Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[CH:11]=2)=[O:9])=[C:6]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:25]=[C:24]2[CH2:34]O)[CH:5]=1)[CH3:2].[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4]1[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[CH:11]=2)=[O:9])=[C:6]([N:23]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:26][N:25]=[C:24]2[CH2:34][N:40]2[C:36](=[O:46])[C:37]3=[CH:45][CH:44]=[CH:43][CH:42]=[C:38]3[C:39]2=[O:41])[CH:5]=1)[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOc1cc(-n2c(CO)nnc2-c2ccccc2)c(C(=O)c2cccc(SC)c2)cc1C(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1cc(-n2c(CN3C(=O)c4ccccc4C3=O)nnc2-c2ccccc2)c(C(=O)c2cccc(SC)c2)cc1C(C)C

Procedure:
In the manner given in Example 3, a mixture of 4-ethoxy-5-isopropyl-3'-methylthio-2-[3-(hydroxymethyl)-5-phenyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 4-ethoxy-5-isopropyl-3'-methylthio-2-[3-(phthalimidomethyl)-5-phenyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]3/[C:13](=[CH:22]/[C:23]#[N:24])/[C:14]4[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=4[CH2:16][CH2:17][C:11]=3[CH:10]=2)[CH:2]=1.Cl[C:34](=[O:40])[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:8][C:9]2[CH:26]=[CH:25][C:12]3/[C:13](=[CH:22]/[C:23]#[N:24])/[C:14]4[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=4[CH2:16][CH2:17][C:11]=3[CH:10]=2)[C:34](=[O:40])[CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:2]=1
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CNc3cccc(-c4ccccc4)c3)ccc21
Reactant: COC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)N(Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N)c1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
[step 1] Compound 43 (200 mg, 0.49 mmol) obtained in Example 43 was dissolved in DMF (1 mL), and the mixture was cooled to 0° C. Methyl 3-chloro-3-oxopropanoate (99 mg, 0.73 mmol) was added, and the mixture was stirred at room temperature for 7 hr. To this mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the precipitate was collected by filtration to give (E)-[2-(N-(biphenyl-3-yl)-3-methoxy-3-oxopropanamido)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile quantitatively.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[CH2:6]1[N:17]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:15][N:14]([CH2:22][C:23]([OH:25])=[O:24])[CH2:13][CH2:12][N:11]([C@@H:26]([C@H:29]([OH:32])[CH2:30][OH:31])[CH2:27][OH:28])[CH2:10][CH2:9][N:8]([CH2:33][C:34]([OH:36])=[O:35])[CH2:7]1.C>O>[CH2:6]1[N:17]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:15][N:14]([CH2:22][C:23]([OH:25])=[O:24])[CH2:13][CH2:12][N:11]([CH:26]([CH:29]([OH:32])[CH2:30][OH:31])[CH2:27][OH:28])[CH2:10][CH2:9][N:8]([CH2:33][C:34]([OH:36])=[O:35])[CH2:7]1
Reactant: O=C(O)CN1CCN(CC(=O)O)CCN([C@H](CO)[C@H](O)CO)CCN(CC(=O)O)CC1
Agent: C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(C(CO)C(O)CO)CCN(CC(=O)O)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A total of 3.356 kg calcium carbonate (99.3%) is added in portions to 15.39 kg butrol (water contents: 2.6%) dissolved in 120 l demineralised water and it is stirred for one hour at 90° C. inner temperature. It is subsequently cooled to 20° C. and 1.5 kg active carbon (Norit SX PLUS; the carbon is first washed thoroughly with water) is added. It is stirred for one hour at 20° C. and the carbon is subsequently filtered off. The carbon is washed three times with 15 l of water each time.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[CH2:27]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:36][C:37](=[O:53])[C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH:31]=1)[CH2:28][CH3:29]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:41]2[CH:42]=[CH:43][C:38]([C:37]([NH:36][C:32]3[CH:31]=[C:30]([CH2:27][CH2:28][CH3:29])[CH:35]=[CH:34][N:33]=3)=[O:53])=[CH:39][CH:40]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCCc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: CCCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Yield: 93 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4-Propylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 8) to afford the title compound (147.8 mg, 93%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]#[N:9].[NH2:10][OH:11]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8](=[N:10][OH:11])[NH2:9]
Reactant: N#CC=Cc1cccs1
Reactant: NO
Solvent: CO
Product: NC(C=Cc1cccs1)=NO
Reaction time: 8 h

Procedure:
β-(Thien-2-yl) acrylonitrile (2.78 g.) was dissolved in dry methanol (60 ml.) and treated with a solution of hydroxylamine in methanol (60 ml.) (prepared by dissolving hydroxylamine hydrochloride (6 g.), in methanol (60 ml.) and neutralising with sodium methoxide in methanol). The solution was refluxed for 6 hr. and left overnight to cool. Evaporation in vacuo left a brown oil which was dissolved in chloroform and washed with water (10 ml.). The chloroform solution was evaporated to dryness leaving the crude amidoxime, 2.76 g. (80%). Recrystallisation from aqueous methanol gave β-(thien-2-yl) acrylamidoxime, m.p. 92° , λmax. (EtOH) 306 nm, (ε 20070) (Found: C, 49.7; H, 4.7; N, 16.8; S, 18.7. C7H8N2OS requires C, 50.0; H, 4.8; N, 16.7; S, 19.05%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15].[I-].[Na+]>O1CCOCC1>[OH:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][OH:18])[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCNCCO
Reactant: ClCCCSc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: OCCN(CCO)CCCSc1ccccc1
Yield: 57 %

Procedure:
A mixture of 8.30 g (44.5 mmols) of 1-chloro-3-phenylthiopropane, 100 ml of diethanolamine, 13.3 g (88.7 mmols) of sodium iodide and 250 ml of dioxan was heated under reflux for 15 hours. The mixture was concentrated under reduced pressure, and an aqueous saturated sodium bicarbonate solution was added to the mixture followed by extraction of the solution with chloroform 5 times. The chloroform layer was drided over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =25/1) to afford 6.46 g (yield: 57%) of 1-bis(hydroxyethyl)amino-3-phenylthiopropane.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:8]([CH3:21])[N:9]=[C:10]2[C:15]=1[C:14](=[O:16])[NH:13][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11]2.O1CCCC1>C(N(CC)CC)C>[CH3:21][N:8]1[C:7]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[C:15]2[C:10]([N:11]=[C:12]([C:17]([CH3:18])([CH3:20])[CH3:19])[NH:13][C:14]2=[O:16])=[N:9]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N(S(C)(=O)=O)S(C)(=O)=O

Procedure:
Methanesulphonyl chloride (12.9 g) was added slowly to a stirred mixture of 3-amino-2-methyl-6-(1,1-dimethylethyl)-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (11 g) prepared as in Example 1, tetrahydrofuran (85 ml) and triethylamine (21 ml), causing the mixture to boil. The mixture was heated under reflux for 3 hours, and was then cooled and filtered. The filtrate was then evaporated to dryness, and the residue was washed with 80:20 ethanol/water to give the title compound, m.p. 258°-259° C.
Reaction SMILES: ClC1C(Cl)=C2C(CCC2=O)=CC=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][C:23]([OH:25])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]2[C:15]=1[CH2:21][CH2:22][C:23]2=[O:25]
Reactant: O=C(O)CCc1cccc(Cl)c1Cl
Agent: O=C1CCc2ccc(Cl)c(Cl)c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2c1ccc(Cl)c2Cl

Procedure:
The 4,5-dichloro-1-indanone is prepared as in Example 15 for the preparation of 6,7-dichloro-1-indanone but star6ing with 26 g of 3-(2,3-dichlorophenyl)propionic acid, 138 ml of thionyl chloride, 550 ml of anhydrous dichloromethane and 20.5 g of aluminium chloride. After recrystallization from 100 ml of boiling ethanol, 12.67 g of 4,5-dichloro-1-indanone are thus obtained which melt at 78° C.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].O=[CH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21]>>[CH2:1]([N:4]([CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])[CH2:2][CH3:3]
Reactant: O=CCCCNC(=O)N1CCN(c2ccccc2)CC1
Reactant: CCCNC1CCc2ncsc2C1
Product: CCCN(CCCCNC(=O)N1CCN(c2ccccc2)CC1)C1CCc2ncsc2C1
Yield: 68 %

Procedure:
Compound 61 is prepared from 1C and 61C as described for 1. The salt of maleic acid is crystallized from acetonitrile/diethylether.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.CC([O-])(C)C.[Na+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)c1
Temperature: 35 °C
Reaction time: 12 h

Procedure:
6-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline (100 mg, 0.35 mmol, 1 eq) was dissolved in 3.5 mL of toluene and NaOt-Bu (50 mg, 0.51 mmol, 1.45 eq) was added followed by 3-methoxy phenylisocyanate (50 μL, 0.39 mmol, 1.1 eq). The reaction mixture was stirred at 35° C. for 12 h, where five grams of Celite was added, the mixture was concentrated under vacuum and purified by column chromatography on silica gel (5% MeOH in CH2Cl2; 40 g column; 35 mL/min). This gave 20 mg (13%) of the title compound as an orange semi-solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[OH-].[Na+].[NH3:12]>[O-]S([O-])(=O)=O.[Cu+2]>[NH2:12][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: N
Reactant: COc1cncc(Br)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COc1cncc(N)c1
Temperature: 135 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-methoxypyridine (15 g) was added to a pressure vessel, and CuSO4(3.9 g) and 25% aq. ammonia (150 mL) were added. The reaction mixture was stirred for 4 h at 135° C., then cooled to RT, basified with aqueous NaOH solution, and extracted with CH2Cl2. After evaporation of volatiles, 3-amino-5-methoxypyridine was obtained as yellow solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C@@H:26]([OH:36])[C@H:27]([NH:30][C:31](=[O:35])[CH:32]([Cl:34])[Cl:33])[CH2:28][F:29])=[CH:22][CH:21]=2)=[CH:16][N:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:34][CH:32]([Cl:33])[C:31]([NH:30][C@H:27]([CH2:28][F:29])[C@H:26]([OH:36])[C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:16]=[N:15][C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:19][CH:18]=2)=[CH:25][CH:24]=1)=[O:35]
Reactant: CC(C)CCN(Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.2 %

Procedure:
To a solution of (5-{4-[(1R,2S)-2-(2,2-Dichloro-acetylamino)-3-fluoro-1-hydroxy-propyl]-phenyl}-pyridin-2-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (8 mg, 0.014 mmol) in dry CH2Cl2 (0.04 mL) is added trifluoroacetic acid (0.04 mL) and resulting reaction mixture is stirred at room temperature for 2 hours. Solvent is evaporated in vacuo to get brown crude, which is washed with diethyl ether:pentane (1:9), to give the title compound (8 mg): 1H-NMR (400 MHz, DMSO-d6) δ0.89 (d, 6H, J=6.40 Hz), 1.52-1.58 (m, 2H), 1.60-1.65 (m, 1H), 3.01 (bs, 1H), 4.20-4.23 (m, 2H), 4.29-4.31 (m, 0.5H), 4.36-4.38 (m, 2H), 4.40-4.44 (m, 0.5H), 4.57-4.59 (m, 0.5H), 4.70-4.71 (m, 0.5H), 4.91-4.93 (m, 1H), 6.02 (d, 1H, J=4.28 Hz), 6.52 (s, 1H), 7.49 (d, 2H, J=8.24), 7.57 (d, 1H, J=8.16 Hz), 7.73 (d, 2H, J=8.28 Hz), 8.19 (dd, 1H, J1=8.16 Hz, J2=2.32 Hz), 8.65 (d, 1H, J=8.96 Hz), 8.96 (d, 1H, J=1.96 Hz), 9.00 (bs, 2H). LC-MS (m/z): [M+H]=456.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](Cl)[C:6]=2[CH:17]=1.[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][Mg]Br)[CH3:19].Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:23][CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:6]=2[CH:17]=1
Reactant: Clc1ccc2c(c1)C(Cl)c1ccccc1C=C2
Reactant: CCOCCC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCOCCCC1c2ccccc2C=Cc2ccc(Cl)cc21

Procedure:
3,5-Dichloro-5H-dibenzo[a,d]cycloheptene, dissolved in absolute ether, is added dropwise with stirring to a solution containing one equivalent of 3-ethoxypropylmagnesium bromide in ether. The mixture is stirred at room temperature for 1 hour, then at reflux for 2 hours. The mixture then is cooled, treated with dilute hydrochloric acid and the ether separated, washed with water and dried. The product is isolated by evaporation of the ether.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:42])[CH2:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([C:28]([NH:30][CH:31]6[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]6)=[O:29])[CH2:24][CH2:23]5)=[C:18]([C:38]([F:41])([F:40])[F:39])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[C:45](B(O)O)[CH:44]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:37][N:34]1[CH2:33][CH2:32][CH:31]([NH:30][C:28]([CH:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:20]=[CH:21][C:16]([N:15]4[C:5]5[C:4]6[CH:3]=[C:2]([C:45]7[CH:44]=[N:43][C:52]8[C:47]([CH:46]=7)=[CH:48][CH:49]=[CH:50][CH:51]=8)[CH:11]=[CH:10][C:9]=6[N:8]=[CH:7][C:6]=5[NH:12][C:13](=[O:42])[CH2:14]4)=[CH:17][C:18]=3[C:38]([F:41])([F:40])[F:39])[CH2:27][CH2:26]2)=[O:29])[CH2:36][CH2:35]1
Reactant: CN1CCC(NC(=O)C2CCN(c3ccc(N4CC(=O)Nc5cnc6ccc(Br)cc6c54)cc3C(F)(F)F)CC2)CC1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCC(NC(=O)C2CCN(c3ccc(N4CC(=O)Nc5cnc6ccc(-c7cnc8ccccc8c7)cc6c54)cc3C(F)(F)F)CC2)CC1
Temperature: 25 °C
Yield: 3.1 %

Procedure:
To a solution of 8.5 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide (46 mg, 0.07 mmol, 1 equiv.) in dioxane (2 mL) and 1N sodium carbonate solution (0.6 mL) in a sealed tube at room temperature was added 7 quinolin-3-yl-boronic acid (24 mg, 0.14 mmol, 2 equiv.), t-butyl-Xphos (3 mg, 0.007 mmol, 0.1 equiv.), and PdCl2(Ph3P)2 (4.9 mg, 0.007 mmol, 0.1 equiv.). The resulting mixture was degassed, sealed and heated overnight to 100° C. Upon cooling to room temperature, the reaction mixture was filtered through celite and washed with EtOAc (2 mL). The collected solution was evaporated and the residue was purified via HPLC to afford the desired product 8.6 N-(1-methylpiperidin-4-yl)-1-(4-(3-oxo-9-(quinolin-3-yl)-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxamide 1.5 mg. LC-MS: (M+H) 694.40
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[S:17]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:19])(=[O:18])[CH3:16]
Reactant: OCC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCCO1
Reaction time: 0.5 h
Yield: 102 %

Procedure:
A stirred solution of 13.9 g of tetrahydro-2-pyranylmethanol and 18.2 g of triethylamine in 250 ml of methylene chloride was cooled to -10° C. and 15.1 g of methansulfonyl chloride was added dropwise over 5 minutes while maintaining the temperature at -10° C. to 0° C. using a cooling bath. The bath was removed and the mixture was stirred for 1/2 hour while the temperature reached 16° C. The reaction mixture was washed successively with 150 ml of ice water, 150 ml of 10% hydrochloric acid solution, 150 ml of saturated sodium bicarbonate solution and 150 ml of saturated sodium chloride solution, then dried (MgSO4) and evaporated under vacuum at 50° C. to give 23.7 g of a yellow oil, which was Claisen distilled to yield 19.7 g of the desired product; b.p. 110° C. (0.2 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:16]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:6]=2[CH:34]=1.O.NN>C(O)C>[NH2:16][CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][C:6]=3[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])=[CH:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
235 mg of 8-chloro-1-(phthalimidomethyl)-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine are dissolved in 15 ml of ethanol and treated with 500 ml of hydrazine hydrate. The mixture is stirred at room temperature for 2 hours and then the ethanol is evaporated in vacuo. The residue is dissolved in ethyl acetate, washed twice with water, dried and evaporated. The residue is chromatographed on 10 g of aluminium oxide (neutral, activity grade III). By elution with chloroform/ethanol (9:1) and crystallization from ethyl acetate there is obtained 1-(aminomethyl)-8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 187°-190°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Cl:25][C:26]1[N:30]([C:31]2[C:36]([Cl:37])=[CH:35][C:34]([C:38]([F:41])([F:40])[F:39])=[CH:33][C:32]=2[Cl:42])[N:29]=[C:28]([C:43]#[N:44])[C:27]=1[CH:45]=O>ClCCl>[Cl:25][C:26]1[N:30]([C:31]2[C:32]([Cl:42])=[CH:33][C:34]([C:38]([F:40])([F:39])[F:41])=[CH:35][C:36]=2[Cl:37])[N:29]=[C:28]([C:43]#[N:44])[C:27]=1[CH:45]=[C:20]([Br:24])[Br:21]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1C=C(Br)Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of triphenylphosphine (0.709 g) in dry dichloromethane (2 ml) at 0° C. under an atmosphere of dry nitrogen was added carbon tetrabromide (0.358 g) in dry dichloromethane (2 ml) followed by 5-chloro-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-formylpyrazole (0.2 g) in dry dichloromethane (3 ml). The mixture was allowed to warm to room temperature and stirring continued overnight. The reaction mixture was washed with water. The aqueous layer was twice extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica get eluted with hexane dichloromethane (1:1). Combination and evaporation of suitable fractions followed by recrystallisation from hexane gave the title compound as a white solid, m.p. 119.1-119.5° C.
Reaction SMILES: [C:1]1(Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(N)cc1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2ccccc2)cc1
Reaction time: 12 h
Yield: 43.7 %

Procedure:
The general procedure from Example 1 was followed using PhCl (122 μl, 1.2 mmol) and p-toluidine (108 mg, 1.0 mmol) with Pd2 (dba)3 (20 mg, 0.0218 mmol) and (Me3C)2PH(O) (14.5 mg, 0.0878 mmol) and NaOtBu (144 mg, 1.5 mmol) in 3.0 mL of toluene. After 12 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 80 mg (44% yield) of N-phenyl-p-toluidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.13 (t, J=7.91 Hz, 2H), 6.98 (m, 2H), 6.89 (m, 4H), 6.78 (t, J=7.32 Hz, 1H), 5.46 (s, br. 1H), 2.20 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d 143.9, 140.3, 130.8, 129.8, 129.2, 120.2, 118.9, 116.8, 20.6 ppm. MS: Calculated for C13H13N(M+): 183.3. Found: 184.1 (M+ +H).
Reaction SMILES: II.[CH:3]12[C:15](=[O:16])[CH:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH:10]1[CH:4]2[C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=13.[CH3:21][N:22]([CH3:27])[C:23](=[O:26])[CH2:24]Br>[Zn].C1C=CC=CC=1.CO.C(O)(=O)C>[CH3:21][N:22]([CH3:27])[C:23](=[O:26])[CH2:24][C:15]1([OH:16])[CH:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH:10]3[CH:3]1[CH:4]3[C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=12
Reactant: O=C1C2c3ccccc3C3C1C3c1ccccc12
Reactant: CN(C)C(=O)CBr
Agent: II
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CN(C)C(=O)CC1(O)C2c3ccccc3C3C(c4ccccc42)C31

Procedure:
An amount of 3.6 g (0.055 mole) of zinc chips and a trace of iodine are placed into a dry reaction vessel; additions are then made of 2 ml of a solution of 7.0 g (0.03 mole) of 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-one and 7.1 g (0.039 mole) of N,N-dimethyl-bromoacetamide in 50 ml of abs. benzene, and the whole is refluxed while stirring is maintained; the remainder of the benzene solution is added dropwise in the course of 30 minutes and refluxing subsequently performed for a further hour. After cooling, the reaction mixture is decomposed with 6 ml of glacial acetic acid and 6 ml of methanol. The formed organic precipitate is taken into solution by the addition of benzene and zinc residues still present are filtered off. The benzene solution is washed with 2N acetic acid, then with 2N sodium bicarbonate solution and finally with water; it is then dried over sodium sulphate and concentrated in a water-jet vacuum. The residue crystallises from benzene/petroleum ether to yield N,N-dimethyl-11-hydroxy-1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e] cyclopropa[c]cycloheptene-11-acetamide; M.P. 203°-204°.