Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2O.FC1C([O:17][C:18](=O)[O:19]C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[C:36]1([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:45][CH2:44][NH:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:52]([OH:59])(=[O:58])[CH2:53][CH2:54][C:55]([OH:57])=[O:56]>ClCCl.CC(C)=O.C(OCC)(=O)C>[CH:39]1[CH:40]=[CH:41][C:36]([C@@H:42]2[N:43]([C:18]([O:19][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:17])[CH2:44][CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:51]2=3)=[CH:37][CH:38]=1.[CH2:53]([C:52]([OH:59])=[O:58])[CH2:54][C:55]([OH:57])=[O:56]
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O[C@@H]1CC2CCN1CC2
Agent: O=C(O)CCC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Reaction time: 0.33 h
Yield: 80.1 %

Procedure:
127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of dichloromethane and then stirred at 25˜30° C. for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of bis(pentafluorophenyl)carbonate was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), the reaction solution was concentrated under reduced pressure. Subsequently, oily matter obtained by adding 1270 mL of ethyl acetate to the reaction solution was dissolved, and then 209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the reaction solution and stirred at 25˜30° C. for 4˜5 hours. After confirming the completion of a reaction using high performance liquid chromatography (HPLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1˜2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, and then the reaction solution was concentrated under reduced pressure. Then, 1270 mL of water was added to the reaction solution, the pH of the reaction solution was adjusted to 9˜10 using ammonium hydroxide, and then an aqueous layer was further extracted from the reaction solution using 1270 mL of toluene. Subsequently, 1270 mL of acetone and 118.1 g (1.0 mol) of succinic acid were added to the reaction solution, stirred at 55˜60° C. for 30 minutes, further stirred at 10˜15° C. for 2 hours, and then filtered to obtain a reaction product. Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone, and then dried in vacuum at 40° C. to obtain 384.9 g (80.1%) of solifenacin succinate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]1[NH:31][C:30](=[O:32])[N:29]2[CH2:33][CH2:34][CH2:35][C@@H:28]12>>[CH3:26][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:4]3[CH:3]=[C:2]([N:31]4[CH2:27][C@@H:28]5[CH2:35][CH2:34][CH2:33][N:29]5[C:30]4=[O:32])[CH:7]=[CH:6][CH:5]=3)[CH2:11][CH2:12]2)[N:21]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Reactant: O=C1NC[C@@H]2CCCN12
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C[C@@H]6CCCN6C5=O)c4)CC3)cccc2n1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and (S)-hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one.
Reaction SMILES: C(N(CC)CC)C.[F:8][CH2:9][C@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:23])[C@@H:11]1O.CS(Cl)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>O.C(Cl)Cl>[N:30]([C@H:11]1[C@@H:10]([CH2:9][F:8])[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12]1=[O:23])=[N+:31]=[N-:32]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CF)[C@@H](O)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@H](CF)[C@H](N=[N+]=[N-])C1=O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
Triethylamine (3.07 ml, 22.02 mmol) was added to a methylene chloride (40 ml) solution of 4-(S)-fluoromethyl-3-(R)-hydroxy-N-[1-(R)-phenylethyl]-2-pyrrolidone (2.61 g, 11.00 mmol), methanesulfonyl chloride (1.28 ml, 16.54 mmol) was added dropwise to the thus prepared solution at −10° C. and then the resulting mixture was stirred for 30 minutes at the same temperature. The reaction solution was washed with 10% citric acid aqueous solution and dried over sodium sulfate and then the solvent was evaporated. The thus obtained residue was dissolved in N,N-dimethylformamide (80 ml), mixed with sodium azide (2.86 g, 44.00 mmol) and then stirred overnight at 100° C. The reaction solution was mixed with water, extracted with ethyl acetate (200 ml×3) and then the resulting organic layers were combined and dried over sodium sulfate, subsequently evaporating the solvent. The thus obtained residue was subjected to a silica gel chromatography to give 1.81 g (63%) of the title compound from the eluate of ethyl acetate:hexane=1:3 in the form of a light yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10]([C:13]1[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][C:19]=2[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:22]=1)(=[O:12])=[O:11])(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[ClH:32].[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:22]=[C:13]([S:10]([CH2:9][CH2:8][NH2:7])(=[O:12])=[O:11])[C:14]3[CH:15]=[CH:16][N:17]=[CH:18][C:19]=3[CH:20]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2cc(S(=O)(=O)CCNC(=O)OC(C)(C)C)c3ccncc3c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2cc(S(=O)(=O)CCN)c3ccncc3c2)cc1
Yield: 99 %

Procedure:
Treat a slurry of {2-[7-(4-methoxy-phenyl)-isoquinoline-5-sulfonyl]-ethyl}-carbamic acid tert-butyl ester (11.00 g, 24.85 mmol) in anhydrous MeOH (150 mL) with 4N HCl in dioxane (350 mL). Stir the resulting reaction mixture at room temperature overnight, then concentrate in vacuo to ½ volume and treat with excess EtOAc, causing a yellow solid to precipitate. Recover the resulting solid by vacuum filtration under an N2 atmosphere; wash with EtOAc and dry under vacuum (under an N2 atmosphere) to afford the title compound (10.23 g, 99% yield) as a yellow solid: MS (ES): m/z 343.0 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>>[NH2:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:7][C:2]=1[Br:1]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cc1Br
Product: CCOP(=O)(Cc1ccc(N)c(Br)c1)OCC
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Di-tert-butyl [2-bromo-4-(bromomethyl)phenyl]imidodicarbonate (Compound 32E, 6.0 g, 13 mmol) was taken up in triethyl phosphite (5.0 mL, 29 mmol) and stirred at 120° C. for 16 h. The reaction mixture was transferred to a microwave vial and was irradiated in the microwave for 4 h at 190° C. The reaction mixture was concentrated in vacuo. The compound was purified by flash column chromatography eluting with 10 to 100% EtOAc in heptane. The product was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J=2.3 Hz, 1H), 7.04 (ddd, J=2.3, 2.4, 8.2 Hz, 1H), 6.71 (dd, J=0.8, 8.1 Hz, 1H), 3.97-4.06 (m, 4H), 2.96-3.04 (m, 2H), 1.26 (t, J=7.1 Hz, 6H); MS (ESI): m/z: 322.00, 323.96 [M+H]+. UPLC: tR=2.83 min (UPLC-TOF: polar—3 min).
Reaction SMILES: O1CCOCC1.[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br.[Br:19][CH2:20][CH2:21][NH2:22].O1CCOCC1.[OH-].[Na+]>C(OCC)(=O)C.O>[Br:19][CH2:20][CH2:21][NH:22][C:15](=[O:16])[O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a 1,4-dioxane (50 mL) solution comprising benzylchloroformate (17.5729 g; manufactured by Wako Pure Chemical Industries, Ltd.), an aqueous solution of 2-bromoethane amine hydrogen bromide salt-1,4-dioxane [104 mL; solution which was prepared by dissolving 2-bromoethane amine hydrogen bromide salt (21.3617 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) in water (54 mL) and 1,4-dioxane (54 mL)] and an aqueous solution of 2 mol/L-sodium hydroxide (104 mL; manufactured by Kanto Chemical Co., Inc.) were added dropwise simultaneously, and stirred at 0° C. for 2 hours. The reaction solution was added with water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with saturated sodium hydride, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=94:6→73:27) to obtain the title compound (19.2014 g).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:22]=[C:16]1[CH:15]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][N:3]([CH3:2])[C:32]([NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:34])([F:35])[F:23])[CH:26]=3)=[O:33])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and α,α,α-trifluoro-m-tolyl-isocyanate (0.29 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-(3-trifluoromethyl-phenyl)-urea (0.58 g, 66%): mp 198-200° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.91 (98%); 1H NMR (DMSO-d6): δ 2.00-2.05 (m, 1H), 2.28-2.39 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.93 (m, 1H), 3.01 (s, 3H), 4.32-4.53 (dd, J=8, 20 Hz, 2H), 4.67 (s, 2H), 5.11-5.18 (dd, J=5.9, 15.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.44-7.57 (m, 3H), 7.65 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 8.81 (s, 1H), 11.02 (s, 1H). 13C NMR (DMSO-d6) δ: 22.56, 31.17, 34.76, 46.25, 48.36, 51.60, 115.71, 118.50, 121.78, 123.15, 126.42, 128.49, 128.83, 129.44, 129.81, 131.94, 133.59, 140.14, 141.33, 155.41, 168.00, 171.01, 172.82. Anal Calcd for C23H21F3N4O4: C, 58.23; H, 4.46; N, 11.81, F, 12.01. Found: C, 58.06; H, 4.30; N, 12.09, F, 11.59.
Reaction SMILES: ClC1C=CC([O:6][C:7]2[C:16]3[C:11](=C[C:13](O)=[C:14](OC)[CH:15]=3)[N:10]=[CH:9]N=2)=C(F)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:9][N:10]1[CH2:13][CH2:14][CH2:15][CH:16]([CH2:7][OH:6])[CH2:11]1.[CH3:9][N:10]1[CH2:13][CH2:14][CH2:15][C@@H:16]([CH2:7][OH:6])[CH2:11]1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCCC(CO)C1
Product: CN1CCC[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (12.1 g, 38 mmol), (prepared as described for the starting material in Example 5), was suspended in dichloromethane (375 ml) and treated with triphenylphosphine (29.6 g, 113 mmol) then stirred at ambient temperature for 30 minutes. (1-Methylpiperidin-3-yl)methanol (8.25 g, 63.8 mmol) and (R)-(1-methylpiperidin-3-yl)methanol (1.46 g, 11.3 mmol), (CAS 205194-11-2), giving R:S (57.5:42.5 by chiral HPLC) (9.7 g, 75 mmol) were dissolved in dichloromethane (75 ml) and added to the suspension. Diethyl azodicarboxylate (17.7 ml, 75 mmol) was added in portions using a syringe pump and the mixture was then allowed to warm to ambient temperature and stirred overnight. The residue was concentrated under vacuum then chromatographed on silica eluting with dichloromethane followed by dichloromethane/methanol/ammonia (93/6/1). The relevant fractions were combined and evaporated to give an oil. The residue was triturated with ether, filtered and dried to give (R,S)-4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline (8.7 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(O[Si](C)(C)C)=NC(O[Si](C)(C)C)=N2)=CC=1.Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Br-].[Na+]>C1(=O)OC(C)CO1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Reactant: CCOC(=O)CCl
Agent: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccc(Cl)cc2n1
Agent: [Br-]
Agent: [Na+]
Solvent: CC1COC(=O)O1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 10 h
Yield: 94 %

Procedure:
As in Example 1, 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (20 g) was silylated and the toluene was distilled off to give a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added propylene carbonate (40 ml), ethyl chloroacetate (16.21 g) and sodium bromide (2.09 g), and the reaction was carried out at an internal temperature of 125˜140° C. for 10 hours. This reaction mixture was cooled to ≦70° C. and worked up as in Example 1 to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (27.02 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46](OC1C(C(O)=O)=NC(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)=NC=1O)[C:47]1C=CC=CC=1.[Si](OCCNC1CC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:47][CH2:46]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1CC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1CC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (250 mg, 0.55 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amine (8d) (177 mg, 0.83 mmol). The yield was 279 mg, 78% (white sticky mass).
Reaction SMILES: [BrH:1].[NH2:2][CH:3]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[Na+].[Br:18]Br>O.CO>[Br:1][C:12]1[CH:11]=[C:10]([Br:18])[N:2]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:8]=1[OH:9]
Reactant: COC(=O)C(N)c1ccco1
Reactant: BrBr
Reactant: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(Br)cc(Br)c1O
Temperature: 25 °C
Yield: 51.6 %

Procedure:
To a magnetically stirred solution of methyl 2-amino-2-(furan-2-yl)acetate hydrobromide (0.84 g, 3.56 mmol) and sodium acetate (1.255 g, 15.30 mmol) in 40 mL of water at 0° C. was added dropwise a solution of bromine (0.788 ml, 15.30 mmol) in 10 mL of MeOH over 30 min. After warming to room temperature for 24 hr, the reaction mixture was filtered through a fritted glass funnel and the white solid was washed with water. Solvent removal gave methyl 4,6-dibromo-3-hydroxypicolinate (577 mg, 1.837 mmol, 51.6% yield) as a white solid; Mp 180-181° C. (recrystallized from heptane). 1H NMR (600 MHz, Chloroform-d) δ 11.35 (s, 1H), 7.86 (s, 1H), 4.07 (s, 3H); 13C NMR (151 MHz, Chloroform-d) δ 168.74, 156.02, 136.85, 130.14, 129.92, 124.67, 53.84. HRMS-ESI (m/z) calc'd for [C7H5Br2NO3]+, 308.8636. found, 308.8638.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1>C1COCC1.O.CCOC(C)=O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,2,2-Trifluoroethanol (0.35 mL, 4.80 mmol) was dissolved in THF (2 mL) and cooled to 0 C under nitrogen. Sodium hydride (60% dispersion in mineral oil, 0.192 g, 4.80 mmol) was added portionwise and the mixture stirred for 10 min. A solution of methyl 4-(bromomethyl)benzoate in THF (3 mL) was added, the mixture was warmed to room temperature and then heated to 50 C for 3 h. The mixture was then diluted with water (15 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous neutralised with 1M hydrochloric acid. The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a colourless oily residue (1.05 g, 97%). 1H NMR (500 MHZ, CDCl3) δ ppm 7.95 (2H, d), 7.33 (2H, d), 4.64 (2H, s), 3.83 (3H, s) and 3.77 (2H, q).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][CH2:64]Cl)[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[C:66]([O:70][C:71]([NH:73][CH2:74][CH2:75][CH2:76][C:77](O)=O)=[O:72])([CH3:69])([CH3:68])[CH3:67].C([O-])([O-])=[O:81].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][C:64](=[O:81])[CH2:77][CH2:76][CH2:75][CH2:74][NH:73][C:71]([O:70][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:72])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCCl)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)CCCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C

Procedure:
The compound of Example 8B is dissolved in DMF; 4-tert-butoxycarbonylamino-butanoic acid (1.3 eq) is added, along with 1.2 equivalents of Cs2CO3. The resultant mixture is stirred overnight at ambient temperature. The reaction mixture is partitioned between aqueous phosphoric acid (1N) and ethyl acetate. The organic extract is dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is purified on silica gel using a gradient of ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH2:14][NH2:15])=[C:8]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:7]=2[CH:23]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>ClCCl>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C:9]([CH2:14][NH:15][C:33](=[O:35])[CH3:34])=[C:8]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:7]=2[CH:23]=1
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2ccc(C(F)(F)F)cc2C(n2ccccc2=O)=C1CN
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1=C(n2ccccc2=O)c2cc(C(F)(F)F)ccc2OC1(C)C
Reaction time: 6 h
Yield: 42 %

Procedure:
To a solution containing 6-trifluoromethyl-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.68 g, 1.82 mmol) and triethylamine (0.3 ml, 2.18 mmol) in dichloromethane (18 ml), acetyl chloride (0.15 ml, 2.18 mmol) was added at room temperature. The solution was stirred for 6 hours and then water added. The organic layer was separated, dried and evaporated, to give crude product which was chromatographed on silica gel. Elution with dichloromethane/methanol (95/5) gave a product which was crystallized from ether to afford 0.3 g of 6-trifluoromethyl-2,2-dimethyl-3-(acetamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)2H-1-benzopyran, m.p. 174° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[CH2:16](Br)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>CCO>[CH2:16]([S:8][C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: S=c1ncc(Br)c[nH]1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CSc1ncc(Br)cn1)c1ccccc1
Reaction time: 1 h
Yield: 71 %

Procedure:
5-Bromopyrimidine-2-thione (10.5 mmol) was added to a solution of triethylamine (11.6 mmol) in EtOH (130 ml) and the mixture stirred for 15 min before addition of phenacyl bromide (10.5 mmol). The reaction mixture was stirred for 1 h before the solvent was removed at reduced pressure, the residue extracted with chloroform and the chloroform solution chromatographed on alumina (100 g, activity I); yield 71%, m.p. 107°-109° C. (iPrOH). 1H NMR (CDCl3): δ4.60 (CH2), 7.5-8.0 (Ph), 8.46 (H-4, H-6).