Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([CH2:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([C@H:22]3[CH2:32][C@H:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([CH2:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([C@H:22]3[CH2:32][C@H:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:34]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc2c(c1C(=O)O)OC[C@@H]1C[C@H]21
Temperature: 80 °C
Yield: 17.9 %

Procedure:
A mixture of methyl cis-(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluoro-benzenesulfonylmethyl]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 1, 0.72 g) and lithium hydroxide (0.622 g) in dioxane (20 mL) and water (5 mL) was stirred and heated at 80° C. for 5 hours. After cooling, the mixture was filtered and the filtrate was concentrated to low volume under vacuum. The aqueous residue was acidified with formic acid to pH 5 and extracted with DCM. The organic layer was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by reverse phase chromatography using a C-18 5 micron cartridge and eluting with a mixture of methanol and water, with a gradient of 10-98%. The product was repurified by HPLC(C18) eluting with a mixture of acetonitrile and water (containing 0.1% formic acid) to give cis-(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylmethyl]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.125 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([CH:9]=O)=[CH:4][NH:3]1.CO.Cl.[NH2:14][OH:15].C([O-])(=O)C.[K+]>O>[OH:15][N:14]=[CH:9][C:5]1[C:6](=[O:8])[NH:7][C:2](=[O:1])[NH:3][CH:4]=1
Reactant: NO
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1[nH]cc(C=NO)c(=O)[nH]1
Yield: 84.4 %

Procedure:
A mixture of 2,4-dioxo-5(1H,3H)-pyrimidinecarbaldehyde (1.79 g, 12.8 mmol), methanol (35 mL) and water (35 mL) was heated at reflux and then a mixture of hydroxylamine hydrochloride (905 mg, 13 mmol), potassium acetate (1.28 g, 13 mmol) and water (15 mL) was added. The mixture was cooled and the solids were collected, washed with water and recrystallized from water/methanol to give 5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione (1.68 g, 10.8 mmol).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)[N:6]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[C:37]([Cl:38])=[C:36]([CH3:39])[NH:35][C:34]=1[C:40]([NH:42][C@@H:43]1[CH2:48][CH2:47][NH:46][CH2:45][C@@H:44]1[O:49][CH3:50])=[O:41]>CN1CCCC1=O.O>[Cl:32][C:33]1[C:37]([Cl:38])=[C:36]([CH3:39])[NH:35][C:34]=1[C:40]([NH:42][C@@H:43]1[CH2:48][CH2:47][N:46]([C:2]2[S:3][C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]3[N:12]=[C:11]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH:10]=[CH:9][N:8]=3)[N:6]=2)[CH2:45][C@@H:44]1[O:49][CH3:50])=[O:41]
Reactant: COC(=O)c1sc(Cl)nc1-c1nccc(N2CCCCC2)n1
Reactant: CO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1-c1nccc(N2CCCCC2)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a stirred solution of methyl 2-chloro-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate (Intermediate 67, 30 mg, 0.08 mmol) in N-methylpyrrolidinone (0.5 mL), N,N-diisopropyl ethylamine (23 mg, 0.18 mmol) and 3,4-dichloro-N-[(3S,4R)-3-methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (WO2006087543, 27 mg, 0.09 mol) were added at room temperature. The above reaction mixture was heated at 90° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and stirred for 1 h. The solid obtained was collected by filtration and dried to obtain methyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate 35 mg (66%).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([NH:7][CH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:22][CH3:23])[C:13]([O:20][CH3:21])=[N:14]2)=[O:6])C.C(=O)([O-])[O-].[K+].[K+].Cl>O.CO>[Br:19][C:17]1[CH:16]=[C:15]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[C:13]([O:20][CH3:21])=[N:14]2)=[C:9]([CH2:8][NH:7][C:5](=[O:6])[C:4]([OH:24])=[O:3])[CH:18]=1
Reactant: CCOC(=O)C(=O)NCc1cc(Br)cc2nc(OC)c(OC)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1nc2cc(Br)cc(CNC(=O)C(=O)O)c2nc1OC
Reaction time: 20 h

Procedure:
276 mg of N-(7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethyl)-oxalamic acid ethyl ester and 150 mg of potassium carbonate are suspended in 2 ml of water and 5 ml of methanol. The mixture is stirred for 20 hours and acidified with 1 N HCl, and the solid is filtered off and washed with methanol and diethyl ether. M.p.>300° C.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[CH:68][C:69]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:74][CH2:73]5)=[N:70][CH:71]=4)[CH:64]=3)[N:59](S(C3C=CC(C)=CC=3)(=O)=O)[CH:58]=2)[C:53]([CH3:92])=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[C:55]([CH3:56])=[C:54]([C:57]2[C:65]3[C:60](=[N:61][CH:62]=[C:63]([C:66]4[CH:67]=[CH:68][C:69]([N:72]5[CH2:77][CH2:76][N:75]([CH2:78][C@@H:79]([OH:81])[CH3:80])[CH2:74][CH2:73]5)=[N:70][CH:71]=4)[CH:64]=3)[NH:59][CH:58]=2)[C:53]([CH3:92])=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C[C@H](C)O)CC4)nc3)cc12
Yield: 24.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (2S)-1-(4-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl)propan-2-ol (165 mg, 0.238 mmol) was hydrolyzed with lithium hydroxide (100 mg, 2.38 mmol) in THF/methanol/water (20/10/5 mL) to yield 31 mg (13% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.64-8.63 (d, 1H), 8.48-8.47 (d, 1H), 8.327-8.321 (d, 1H), 8.23-8.19 (dd, 1H), 7.64 (s, 1H), 7.42-7.35 (m, 1H), 7.31-7.28 (d, 1H), 7.07-7.02 (m, 2H), 6.95-6.91 (dt, 1H), 5.41 (s, 2H), 4.45-4.30 (m, 1H), 3.56 (s, 4H), 3.30-3.10 (m, 2H), 2.24 (s, 3H), 2.23 (s, 3H), 1.26-1.24 (d, 3H). MS: m/z=539.9 (M+1), HPLC: 95.5% in method A.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 1541.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (103 mg) and commercially available 4-methoxyphenol (286 mg) were mixed and stirred at 150° C. for 6 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting first with hexane/ethyl acetate and then with chloroform/ethyl acetate to obtain 2.21 g of the title compound (yield: 88%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:40][C@@H:41]2[NH:45][C:44](=[O:46])[CH2:43][CH2:42]2)(=O)=O)=CC=1.CCOCC>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][C@@H:41]1[NH:45][C:44](=[O:46])[CH2:43][CH2:42]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)C[C@H]2CCC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.3 %

Procedure:
To a suspension of 7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (1.36 g, 4.24 mmol), (prepared as described in Example 49), in DMF (70 ml), was added potassium carbonate (2.34 g, 17.0 mmol, 4eq.) followed by (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.25 g, 4.66 mmol, 1.1 eq.), (prepared as described for the starting material in Example 317), and the resulting yellow suspension heated at reflux. After 4 hours, some starting material remained, and a further addition of (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (0.57 g, 2.12 mmol, 0.5eq.) was made. The reaction was heated at reflux for a further 2 hours resulting in consumption of starting material. The reaction was cooled to ambient temperature, the inorganic residue filtered off and the filtrate evaporated in vacuo to leave a brown oil which was purified by column chromatography (methylene chloride/methanol, (100/0 to 90/10)) to give a light brown oil. Trituration with ether afforded a thick oil, which upon chromatography eluting as above gave a yellow oil. Trituration of this oil with ether gave an initial crop of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (5 mg) as an off-white solid (ca. 90% pure by nmr). Chromatography of the residues (eluting as above) followed by ether trituration gave further crops of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline as a white solid (180 mg, >95% pure by nmr), as an off-white solid (800 mg, ca. 95% pure by nmr).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:22])[C:19]=1[O:20][CH3:21])[CH2:15][NH2:16].C([O-])(=O)C.[NH4+]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:22])[C:19]=1[O:20][CH3:21])[CH2:15][NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1c(F)cc(CN)cc1F
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1c(F)cc(CNc2ccccc2[N+](=O)[O-])cc1F
Yield: 100 %

Procedure:
A mixture of 2-fluoronitrobenzene (0.82 g, 5.8 mmole), 3,5-difluoro-4-methoxybenzylamine, (3.0 g, 17.3 mmole) and ammonium acetate (0.5 g) was reacted substantially as described in 1C above to yield 1.7 g, (100%) of the title compound as orange crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1.Cl>CN(C)C=O>[CH3:18][C:19]1[N:23]=[CH:22][N:21]([C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[N:20]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1nc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2cnc(C(=O)O)cn2)n1
Temperature: 100 °C

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2CO3 (1.8 g) and 3-methyl-1H-1,2,4-triazole (1.2 g) in N,N-dimethylformamide (6 mL) is heated to 100° C. overnight. Analysis of the crude mixture by LCMS shows saponified product. The product is acidified with 1N HCl and the precipitate is filtered and washed with water and diethyl ether to afford the title compound. LC (method 20): tR=1.21 min; Mass spectrum (APCI): m/z=206 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20]2.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[CH2:22][CH2:21][CH2:20]4)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: Brc1ccc2c(c1)CCC2
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3c(c2)CCC3)CCN1c1cnccc1C1CC1
Yield: 7.6 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 5-bromo-2,3-dihydro-1H-indene (132 mg, 0.5418 mmol), 1,4-dioxane (4 mL), copper iodide (9.5 mg, 0.0492 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (7.0 mg, 0.0492 mmol) and potassium phosphate (261 mg, 1.231 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in CHCl3) afforded 12 mg of the product (8% yield).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27](=[O:29])[CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH:26]([C:27](=[O:29])[CH3:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)/C=C/c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (32.78 g, 0.138 mol) in CH2Cl2 (50 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-4-(3,4-dichloro-phenyl)-but-3-en-2-one (19.80 g, 0.092 mol) and trifluoroacetic acid (1.05 mL, 0.009 mol) in CH2Cl2 (100 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2/MeOH 98:2) afforded 28.3 g (88%) of the title compound as a yellow oil. ES-MS m/e: 348.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[H-].[Na+].[NH2:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[C:25]([Cl:30])[N:24]=1.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:30][C:25]1[CH:26]=[C:27]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[CH:7][CH:6]=2)[C:2]([F:1])([F:18])[F:19])[N:28]=[C:23]([NH2:22])[N:24]=1
Reactant: OC(c1ccc(-c2cccc(F)c2)cc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To 2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethanol (1.4 g, 5.18 mmol) in THF (50 mls) at 0° C. was added NaH (60% in mineral oil, 0.31 g, 7.77 mmol). The ice bath was removed and the mixture was stirred for 30 minutes. 2-Amino-4,6-dichloropyrimidine (1.0 g, 6.22 mmol) in THF (25 mls) was added at once. The mixture was heated to 50° C. for 5 hours. The reaction was complete by LCMS (Sunfire, TFA). The mixture was cooled, quenched with brine, and extracted 3 times with CH2Cl2. The organics were combined, washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, CH2Cl2) afforded 1.48 g of 4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine. Yield 73%.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:24])[C:9]([O:11][CH2:12][O:13][C:14](ON1C(=O)CCC1=O)=[O:15])=[O:10]>>[CH3:2][N:1]([C:14]([O:13][CH2:12][O:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])=[O:15])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: CC(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Product: CC(C)C(=O)OCOC(=O)N(C)CC(=O)O

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.123 g, 1.3 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (0.300 g, 1.1 mmol) were reacted to provide 0.138 g (5.1.3% yield) of the title compound (46) as a colorless semi-solid material after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=5.78 (d, 2H), 4.12 (d, 3H), 3.02 (d, 3H), 2.62 (m, 1H), 1.2 (t, 6H). MS (ESI) m/z 256.05 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]=[C:12]2[CH:15]2[CH2:17][CH2:16]2)=[C:7]([OH:18])[CH:6]=1)=[O:4].[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]=[C:12]2[CH:15]2[CH2:16][CH2:17]2)=[C:7]([O:18][CH3:19])[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c2ccnc(C3CC3)c2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c2ccnc(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Cyclopropyl-5-hydroxy-isoquinoline-7-carboxylic acid methyl ester (5.00 g, 20.6 mmol) was dissolved in DMF (50 ml) and K2CO3 (5.69 g, 41.2 mmol) and MeI (1.54 ml, 24.7 mmol) was added thereto. After stirred at room temperature for 2 h, the reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to 6/4) to obtain the intended compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]2[CH2:25][NH:24][C:23](=[O:26])[CH2:22]2)([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH2:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O.O1CCCC1>[CH2:34]([N:24]1[CH2:25][CH:21]([C:11]2([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:22][C:23]1=[O:26])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1(C2CNC(=O)C2)CC(OCc2ccccc2)C1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
A 20.53 g (56.96 mmol) portion of 4-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-2-pyrrolidone was dissolved in a mixed solvent consisting of 200 ml of dimethylformamide and 60 ml of tetrahydrofuran, and to the resulting solution which was cooled in an ice bath and stirred was subsequently added 2.51 g (62.7 mmol) of 60% sodium hydride gradually. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 1 hour. While cooling in an ice bath with stirring, 7.21 ml (62.7 mmol) of benzyl chloride was added dropwise thereto, and the resulting reaction solution was stirred for 1 hour at the same temperature and then for 12 hours at room temperature. Water was added to the reaction solution which was cooled in an ice bath and stirred, and then separation of layers was effected by adding ethyl acetate. The thus separated organic layer was washed with saturated brine, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 18.00 g (70.1%) of the title compound as a 1:1 diastereomer mixture. Thereafter, the thus obtained title compound was again subjected to a silica gel column chromatography to separate it into diastereoisomers A and B, and the following reaction was carried out using the Isomer B.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[C:5](Cl)=[O:6].[F:9][C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH2:12][OH:13].O>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][N:4]([CH3:8])[C:5](=[O:6])[O:13][CH2:12][CH:11]=[C:10]([F:9])[S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CN(C)C(=O)Cl
Reactant: CCCCCCSC(F)=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCSC(F)=CCOC(=O)N(C)C
Reaction time: 1 h

Procedure:
To a slurry of sodium hydride (125 mg, 5.2 mmol) in 5 ml of THF and 2 ml of HMPA under N2 is added dimethylcarbamoyl chloride (0.37 ml, 430 mg, 4.0 mmol). The slurry is cooled in an ice bath and 3-fluoro-3-hexylthio-2-propen-1-ol (450 mg, 2.34 mmol) is added gradually. After 1 hour, the mixture is cautiously poured into water, extracted with ether and stripped to give 3-fluoro-3-hexylthio-2-propenyl dimethylcarbamate.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:11][C:12]#[CH:13])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.C([Li])CCC.CN(C)[C:21](=[O:23])[CH3:22].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCCCCC>[CH3:1][C@H:2]([CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[CH2:11][C:12]#[C:13][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)N(C)C
Reactant: C#CC[C@H](C)COC1CCCCO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)C#CC[C@H](C)COC1CCCCO1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a solution of 100.0 g (RS)-2-{[(S)-2-Methylpent-4-in-1-yl]oxy}3,4,5,6-tetrahydro-2H-pyran (Ireland, Robert E. et al., Tetrahedron, 1997, 53, 39, 13221-13256) in 200 ml THF were added, dropwise at −30° C., 439 ml n-butyllithium (15% in hexane). The solution was stirred for 20 minutes at −30° C. and 20 minutes at −20° C. After cooling to −30° C., a solution of 95.6 g N,N-dimethylacetamide in 200 ml THF was added during 15 minutes and the reaction mixture was stirred for 30 minutes at −20°. The reaction mixture was then poured into a stirred precooled (0° C.) mixture of 1000 ml hexane and a solution of 104,8 g citric acid monohydrate in 700 ml water. The aqueous phase was separated and the organic phase was washed with 300 ml water and then filtered over 100 g silica gel. The silica gel was washed with 1000 ml hexane. The combined eluates were reduced to an oil by vacuum distillation.