Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:3]1[NH:12][C:13]([CH3:15])=[O:14].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[CH:47]1[C:53](=[O:54])[NH:52][C:50](=[O:51])[N:49]([C@@H:55]2[O:59][C@H:58]([CH2:60][O:61][P:62]([O:65][P:66](OP(O)(O)=O)([OH:68])=[O:67])([OH:64])=[O:63])[C@@H:57]([OH:74])[C@H:56]2[OH:75])[CH:48]=1.C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-]>O.CO.CCOC(C)=O>[CH3:15][C:13]([NH:12][C@H:3]1[C@@H:2]([O:1][P:66]([O:65][P:62]([O:61][CH2:60][C@H:58]2[O:59][C@@H:55]([N:49]3[C:50](=[O:51])[NH:52][C:53](=[O:54])[CH:47]=[CH:48]3)[C@H:56]([OH:75])[C@@H:57]2[OH:74])([OH:64])=[O:63])([OH:68])=[O:67])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@@H:4]1[OH:5])=[O:14]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
One-Pot Three-Enzyme Synthesis of uridine 5′-diphospho-2-acetamido-2-deoxy-α-D-glacopyranoside (UDP-GalNAc). GalNAc (100 mg, 1.0 eq), ATP (1.2 eq.), and UTP (1.2 eq.) were dissolved in water in a 50 mL centrifuge tube containing Tris-HCl buffer (100 mM, pH 8.0) and MgCl2 (10 mM). After the addition of NanK_ATCC55813 (3.5 mg), PmGlmU (5 mg), and PmPpA (2.5 mg), water was added to bring the volume of the reaction mixture to 20 mL. The reaction was carried out by incubating the solution in an isotherm incubator at 37° C. for 24 h with gentle shaking. Product formation was monitored by TLC (EtOAc:MeOH:H2O=3:2:1 by volume) with p-anisaldehyde sugar staining. The reaction was stopped by adding the same volume of ice-cold ethanol and incubating at 4° C. for 30 min. The mixture was concentrated and passed through a BioGel P-2 gel filtration column to obtain the desired product. Silica gel column purification (EtOAc:MeOH:H2O=4:2:1) was applied for further purification to give pure target compound. Yield, 83% (228 mg); white foam. 1H NMR (600 MHz, D2O) δ 7.93 (d, J=8.4 Hz, 1H), 5.94-5.96 (m, 2H), 5.55 (dd, J=6.6, 3.0 Hz, 1H), 4.27-4.36 (m, 2H), 4.22-4.27 (m, 3H), 4.16-4.18 (m, 2H), 4.02 (d, J=3.0 Hz, 1H), 3.95 (dd, J=10.8, 3.0 Hz, 1H), 3.71-3.78 (m, 2H), 2.06 (s, 3H). 13C NMR (150 MHz, D2O) δ 175.05, 166.31, 151.85, 141.89, 102.82, 94.75, 88.70, 83.03 (d, J=8.6 Hz), 73.97, 72.32, 69.79, 68.50, 67.64, 65.14, 61.17, 49.95 (d, J=7.8 Hz), 22.24. HRMS (ESI) m/z calcd for C17H28N3O17P2 (M+H) 608.0894, found 608.0906.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[O:11][CH:12]=2)=[C:6]([CH3:16])[CH:5]=[N:4]1)[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=1)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[O:63]=[C:54]1[C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:61](=[O:62])[N:53]1[CH2:52][C@@H:51]([NH:50][C:13]([C:10]1[O:11][CH:12]=[C:8]([C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[CH3:16])[CH:9]=1)=[O:15])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=1
Reactant: CCn1ncc(C)c1-c1coc(C(=O)O)c1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(C)c1-c1coc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To the crude 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid in DCM (5 mL) at 25° C. was added PyBrOP (370 mg, 0.79 mmol) in one portion, followed by the addition of DIPEA (0.8 mL, 4.58 mmol). After 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (220 mg, 0.74 mmol) was added to the reaction solution. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (164 mg, 54%) as a white solid: LC-MS (ES) m/z 501 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[ClH:8].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([NH:17][C:18](C1SC(C#N)=CC=1)=[O:19])[CH2:10]2>>[ClH:8].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([NH:17][C:18]([C:5]1[S:4][C:3]([O:2][CH3:1])=[CH:7][CH:6]=1)=[O:19])[CH2:10]2
Reactant: COc1cccs1
Reactant: N#Cc1ccc(C(=O)N[C@H]2CN3CCC2CC3)s1
Agent: Cl
Product: COc1ccc(C(=O)N[C@H]2CN3CCC2CC3)s1

Procedure:
This compound is prepared from 2-methoxythiophene according to the procedure used to make the compound of Example 18, making noncritical variations. Yield for 2 steps 33%. mRMS (FAB) calculated for C13H18N2O2S+H 267.1167, found 267.1167.
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([NH2:37])=[CH:36][C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([NH:37][C:2]3[N:18]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[O:16][CH3:17])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:36][C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: COc1ccccc1-c1cccn2nc(Cl)nc12
Agent: [Pd+2]
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12
Temperature: 100 °C
Yield: 86.6 %

Procedure:
A Schlenck flask was charged with palladium acetate (0.0966 g, 0.430 mmol), triphenylphosphine (0.4513 g, 1.721 mmol), and 1,4-dioxane (6 mL) and the mixture was stirred for 5 min until it turned bright yellow. 8-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol), 2-methoxybenzeneboronic acid (0.490 g, 3.23 mmol), N,N-dimethylformamide (10.00 mL), and 1.00 N sodium carbonate in water (4.3 mL, 4.3 mmol) were added successively and the reaction was heated at 80° C. overnight, cooled to room temperature, diluted with dichloromethane, filtered through diatomaceous earth and concentrated. The reaction was purified via chromatography (silica gel 10%→20% ethyl acetate in hexanes) and concentrated to give 2-chloro-8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.464 g, 83%). MS=260 (MH)+. 311b) To an oven-dried Schlenck flask under an atmosphere of argon was added 2-chloro-8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.460 g, 1.77 mmol), 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.558 g, 2.12 mmol), palladium acetate (0.0875 g, 0.390 mmol), 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.242 g, 0.443 mmol), cesium carbonate (1.44 g, 4.43 mmol), followed by 1,4-dioxane (12.00 mL) and was degassed under an atmosphere of argon for 5 min and heated at 100° C. overnight, cooled at room temperature, diluted with dichloromethane, filtered through diatomaceous earth and concentrated. The reaction was purified via chromatography (silica gel 20%-30% ethyl acetate/hexanes) and concentrated to give 7-[8-(2-methoxy-phenyl)[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.744 g, 87%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.78 (d, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 7.35 (s, 1H) 7.15 (m, 1H), 7.05 (m, 3H), 3.74 (s, 3H), 3.48 (m, 4H), 2.78 (m, 4H), 1.41 (s, 9H): MS=486 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25]([OH:27])=O)=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][C:21]=3[C:25](=[O:27])[NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:32]=3[O:31][CH3:30])=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ocnc3C(=O)O)cc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2ncoc2-c2ccc(N3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-[4-(4-Carboxy-oxazol-5-yl)-phenyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 30 mL DMF. To the solution was added 2,4-dimethoxybenzylamine (1.26 g, 7.6 mmol), HATU (2.8 g, 7.4 mmol) and TEA (1 g, 10 mmol). The mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to DCM:MeOH=200:1) to afford the title compound (1.6 g, 3 mmol, yield: 54% over two steps).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20].CN(C=O)C>O>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:19][CH3:20]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a 500 ml three-neck flask equipped with a mechanical stirrer and an inert gas tube were added 30.5 g of isovanillin, 55.2 g of potassium carbonate, 49.9 g of iodoethane and 140 ml of DMF. The mixture was stirred overnight at the room temperature. The mixture was poured into 1400 ml of water, and then the resultant mixture was extracted with ethyl acetate (600 ml×2). The ethyl acetate layers were combined. The organic phase was washed with saturated Na2CO3 (200 ml×3), 200 ml of water and 200 ml saturated NaCl, dried over anhydrous MgSO4, and filtered. The solvent was evaporated to give a straw yellow solid. The solid was recrystallized with a mixed solvent of ethyl acetate and petroleum ether (1:4) to give a white needle crystal (32.9 g). MS (m/z): 181 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[NH:4][C@@H:5]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:6](=[O:46])[NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16](=[O:19])[O:17][CH3:18].[CH2:52]([S:54][CH2:55][CH3:56])[CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:39]([C@H:8]([NH:7][C:6]([C@@H:5]([NH:4][C:3](=[O:51])[O:2][CH3:1])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])[C@@H:9]([O:38][CH:52]([S:54][CH2:55][CH3:56])[CH3:53])[CH2:10][C@@H:11]([NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16]([O:17][CH3:18])=[O:19])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Reactant: CCSCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 104.5 %

Procedure:
To a slurry of the compound of Example 2D (2.00 g, 2.84 mmol) and ethyl sulfide (8.0 mL, 74.06 mmol) in acetonitrile (28.0 mL) at room temperature was added benzoyl peroxide (4.95 g, 20.45 mmol) in three portions over 2 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (2.35 g, 84% yield).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[C:14]([CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31](O)=[O:32])=[CH:28][CH:29]=2)[C:24]([CH3:34])=[C:23]1[CH3:35])#[N:15]>>[C:14]([CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[O:32])=[CH:28][CH:29]=2)[C:24]([CH3:34])=[C:23]1[CH3:35])#[N:15]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: Cc1c(C)n(Cc2cccc(OCC#N)c2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2cccc(OCC#N)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 480 [M+H]+.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:12][C:13]([F:30])([F:29])[S:14]([O:17][C:18]1[CH:28]=[CH:27][C:21]([C:22](OCC)=[O:23])=[CH:20][N:19]=1)(=[O:16])=[O:15].[OH-].[Na+]>C(OCC)(=O)C>[F:30][C:13]([F:12])([F:29])[S:14]([O:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][OH:23])=[CH:20][N:19]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Oc1ccc(CO)cn1)C(F)(F)F
Yield: 65.2 %

Procedure:
To a tetrahydrofuran solution (2.0 mL) of lithium aluminum hydride (19.0 mg, 0.450 mmol), ethyl 6-{[(trifluoromethyl)sulfonyl]oxy}nicotinate (112 mg, 0.375 mmol) was added and the resultant solution was stirred at 0° C. for 5 minutes. After completion of the reaction, 1 M sodium hydroxide aqueous solution, Celite, and ethyl acetate were added to the reaction solution and the resultant mixture was filtered with Celite, followed by extraction from the filtrate with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound (62.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[CH2:16][C:15]3[C:10](=[C:11]([Cl:19])[C:12]([Cl:18])=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O:30][C:31](=[O:34])[CH2:32]Br)C.[OH-].[Na+].Cl>CN(C)C=O.O>[OH2:17].[O:20]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][CH2:32][C:31]([OH:34])=[O:30])=[C:12]([Cl:18])[C:11]=2[Cl:19])[CH2:16][C:8]1([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:21].[O:20]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][CH2:32][C:31]([OH:34])=[O:30])=[C:12]([Cl:18])[C:11]=2[Cl:19])[CH2:16][C:8]1([CH3:21])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC1(c2ccc(Cl)cc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccc(Cl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 80 °C

Procedure:
A stirred mixture of 2-(4-chlorophenyl)-2-methyl-5-hydroxy 6,7-dichloro-1-indanone (2.95 g., 0.00863 mole), potassium carbonate (2.26 g., 0.0163 mole) and ethylbromoacetate (2.72 g., 0.0163 mole) in dimethylformamide (50 ml.) is warmed at 55°-60° C. for two hours, then treated with water (50 ml.)-10 N sodium hydroxide solution (2.5 ml., 0.025 mole) and heated at 80° C. for one hour. The reaction mixture is added slowly to water (500 ml.)-12 N hydrochloric acid (10 ml.) to precipitate 1.37 g. of [1-oxo-2-(4-chlorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid hemihydrate which melts at 141°-142° C. after crystallization from acetic acid: water, 1:1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[N:37]=[CH:38][S:39][CH:40]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[N:37]=[CH:38][S:39][CH:40]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cscn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 62 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.22 mmol), 4-tributylstannanyl-thiazole (121 mg, 0.32 mmol) and PdCl2(PPh3)2 (30 mg, 0.043 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified twice by silica gel chromatography (0-40% EtOAc/CH2Cl2, then 5-30% EtOAc/hexanes+1% AcOH) to give 64 mg of the title compound. MS: (+) m/z 470.33 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:30])[C:16]([C:19]([NH:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:35][C:33]1[CH:32]=[CH:31][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]([CH3:30])[C:16]([C:19]([NH:21][CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:20])=[CH:17][N:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:34]=1
Reactant: Cn1c(C(=O)NCCN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1c(C(=O)NCCN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Yield: 76.6 %

Procedure:
The reaction mixture of the nitro compound 215 (180 mg, 0.342 mmol), iron powder (162 mmol), and ammonium chloride (15.7 mg, 0.294 mmol) in EtOH/water mixture (10 mL/5 mL) was heated to reflux for 1 hr. The reaction mixture was filtered while hot. The filtrate was concentrated to give title compound 216 (130 mg, 0.262 mmol, 77% yield) as a white solid. MS: 497.5 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12]
Reactant: Oc1ncnc2ccc(Br)cc12
Reactant: COc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2ncnc(O)c2c1
Temperature: 150 °C
Yield: 98.1 %

Procedure:
Preparation D6, Step 2: A mixture of 6-bromoquinazolin-4-ol (227 mg, 1.01 mmol), 2-methoxyphenylboronic acid (307 mg, 2.02 mmol), 2.0 M potassium phosphate (aq) (1.5 mL, 3.0 mmol), and DMF (3 mL) in a 5 mL microwave tube was degassed under vacuum/Ar. A catalytic amount of tetrakis(triphenylphosphine)palladium(0) was added to the tube, the mixture was degassed again, the tube was sealed, and the reaction was heated at 150° C. in the microwave for 30 min. The resulting black mixture was filtered, then concentrated in-vacuo. The residue was taken up in 9:1 ethyl acetate/heptane (50 mL), washed with water (3×20 mL), then brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over silica gel, eluting with 1:1 ethyl acetate/heptane, 100% ethyl acetate, then 9:1 ethyl acetate/methanol, to yield 250 mg of 6-(2-methoxyphenyl)quinazolin-4-ol as a white powder. MS (ES+)=253 (M+H+).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:25][CH:26]([F:28])Cl>O1CCCC1.O>[F:25][CH:26]([F:28])[C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: FC(F)Cl
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C(F)F)c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
16.8 g (0.07 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 300 mL of tetrahydrofuran and 9.1 g (0.077 mol) of potassium tert-butoxide are added batchwise while cooling. Then difluorochloromethane is piped in at 0° C. over a period of 1.5 hours. After all the gas has been piped in, the reaction mixture is left to stand for 72 hours at ambient temperature. The reaction mixture is then diluted with water to a total volume of about 2000 mL, extracted with ethyl acetate, the organic phase is separated off and washed with 5% aqueous sodium carbonate solution. After being extracted again with water, the organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product is purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate (98:2)) or by recrystallization from cyclohexane. Yield: 5.35 g of white crystals (26% of theoretical yield); melting point: 101° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
A mixture of methyl 6-chloronicotinate (1.02 g, 5.93 mmol), morpholine (0.57 ml, 6.52 mmol), potassium carbonate (1.06 g, 7.71 mmol) and DMF (20 ml) was stirred at 100° C. for 6 hrs. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropy ether to give the title compound (0.93 g, 71%) as a colorless powder.