Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH3:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Reactant: N
Product: NC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 2 h

Procedure:
A mixture of 74.9 g. (0.25 mole) of 2,4-dichloro-3,5-dinitrobenzoyl chloride and 200 ml. of concentrated ammonia is placed in a mortar and ground with a pestle for ten minutes. The mixture stands for two hours at room temperature. The yellow precipitate is removed by filtration and washed with water. There is obtained 67.7 gm. (97%) of yellow needles melting at 263°-265°. Recrystallization of 1.00 g. of material from ethanol yields 390 mg. of yellow needles melting at 262°-263°.
Reaction SMILES: [C:1]([CH:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[CH:5]1[CH3:12])([OH:3])=[O:2].S(Cl)(Cl)=O.S(Cl)(Cl)(=O)=O.[CH3:22]O>>[CH3:22][O:2][C:1]([C:4]1[C:8]([CH3:9])([CH3:10])[CH2:7][C:6](=[O:11])[C:5]=1[CH3:12])=[O:3]
Reactant: CO
Reactant: CC1C(=O)CC(C)(C)C1C(=O)O
Solvent: O=S(=O)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1=C(C)C(=O)CC1(C)C

Procedure:
1-Carboxy-3-oxo-2,5,5-trimethyl-cyclopentane is first dehydrogenated and halogenated and subsequently esterified by treatment with thionyl chloride/sulphuryl chloride followed by the addition of methanol. The 1-methoxycarbonyl-3-oxo-2,5,5-trimethyl-cyclopent-1-ene obtained is then reduced with the aid of a reducing agent (e.g. sodium borohydride) firstly to 1-methoxycarbonyl-3-hydroxy-2,5,5-trimethyl-cyclopent-1-ene and subsequently with the aid of diisobutyl aluminum hydride to 1-hydroxymethyl-3-hydroxy-2,5,5-trimethyl-cyclopent-1-ene.
Reaction SMILES: O1CCOC1[C:6]1[CH:7]=[C:8]([N:14]2[CH:18]=[N:17]N=N2)C=[CH:10][C:11]=1[O:12][CH3:13].C([Li])CCC.C(=O)(O)[O-].[Na+].[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>O1CCCC1.CCCCCC>[O:32]1[CH2:33][CH2:34][O:31][CH:29]1[C:30]1[CH:10]=[C:11]([O:12][CH3:13])[CH:6]=[CH:7][C:8]=1[NH:14][C:18]#[N:17]
Reactant: COc1ccc(-n2cnnn2)cc1C1OCCO1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(NC#N)c(C2OCCO2)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1-(3-[1,3]dioxolan-2-yl-4-methoxy-phenyl)-1H-tetrazole (9.09 g) in dry tetrahydrofuran (200 ml) at -78° under nitrogen, n-butyl lithium solution in hexane (30 ml of 1.6 mol dm-3) was added. Nitrogen gas was evolved. After stirring under nitrogen for 5 min the mixture was allowed to warm to 0° over 10 min and 8% aqueous sodium bicarbonate (200 ml) was then added. After stirring for 10min ethyl acetate (150 ml) was added and the layers separated. The aqueous layer was then extracted with dichloromethane (2×200 ml) and the organic layers combined, dried (Na2SO4) and evaporated in vacuo to yield the title compound as an oil (8.0 g).
Reaction SMILES: C[O:2][C:3]1[N:7]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:13])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1.[Cl-].[Li+]>CC(N(C)C)=O.CS(C)=O>[OH:2][C:3]1[N:7]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:13])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1
Reactant: COc1c(-c2ccnc(C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: Cc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
Combined 6-(5-methoxy-4-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25.8 mg, 0.063 mmol) and lithium chloride (13.42 mg, 0.317 mmol) in DMA (0.5 mL) and then heated at 50° C. using a heating block for 2 days. Additional portion of lithium chloride (13.42 mg, 0.317 mmol) was added and the reaction mixture was stirred at 100° C. for 17 hours. The reaction mixture was cooled to 23° C., filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO (2×0.5 mL), and purified via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 10-40% ACN (with 0.035% TFA) in water (with 0.05% TFA) to give a residue. The residue was dissolved in DMSO, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO, and purified again via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using an isocratic method of 17% ACN (with 0.05% TFA) in water (with 0.05% TFA) to give the title compound, as a TFA salt, (6.2 mg, 19.30% yield) as a green oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.26 (m, 2 H) 1.55-1.67 (m, 2 H) 1.77-1.84 (m, 1 H) 2.51 (br. s., 3 H) 3.17-3.24 (m, 2 H) 3.24-3.32 (m, 2 H) 3.83-3.88 (m, 2 H) 7.77-8.07 (m, 2 H) 8.07-8.22 (m, 1 H) 8.22-8.30 (m, 1 H) 8.36-8.44 (m, 1 H) 8.58-8.67 (m, 1 H) 8.67-8.81 (m, 1 H) 8.81-8.92 (m, 1 H) 13.58 (br. s., 1 H). MS m/z [M+H]+ 394.5.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Br[CH2:19][C:20]([C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])=[O:21].C(O)(=O)C>CN(C)C=O>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:23][C:22]=1[C:20](=[O:21])[CH2:19][O:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(C=C2SC(=O)NC2=O)cc1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
60% sodium hydride in oil (0.24 g) was added to a solution of 5-(4-hydroxybenzylidene)-2,4-thiazolidinedione (0.663 g) in N,N-dimethylformamide (20 ml) and the mixture was stirred for 30 minutes. Then, a solution of 4-bromoacetyl-5-methyl-2-phenyloxazole (0.841 g) in N,N-dimethylformamide (10 ml) was added dropwise to the mixture under ice-cooling. After stirring under ice-cooling for 30 minutes, the reaction solution was poured into ice-cold water. The aqueous mixture was made acid with acetic acid. The solid which precipitated was collected by filtration, washed with water, and crystallized from acetone to give 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]benzylidene}-2,4-thiazolidinedione (0.42 g, 32.3%). Recrystallization from chloroform-ethanol yielded colorless needles, m.p. 244°-245° C. Elemental analysis for C22H16N2O5S, Calcd.: C, 62.85; H, 3.84; N, 6.66. Found: C, 62.80; H, 3.69; N, 6.93.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:16]=1[CH:17]=O>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:16]([CH2:17][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=3)[CH2:2][CH2:3]2)=[C:15]([CH3:14])[C:22]=1[CH3:23]
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: COc1ccc(C=O)c(C)c1C
Product: COc1ccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c(C)c1C

Procedure:
6-[4-(4-Methoxy-2,3-dimethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,3-dimethylanisaldehyde. Mass spectrum (ES) MH+=329.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[N:14]([CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)ccc2c1=O
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
7-Benzyloxy-3,4-dihydroquinazolin-4-one (7.0 g, 27 mmol) was suspended in dry DMF (50 ml) and cooled to 5-10° C., then sodium hydride was added (1.22 g of a 60% suspension in mineral oil, 30 mmol). The reaction mixture was allowed to return to ambient temperature and chloromethyl pivalate (4.75 g, 31.5 mmol) was added over 10 minutes and the mixture stirred for 1 hour. The reaction mixture was quenched with water (250 ml), the aqueous phase adjusted to pH5 and extracted with ether (300 ml×3). The combined ether phases were washed with brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with isohexane, collected by filtration and dried under vacuum to give 7-benzyloxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (9.1 g, 90%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=O)[CH3:2].[CH3:11][CH:12]([NH2:16])[CH2:13][O:14][CH3:15]>C1(C)C=CC=CC=1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[N:16][CH:12]([CH3:11])[CH2:13][O:14][CH3:15])[CH3:2]
Reactant: COCC(C)N
Reactant: CCC1CCCC(C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC1CCCC(C)C1=NC(C)COC
Yield: 50.2 %

Procedure:
163 g of titanium tetrachloride in 800 ml of toluene were added dropwise to a solution of 229 g (1,64 mole) of 2-ethyl-6-methyl-cyclohexanon and 435 g (4,9 mole) of 1-methyl-2-methoxy-ethylamine in 1000 ml toluene and 110 ml of ether over a period of two hours with stirring and at a temperature of between 0°-10°C. After distilling off the ether the reaction mixture was refluxed for 61/2 hours. After cooling the precipitate was filtered off and the filtrate concentrated in a rotary evaporator at 50° C. Distillation of the residue under reduced pressure gave 174 g 2-ethyl-6-methyl-N-(1-methyl-2-methoxy-ethyl)-cyclohexylidene-amine, m.p. 109°-113°C/15 Torr.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][C:11]([CH3:14])=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[S:10][C:11]([CH3:14])=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: Cc1cnc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1cnc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(5-methyl-thiazol-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10](=O)([O:12]C)[NH2:11].C1(C)C=CC=CC=1>C([Sn](=O)CCCC)CCC.CO>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:10]([NH2:11])=[O:12])[CH3:2]
Reactant: CCCCC(CC)CN
Reactant: COC(N)=O
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCC(CC)CNC(N)=O
Temperature: 110 °C
Yield: 91.7 %

Procedure:
Into a 300 ml reaction vessel equipped with a distillation apparatus were introduced 50 g of 2-ethylhexylamine, 29 g of methyl carbamate and 100 ml of toluene, and to the mixture was added 0.1 g of dibutyl tin oxide as a catalyst and heated with stirring. Methanol formed during the reaction was removed, when the reflux temperature was raised to 110° C., i.e., the boiling point of toluene, the distillation apparatus was taken off and instead a reflux condenser was attached and the mixture was refluxed by heating for 30 minutes with stirring, then allowed to cool. The toluene was distilled off under reduced pressure, and the residue was washed with n-hexane and collected by filtration to obtain 61 g of N-(2-ethylhexyl)urea.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][N:13]([C:18]([C:20]4([C:23]#[N:24])[CH2:22][CH2:21]4)=[O:19])[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:23]([C:20]1([C:18]([N:13]2[CH2:14][C@H:15]([O:16][CH3:17])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:34]5[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[O:19])[CH2:22][CH2:21]1)#[N:24]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CO[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3c(N[C@@H]4CN(C(=O)C5(C#N)CC5)C[C@@H]4OC)c(C(N)=O)cnn3c2)cc1
Temperature: 85 °C
Reaction time: 0.42 h
Yield: 42.1 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.045 mmol) in 1,4-dioxane (0.3 mL), was added (4-methoxyphenyl)boronic acid (10.2 mg, 0.07 mmol), [1,1′-(diphenylphosphino)ferrocene]-dichloropalladium (II) (3.27 mg, 4.5 μmol), potassium phosphate (0.08 mL, 0.16 mmol). The reaction vial was purged with N2, sealed and heated at 85° C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (9 mg 42% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.19 (d, J=7.0 Hz, 1H), 7.95 (d, J=7.0 Hz, 1H), 7.72-7.65 (m, 2H), 7.28 (d, J=14.5 Hz, 1H), 7.02-6.95 (m, 2H), 5.23-5.11 (m, 1H), 4.57 (dd, J=10.1, 7.0 Hz, 1H), 4.32-4.24 (m, 1H), 4.24-4.16 (m, 1H), 4.14-4.06 (m, 1H), 3.94-3.88 (m, 1H), 3.86 (s, 3H), 3.78-3.71 (m, 1H), 3.60-3.53 (m, 2H), 3.40 (s, 3H), 1.79-1.52 (m, 3H), 1.45-1.35 (m, 1H); MS (ES+) m/z: 475.2 (M+H); LC retention time: 3.49 min (analytical HPLC Method B).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]2[N:4]([CH2:5][CH2:6][CH:7]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.[CH2:20]1[C:27]2[N:23]([C:24]([C:28](Cl)=[O:29])=[CH:25][CH:26]=2)[CH2:22][CH2:21]1>C(Cl)Cl>[CH2:20]1[C:27]2[N:23]([C:24]([C:28]([C:3]3[N:4]4[C:8](=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]=3[CH3:1])[CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:5]4)=[O:29])=[CH:25][CH:26]=2)[CH2:22][CH2:21]1
Reactant: O=C(Cl)c1ccc2n1CCC2
Reactant: CCOC(=O)c1c(C)cn2c1C(C(=O)OCC)CC2
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c(C(=O)c2ccc3n2CCC3)n2c1C(C(=O)OCC)CC2

Procedure:
To an ice-bath cooled solution of diethyl 6-methyl-2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylate (2.0 g, 0.0075 m) in methylene chloride (25 ml) was added stannic chloride (2.6 ml, 0.0225 m) all at once. A solution of 2,3-dihydro-1H-pyrrolizine-5-carbonyl chloride (1.1 g, 0.0075 m) in methylene chloride (10 ml) was then added dropwise, and the resultant mixture stirred cold for two hours, then at ambient temperatures overnight. The reaction mixture was then quenched with excess ice-H2O and ether, the organic layer removed, washed well with water, dried over sodium sulfate, filtered, and concentrated in vacuo to a residue. Trituration with either yielded 1.75 g of diethyl 5-(2,3-dihydro-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylate as a white solid.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH:5]1[CH:10]=[C:9]2[CH:11]=[CH:12][C:13]([OH:26])=[C:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][C:16]=3[OH:25])[C:8]2=[CH:7][CH:6]=1>>[P:1]1([Cl:4])[O:26][C:13]2[CH:12]=[CH:11][C:9]3[C:8]([C:14]=2[C:15]2[C:24]4[C:19]([CH:18]=[CH:17][C:16]=2[O:25]1)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:7][CH:6]=[CH:5][CH:10]=3
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: ClP(Cl)Cl
Product: Clp1oc2ccc3ccccc3c2c2c(ccc3ccccc32)o1

Procedure:
The phosphinite-phosphites are synthesized as follows. Phosphorus trichloride is reacted with 1,1'-bi-2-naphthol to give the 1,1'-binaphthyl-2,2'-diyl phosphorochloridite. The chloridite is then reacted with either 1,1'-bi-2-naphthol or 2,2'-biphenol, followed by diphenylchlorophosphine. These reactions are all conducted stepwise in toluene with excess triethylamine present. The product is isolated by filtering off the triethylamine hydrochloride, then removing the solvent under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=O)[CH3:13].[O-]CC.[Na+]>C(O)C.CCOCC>[C:15]([C:16]1[O:11][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[C:8](=[O:9])[CH:10]=1)([O:14][CH2:12][CH3:13])=[O:21]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C)cc1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccc(C)cc2o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of 10.7 g (71.25 mmoles) of 2-hydroxy-4-methylacetophenone and 31.24 g (214 mmoles) of diethyloxalate in 25 ml of ethanol is added dropwise to a solution of sodium ethoxide (formed by adding 6.55 g of sodium metal to 120 ml of ethanol). The mixture is refluxed for 4 hours, cooled to 0° C. and diluted with 500 ml of ether. The precipitate which forms on standing overnight is filtered off and redissolved in water and the solution acidified (pH approximately 1) with 1 N hydrochloric acid. The mixture is extracted with ethyl acetate which is dried and concentrated in vacuo. The residue is dissolved in 100 ml of ethanol and 3 ml of concentrated hydrochloric acid. This solution is refluxed for 1.5 hours, then concentrated in vacuo. The residue is poured into ice water and the precipitate which formed on standing overnight is filtered off and dissolved in ethyl acetate. The ethyl acetate solution is dried and concentrated in vacuo. The residue is purified by flash column chromatography through silica gel and recrystallization from ether/hexanes to give 8.75 g of 2-carboethoxy-7-methyl-4-oxo-4H-1-benzopyran as a white crystalline solid having an m.p. of 62°-4° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:27])[C:13]=3[NH:17][C:18](=[O:26])[CH2:19][CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:8]=2)[CH2:3]1.[CH3:28][C:29]([Si:32]([CH3:38])([CH3:37])[O:33][CH2:34][CH:35]=O)([CH3:31])[CH3:30]>>[Cl:27][C:12]1[C:13]([NH:17][C:18](=[O:26])[CH2:19][CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][CH2:35][CH2:34][O:33][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:38])[CH3:37])[CH2:3]1)[CH:16]=[CH:15]2
Reactant: N[C@H]1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)C1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 50(a), using N-[2-[(3S)-3-amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclopentanepropanamide (Example 62) (300 mg) and [[(1,1-dimethylethyl)dimethylsilyl]oxy]-acetaldehyde (133 μl). Purification (SiO2, methanol:dichloromethane 3:97 as eluant) gave the sub-title compound as a solid (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:10]Br>C(=S)=S.C(OCC)C>[Br:10][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[OH:9]
Reactant: BrBr
Reactant: Oc1cc(F)cc(F)c1
Solvent: S=C=S
Solvent: CCOCC
Product: Oc1cc(F)cc(F)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 2.6 gm (20 mMol) 3,5-difluorophenol in 20 mL carbon disulfide was cooled to 0° C. and then a solution of 1.02 mL (20 mMol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes. After stirring for an additional 30 minutes, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with 200 mL diethyl ether and was washed sequentially with aqueous sodium metabisulfite and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was vacuum distilled to provide 2.5 gm (60%) of 2-bromo-3,5-difluorophenol (b.p.=65° C. (5 mm Hg)).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].CC1C=C(C)[N:29]([C:33](N)=[NH:34])N=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:33](=[NH:29])[NH2:34])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: c1ccncc1
Product: N#Cc1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Temperature: 110 °C
Yield: 74.7 %

Procedure:
N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (0.05 g, 0.126 mmol) was dissolved in pyridine (2 ml) and 3,5-dimethylpyrazole-1-carboxamidine (0.037 g, 0.188 mmol) was added under a nitrogen atmosphere. The reaction was heated to 110° C. for 6 h, then was allowed to cool and was concentrated to give a viscous amber oil. The product was purfied by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The product eluted at 13.8 minutes was concentrated to give N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea as an amorphous solid (0.036 g); LRMS (M+H)+ m/z 341.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=O)[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>O1CCOCC1>[CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[S:22])[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1c(=O)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: CCCCCn1c(=O)[nH]c(=S)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C
Yield: 17.5 %

Procedure:
A mixture of 3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione (0.81 g, 2.8 mmol) and phosphorus pentasulfide (1.2 g, 2.8 mmol) in 1,4-dioxane (20 mL) was heated at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography twice (0-50% MeOH in CH2Cl2) to yield 0.15 g of pure product as a yellow solid (0.15 g, 18% yield). LCMS calculated for C11H14F3N4OS (M+H): 307.1. found: 307.1.