Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C)C=O.C1C=CC=CC=1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:19][C:16]1[CH:15]=[CH:14][C:3]2[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[F:11])=[N:12][O:13][C:2]=2[C:17]=1[Cl:18])[CH3:28]
Reactant: ON=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reaction time: 0.5 h

Procedure:
A solution of 18.4 g of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime and 3.6 g of sodium hydride in 120 ml of dimethylformamide and 120 ml of benzene is maintained at a temperature of from 80°-85° C. for 3 hours. Thereafter, the mixture is permitted to reach ambient temperature after which a solution of 11.0 g of ethyl bromoacetate in 20 ml of dimethylformamide is added dropwise. After the addition is complete, the mixture is stirred for 30 minutes and then water is added to decompose any excess sodium hydride. The mixture is extracted with ethyl acetate and the combined extracts are dried and evaporated to dryness leaving a solid residue. The residue is recrystallized several times from 95% ethyl alcohol to yield the pure product ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate having a melting point of 102° to 104° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:19]3[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([F:35])[CH:22]=3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:19]3[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:35])[CH:22]=3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(Cc2cc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)c3c(N)ncnn23)CC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(Cc2cc(-c3ccc(N)c(F)c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
To a solution of t-butyl (4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)carbamate (320 mg, 0.62 mmol) in CH2Cl2 (8 ml) was added TFA (3 ml) and was stirred at rt for 3 h. The reaction mixture was partially evaporated and was added 10 ml ethyl acetate and washed with saturated aq. NaHCO3. The organic was dried over Na2SO4, concentrated and purified via column chromatography (95:5, v/v, CH2Cl2—CH3OH) to afford 74 mg of the title compound (yield 30%). 1H-NMR (CH3OH-d4) δ 7.85 (s, 1H), 7.10 to 7.00 (m, 3H), 6.66 (s, 1H), 4.00(s, 2H), 3.60 to 3.50(m, 4H), 2.63 to 2.55(m, 4H), 20.6(s, 3H); MS [M+H]+=383.9; LCMS RT=1.10 min.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[CH3:13][N:14]1[C:22]2[CH:21]=[C:20]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])[CH:19]=[CH:18][C:17]=2[C:16]2[CH2:40][NH:41][CH2:42][CH2:43][CH2:44][C:15]1=2>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:41]1[CH2:42][CH2:43][CH2:44][C:15]2[N:14]([CH3:13])[C:22]3[CH:21]=[C:20]([N:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=5)=[CH:25][C:24]4=[O:39])[CH:19]=[CH:18][C:17]=3[C:16]=2[CH2:40]1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CNCCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
Triethylamine (58 μL, 0.41 mmol), DMAP (5.0 mg, 0.041 mmol) and acetyl chloride (22 μL, 0.31 mmol) were added to a solution of 1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride (97 mg, 0.21 mmol) in CH2Cl2 (15 mL), and the resulting solution was stirred at ambient temperature for 18 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 1 column volume, then increased to 0:100 over 10 column volumes and held for 12 column volumes) gave the title compound (58 mg, 59%) as a yellow powder: mp 156-162° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.72-7.49 (m, 2H), 7.07-6.99 (m, 2H), 6.80-6.78 (m, 1H), 4.72-4.70 (m, 2H), 3.79-3.76 (m, 2H), 3.69-3.68 (m, 3H), 3.05-2.98 (m, 2H), 2.02-1.90 (m, 5H); ESI MS m/z 481 [M+H]+; HPLC (Method A)>99% (AUC), tR=18.1 min.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[O:32])[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:6])[C:3]([O-:5])=[O:4]>[OH-].[K+].O1CCOCC1>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[O:32])[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COc1ccc(Cl)cc1C(=O)NCc1ccc(-c2ccc(OC(C)(C)C(=O)[O-])cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)NCc1ccc(-c2ccc(OC(C)(C)C(=O)O)cc2)cc1
Yield: 72 %

Procedure:
2-Methyl-2-{4-(2-methoxy-5-chloro-benzamido-methyl)-biphenyl-4'-oxy}-propionic acid was prepared by alkaline hydrolysis of 2-methyl-2-{4-[2-methoxy-5-chloro-benzamido-methyl]-biphenyl-4'-oxy}-propionate in 1 N potassium hydroxide and dioxane (1:5) at room temperature. Yield: 72% of theory; m.p. 104° C
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][C@H:37]([OH:47])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][CH:31]([NH:35][CH2:36][C@H:37]([OH:47])[CH2:38][O:39][C:40]5[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=5)[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[C:18](=[O:20])[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1N=C(NC2CCN(Cc3ccccc3)CC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 21) and 4-[(2S)-3-amino-2-hydroxy-propoxyl]-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a pale yellowish solid; mp >175° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.5 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.70-4.00 (m, 5H), 4.92 (brs, 1 H), 6.66 (d, J=6.8 Hz, 2 H), 6.75 (d, J=6.8 Hz, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8H), 8.89 (brs, 1 H), 9.29 (brs, 1 H); MS (ES) m/z:321.6 ((M+2 H)2+, 100%); 642.1 (MH+, 5%); HRMS Calcd. for C36H44N5O4S (MH+): 642.3114. Found: 642.3095.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH2:6].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH:6][C:18](=[O:20])[CH3:19]
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(C)=O
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Compound 2 (4.10 g, 15.7 mmol) was suspended in a mixture of distilled pyridine (40 ml) and acetic anhydride (5 ml). A solution formed after several minutes, and stirring was continued overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was then extracted with 0.1N HCl, 1M sodium bicarbonate, and water and dried (MgSO4). Precipitation with hexanes gave 3.57 g (85.1%) of a solid melting at 113°-117° C. Recrystallization from ethyl acetate/hexanes gave 2.75 g, mp 118°-120° C., [α]D25 =+15.1° (c=2.1, ethanol).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([C:20](=O)[CH3:21])[C:15]=3[CH2:23][CH2:24][CH3:25])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.C(O)=O.[CH:29]([NH2:31])=[O:30].[OH-].[Na+]>O>[F:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([CH:20]([NH:31][CH:29]=[O:30])[CH3:21])[C:15]=3[CH2:23][CH2:24][CH3:25])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1C(C)NC=O
Temperature: 25 °C

Procedure:
214 (0.1 g) and formic acid (0.1 mL) are added to 2 mL of formamide at 160–180° C. The mixture is heated at 160–180° C. for an additional 3 hours. During this period, additional formic acid (0.2 mL) is added. The mixture is cooled to room temperature and poured into water (10 mL). The solution is made alkaline to at least pH 11 with concentrated sodium hydroxide. The solution is extracted with ethyl acetate. The combined organic layers are dried over MgSO4, and the solvent is removed to give the crude product. PTLC separation with 10% MeOH in methylene chloride gives the title product (215). 1H NMR δ (CDCL3) 1.06 (t, 3H, J=7.5 Hz), 1.43 (d, 3H, J=5.1 Hz), 1.55 –1.72 (m, 2H), 2.72–2.80 (m, 1H), 2.86–2.95 (m, 1H), 5.52 (p, 1H, J=5.4 Hz), 5.81 (d, 1H, J=12.3 Hz), 6.08 (d, 1H, J=12.3 Hz), 6.73 (dd, 1 H, J=6, 2.1 Hz)), 6.99 (d, 1H, J=5.7 Hz), 7.12 (d, 1H, J=2.7 Hz), 7.23 (d, 1H, J=2.7 Hz), 7.78 (q, 1H, J=6.0 Hz), 8.12 (dd, 1H, J=6.0, 2.1 Hz), 8.18 (s, 1H), 8.79 (s, 1H). LC-MS: (M+1) 369.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=3)[C:20]([NH:22][CH2:23][CH:24]=O)=[O:21])[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.COC(NS([N+](CC)(CC)CC)(=O)=O)=O.C[N+](CC(O)=O)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:28]=[CH:27][CH:26]=[C:19]([C:20]4[O:21][CH:24]=[CH:23][N:22]=4)[CH:18]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=CCNC(=O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: C[N+](C)(C)CC(=O)O
Solvent: C1CCOC1
Product: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(-c2ncco2)c1

Procedure:
A solution of 1.01 g (2.64 mmol) of 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-N-(2-oxoethyl)benzamide and 1.26 g (5.27 mmol) of (methoxycarbonylsulfamoyl)triethylammonium betaine (Burgess reagent) in 5.3 ml of THF is stirred at a temperature of 150° C. in a sealed vessel for 5 minutes. The reaction mixture is partitioned between saturated sodium hydrogencarbonate solution and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 6-(3,5-difluorophenyl)-2-(3-oxazol-2-ylbenzyl)-2H-pyridazin-3-one as colourless crystals; ESI 366.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][CH:11]([O:15][CH2:16][CH3:17])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:14]
Reactant: Oc1ccccc1F
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccccc1F)OCC
Temperature: 110 °C
Yield: 81 %

Procedure:
A stirred mixture of 2-fluorophenol (1.00 g, 8.92 mmol), 2-bromo-1,1-diethoxyethane (1.75 g, 8.92 mmol), and K2CO3 (1.47 g, 10.7 mmol) in anhydrous DMF (10 mL) was heated at 110° C. overnight. The reaction mixture was poured into ice cold water (15 mL) and extracted with EtOAc (2×100 mL). The EtOAc solution was washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 1-(2,2-diethoxyethoxy)-2-fluorobenzene (1.65 g, 81%) as a viscous liquid. 1H NMR (400 MHz, CDCl3): δ 7.09-6.96 (m, 3H), 6.93-6.87 (m, 1H), 4.85 (t, 1H, J=5.2 Hz), 4.07 (d, 2H, J=5.2 Hz), 3.82-3.74 (m, 2H), 3.69-3.61 (m, 2H), 1.24 (t, 6H, J=7.0 Hz).
Reaction SMILES: CN1C=C(C2C=CC3N(C(CC4C=C5C(=CC=4)N=CC=C5)=CN=3)N=2)C=N1.[NH:27]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]([C:38]3[N:42]4[N:43]=[C:44]([C:47]5[CH:48]=[N:49][N:50]([CH3:52])[CH:51]=5)[CH:45]=[CH:46][C:41]4=[N:40][CH:39]=3)O)=[CH:33][CH:34]=2)[CH:29]=[N:28]1>>[NH:27]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36][C:38]3[N:42]4[N:43]=[C:44]([C:47]5[CH:48]=[N:49][N:50]([CH3:52])[CH:51]=5)[CH:45]=[CH:46][C:41]4=[N:40][CH:39]=3)=[CH:33][CH:34]=2)[CH:29]=[N:28]1
Reactant: Cn1cc(-c2ccc3ncc(C(O)c4ccc5[nH]ncc5c4)n3n2)cn1
Agent: Cn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5[nH]ncc5c4)n3n2)cn1

Procedure:
The title compound was prepared in analogy to the synthesis of compound of Example 2 using (rac)-(1H-Indazol-5-yl)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanol (Stage 150.1) as starting material (tR 1.10 min (conditions 2), MH+=330).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(Cl)c1cccc(Br)n1

Procedure:
4 g of 6-bromopyridine-2-carboxylic acid and 25 g of thionyl chloride are refluxed for 1 hour. The excess thionyl chloride is removed in a vacuum and the residue is distilled on a bulb tube at 110° C. and 0.04 mbar. The 6-bromopyridine-2-carboxylic acid chloride thus obtained is dissolved together with 3.32 g of 4-aminobutyric acid ethyl ester, hydrochloride in 40 ml of dioxane, mixed under ice cooling with 6 g of triethylamine and stirred for 5 hours at room temperature. The reaction mixture is added to water, extracted with diethyl ether, dried (sodium sulfate) and concentrated by evaporation. The residue is distilled on a bulb tube at 170° C. and 0.04 mbar and 3.2 g of 4-(6-bromo-2-pyridylcarbonylamino)-butyric acid ethyl ester is thus obtained as bright yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(O)c1ccnc(-c2ccccc2)c1
Temperature: 95 °C
Reaction time: 0.25 h

Procedure:
2-bromoisonicotinic acid (0.210 g, 1.040 mmol) was dissolved in degassed DME (Volume: 8 ml) under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol) was added, the resulting reaction mixture was stirred for 15 min. Then aqueous potassium carbonate (4.16 ml, 8.32 mmol) and phenylboronic acid (0.171 g, 1.403 mmol) were added subsequently. The resulting RM was refluxed at 95° C. for 18 h and then cooled to rt. After filtration over celite the reaction mixture was acidified to pH 3-4 and the white precipitate was filtered off and washed with water
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:16])[O:8][C:7]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]#[N:15])=[CH:12][C:6]=2[O:5]1.[CH2:17]([N+](CC)(CC)CC)[C:18]1C=CC=CC=1.[Cl-].BrCCCl>O>[F:16][C:4]1([F:3])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]3([C:14]#[N:15])[CH2:18][CH2:17]3)=[CH:12][C:6]=2[O:5]1
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Reactant: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCBr
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to a mixture of crude (2,2-difluoro-benzo[1,3]dioxol-5-yl-acetonitrile, benzyltriethylammonium, chloride (3.00 g, 15.3 mmol), and 1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70° C. The mixture was stirred overnight at 70° C. before the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to give crude 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile, which was used directly in the next step.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>Cl>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: Cl
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.1 h

Procedure:
Enzyme Activity and Reactor Stability. Three batches of starch-g-PAN copolymer (Table I, #91, 34, 50) were prepared, hydrolyzed, treated with glucoamylase and then reacted with maltose fed at a 0.1 h-1 dilution rate. Two additional runs were made in which faster dilution rates were used. It was found that acid hydrolysis (90 min reflux in 0.5N HCl) removed all but about 2% of the polysaccharide and yielded copolymer-enzyme granules having a size of about 5 to 26 microns. The activity of glucoamylase (mass of glucose produced per liter reactor volume per hour) immobilized on five similarly prepared batches of 28% add-on starch-g-PAN was measured over time in the continuous reactor. The data indicated that the enzyme was immobilized on the copolymer and that the decline in activity of the enzyme over time was independent of dilution rate. Further, free glucoamylase was not detected in the effluent stream. This indicates that the decline in enzyme activity was due to inactivation of the enzyme and not to loss of the enzyme from the copolymer. The gradual loss of glucose productivity was consistent with first-order enzyme deactivation kinetics. It should be noted that Lee et al., 1976, supra, found that silica-immobilized glucoamylase exhibited a first order decay rate. Based on chromatography data, there was no evidence of reversion products in any of the runs, and mass balances on the reactor indicated that glucose yields were essentially 100% of theoretical based on maltose consumed.
Reaction SMILES: [C:1]1([CH3:36])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH:27]([OH:35])[CH:28]([OH:34])[CH2:29][C:30]([O:32]C)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([CH3:36])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH:27]([OH:35])[CH:28]([OH:34])[CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)CC(O)C(O)CCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCC(O)C(O)CC(=O)O)CCC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To rac-Methyl 7-(2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)-3,4-dihydroxyheptanoate (Step 2) (30 mg, 0.061 mmol) in methanol (1 ml) was added 2M NaOH (0.061 ml, 0.123 mmol). The solution was stirred at room temperature for 3 h. 2M HCl (0.061 ml) was added and the solution was evaporated to dryness. The crude product was purified by chromatography on silica eluting with 0-15% DCM/MeOH to afford the title compound;
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[C:10]2([C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>O1CCCC1>[C:1]([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][O:16][C:43](=[O:45])[CH3:44])[C:10]2([C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (0.3 g, 0.56 mmol) in tetrahydrofuran (2 mL) at 0° C. was added pyridine (44 mg, 0.56 mmol) and acetyl chloride (44 mg, 0.56 mmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous CuSO4, brine, dried over MgSO4, and concentrated to give as rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester as a yellow oil (0.24 g, 74%)
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:18](OCC)(=O)[CH2:19][OH:20].Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:18]([CH2:19][OH:20])=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)CO
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(CO)nc(=O)c1-2
Yield: 23.4 %

Procedure:
Sodium (0.68 g) was dissolved in ethanol and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0 g, 13.5 mmol), followed by ethyl glycolate (2.8 g, 27 mmol) were added. The reaction mixture was refluxed overnight, the ethanol was stripped and water, followed by 2N HCl were added to the residue. A precipitate formed which was collected by filtration, washed with saturated NaHCO3, and then water. The product was recrystallized from ethyl acetate, then ether to afford 0.83 g of 1-cyclopentyl-3-ethyl-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 183°-184° C.