Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35]([OH:44])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[CH:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:29]3[N:30]=[CH:31][C:32]([C:35]([OH:44])([C:36]([F:37])([F:38])[F:39])[C:40]([F:42])([F:43])[F:41])=[CH:33][N:34]=3)[C@@H:14]([CH2:18][N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1)S(C)(=O)=O
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 21 h
Yield: 17.2 %

Procedure:
A 5-mL vial was charged with N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.170 g, 0.386 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.124 g, 0.442 mmol, Intermediate D), DIPEA (0.202 mL, 1.16 mmol), and 1,4-dioxane (2 mL). The vial was sealed and stirred at 100° C. for 21 h. The reaction mixture was allowed to cool to room temperature and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 40 to 100% EtOAc in hexanes followed by 0-10% (2M NH3 in MeOH) in CH2Cl2) to afford N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.0454 g) as a brown solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:27][CH2:28][CH2:29][CH:30]=[CH2:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CN(C)C=[O:35]>>[CH2:1]([O:8][CH2:31][CH:30]([OH:35])[CH2:29][CH2:28][O:27][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CN(C)C=O
Reactant: C=CCCOCCCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCOCCC(O)COCc1ccccc1
Temperature: 80 °C

Procedure:
To 12.0 g of 60% sodium hydride in mineral oil (30 mmol, washed free of oil by the use of petroleum ether) was added 32.4 g (0.3 mol) of benzyl alcohol in 200 ml of dry dimethylformamide. The suspension was heated under a flow of nitrogen to 80° C. and maintained at this temperature for 45 minutes, after which time 66.1 g (0.19 mol) of an epoxide (prepared by the peracid oxidation of octadecyl-3-butenyl ether) in 100 ml of dimethylformamide was added and the temperature maintained at 80° C. for 15 hours. The solvent was then removed in vacuo and the residue chromatographed on silica gel employing a mixture of petroleum ether and diethyl ether in a ratio of 3:2 as the eluent to yield a wax-like solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:16][CH2:15][C:14]3[C:13]([C:17](=[O:30])[CH:18]([C:28]#[N:29])[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:20])=[N:12][N:11]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:10]=3[C:8]=2[CH:9]=1)([OH:3])=[O:2].CI.[C:39](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([CH:18]([C:17]([C:13]1[C:14]2[CH2:15][S:16][C:7]3[CH:6]=[CH:5][C:4]([C:1]([O:3][CH3:39])=[O:2])=[CH:9][C:8]=3[C:10]=2[N:11]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:12]=1)=[O:30])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])#[N:29]
Reactant: O=C([O-])[O-]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccc(C(=O)O)cc1-2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2c(c1)-c1c(c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn1-c1ccccc1)CS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
3-(8-Carboxy-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (0.65 g) dissolved in dimethylformamide (50 ml) is reacted with methyl iodide (0.37 g) in the presence of anhydrous potassium carbonate (0.36 g) under stirring at room temperature for 2 hours. The reaction mixture is diluted with ice water and the precipitate is filtered, dissolved in chloroform and washed with 1N HCl and then with water. Evaporation of the solvent in vacuo gives a residue which is crystallized from CH2Cl2 /methanol to yield 0.48 g of 2-cyano-3-(1,4-dihydro-8-methoxycarbonyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 228°-230° C.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[C-:18]#[N:19].[Na+].CS(C)=O.[CH3:25][NH2:26]>O>[C:18]([C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:26][CH3:25])=[O:15])#[N:19]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1cnn(-c2ccccc2)c1C#N
Temperature: 125 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
A 500 ml 3-neck round bottom flask fitted with a mechanical stirrer was sequentially charged with 40.0 g (0.16 mol) of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester, 15.68 g (0.32 mol) of sodium cyanide and 96 ml of dimethylsulfoxide. The reaction mixture was heated to about 125° C. and cooled to 100° C., at which temperature the reaction mixture was stirred for 6 hours. The mixture was stirred at room temperature overnight and charged with 43.4 g (0.56 mol) of 40% queous methylamine dropwise. The resulting mixture was stirred for 61/2 hours at room temperature and 96 ml of water was added thereto. The mixture was stirred for one hour and the precipitated solid was collected by vacuum filtration. The resulting solid was washed with water and vacuum dried to afford 27.5 g of 96.19% pure 5-cyano-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide. Corrected yield 73.6%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(CCN4CCCCC4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A mixture of (S)-N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5oxazolidinyl]methyl]acetamide (0.200 g, 0.595 mmol), 1-(2-chloroethyl)piperidine monohydrochloride (0.131 g, 0.714 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in acetonitrile (12 mL) was heated to reflux for 1.0 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with dichloromethane, the solids filtered off, and the filtrate concentrated in vacuo to give the crude product (0.308 g). This crude material was chromatographed over silica gel (5 g), eluting with 5% and then 10% methanol/chloroform, to afford, after concentration of appropriate fractions, 0.192 g (72%) of the title compound as an off-white solid with mp 169°-170° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.[C:21]([O-])([O-])=O.[K+].[K+].C([Si]([O:34][C:35]1([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([F:45])[CH:39]=2)[CH2:37][O:36]1)(C)C)(C)(C)C>CN(C=O)C.O>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:35]([OH:34])([CH2:37][OH:36])[CH2:21][N:17]2[CH:18]=[CH:19][C:14]([C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[N:13]=3)=[CH:15][C:16]2=[O:20])=[CH:39][C:40]=1[F:45]
Reactant: CC(C)(C)[Si](C)(C)OC1(c2ccc(Cl)c(F)c2)CO1
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1CC(O)(CO)c1ccc(Cl)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
4-(2-(Tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (136 mg, 0.500 mmol) and K2CO3 (248 mg, 1.80 mmol) were added to a solution of tert-butyl (2-(4-chloro-3-fluorophenyl)oxiran-2-yloxy)dimethylsilane (200 mg, 0.600 mmol) in DMF (5.0 mL). After being heated at 80° C. overnight, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (3×100 mL). The organic phases were washed with brine (3×30 mL), dried, and concentrated. The residue was dissolved in CH2Cl2, followed by addition of TFA (5.0 mL). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was purified by prep-HPLC to give 1-(2-(4-chloro-3-fluorophenyl)-2,3-dihydroxypropyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridine-2(1H)-one (70 mg, 30% yield). 1H NMR (500 MHz, CD3OD) δ 8.39 (m, 1H), 7.67-7.66 (m, 1H), 7.51-7.49 (m, 1H), 7.45-7.38 (m, 1H), 7.22 (s, 2H), 7.08-7.07 (m, 1H), 6.97-6.95 (m, 1H), 4.69-4.66 (m, 1H), 4.31-4.28 (m, 1H), 4.10 (s, 1H), 4.01-3.99 (m, 2H), 3.72-3.66 (m, 2H), 3.60-3.56 (m, 2H), 2.03-2.00 (m, 2H), 1.67-1.59 (m, 2H); LCMS (ESI) m/z: 475.1 [M+H]+.
Reaction SMILES: ClC(Cl)C.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:18]2[CH:19]=[C:20]([N:23]=[C:24]=[O:25])[CH:21]=[CH:22][C:17]=2[N:16]([CH3:26])[C:15](=[O:27])[CH2:14][N:13]=1.NC1C=CC2N(C)C(=O)CN=C(C3C=CC=CC=3F)C=2C=1.[NH2:49][CH2:50][CH:51]([OH:53])[CH3:52]>ClCCCl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:18]2[CH:19]=[C:20]([NH:23][C:24]([NH:49][CH2:50][CH:51]([OH:53])[CH3:52])=[O:25])[CH:21]=[CH:22][C:17]=2[N:16]([CH3:26])[C:15](=[O:27])[CH2:14][N:13]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N=C=O)ccc21
Reactant: CC(O)CN
Agent: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CC(O)CNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A dichloroethane solution of [5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, prepared as described in paragraph (a) of Example 1 from 12.5 g (0.044 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, is added to a solution of 8 g of 1-amino-2-propanol in 100 ml of 1,2-dichloroethane, the mixture is stirred at room temperature for 15 minutes and then concentrated. The residue is purified on a 300 g silica gel column using methylene chloride and then acetone as the eluting agent. This operation is repeated once using ethyl acetate as the eluting agent. After crystallisation from ethyl acetate, there is obtained rac-1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxypropyl)urea which melts at 149°-151° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:33](Cl)(=[O:36])[CH2:34][CH3:35].O>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC(=O)Nc1cnc2ccccc2c1NCCOCCNC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (32.0 g, 92.0 mmol) in 300 mL of CH2Cl2 was treated with triethylamine (19.2 mL; 138.0 mmol). The reaction was chilled in an ice water bath and then propionyl chloride (9.40 mL, 108.2 mmol) was added dropwise. After stirring for 18 h, the reaction was treated with water (150 mL) and the layers were separated. The aqueous portion was extracted with CH2Cl2 (3×50 mL). The combined organic portions were washed with 1% Na2CO3, water, brine, dried over Na2SO4, filtered and concentrated to yield a red sticky solid. The solid was triturated with ether and filtered to yield 16.5 g of tert-butyl 2-(2-{[3-(propionylamino)quinolin-4-yl]amino}ethoxy)ethylcarbamate as an off white powder.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=4[F:36])=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C=O>C(Cl)Cl>[F:36][C:28]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:27]=1[O:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[C:17]([O:37][CH3:38])[CH:18]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C)CC1
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To a solution of 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (305 mg, 0.58 mmol) in CH2Cl2 (1 mL) was added 0.4 mL of TFA. The reaction mixture was stirred for 1.5 h and the solvents were removed under reduced pressure. The crude product was treated with NaBH(OAc)3 (381 mg, 1.80 mmol) and formaldehyde (0.5 mL, 37% in H2O). The stirring was continued for 12 h. The reaction was quenched with sat. aqueous NaHCO3. 15% NaOH was added until PH=14. The product was extracted with EtOAc. Removal of the solvent in vacuo gave the crude product, 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinoline, (240 mg, 93%), which was used directly in the next reaction.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[NH2:5][CH:6]1[CH2:15][C:14]2[C:9]3=[C:10]([NH:16][C:17](=[O:18])[N:8]3[CH2:7]1)[CH:11]=[CH:12][CH:13]=2.Cl.Cl.Br[C:22]1[CH:23]=C2C(=C([N+]([O-])=O)[CH:31]=1)NCC(N)C2>C(OCC)(=O)C>[CH2:2]([N:5]([CH2:23][CH:22]=[CH2:31])[CH:6]1[CH2:15][C:14]2[C:9]3=[C:10]([NH:16][C:17](=[O:18])[N:8]3[CH2:7]1)[CH:11]=[CH:12][CH:13]=2)[CH:3]=[CH2:4].[CH2:2]([NH:5][CH:6]1[CH2:15][C:14]2[C:9]3=[C:10]([NH:16][C:17](=[O:18])[N:8]3[CH2:7]1)[CH:11]=[CH:12][CH:13]=2)[CH:3]=[CH2:4]
Reactant: NC1Cc2cccc3[nH]c(=O)n(c23)C1
Reactant: CCCI
Reactant: NC1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCN(CC=C)C1Cc2cccc3[nH]c(=O)n(c23)C1
Product: C=CCNC1Cc2cccc3[nH]c(=O)n(c23)C1

Procedure:
Following the procedure of Example 54, but substituting allyl bromide for iodopropane and 5 -(amino)-5,6-dihydro-4H-imidazo [4,5,1 -i j]quinolin-2(1H)-one for 6-bromo-1,2,3, 4-tetrahydro-8-nitro-3-quinolinamine dihydrochloride there were obtained 5-(diallylamino)-5, 6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one, mp 150-152 from ethyl acetate and 5-(allyl-amino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one. The latter compound was converted to the hydrochloride salt, mp 260° C. from methanol:ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]=1[NH:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[O:4].OS(O)(=O)=O.[CH2:22](O)[CH2:23][CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[C:9]([O:10][CH2:22][CH2:23][CH3:24])=[CH:8][S:7][C:6]=1[NH:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[O:4]
Reactant: CCCO
Reactant: COC(=O)C1=C(NC(=O)N(C)C)SCC1=O
Agent: O=S(=O)(O)O
Product: CCCOc1csc(NC(=O)N(C)C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
A solution of 2-(3,3-Dimethyl-ureido)-4-oxo-4,5-dihydro-thiophene-3-carboxylic acid methyl ester (50 mg, 0.205 mmol) in n-propanol (5 mL) was treated with H2SO4 (5 microliters) and stirred at ambient temperature for 12 hours. Little reaction was observed so the temperature was increased to 100° C. Little reaction was observed after 2 hours so four angstrom seives were added and the reaction continued at 100° C. for two additional hours at which point sufficient product was observed. The mixture was then concentrated and the residue purified via radial chromatography on a 4 mm plate using hexanes/ethyl acetate (1/1) to afford the title compound as a white solid (31 mg, 0.108 mmol, 53%) 1H NMR (CDCL3, 400 MHz) 1.03 (t, 3H, J=7.3 Hz), 1.78-1.84 (m, 2H), 3.06 (s, 6H), 3.84-3.89 (m, 5H), 5.51 (s, 1H), 11.08 (s, 1H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[C:9]=1[Br:39].C(O)(C(F)(F)F)=O.O>>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=2)[C:9]=1[Br:39]
Reactant: COC(=O)Cc1ccc(Oc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)Cc1ccc(Oc2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate from above step D was treated with 50% TFA/H2O (3 mL) and stirred at room temperature for 1 h. Solvent was removed to yield thick oil, methyl 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate, which was used in the next step directly without further purification. HPLC-MS tR=1.60 min (UV254 nm); Mass calculated for formula C24H18BrN5O3, 503.1, observed LCMS m/z 504.1 (M+Na).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:20][OH:21])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C1OCCOCCOCCOCCOCCOC1.[H-].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:18][C@H:19]([C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:20][O:21][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](COCc3ccccc3)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Yield: 79.3 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 156; 0.7749 g, 1.35 mmol), benzyl bromide (0.4618 g, 0.321 ml, 2.7 mmol), 18-crown-6 (0.714 g, 2.7 mmol) and sodium hydride (0.1037 g, 4.32 mmol) in THF (6 ml) were heated at 60° C. for 1 hour. The mixture was diluted with water and extracted into ethyl acetate. The organics were collected and dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 15% ethyl acetate/iso-hexane, to afford the title compound as a clear oil (712 mg, 79%).
Reaction SMILES: [C:1]([C:9]([OH:11])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:12][CH:13](O)[C:14]#[CH:15].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[I:12][C:13]#[C:14][CH2:15][O:10][C:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: C#CC(O)I
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCC#CI)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a cold, stirred solution of benzoyl formic acid (1.5 g, 0.01 mole) in methylene chloride (75 mL) at 4° C. were added iodopropargyl alcohol (1.9 g, 0.0105 mole) followed by 4-dimethylaminopyridine (0.122 g, 0.001 mole) and ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 g, 0.0104 mole). After stirring at 0° to 10° C. for one hour, the reaction mixture was diluted with methylene chloride (100 mL) and was washed with water (3×50 mL) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to a residue. The residue was triturated with hexane and the product, a pale yellow solid, was collected by suction-filtration yielding 1.75 g (60%), mp=48°-50° C. An nmr spectrum showed the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.C([Li])CCC.[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1.CO>[C:33]([O:29][CH:28]([C:27]1[C:26]([O:31][CH3:32])=[CH:25][CH:24]=[C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:30]=1)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1)(=[O:35])[CH3:34]
Reactant: COc1ccc(Br)nc1
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Reactant: CC(=O)OC(C)=O
Agent: [Li]CCCC
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC(C)=O)c2cc(OCc3ccccc3)ccc2OC)nc1
Yield: 50 %

Procedure:
2-Bromo-5-methoxypyridine (15.35 g) was successively treated with n-butyl lithium and 5-benzyloxy-2-methoxybenzaldehyde (16.47 g, Example 1(i)) under the conditions of Example 1(j). The crude carbinol (19.4 g) was treated with acetic anhydride and pyridine as described in Example 1(k). The product was purified by column chromatography on silica gel (550 g). Elution with petroleum spirit (60°-80°)/ethyl acetate (2:1), then recrystallisation from dichloromethane/petroleum spirit gave 1-(3-benzyloxy-6-methoxyphenyl)-1-(5-methoxy-2-pyridyl)-methyl acetate (13.29 g, 50%), m.p. 105°-110°.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][O:14][C:15](=[O:36])[CH2:16][O:17][CH2:18][C:19]#[C:20][CH2:21][N:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:29][O:30]C(OCC)C>CO>[CH3:13][O:14][C:15](=[O:36])[CH2:16][O:17][CH2:18][C:19]#[C:20][CH2:21][N:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:29][OH:30]
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1CC#CCOCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CO
Reaction time: 20 h
Yield: 25.6 %

Procedure:
p-Toluenesulfonic acid hydrate (289 mg, 1.52 mmol) was added to a solution of {4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester (494 mg, 1.45 mmol) in MeOH (5.0 mL) at rt. After 20 h at rt, the mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 100 mg (26%) of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester.