Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:22]=[C:17]([C:15]([NH:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:16])[CH:18]=[N:19][C:20]=2[O:30][CH2:31][C:32]([F:34])([F:33])[F:35])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NN1CCNCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
4-{[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-amino}-piperazine-1-carboxylic acid tert-butyl ester (1.047 g, 2.03 mmol) was combined with dichloromethane (25 mL) to give a white suspension. Subsequently trifluoroacetic acid (7.4 g, 5 ml, 64.9 mmol) was added at 0° C. and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from ethyl acetate and n-heptane to afford the title compound (1.0 g, quant.) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([NH:11][C:12](=O)[CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[N:15]2)[N:4]=1.Cl>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[N:15]2)[N:4]=1
Reactant: COc1cnc(NC(=O)Cn2cc([N+](=O)[O-])cn2)nc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cnc(NCCn2cc([N+](=O)[O-])cn2)nc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To N-(4,5-dimethoxypyrimidin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide (318 mg, 1.03 mmol) in THF (2.0 mL), BH3 THF-complex solution (1 M in THF, 4.13 mL, 4.13 mmol) was added. After stirring at rt for 1.5 h, the reaction mixture was quenched with 1 N aq. HCl-solution (4 mL, 4 mmol) followed by concentrated HCl-solution (32%, 0.5 mL). After stirring for 10 min at rt, the reaction mixture was diluted with EtOAc, washed with sat. Na2CO3-solution. The aq. layer was reextracted with EtOAc and the comb. org. layers were evaporated, dissolved in DCM and washed with brine. The org. layer was dried (MgSO4), filtered and the solvent was removed by reduced pressure. Purification was performed by FC (EtOAc/hex 1:1 to 100% EtOAc) to yield 4,5-dimethoxy-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine as a yellow solid. LC-MS conditions B: tR=0.43 min, [M+H]+=295.14.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][C:15]1([NH2:18])C[CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:18][CH:15]([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reaction time: 4 h
Yield: 42.9 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (250 mg, 1.03 mmol), 1-methylcyclopropanamine (150 mg, 2.2 mmol) and HATU (456 mg, 1.2 mmol) in 20 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, the residue suspended in 20 mL of 0.5 N HCl, product extracted with ethyl acetate (3×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether (2 mL) then decanted and dried to give 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (125 mg, crude). LCMS: (M+H)+=285/287.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH:5]([CH3:29])[C:4]1=[O:30])[CH3:2].[CH:31]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[CH2:1]([N:3]1[CH:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:5]([CH3:31])([CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: CCN1C(=O)C(C)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol) at −78° C. was added, drop-wise, a solution of 1-ethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (1.34 g, 3.48 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was stirred for 1 hr at −78° C. Iodomethane (0.239 ml, 3.82 mmol) was then added and after stirring for a further 1 hr at −78° C. the mixture was allowed to warm to room temperature over 3 hrs. The mixture was then re-cooled to −78° C. and treated, drop-wise, with a further aliquot of a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol). After stirring for an additional 1 hr at −78° C. the mixture was again treated with iodomethane (0.239 ml, 3.82 mmol) and then the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride and then extracted with ethyl acetate (2×). The combined organic extracts were then washed with water (3×) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated to a crude oily solid (1.7 g). The crude solid was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give pure product fractions (i.e. 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.468 g)) as well as pure monoalkyated material (i.e. 1-ethyl-3-methyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.524 g)) and a mixture of these two (0.240 g). The desired product was set aside while the 1-ethyl-3-methyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone and the mixed material were combined and dissolved in tetrahydrofuran (20 ml). This solution was then added drop wise to a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol) at −78° C. and stirring at this temperature was continued for 1 hr. Iodomethane (0.239 ml, 3.82 mmol) was then added to the mixture and the mixture was allowed to warm to room temperature over 4 hrs. Workup as described above gave an additional batch of 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.846 g) as an oil which was combined with the material set aside earlier (total mass=1.08 g) and used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:43][C:44]1[C:45](F)=[CH:46][C:47]([F:71])=[C:48]([S:50]([N:53]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=2[O:69][CH3:70])[C:54]2[CH:59]=[CH:58][N:57]=[CH:56][N:55]=2)(=[O:52])=[O:51])[CH:49]=1>CS(C)=O>[Cl:43][C:44]1[CH:49]=[C:48]([S:50]([N:53]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=2[O:69][CH3:70])[C:54]2[CH:59]=[CH:58][N:57]=[CH:56][N:55]=2)(=[O:51])=[O:52])[C:47]([F:71])=[CH:46][C:45]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3O)ccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of tert-butyl 4-(4-(4-hydroxy-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 114, 200 mg, 0.401 mmol) in dimethyl sulfoxide (5 mL) was added potassium carbonate (111 mg, 0.802 mmol) followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (Preparation 110, 182 mg, 0.401 mmol). The reaction mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 30% heptane in ethyl acetate to give the title compound (320 mg, 85%) as yellow foam.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([OH:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:12][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 70 %

Procedure:
3-Methyl-2-phenyl-1-naphthalenol (86) (0.11 g, 0.48 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.12 g (70%) of the title compound (87) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H), 6.71 (d, J=8.8 Hz, 2H), 7.10-7.16 (m, 2H), 7.20-7.30 (m, 3H), 7.39 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.2 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.71 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 9.80 (s, 1H). LCMS (ESI): m/z 339 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:15][CH:14]=[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[NH:9][C:4]2=[C:3]1[C:16]#[N:17].IC.[C:20](=O)([O-])[O-].[K+].[K+]>O>[CH3:20][N:15]1[C:2](=[O:1])[C:3]([C:16]#[N:17])=[C:4]2[C:5]([S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[NH:9]2)=[CH:14]1
Reactant: N#Cc1c2c(c[nH]c1=O)Sc1ccccc1N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1cc2c(c(C#N)c1=O)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 24 parts of 2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile, 14 parts of iodomethane and 14 parts of potassium carbonate is stirred at room temperature for 21/4 hours, then diluted with 2 volumes of water. The precipitate which forms is filtered out, dried in vacuo, and recrystallized from acetonitrile to give yellow needles of 2,3-dihydro-2-methyl-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile melting at 292°-295° with decomposition.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]2[N:7]([CH:22]3[CH2:27][O:26]C(C)(C)[O:24][CH2:23]3)[C:8](=[O:21])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[C:5]=2[CH:4]=1)#[N:2].Cl>O1CCCC1>[C:1]([C:3]1[CH:31]=[CH:30][C:6]2[N:7]([CH:22]([CH2:23][OH:24])[CH2:27][OH:26])[C:8](=[O:21])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(Cn2c(=O)n(C3COC(C)(C)OC3)c3ccc(C#N)cc32)cc1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n(C(CO)CO)c3ccc(C#N)cc32)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of 5-cyano-3-(3,4-dimethoxybenzyl)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-2,3-dihydro-1H-benzimidazol-2-one (140 mg) in tetrahydrofuran (2 mL) was added 1 N-hydrochloric acid (1.5 mL), and the mixture was stirred at ambient temperature for 8 hours. After evaporation of the solvent, the residue was partitioned between water and a mixture of chloroform and methanol (10:1). The separated organic layer was washed with brine and dried over magnesium sulfate. After evaporation of solvent, the residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (10:1). The obtained substance was triturated with diethyl ether to give 5-cyano-3-(3,4-dimethoxybenzyl)-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one (92 mg) as powders.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:17]2[CH2:18][CH2:19][CH:14]([N:13]([CH3:20])[CH3:12])[CH2:15][CH2:16]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CN(C)C1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
To 5-chloro-2-nitroaniline (16.9 mmol) in DMF (56 mL) was added 4-(dimethylamino)piperidine (18.5 mmol) and K2CO3 (18.5 mmol). The reaction was stirred at 140° C. overnight after which another further 9.2 mmol of the amine was added. Stirring at 140° C. was continued for a further 5 hours. The mixture was allowed to cool and then the precipitate was collected by filtration. The precipitate was washed with EtOAc and then the combined filtrates were evaporated to dryness. The residue suspended in water and the resulting precipitate collected by filtration. The product was washed with water and then dried to give a [1-(3-amino-4-nitro-phenyl)-piperidin-4-yl]-dimethyl-amine as a brown/orange solid (3.9 g).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O.[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1>>[CH2:1]([Sn:5]([C:2]#[C:1][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:18][CH2:17][CH2:16][CH3:20])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1CCOC1
Solvent: O
Product: CCCC[Sn](C#C[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Yield: 88 %

Procedure:
A mixture of 48.8 g (0.150 Mol) of tri-n-butyl-tin chloride and 20.7 g (0.225 Mol) of lithium acetylide ethylenediamine complex in 300 mL of anhydrous THF was heated at reflux under argon for 24 h, cooled and treated with 200 mL of water. The layers were separated and the THF phase was suction-filtered through Celite with a 150 mL THF wash to afford a clear solution. This solution was washed with water (3×200 mL), saturated aqueous sodium bicarbonate (2×100 mL), 5% HCl (2×100 mL), and dried over anhydrous sodium sulfate. Removal of the solvent gave 40.2 g (88%) of the bis(tri-n-butylstannyl)ethyne as a colorless liquid. A mixture of 42.0 g (120 mMol) of 4-bromofluorobenzene, 30.2 g (50 mMol) of bis(tri-n-butylstannyl)acetylene and 2.5 g (2.24 mMol) of tetrakis(triphenylphosphine)palladium[0] under an argon atmosphere was dissolved in 200 mL of dry THF. The reaction mixture was refluxed under an argon atmosphere for 60 h. The solution was cooled to room temperature and subsequent cooling in a refrigerator overnight yielded 11.2 g (67%). The reaction was run at double the scale mentioned above and gave similar yields without any complication in the work-up procedure.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7](Br)=[C:8]([CH3:32])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=3[CH:31]=2)[N:12]=1)=[O:4].[CH3:34]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([CH3:34])=[C:8]([CH3:32])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=3[CH:31]=2)[N:12]=1)=[O:4]
Reactant: CNC(=O)c1sc(Br)c(C)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CNC(=O)c1sc(C)c(C)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Yield: 4.6 %

Procedure:
A solution of 5-bromo-3-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide (50 mg, 0.09 mmol), methylboronic acid (16.4 mg, 0.27 mmol), 2 M aqueous potassium phosphate solution (2 mL) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.004 mmol) in 1,4-dioxane (2 mL) was heated at 100° C. for 24 hours. The mixture was cooled and extracted with methyl ene chloride. The organic layer was washed with brine, dried over by sodium sulfate, and concentrated. Chromatography with preparative TLC (methylene chloride and methanol (40:1)) followed by semipreparative HPLC gave of 5-methyl-3-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide (2 mg, 5%): 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.44 (d, 1H), 7.33 (d, 1H), 7.0 (d, 1H), 6.53 (q, 1H), 4.48 (t, 2H), 3.38 (s, 3H), 2.94 (d, 3H), 2.83 (t, 2H), 2.43 (s, 3H), 1.95 (s, 3H); MS (m/e): 487.3 (M+1).
Reaction SMILES: CS(O[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16](=[O:31])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]1)[NH:12][C:11](=[O:32])[CH2:10][CH2:9]2)(=O)=O.[H][H]>C(O)C.[Pd]>[O:31]=[C:16]([C:15]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=[O:32])[NH:12]2)=[CH:7][CH:6]=1)[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1
Reactant: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCN1CCC(c3ccccc3)CC1)NC(=O)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2ccc(C(=O)CCN3CCC(c4ccccc4)CC3)cc2N1

Procedure:
2.0 Grams of 6-methylsulfonyloxy-7-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril and 0.5 g of palladium black were dispersed in 50 ml of ethanol and the mixture was catalytically reduced under 3 atmospheric pressure of hydrogen gas for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure to obtain a residue. Then the residue was recrystallized from ethanol to obtain 1.1 g of 7-[1-oxo-3-(4-phenyl-1-piperidyl)-propyl]3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: C1(C[O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)C=CC=CC=1.Cl>C(O)C.[Pd]>[C:31]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:16]2[CH:17]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[N:14]=[CH:15]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C(=C\c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)\CCOCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
A mixture of the olefinic ether (17) (18.27 g, 38.8 mmol) in anhydrous ethanol (350 mL), 1.0M ethereal hydrochloric acid (38.8 mL, 38.8 mmol) and 10% palladium-on-carbon catalyst was hydrogenated at 48 psi for 30 min. on a Parr shaker. It was then filtered through celite and the filter cake was washed with methanol. The combined filtrate and washings were concentrated and dried under high vacuum to obtain the title compound (18) as an off-white solid. MP 144-146° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[CH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[CH:14](NC(C)C)(C)C.O1CCOCC1>CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[C:11]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Agent: C=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=C=CCNC(=O)OC(C)(C)C

Procedure:
Reflux a mixture containing N-(t-butoxycarbonyl)-propargylamine (70 gm), 93.5 ml of 32% formaldehyde, 76.4 ml of diisopropylamine, 19.66 gm of cuprous bromide and 860 ml of p-dioxane for 12 hours. Cool and dilute the resulting mixture with 3000 ml of Et2O, wash with 500 ml of water, 1000 ml acetic acid, 500 ml of water (2×), 200 ml sat'd. sodium chloride, dry (MgSO4) and evaporate in vacuo. Flash chromatograph the residue eluting from silica gel with 10% Et2O/hexane to yield 40.8 g of the desired compound. Rf is 0.31 (eluted from silica gel with 10% EtOAc/hexane).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:3][N:2]=1.O=C1CCC(=O)N1[O:22][C:23](=O)[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>CN(C=O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:23]([N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][NH:7][C:4]3[CH:5]=[CH:6][N:1]=[N:2][CH:3]=3)[CH2:14][CH2:13]2)=[O:22])=[CH:31][CH:30]=1
Reactant: c1cc(NCC2CCNCC2)cnn1
Reactant: O=C(OCc1ccc(F)cc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2ccnnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(pyridazin-4-ylamino)-methyl]-piperidine (0.20 g, 1.04 mmol, from EXAMPLE 66, Step 1) in DMF (3 mL) was added carbonic acid-4-fluoro-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.28 g, 1.04 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1–7 (10% NH4OH in MeOH)/99–93 CH2Cl2) to give 4-[(pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid-4-fluoro-benzyl ester. M.S. (M+1): 345.29
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][S@@](C(C)(C)C)=O)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([NH2:30])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.5 %

Procedure:
To a solution of (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (38 mg, 0.081 mmol) in methanol (0.2 mL) was added 4N HCl in dioxane (0.2 mL). The resulting reaction was stirred at room temperature for 5 minutes and the solvent was evaporated under reduced pressure. The crude product was diluted in EtOAc and washed with sat'd. NaHCO3 and dried over Na2SO4. The EtOAc was evaporated under reduced pressure and pumped to dryness to afford (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (26 mg, 92% yield) as a colorless oil. LC-MS (ESI) 345.17 (M+H−17), 362.19 (M+H), retention time=3.26 minutes (0-100% MeOH/H2O/0.1% TFA, 4 min run).