Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Oc1ccccc1
Temperature: 150 °C
Yield: 19.8 %

Procedure:
(R)-N-[2-Chloro-3-fluoro-4-(ethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 15; 0.308 g) was added to a stirred suspension of phenol (0.150 g) and anhydrous potassium carbonate (0.220 g) in anhydrous DMF (2 ml). The reaction mixture was heated to 150° C. under argon for 17 hours and allowed to cool to ambient temperature. EtOAc (50 ml) was added and the organic phase was washed with brine (4×50 ml), separated, dried and volatile material was removed by evaporation. The residue was purified on a 8 g silica Biotage cartridge eluting 40% EtOAc/isohexane to give the title compound (0.073 g) as a pale yellow foam. NMR (CDCl3): 1.18 (t, 3H), 1.69 (s, 3H), 3.23-3.30 (q, 2H), 3.48 (s, 1H), 6.78 (d, 2H), 7.02 (t, 1H), 7.24 (t, 2H), 7.97 (d, 1), 8.50 (d, 1H), 9.24 (brs, 1H); m/z: 450.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([Cl:19])=[N:16]3)=[CH:11][CH:10]=2)[C:4]1=[O:20].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[S:27][C:26]=2[CH:34]=1.COC1C=C2C(C=CC(S(Cl)(=O)=O)=C2)=CC=1>C(Cl)Cl>[Cl:19][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:28]4[S:27][C:26]5[CH:34]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=5[CH:29]=4)(=[O:32])=[O:31])[C:4]3=[O:20])=[CH:10][CH:11]=2)[N:16]=1
Reactant: N[C@H]1CCN(Cc2ccc3ccc(Cl)nc3c2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClCCl
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1ccc2ccc(Cl)nc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN from 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 9, Parts A, B and C in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated from EtOAc/hexanes to afford the title compound as a beige solid.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][N:3]1[CH2:4][CH2:5][CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[C:2]1=[O:1])=[O:34])[CH3:37]
Reactant: O=C1NCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-[2-(2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (740 mg) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride in mineral oil (120 mg) at 0° C. After the mixture was stirred for 30 minutes, to this was added ethyl 2-bromoacetate (0.22 ml). After the reaction mixture was stirred at 0° C. for 1 hour, it was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (CHCl3—CHCl3:MeOH (30:1)) to give 3-[2-(1-ethoxycarbonylmethyl-2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.7 g) (yellow oil).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH2:22][C:23]2([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH2:22][C:23]1([C:26]([F:27])([F:28])[F:29])[CH2:25][CH2:24]1)=[O:6]
Reactant: Cc1ncc(C(CN)CC2(C(F)(F)F)CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)CC2(C(F)(F)F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=377.1, tR (minutes, Method F)=1.68
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.C[O-].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:5][CH:4]=1
Reactant: OCCCCCCCCCCCCBr
Reactant: COc1ccc(CS)cc1
Agent: C[O-]
Solvent: CO
Product: COc1ccc(CSCCCCCCCCCCCCO)cc1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
Na (800 mg, 34.8 mmol) was dissolved in 30 mL of dry MeOH. Under argon, p-methoxybenzylmercaptan (2.75 mL, 3.04 g, 19.7 mmol) was added to the methoxide solution. After a few minutes, 12-bromododecanol (2.5 g, 9.43 mmol) was dropped into the reaction mixture. Within 5 minutes a solid began to come out of solution. After a minimum of 3 h, the reaction was filtered and washed 3× with cold MeOH, yielding 2.874 g (8.49 mmol, 90%) of pure product after drying. 1H NMR (CDCl3): d 7.23 (d, J=8.8 Hz, 2H, AA′ of AA′BB′ aromatic system), 6.85 (d, J=8.8 Hz, 2H, BB′ of AA′BB′ aromatic system), 3.80 (s, 3H, methoxy), 3.66 (s, 2H, benzyl), 3.64 (dt, J1=6.6 Hz, J2=5.5 Hz, 2H, RCH2OH), 2.40 (t, J=7.3 Hz, 2H, RSCH2R), 1.50-1.65 (cm, 4H, CH2 b to heteroatoms), 1.2-1.4 (cm, 16H, bulk methylenes).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[I:12]N1C(=O)CCC1=O>C(O)(=O)C.O>[I:12][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[CH2:4]2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(I)ccc2c1CC(=O)N2
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To 2 g of 4-methyl-2-oxindole in 40 mL of glacial acetic acid in an ice bath was added 3.67 g N-iodosuccinimide. The mixture was stirred for 1 hour, diluted with 100 mL 50% acetic acid in water and filtered. The resulting white solid was dried under high vacuum to give 3.27 g (88% yield) of the title compound as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:31]2[CH2:32][CH2:33][N:34]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:35][CH2:36]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(c1ccc(-c2ccccn2)cc1)N1CCNCC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Yield: 54 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[4-(2-pyridyl)phenylsulphonyl]piperazine to give 1-[4-(2-pyridyl)phenyl-sulphonyl]4-[1(4-pyridyl)piperidine-4-ylcarbonyl]piperazine in 54% yield, m.p. 224-226° C.;
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCCCCN1
Reactant: CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCN1CCCCCC1=O
Yield: 84.8 %

Procedure:
Following example 10, 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 44.2 g (0.2 M) of 1-bromodecane on 19 hr. reflux gave 38 g (84.7%) of product; b.p. 158°-163 °/0.25-0.3 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:28])[C@@H:14]([NH:24][C:25](=[O:27])[CH3:26])[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([O:28][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:14]([NH:24][C:25](=[O:27])[CH3:26])[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
Suspend (R)-4-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (4.78 g, 11.2 mmol) in dry tetrahydrofuran (115 ml) under a nitrogen atmosphere and add sodium hydride NaH (60% weight dispersion in mineral oil, 1.17 g, 29.3 mmol). Stir the resulting mixture for 30 minutes and then add sequentially sodium iodide (600 mg, 4.0 mmol) and benzyl bromide (2.7 mL, 22.7 mmol). Stir the resulting mixture for 2.5 hours and then quench by the addition of a 1:1 mixture of saturated aqueous ammonium chloride and saturated aqueous sodium chloride. Dilute the resulting mixture with ethyl acetate and discard the aqueous phase. Wash the organic phase with saturated aqueous sodium chloride, dry over magnesium sulfate, filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 40:60 ethyl acetate:hexanes) to give the desired compound as a white foam (4.96 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[N:17]=[CH:16][C:15]2[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1>>[CH:21]1([N:20]2[C:14]3[CH:13]=[C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=4)[N:17]=[CH:16][C:15]=3[C:18]([CH3:25])([CH3:26])[C:19]2=[O:24])[CH2:23][CH2:22]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Reactant: Cc1cc(C(=O)O)ccn1
Product: Cc1cc(C(=O)Nc2cc3c(cn2)C(C)(C)C(=O)N3C2CC2)ccn1

Procedure:
Prepared in analogy to example 26 from 2-methylisonicotinic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as off-white foam.
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=CC(OCC)=O)=[CH:6]1.CN(CCC1C=CC=CC=1)C(=O)CC1C=C2C(=CC=1)N(OCC1C=CC=CC=1)C=[C:45]2[CH:59]=[C:60]([C:62]([O:64]CC)=[O:63])C.CN(CCC1C=CC=CC=1)C(=O)CN1C2C(=CC(OCC3C=CC=CC=3)=CC=2)C(C=C(C(O)=O)C=C)=C1>CC(C)=O.CCOCC>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:45][CH:59]=[CH:60][C:62]([OH:64])=[O:63])=[CH:6]1
Reactant: CCOC(=O)C(C)=Cc1cn(OCc2ccccc2)c2ccc(CC(=O)N(C)CCc3ccccc3)cc12
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: C=CC(=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12)C(=O)O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CN(CCc1ccccc1)C(=O)Cn1cc(C=CC=CC(=O)O)c2cc(OCc3ccccc3)ccc21

Procedure:
When N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamide in the procedure of Example 23 is replaced with N-methyl-N-phenethyl-2-[1-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-5-yl]acetamide then the product prepared is N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxy-1,3-butadienyl)indol-1-yl]acetamide. (solvent system (acetone/ether) m.p. 189°-190° C.)
Reaction SMILES: O[C:2]1[C:3](=[O:17])[O:4][CH:5]([CH2:13][CH2:14][CH2:15][OH:16])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28].Cl>O1CCCC1>[OH:16][CH2:15][CH2:14][CH2:13][CH:5]1[O:4][C:3](=[O:17])[C:2]([C:25]([O:26][CH2:27][CH3:28])=[O:29])=[C:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1OC(CCCO)C(c2ccccc2)=C1O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(c2ccccc2)C(CCCO)OC1=O

Procedure:
3-Hydroxy-5-(3-hydroxypropyl)-4-phenyl-2(5H)-furanone (25 mg) was dissolved in tetrahydrofuran (6 ml), and triethylamine (0.018 ml) was added with ice-cooling and stirring, followed by dropwise addition of ethyl chlorocarbonate (0.012 ml). The mixture was stirred at the same temperature for 5 minutes, and the reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off. The remaining oil was purified by preparative thin layer chromatography (silica gel; developer: 4% methanol-chloroform) to give ethyl 5-(3-hydroxypropyl)-2-oxo-4-phenyl-2,5-dihydro-3-furancarboxylate (30 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=[O:8].[CH:14]([NH2:16])=O>>[OH:8][C:7]1[C:6]2[C:5]([CH3:12])=[C:4]([CH3:13])[S:3][C:2]=2[N:1]=[CH:14][N:16]=1
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: NC=O
Product: Cc1sc2ncnc(O)c2c1C

Procedure:
Using ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (500 mg, 2.5 mmol) and formamide (5 ml), a similar procedure to a) in Production Example 208 was carried out to obtain 4-hydroxy-5,6-dimethylthieno[2,3-d]pyrimidine (380 mg, 2.1 mmol) having the following physical properties:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60]O>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH3:54])[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: COCCOCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOCCOc1cc2ncn(COC(=O)C(C)(C)C)c(=O)c2cc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 106.7 %

Procedure:
Diethyl azodicarboxylate (864 μl, 5.5 mmol) was added dropwise to a mixture of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.2 g, 3.9 mmol) (prepared as described for the starting material in Example 12), triphenylphosphine (1.44 g, 5.5 mmol) and 2-(2-methoxyethoxy)ethanol (653 μl, 5.5 mmol) in methylene chloride (70 ml) cooled at 0° C. The mixture was stirred for 1.5 hours at ambient temperature and the solvent was removed by evaporation. The residue was purified by column chromatography eluting with a mixture of ethyl acetate/methylene chloride (50/50 followed by 80/20). The purified solid was suspended in ether, collected by filtration and dried under vacuum to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.70 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.O1CCC[CH2:35]1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:35])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Dissolve 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (860 mg, 2.08 mmoles) in diethyl ether (100 mL) under N2. Cool the solution to 0° C. in an ice bath, and add sodium hydride (1.1 equiv; 2.29 mmoles; 91.52 mg), followed by injecting methyl iodide (2.00 equiv; 4.16 mmoles; 259.12 μL). Stir the mixture for 1 hour at 0° C., and then warm to room temperature. Inject tetrahydrofuran (40 mL) into the above mixture, and then stir at room temperature overnight. Concentrate the mixture under reduced pressure, and then dissolve the residue in EtOAc. Wash with saturated aqueous sodium chloride. Purify the residue via silica gel chromatography, eluting with EtOAc:hexane (7:3) to offer 270 mg (30% yield) of a title compound.
Reaction SMILES: [OH:1][CH:2]([CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].[C:16](OC(=O)C)(=[O:18])[CH3:17].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:16]([O:1][CH:2]([CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])(=[O:18])[CH3:17]
Reactant: COCCCCC(O)C1CC2C=CC1C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COCCCCC(OC(C)=O)C1CC2C=CC1C2
Yield: 97 %

Procedure:
In 63.3 g of pyridine, 105.2 g of 5-(1-hydroxy-5-methoxypentyl)-2-norbornene (Monomer 1) was reacted with 61.3 g of acetic anhydride in the presence of 2 g of 4-dimethylaminopyridine at room temperature for 10 hours. The reaction was stopped by adding 30 g of water. Extraction with hexane gave the organic layer, which was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The oily matter thus obtained was distilled in vacuum, obtaining 122.4 g of 5-(1-acetoxy-5-methoxypentyl)-2-norbornene. The yield was 97.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]([NH:18][C:19]([O:21]C(C)(C)C)=O)[C:12]2=[O:26])=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:51][C:52]1[CH:61]=[C:60]2[C:55]([C:56]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)=[CH:57][C:58]([NH2:62])=[N:59]2)=[CH:54][CH:53]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]([NH:18][C:19]([N:66]3[CH2:67][CH2:68][N:63]([C:56]4[C:55]5[C:60](=[CH:61][C:52]([Cl:51])=[CH:53][CH:54]=5)[N:59]=[C:58]([NH2:62])[CH:57]=4)[CH2:64][CH2:65]3)=[O:21])[C:12]2=[O:26])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)Oc2ccc(F)cc2)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)Oc4ccc(F)cc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid-4-fluorophenyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 555 (M++1). 1H NMR (CDCl3): δ 1.54˜2.10 (m, 5H), 2.16–2.24 (m, 1H), 3.14 (m, 4H), 3.54 (dd, 1H), 3.68 (m, 4H), 4.52 (dd, 1H), 4.84 (br.s, 2H), 4.90 (ddd, 1H), 5.94 (d, 1H), 6.15 (s, 1H), 7.06–7.13 (m, 2H), 7.13–7.20 (m, 3H), 7.62 (d, 1H), 7.72 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:31][CH:32]=[O:33])[C:27]=1[CH3:34].C1(C=CC=C(O)C=1)[OH:36].Cl([O-])=O.[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:36])=[O:33])[C:27]=1[CH3:34]
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC=O)CC1)C(=O)OC2
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Reaction time: 0.03 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetaldehyde was dissolved in dioxane (8 mL) and pH 5 buffer (3 mL) and treated with resorcinol (0.10 g). To this mixture was then added sodium chlorite (0.080 g). After 2 minutes, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate. The residue, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid obtained after solvent removal was carried on without further purification.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[CH3:18][C:19]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>O1CCCC1>[CH3:18][C:19]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)[OH:22]
Reactant: Cc1cccc(C=O)c1C
Reactant: CCOC(OCC)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(O)c2ncc[nH]2)c1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 1-(diethoxymethyl)-1H-imidazole (698 mg, 4.10 mmol) in anhydrous tetrahydrofuran (7 ml), at −78° C., was added n-butyllithium (2.5 M in hexane, 1.64 ml, 4.1 mmol). The reaction mixture was stirred at −78° C. for 1 h, before addition of a solution of 2,3-dimethylbenzaldehyde (500 mg, 3.73 mmol) in tetrahydrofuran (3 ml). The reaction mixture was stirred at −78° C. for 2 h, warmed to room temperature and quenched with ice cold hydrochloric acid (4M, 20 ml). The reaction mixture was concentrated in vacuo and to the residue was added water (20 ml). The solution was extracted with diethyl ether (2×20 ml) and the aqueous layer was basified by addition of solid sodium hydrogen carbonate. This solution was extracted with ethyl acetate (3×20 ml) and the combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound (543 mg)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH-].[Na+]>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Reaction time: 2 h
Yield: 98 %

Procedure:
Pyrrolidine (2.5 g, 35.2 mmol) was added to a solution of 4-bromobenzenesulfonyl chloride (4.5 g, 17.6 mmol) in methylene chloride (10 mL) at 0° C. The mixture was stirred for 2 h and an aqueous sodium hydroxide solution (1 M, 5 mL) was added and sting was continued for another 10 min. The organic phase was separated and diluted with methylene chloride (40 mL), washed with aqueous HCl (1 M, 10 mL), and water (2×10 mL). The organic phase was dried (sodium sulfate) and the solvent was evaporated. The title compound was isolated in 5.0 g (98% yield) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.65 (m, 4H), 3.20 (m, 4H), 1.74 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 135.93, 132.17, 128.84, 127.39, 47.84, 25.13; MS (ES) m/z 290 and 292 (M++1).