Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23](=[O:31])[C@@H:22]3[CH2:32][CH2:33][C@H:34]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[F-].[K+].C(OCC)(=O)C>CO>[Si:43]([O:42][C@H:34]([C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[CH2:33][CH2:32][C@@H:22]1[C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)=[CH:16][CH:17]=2)[N:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]1=[O:31])([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)c1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(-c2cccc(O)c2)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
(3R,4S)-4-(3′-{[tert-Butyl(dimethyl)silyl]oxy}biphenyl-4-yl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.60 g, 0.86 mmol) was stirred at room temperature in dry methanol (20 mL) under a nitrogen atmosphere. Potassium fluoride (0.10 g, 1.72 mmol) was added and the reaction mixture was stirred 1.5 h at room temperature. The solution was poured into ethyl acetate and washed successively with water (2×), 10% aqueous sodium bicarbonate, water and brine. The organic solution was dried over sodium sulfate, filtered, concentrated and purified by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 50%) to afford (3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-(3′-hydroxybiphenyl-4-yl)-1-phenylazetidin-2-one (0.46 g, 92%) as a white foam; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.2, Hz, 2H,) 7.37 (d, J=8.2 Hz, 2H), 6.9-7.4 (m, 12H), 6.8 (m, 1H), 4.9 (br s, 1H), 4.67 (t, J=6.0 Hz, 1H), 4.63 (d, J=2.5 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.0 (m, 4H), 0.87 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[Br:15]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH2:1]([N:5]1[C:9]2[C:10]([Br:15])=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: BrBr
Reactant: CC(C)Cn1cnc2ccc(N)cc21
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2ccc(N)c(Br)c21
Yield: 29 %

Procedure:
To a solution of 3-isobutyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.0 g (3.7 mmol, 29%) of the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Cu])#N.C[N:13]([CH:15]=[O:16])C>Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([NH2:13])=[O:16])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: N#C[Cu]
Agent: Cl
Product: NC(=O)c1ccc(F)cn1
Temperature: 100 °C
Reaction time: 15.5 h
Yield: 31.2 %

Procedure:
Take up 2-bromo-5-fluoropyridine (0.750 g, 4.26 mmol) and CuCN (0.954 g, 10.7 mmol) in DMF (10.7 mL). Heat to reflux for 5 hours. Cool the reaction mixture to 100° C. Add a solution of FeCl3.6H2O (0.654 g) in 10% HCl solution (30 mL) and stir for 15.5 hours. Cool the reaction mixture to 80° C. and filter. Add 1.0 N NaOH until the reaction mixture becomes basic and extract with dichloromethane (3× 200 mL). Wash the organic layer with brine (1× 75 mL), dry over Na2SO4, filter and concentrate to give the title compound (0.186 g, 31.2%): TOF MS EI+ 140.0 (M)+, base peak EI+ 97.0 (M-CONH)+, HRMS calcd for C6H5N2OF 140.0386 found 140.0378, time 3.40 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=7.5 min, 100% purity.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[S:36]1[CH:40]=[CH:39][NH:38][C:37]1=[S:41].O>C1COCC1.C(N(CC)CC)C>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][S:41][C:37]5[S:36][CH:40]=[CH:39][N:38]=5)=[CH:8][CH:7]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: S=c1[nH]ccs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(CSc2nccs2)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (0.0002 mol), obtained in Example B14, and 2(3H)-thiazolethione (0.001 mol) in THF (1 ml) and triethylamine (0.1 ml) was stirred at room temperature for 18 hours, poured out into water and extracted with CH2Cl2/CH3OH. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over kromasil 60 μm (eluent: CH2Cl2/CH3OH; 90/10). The pure fractions were collected and the solvent was evaporated, yielding (70%) of 4(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)[4-[(2-thiazolylthio)methyl]phenyl]methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:585, 586 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(Br)nc1C(=O)O
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Methy 3-amino-6-bromopyrazine-2-carboxylate (1.4 Kg), 5N NaOH solution (5.6 L) and methanol (8.4 L) were charged into reactor. The resulting suspension was warmed at 50° C. for 3 hours with vigorous stirring. The mixture was analysed for reaction completion. The mixture was cooled to 25° C. and the solids were collected by filtration. Filter cake was washed with water (1 L). The resultant solids were suspended in water (5 L) and pH value of this suspension was adjusted to 3 by adding 6 N HCl solution. The acidic solution was vigorously stirred at 25° C. for 48 h. During this period, pH value was checked, additional acid was charged if pH value >3. The suspension was filtered to collect a yellow-brown solid, which was dried in oven at 40° C. under a flow of N2. The crude subtitle material was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:18])([C:13]#[C:14][CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:27][C:28](Br)=[O:29].[H-].[Na+]>CCOCC>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:28](=[O:29])[CH2:27][O:18][C:8]([C:13]#[C:14][CH:15]([CH3:16])[CH3:17])([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: CC(C)C#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Reactant: O=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)C#CC1(C(F)(F)F)OCC(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a stirred ice-cooled solution of 4.37 g (15 mmol) of 6-amino-3-chloro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 200 mL of dry ether was added 2.4 mL of dry pyridine and, quickly dropwise, 1.40 mL (16 mmol) of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 150 mL of dry DMF and was treated at 0° with 400 mg of 100% sodium hydride (16.7 mmol) for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1.5 h. The reaction mixture was poured onto a mixture of 1.2 L of water and 300 mL of saturated aqueous sodium chloride and this was extracted 3 times with ether. The combined extracts were washed with brine, dried, and evaporated to a solid which was crystallized by dissolving in hot ethyl acetate and adding hexanes. This material was recrystallized from ethyl acetate/hexane to afford 3.125 g of pure title compound as a crystalline solid: mp 183-183.5°; HRMS Calcd. for C15H14NO2ClF3 (M+H)+: 332.066516. Found: 332.065892.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]3([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[CH3:28][CH2:29][Mg+].[Br-]>C1COCC1>[C:23]([O:22][C:20](=[O:21])[NH:19][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]4([OH:27])[CH2:29][CH2:28]4)=[CH:5][CH:6]=3)=[CH:11][N:12]=2)[CH2:17][CH2:18]1)([CH3:25])([CH3:26])[CH3:24]
Reactant: COC(=O)c1ccc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nc2)cc1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3ccc(C4(O)CC4)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 4-[6-(1-tert-butoxycarbonylamino-cyclopropyl)-pyridin-3-yl]-benzoic acid methyl ester (0.68 g, 1.8 mmol) in THF (20 mL) was added Ti(Oi-Pr)4 (0.54 mL, 1.8 mmol). To this mixture was slowly added EtMgBr (3M in Et2O, 1.2 mL, 3.7 mmol) over 30 minutes. The reaction was allowed to stir at room temperature for 1 h. Ti(Oi-Pr)4 (1.1 mL, 3.2 mmol) and EtMgBr (3M in Et2O, 1.2 mL, 3.7 mmol) were again added to the solution and the reaction stirred for 30 minutes. The mixture was quenched with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered, concentrated and the residue purified by reverse phase HPLC to give (1-{5-[4-(1-hydroxy-cyclopropyl)-phenyl]-pyridin-2-yl}-cyclopropyl)-carbamic acid tert-butyl ester (0.05 g, 1.4 mmol) as a brown solid, m/z 367.7 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:9]=1[O:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:31][CH2:30][C:18]2([N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][NH:20][C:19]2=[O:29])[CH2:17][CH2:16]1)=O.O1CCCC1.O>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:15]1[CH2:16][CH2:17][C:18]2([N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][NH:20][C:19]2=[O:29])[CH2:30][CH2:31]1
Reactant: O=C(CCOc1ccc(F)cc1Cl)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCOc1ccc(F)cc1Cl)CC2

Procedure:
A mixture of 0.4 g of lithium aluminum hydride, 2.2 g of 8-{3-(2-chloro-4-fluorophenoxy)propionyl}-1-phenyl-4-oxo-1,3,8-triazaspiro[4,5]decane and 40 ml of tetrahydrofuran was heated under reflux for 3 hours. To the reaction mixture were added gradually water and chloroform under cooling, and the precipitate was filtered off. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with ether, cooled and filtered to give 8-{3-(2-chloro-4-fluorophenoxy)propyl}-1-phenyl-4-oxo-1,3,8-triazaspiro-[4,5]decane, m.p. 154° - 155° C; recrystallized from benzenecyclohexane, m.p. 155° - 156° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O.CN(C=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(I)c(F)cc1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)c(F)cc1F
Temperature: 60 °C

Procedure:
To a solution of 11 (74.0 g, 260 mmol) in toluene (370 mL) was added thionyl chloride (95 mL, 1300 mmol) in DMF (2.5 mL, 26 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to approximately 60° C. and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure and residual thionyl chloride was co-evaporated with toluene (2×120 mL) to give crude 12 which was used without purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([CH3:15])[CH:17]=3)[NH:21][C:20]2=[O:25])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: Cc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=Cc1[nH]c(C)c(CCC(=O)O)c1C)C(=O)N2
Yield: 64.2 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 74 mg 5-methyl-2-oxindole, and 75 μL piperidine in 3 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 104 mg (64%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:22]([Br:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=[O:31]>C(#N)C.O>[CH2:1]([O:8][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:22]([Br:23])=[CH:21][N:20]=[C:19]([NH:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=[O:31])[N:18]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCCNc1nc(Cl)ncc1Br)OCc1ccccc1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CC#N
Solvent: O
Product: O=C(NCCCCCNc1nc(Nc2cccc(C(=O)O)c2)ncc1Br)OCc1ccccc1

Procedure:
A reaction mixture of 1.20 g (2.8 mmol) of [5-(5-bromo-2-chloro-pynmidin-4-ylamino)-pentyl]-carbamic acid-benzyl ester and 0.37 g (2.7 mmol) of 3-aminobenzoic acid in acetonitrile/water (8 ml/1.5 ml) is stirred under reflux for 20 hours. The reaction mixture is spun in, and the remaining residue is purified by chromatography (dichloromethane/methanol 9:1, Flashmaster II). 1.27 g (2.4 mmol, corresponding to 86% of theory) of the product is obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[F:34][C:33]([F:36])([F:35])[C:29]1[N:28]=[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
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: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3cccc(C(F)(F)F)n3)cc2C1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (190 mg, 0.52 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (10 mg, 0.5 mmol/g, 0.005 mmol) was added along with 2-Bromo-6-trifluoromethylpyridine (174 mg, 0.78 mmol) and 500 μl of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 95 mg of title compound were recovered as whitish solid (47%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-{(2S)-5-[6-(trifluoromethyl)-2-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(N(CC)CC)C.C(O)(=O)C.Cl.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1([C:47](=N)OCC)[CH2:46][CH2:45]1>C(O)C>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1([C:47]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH2:45][CH2:46]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(c2ccccc2OC)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccccc1C1(c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)CC1
Temperature: 75 °C

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (32 mg, 0.088 mmol) in ethanol (0.5 mL) was added triethylamine (50 μL, 1.42 mmol) and acetic acid (82 μL, 1.42 mmol). Then a solution of ethyl 1-(2-methoxyphenyl)cyclopropanecarbimidate hydrochloride (50 mg, 0.09 mmol) in ethanol (0.3 mL) was added and the reaction mixture was heated to 75° C. for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 446.1; HPLC retention time: 2.299 min (Method A).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:15][C:14]([NH:13][C:4]1[N:3]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=1)([CH3:17])[CH3:16]
Reactant: C1CNCCN1
Reactant: CC(C)(C)Nc1nc(Cl)cc(N2CCCC2)n1
Product: CC(C)(C)Nc1nc(N2CCCC2)cc(N2CCNCC2)n1
Yield: 78.1 %

Procedure:
The reaction of 4-chloro-2-(1,1-dimethylethylamino)-6-pyrrolidinopyrimidine with piperazine as described in Example 4 gives the title product in a yield of 78.1%, m.p.: 162°-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>CC(N(C)C)=O>[C:4]([C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: N#Cc1cc(F)ccc1N
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(F)ccc1NS(N)(=O)=O

Procedure:
A solution of 2-amino-5-fluorobenzonitrile (136 mg, 1 mmol) and sulfamoyl chloride (114 mg, 1 mmol) in DMA (2 mL) was stirred at room temperature for 2 hours. The reaction was purified by Varian HPLC (10% Acetonitrile/Water) to give N-(2-Cyano-4-fluorophenyl)sulfamide as a pale-white solid. 1H NMR (400 MHz, DMSO-d6) 7.18 (m, 2H), 7.56-7.60 (dd J=8.8 Hz, 2.8 Hz 2H), 9.44 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:19]=[CH:20][C:21]3[C:26]([C:4]=2[NH:3]1)=[CH:25][CH:24]=[CH:23][CH:22]=3.CCN=C=NCCCN(C)C.Cl.[CH:39]1[CH:40]=[CH:41][C:42]2N(O)N=[N:45][C:43]=2[CH:44]=1.CN1CCOCC1.NC1C=CC=CC=1>CN(C=O)C>[C:43]1([NH:45][C:14]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[C:7](=[O:9])[CH2:8][C:2](=[O:1])[NH:3][C:4]4[C:26]5[C:21]([CH:20]=[CH:19][C:5]3=4)=[CH:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][CH:17]=2)=[O:15])[CH:44]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: On1nnc2ccccc21
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: Nc1ccccc1
Product: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 49.4 %

Procedure:
4-[2,4-Dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid (50 mg, 0.144 mmol) obtained in Example 102, (4), WSC.HCl (39 mg, 0.202 mmol), HOBt (31 mg, 0.202 mmol), N-methylmorpholine (47 μL, 0.432 mmol), and aniline (14 L, 0.158 mmol) were stirred at room temperature for 16 hours in anhydrous DMF (1.5 mL). The reaction mixture was post-treated in a conventional manner to give the title compound (30 mg, yield 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:14][CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(CC)(CC)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(CC)(CC)N=C=Nc1cc(Cl)cc(Cl)c1
Yield: 88.5 %

Procedure:
To a solution of 810 mg of N-(3,5-dichlorophenyl)-N'-(1,1-diethylpropyl)thiourea produced in Example A-7 and 800 mg of triphenylphosphine in 10 ml of dichloromethane were added 380 mg of triethylamine and 590 mg of carbon tetrachloride. The mixture was refluxed for 4 hours and evaporated in vacuo. The residue was stirred with n-hexane and filtered to remove solid matter. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography using n-hexane as a solvent to give 640 mg of N-(3,5-dichlorophenyl)-N'-(1,1-diethylpropyl)carbodiimide as an oil. To a solution of this oil in 5 ml of DMF were added 470 mg of cyanamide and 0.05 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 3 hours, cooled to room temperature and poured into water. The resulting crystals were collected and recrystallized from benzene to give 480 mg of the title compound as colorless needles melting at 178.5°-180.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCN(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CN(C)CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2 (PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 5% MeOH in CH2Cl2 (1L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 153.5 mg (55%) of the desired product as a white solid.