were added thereto. The catalytic reduction was conducted at room temperature for 5 hours in a hydrogen gas stream. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The crystal residue was washed with 10 ml of acetone to obtain 650 mg of the above identified compound.
Reaction SMILES: [C:1]([N:5]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:6][C:7]([N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O-:17])=[O:16])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[C:1]([N:5]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:6][C:7]([N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=[O:16])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(CC(=O)N1C(=O)CC[C@H]1C(=O)[O-])C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)N(CC(=O)N1C(=O)CC[C@H]1C(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Carbamate 4 (0.74 g, 1.97 mmol) was dissolved in dichloromethane (12 cm3) under nitrogen and cooled to 0° C. Trifluoroacetic acid (6 cm3) was added dropwise over a period of 5 min and the solution stirred for 1.5 h. The solution was evaporated under reduced pressure to give an orange gum, that was dissolved in toluene and evaporated under reduced pressure (2×10 cm3) to give crude acid 5 as an orange gum. The material was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[C:19](=[O:20])[C:18]2[C:17]3[N:16]([CH3:21])[C:15]4[N:14]=[C:13]5[CH:22]=[CH:23][CH:24]=[CH:25][C:12]5=[CH:11][C:10]=4[C:9](=[O:26])[C:8]=3[C:7]([O:27][CH3:28])=[CH:6][C:5]=2[O:4][C:3]1([CH3:30])[CH3:29].[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:31]([O:1][CH:2]1[C:19](=[O:20])[C:18]2[C:17]3[N:16]([CH3:21])[C:15]4[N:14]=[C:13]5[CH:22]=[CH:23][CH:24]=[CH:25][C:12]5=[CH:11][C:10]=4[C:9](=[O:26])[C:8]=3[C:7]([O:27][CH3:28])=[CH:6][C:5]=2[O:4][C:3]1([CH3:30])[CH3:29])(=[O:33])[CH3:32]
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)C(=O)C(O)C(C)(C)O2
Reactant: CC(=O)OC(C)=O
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)C(=O)C(OC(C)=O)C(C)(C)O2

Procedure:
The product is obtained according to the procedure of Example 13 starting from the compound of Example 15 and using acetic anhydride instead of butyryl chloride.
Reaction SMILES: Br[C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].C([Li])(C)(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[OH:33][C:30]1([C:2]2[C:3](=[O:12])[NH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=c1[nH]c2ccccc2cc1Br
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc3ccccc3[nH]c2=O)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A flask was charged with 3-bromoquinolin-2(1H)-one (U.S. Pat. Appl. Publ. 2002, U.S. 2002099208 A1; Payack, J. F. et al. J. Org. Chem. 2005, 70, 1, 175.) (1.0 g, 4.46 mmol) and sodium hydride (118 mg, 4.91 mmol). The solids were dissolved in tetrahydrofuran (30 mL), stirred for 15 min, and cooled to −78° C. The solution was treated with tert-butyllithium (1.7 M in pentane, 5.25 mL, 8.93 mmol) and stirred for 1 h. To this was added N-tert-butoxycarbonyl-4-piperidone (889 mg, 1.0 equiv). The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of saturated ammonium chloride. The reaction was diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. The resulting oil was triturated with diethyl ether to give a white solid which was filtered, washed with diethyl ether, and air dried to give 430 mg (28%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 1.48 (s, 9H), 1.57 (bs, 2H), 1.87 (m, 2H), 2.13 (m, 2H), 3.37 (m, 2H), 4.06 (m, 2H), 7.28 (m, 2H), 7.53 (m, 2H), 7.60 (m, 1H), 7.69 (s, 1H). Mass spec.: 367.35 (MNa)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:25]N1C(=O)CCC1=O>ClCCl>[F:24][C:2]([F:1])([F:23])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:22])[N:19]=[CH:20][C:21]=3[Br:25])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3ccnn3C)ccc21
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3c(Br)cnn3C)ccc21
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a solution of N-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (30 mg, 0.082 mmol) in dichloromethane (1 mL) was treated with N-bromosuccinimide (15.3 mg, 0.086 mmol) and stirred overnight at 20 C. The product mixture was absorbed on silica and purified by flash chromatography (2-5% MeOH in CH2Cl2, silica) resulting in 37 mg of a white crystalline solid. MS calculated for C17H17BrF3N3O+H: 416, observed: 416.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.ClCCl.CCCCCC.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.CO>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:3]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])c(-c3ccccc3F)c2)CC1
Yield: 120.5 %

Procedure:
The procedure of Example 9, step (b) was followed using 75.0 mg (0.250 mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example 9, step (a)), 136 mg (0.999 mmol) 2-fluorophenylboronic acid, 26.8 mg (0.0232 mmol) of tetrakis(triphenylphosphine)palladium (0) and 400 μL (0.799 mmol) of 2.0 M aq Na2CO3 in DME except the mnixture was heated for 22 h. Chromatography on a 5-g silica SPE column with 1-5% MeOH in dichloromethane-hexane (1:1) afforded 95.0 mg of the title compound (76% purity by 1H-NMR as a mixture with triphenylphosphine) as a yellow resin that was used in the following reaction without further purification. Mass spectrum (ESI, m/z): Calcd. for C17H18FN3O3, 316.1 (M+H), found 316.2.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:42][C:43]1[N:44]([CH2:48][CH2:49][CH3:50])[CH:45]=[CH:46][N:47]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:42][C:43]5[N:44]([CH2:48][CH2:49][CH3:50])[CH:45]=[CH:46][N:47]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CC(C)C)cc1
Reactant: CCCn1ccnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nccn4CCC)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g), 2-chloromethyl-1-propylimidazole hydrochloride (0.22 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (15 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(1-propylimidazole-2-yl) methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 25) (0.51 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11]3[CH2:12][CH2:13][N:14]4[C:19]([C:10]=3[N:9]([CH3:21])[C:6]2=[CH:7][CH:8]=1)=[CH:18][CH2:17][CH2:16][C:15]4=[O:20].[H][H]>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11]3[CH2:12][CH2:13][N:14]4[CH:19]([C:10]=3[N:9]([CH3:21])[C:6]2=[CH:7][CH:8]=1)[CH2:18][CH2:17][CH2:16][C:15]4=[O:20]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)c1c(n2C)C2=CCCC(=O)N2CC1
Agent: [Pd]
Product: COc1ccc2c(c1)c1c(n2C)C2CCCC(=O)N2CC1

Procedure:
Hydrogenation of 9-methoxy-12-methyl-2,3,4,6,7,1 2-hexahydroindolo[2,3-a]quinolizin-4-one with hydrogen in the presence of palladium-on-charcoal and sodium bicarbonate leadsto9-methoxy-12-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3a]quinolizin-4-one
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:13].CCOCC.OS([O-])(=O)=O.[K+].Br[CH2:39][Cl:40]>>[C:12]([Si:16]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH2:39][Cl:40])[CH:19]=1)([CH3:26])[CH3:25])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Reactant: ClCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(SCCl)c1
Reaction time: 2 h

Procedure:
DBU (914 mg, 6.0 mmol) was added to a solution of 3-(tert-Butyl-dimethyl-silanyloxy)-benzenethiol (1.00 g, 4.16 mmol) in bromo-chloro methane (5 ml) at room temperature. Stirring was continued for 2 hours and Et2O (50 ml) and 2M KHSO4 (30 ml) were added. The organic layer was separated, washed with 2M KHSO4 (30 ml) and brine (30 ml), dried (Na2SO4) and concentrated under reduced pressure. The resulting oil was analysed by 1H-NMR spectroscopy and was used without further purification. Yield: 1.01 g (84%).