Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])=[CH:16][C@H:15]4[O:41]C(OC)=O)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3OC(OC)=O)=C[C@H]4OC(OC)=O)CC2)C)OC1>>[CH3:46][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])=[CH:16][C@H:15]4[OH:41])[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: COC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 59.3 %

Procedure:
The reaction and workup procedures of Example 140 were repeated except that 120 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β,7α-tris(methoxycarbonyloxy)pregn-5-ene to give 65 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregn-5-en-7α-ol showing the following physical properties.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]2[CH:12]=1.[N:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(O)CO>O>[CH3:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:12]=[C:3]([CH2:2][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:25])=[O:24])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[N:4]=[C:5]2[CH:10]=1
Reactant: Cc1ccn2cc(CCl)nc2c1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccn2cc(CN3CCN(c4ccc(C(N)=O)cc4)CC3)nc2c1
Temperature: 82.5 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A mixture of 2-(chloromethyl)-7-methylimidazo[1,2-α]pyridine (Example 6, Step 1; 0.300 g), 4-(piperazin-1-yl)benzamide (Example 3, Step 1; 0.357 g), triethylamine (Aldrich; 0.26 mL), and ethylene glycol (2 mL) is stirred for 30 min at 80-85° C. Additional ethylene glycol (1 mL) is added and the mixture is stirred for another 1.5 h. Water (8 mL) is added to the cooled mixture and the resulting solid is collected and dried. This material is adsorbed to silica gel and chromatographed on silica gel using methanol/dichloromethane/ammonium hydroxide (8/92/0.5). The appropriate fractions are combined and concentrated and the residue is crystallized from ethyl acetate/methanol to give 0.211 g of the title compound; mp 217-218° C.; ms m/z 349; IR (mineral oil) 1608, 1662, 1239, 3393, 1520 cm-1 ; 1H NMR (CDCl3) δ2.39, 2.74. 3.35. 3.75, 6.60. 6.88, 7.32, 7.46, 7.70 7.95.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([NH2:13])=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][OH:18])([O-:3])=[O:2].C([O-])([O-])OC.C([O-])(=O)C.[NH4+:28].[CH3:29]O>O>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][OH:18])[N:13]=[CH:29][NH:28][C:9]2=[O:11])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: Nc1cc(OCCCO)c([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Solvent: O
Product: O=c1[nH]cnc2cc(OCCCO)c([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 79 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 0.65 g (2.5 mmol) of 5-nitro-4-(3-hydroxypropoxy)anthranilic acid, 1.06 g (10.0 mmol) of methyl orthoformate, 0.77 g (10.0 mmol) of ammonium acetate, and 6.0 mL of methanol. The reaction was carried out at 140° C. for 6.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 50 mL of water was added to the reaction mixture. The precipitated crystalline product was collected by filtration and dried under reduced pressure to give 0.52 g (isolated yield: 79%) of 6-nitro-7-(3-hydroxypropoxy)quinazolin-4-one as a gray crystalline product.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:37][C:38]([NH2:40])=[S:39].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C>[NH2:40][C:38]1[S:39][CH:2]=[C:3]([CH2:4][C:5]([NH:7][CH:8]2[C:34](=[O:35])[N:10]3[C:11]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]23)=[O:6])[N:37]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(/C=C/Cl)CS[C@H]23)cs1
Temperature: 30 °C
Yield: 71.9 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (1.2 g) in a mixture of tetrahydrofuran (15 ml) and ethyl alcohol (15 ml) was added thiourea (0.46 g). The mixture was stirred for an hour at 30° C., poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with 10% aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (0.83 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[CH2:14][S:13]/[C:12]/1=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)=[CH:25][CH:24]=1)=[O:19])([CH3:3])[CH3:2].[Br:45]Br>ClCCl>[Br:45][CH:14]1[S:13]/[C:12](=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:33]=[CH:32][N:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=4)[N:30]=3)=[CH:27][CH:28]=2)=[O:19])/[N:11]([C:5]2[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:15]1=[O:16]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(N2C(=O)C(Br)S/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To a dry 2 dram vial equipped with magnetic stirrer was added (Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (F5) (0.20 g, 0.32 mmol) and anhydrous dichloromethane (0.5 mL). To this solution was added bromine (0.033 mL, 0.64 mmol). The reaction was stirred overnight at room temperature. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a clear colorless oil (0.041 g, 18%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:23][C:24]([N:26]2[CH2:35][CH2:34][C:33]3[CH:32]=[N:31][C:30]([NH:36][CH:37]([CH3:39])[CH3:38])=[N:29][C:28]=3[CH2:27]2)=[O:25])[CH2:13][N:14](C)[C:15](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(O)(C(F)(F)F)=O.C(Cl)[Cl:48]>>[ClH:48].[F:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:23][C:24]([N:26]2[CH2:35][CH2:34][C:33]3[CH:32]=[N:31][C:30]([NH:36][CH:37]([CH3:39])[CH3:38])=[N:29][C:28]=3[CH2:27]2)=[O:25])[CH2:13][NH:14][CH3:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(F)c1)CC2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@@H](NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(C(F)(F)F)c(F)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 268 (0.075 g, 0.14 mmol) and DCM (3 mL) at RT was added TFA (2 mL) and the reaction was stirred at RT for 1 h then concentrated to dryness. The resulting product was next dissolved in minimal DCM (with MeOH to increase solubility) and added with stirring to a solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to afford 0.050 g (75%) of I-66: MS m/z (APCI-pos) M+1=455.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].[C:20](O)(=[O:22])[CH3:21]>>[C:13]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:20](=[O:22])[CH3:21])[CH:8]=2)[CH:3]=1)(=[O:15])[CH3:14]
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2cc(OC(C)=O)ccc2c1

Procedure:
In the same manner as in Example 7, 13.0 g of the thus obtained 2,6-dihydroxynaphthalene were acetylated with 5.9 g of acetic acid and 17.6 g of acetic anhydride to obtain 17.5 g of 2,6-diacetoxynaphthalene of the purity of 99.82% (by DSC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:5][CH:4]=1.[H][H]>[Pd].CCO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:11]2[CH2:12][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C2CC(O)(c3ccc(OC)cc3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CC(c3ccc(OC)cc3)C2)cc1
Yield: 55.1 %

Procedure:
1,3-bis(p-methoxyphenyl)cyclobutanol (13.2 g., 0.046 mole), 3.0 g. of 10% Pd/C, 1 ml. of 70% HClO4, and 100 ml. of 95% EtOH is shaken under 50 psi of H2 until hydrogen absorption is complete. The catalyst is removed by filtration and the filtrate is evaporated. A solution of the residue in ether is washed (5% NaHCO3, water) and dried (MgSO4). Evaporation of the ether yields a residue (11.4 g.) which is recrystallized (EtOH), affording 6.8 g (55%) of the desired intermediate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[N:5]=1.O.[NH2:26][NH2:27]>CO>[CH3:11][O:10][C:8]1[CH:7]=[C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[N:5]=[C:4]([C:3]([NH:26][NH2:27])=[O:2])[CH:9]=1
Reactant: NN
Reactant: COC(=O)c1cc(OC)cc(Oc2cccc(OC(F)(F)F)c2)n1
Solvent: O
Solvent: CO
Product: COc1cc(Oc2cccc(OC(F)(F)F)c2)nc(C(=O)NN)c1

Procedure:
4-methoxy-6-[3-(trifluoromethoxy)phenoxy] picolinic acid methyl ester (0.74 g, 0.00216 mol) was dissolved in methanol (about 10 ml), and then mixed with hydrazine monohydrate (1.08 g, 0.00216×10 mol). The resultant mixture was refluxed for about 3 hours. The obtained reaction solution was concentrated and dissolved in ethyl acetate, and then distributed in ethyl acetate-saturated sodium bicarbonate water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated, thereby obtaining an aimed product.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N:31]1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH4+].[OH-]>O.O1CCCC1>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH2:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)O)ccc1F
Reactant: CN1CCOCC1
Agent: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(N)=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (3.65 g, 7.8 mmol), 4-methylmorpholine (2.6 mL, 23.4 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.64 g, 9.36 mmol) and tetrahydrofuran (40 mL). After stirring the mixture for 30 min at 25° C., NH4OH (20.0 mL) was added. The mixture was stirred for 30 min and diluted with water. The product precipitated from solution. The precipitated was filtered and washed with water and diethyl ether to give the title compound (2.37 g, 65%) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 7.9 (d, J=7.3 Hz, 1H), 7.61 (q, J=8.6 and 6.7 Hz, 1H), 7.5 (m, 2H), 7.3 (t, J=9.6 Hz, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.7 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 469.0172 (M+H calcd for C20H15BrF3N2O3 requires 469.0195).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:2][CH2:3][CH3:4].C12(C3C=CC([Br:34])=CC=3O)CC3CC(CC(C3)C1)C2.[C:36]1([CH3:46])[CH:41]=C[C:39](S([O-])(=O)=O)=[CH:38][CH:37]=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[C:1]12([C:5]3[CH:10]=[C:9]([Br:34])[CH:8]=[CH:7][C:6]=3[O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:39][CH:38]3[CH2:37][CH:36]([CH2:46][CH:3]([CH2:4]3)[CH2:2]1)[CH2:41]2
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: CCCCc1ccccc1OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: C1=COCCC1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc(OC2CCCCO2)c(C23CC4CC(CC(C4)C2)C3)c1

Procedure:
Using the same general procedure as for the preparation of of 4-bromo-2-| -butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 9.17 g (29.9 mmol) of 2-(1-adamantyl)-4-bromophenol (Compound F), 0.75 g (3.0 mmol) of pyridinium p-toluenesulfonate, 3.77 g (4.1 ml, 44.8 mmol) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane produced a bright yellow solid. Purification by flash chromatography (preabsorbed onto silica with chloroform, eluted with 2% ethyl acetate in hexane) yielded the title compound as a nearly white solid. PMR (CDCl3): d 1.6-2.2 (21H, m), 3.6-3.7 (1H, m), 3.8-3.9 (1H, m), 5.43 (1H, t, J=2.4 Hz), 7.05 (1H, d, J=8.7 Hz), 7.23 (1H, dd, J=8.7, 2.5 Hz), 7.30 (1H, d, J=2.5 Hz).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[CH2:12][C:13]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[C:17]([OH:19])[CH:18]=3)[C:9]3[C:10]2=[C:5]([CH:6]=[C:7]([OH:24])[C:8]=3[O:22][CH3:23])[CH2:4][CH2:3]1.C(Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:33]N(C=O)C>>[CH3:33][N:2]([CH2:1][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:12][C:13]1[C:14]2[CH:9]=[CH:10][C:5]3[C:4]([C:15]=2[C:16]([O:20][CH3:21])=[C:17]([OH:19])[CH:18]=1)=[CH:3][C:8]([O:22][CH3:23])=[C:7]([OH:24])[CH:6]=3
Reactant: ClCc1ccccc1
Reactant: COc1cc2c(cc1O)C[C@H]1c3c(cc(O)c(OC)c3-2)CCN1C
Reactant: CN(C)C=O
Product: COc1cc2c(ccc3c(CCN(C)Cc4ccccc4)cc(O)c(OC)c32)cc1O

Procedure:
1 g of boldine was dissolved in 30 ml of (DMF), the mixture was reacted with 1.2 ml of benzyl chloride at 100°-110° C. for 2 hrs. The residue obtained after evaporation under reduced pressure was purified to give the pure compound (5) N-benzylsecoboldine.
Reaction SMILES: [OH-].[NH4+].O.C1(S([O-])(=O)=O)C=CC=CC=1.[NH:14]=[C:15]1[NH2+:19][C:18](=[NH:20])[CH2:17][S:16]1.[NH:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=N)[NH:23]1>CO>[NH:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[C:17]2[S:16][C:15](=[NH:14])[NH:19][C:18]2=[NH:20])[NH:23]1
Reactant: N=C1CSC(=N)[NH2+]1
Reactant: N=C1NC(=N)c2ccccc21
Agent: O=S(=O)([O-])c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C1NC(=N)C(=C2NC(=N)c3ccccc32)S1

Procedure:
To a stirred solution of 61 parts of 28 percent aqueous ammonium hydroxide solution and 2500 parts of water under at atmosphere of nitrogen there was simultaneously added at ambient temperature during a period of ninety minutes 273 parts of 2,4-diiminothiazolidinium benzenesulfonate and 853 parts of a 17.1 percent by weight methyl alcohol solution of 1,3-diiminoisoindoline. A yellow solid separated during the addition. Stirring was continued at room temperature for approximately sixteen hours after the additions were complete and the thick yellow reaction slurry was then filtered. The product collected on the funnel was washed copiously with distilled water and finely dried at 50° C in vacuo to obtain 233 parts of 1-imino-3-(2,4-diimino-5-thiazolidinylidene)-isoindoline as a yellow solid melting at 252°-263° C (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[O:4][CH2:3]1.O.[NH2:18][NH2:19]>CO.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:16])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:18][NH2:19])=[O:12])=[CH:9][CH:8]=2)[O:4][CH2:3]1
Reactant: CC1(C)COB(c2ccc(C(=O)O)cc2)O1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: O
Product: CC1(C)COB(c2ccc(C(=O)NN)cc2)O1
Yield: 72 %

Procedure:
58.5 g (250 mmol) of 4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)benzoic acid are dissolved in 250 ml of methanol, and 12.5 g (250 mmol) of hydrazine hydrate and 1.5 g (12.5 mmol) of 4-dimethylaminopyridine are added. The solution is refluxed for 12 hours. Removal of 200 ml of methanol by distillation gives 44.6 g (180 mmol, 72%) of product.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>O>[C:1]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCO
Reactant: CCOC(=O)c1ccccc1
Solvent: O
Product: CN(CCO)C(=O)c1ccccc1

Procedure:
Ethyl benzoate (16.0 g, 15.3 ml) was dissolved in 2-(N-methylamino)ethanol (200 ml) and the mixture heated at reflux for 17.5 hours, cooled and diluted with water (1 l). The mixture was extracted with dichloromethane (4×200 ml), and the combined dichloromethane solutions washed with brine (300 ml), dried (MgSO4) and evaporated. The title compound, an oil, was used without further purification.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1B(O)O>O1CCOCC1>[F:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]2=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c2nc(-c3ccccc3F)ccc12
Temperature: 100 °C
Yield: 97.9 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25.0 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-fluorophenylboronic acid (265 mg, 1.89 mmol) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and microwaved for 1 hr. The reaction mixture was poured into 50 mL EtOAc and washed with H2O. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (220 mg, 98%).
Reaction SMILES: CC1C=CC(S(O[C@H:12]2[CH2:15][C@@H:14]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)(=O)=O)=CC=1.[O:27]1[CH2:32][C:31](=[O:33])[NH:30][C:29]2N=[CH:35][CH:36]=[CH:37][C:28]1=2.[C:38](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[O:33]=[C:31]1[CH2:32][O:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:38][C:29]=2[N:30]1[C@H:12]1[CH2:13][C@H:14]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](NC(=O)OCc3ccccc3)C2)cc1
Reactant: O=C1COc2cccnc2N1
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1C[C@H](N2C(=O)COc3ccccc32)C1)OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of cis-3-(((benzyloxy)carbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (0.563 g, 1.5 mmol) in DMF (3.00 ml) was added 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (FSSI, 0.225 g, 1.500 mmol) and potassium carbonate (EMD, 0.415 g, 3.00 mmol). The resulting mixture was heated to 50° C. overnight. Reaction mixture was heated to 85° C. for 3 hr then at 110° C. overnight. Reaction mixture was diluted with DCM and washed with water and brine. Purification by Biotage (0-10% MeOH/DCM) produced product. Material was advanced to the next step. M+1: 353.9
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
1,2,3,4-Tetrahydroquinoline (5 g, 0.0375 mol) was dissolved in 16 mL of sulfuric acid and the temperature lowered to 0° C., then 90% fuming nitric acid (1.67 mL, 0.0375 mol) was added slowly and the mixture stirred at 0° C., for 30 min. It was then poured onto 100 g of ice and extracted with dichloromethane (2×100 mL). The organic phase was washed with saturated aqueous solution of NaHCO3 (75 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 4.1 g (61%) of 7-nitro-1,2,3,4-tetrahydroquinoline. Data for 7-nitro-1,2,3,4-tetrahydroquinoline: 1H NMR (400 MHz, CDCl3) 7.39 (dd, J=8.3, 2.2, 1H), 7.26 (d, J=3.5, 1H), 7.01 (d, J=8.3, 1H), 4.16 (bs, 1H), 3.35 (t, J=5.0, 2H), 2.8 (t, J=6.3, 2H), 1.95 (quintet, J=6.1, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[CH:4][C:3]=1[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[N:20]2)=[O:16].Cl.[OH-].[Na+]>CC(O)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[N:20]3)=[O:16])[CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 105.3 %

Procedure:
To a solution of N-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)pivalamide (495 mg, 1.35 mmol, 1.0 eq.) in HOAc (10 mL) was added conc. HCl (8 mL). The mixture was stirred at 110° C. for 4 h, then poured onto ice. The mixture was basified to pH 10 by the addition of aqueous NaOH (1 N) and extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified via flash column chromatography (PE/EA=½, v/v) to afford (5-amino-2-fluorophenyl)(quinoxalin-6-yl)methanone (380 mg, 99%).