Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[O:17]=[C:11]([CH2:9][C:8](=[O:10])[C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(=O)c1ccncc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccncc1

Procedure:
The title compound was prepared in the same manner as intermediate 29 using sodium metal (0.466 g, 20.26 mmol), 1-(4-pyridinyl)ethanone (1 g, 6.66 mmol), and diethyl ethanedioate (2.388 mL, 17.62 mmol). The crude product was purified using column chromatography (0 to 100% EtOAc/hexanes) to give 0.95 g of product (24%). LCMS E-S (M+H)=222.0 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37-1.55 (m, 3H), 4.43 (q, J=7.07 Hz, 2H), 7.06-7.16 (m, 1H), 7.72-7.92 (m, 2H), 8.82-8.94 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:27]([OH:29])=O)=[CH:18][C:17]=3[CH:30]=2)=[CH:9][CH:8]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:35][N:36]([CH:38]=O)[CH3:37]>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:27]([NH:22][C:16]4[CH:17]=[CH:30][C:13]([CH2:38][N:36]([CH3:35])[CH:37]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:14][CH:15]=4)=[O:29])=[CH:18][C:17]=3[CH:30]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (15 ml) was suspended 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.14 g). To the suspension were added, under ice-cooling, thionyl chloride (0.04 ml) and DMF (catalytic amount), and the mixture was stirred at room temperature for 1.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (15 ml). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.08 g) and triethylamine (0.14 ml) in THF (15 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 7) (0.15 g) as colorless amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23]C2C=CC(F)=CC=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Cl:55][C:56]1[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:57]=1C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:57]2[C:60]([F:64])=[CH:61][CH:62]=[CH:63][C:56]=2[Cl:55])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: Fc1cccc(Cl)c1C[Zn+]
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Cl-]
Product: Fc1cccc(Cl)c1Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 23 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (2-chloro-6-fluorobenzyl)zinc(II) chloride in 23% yield.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][C:21]=1[OH:33].CO[C@@H](CC1C=CC=CC=1OCCCOC1C=CC=CC=1)C(O)=O>>[CH:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][C:21]=1[O:33][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1
Reactant: Oc1ccc2c(c1)Cc1ccccc1-2
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccccc1OCCCOc1ccccc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3c(c2)Cc2ccccc2-3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 9H-fluoren-2-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C25H24O5 [M+Na]+: 427.3.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15](O)=O.N>>[N+:21]([C:20]1[CH:19]=[CH:18][C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:13][C:12]=1[OH:11])([O-:23])=[O:22]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: N
Product: O=[N+]([O-])c1ccc(-c2nc(-c3cccnc3)no2)cc1O

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-hydroxy-4-nitrobenzoic acid (Maybridge). 1H NMR (300 MHz, DMSO-d6) δ 6.51 (d, J=9.1 Hz, 1 H), 6.92-7.31 (s (broad), 1 H), 7.61 (ddd, J=7.9, 4.8, 0.8 Hz, 1 H), 7.68 (dd, J=9.1, 2.4 Hz, 1 H), 8.40 (dt, J=7.9, 2.0 Hz, 1 H), 8.53 (d, J=2.4 Hz, 1 H), 8.77 (dd, J=4.8, 1.6 Hz, 1 H), 9.20 (d, J=1.6 Hz, 1 H) ppm; MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]([NH:15][NH2:16])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=1.[C:17](Cl)(=O)C>CO>[OH:10][C:8]1[CH:9]=[C:4]([CH2:3][C:2]([NH:15][NH2:16])([CH3:1])[C:12]([O:14][CH3:17])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:11]
Reactant: CC(=O)Cl
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Solvent: CO
Product: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NN
Temperature: 65 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of carbidopa (226 mg, 1 mmol) in anhydrous methanol (20 mL), was added acetyl chloride (1 mL) at 0° C. The mixture was stirred at 65° C. in a pressure vessel for 4 h. Removal of solvent yielded 270 mg (99%) of the title compound as its hydrochloride salt. 1H NMR (CD3OD, 400 MHz): 1.46 (s, 3H), 2.86 (dd, 2H), 3.78 (s, 3H), 6.45 (dd, J=8 Hz, J=2 Hz), 6.56 (d, J=2.4 Hz), 6.69 (d, J=8.4 Hz). MS (ESI) m/z 241.15 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1.[CH3:26][NH:27][CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([N:27]([CH3:28])[CH3:26])=[O:18])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]1
Reactant: O=C(Cl)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 1 dram vial was added 4-[2-(2-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-benzoyl chloride (300 mL, 0.3 mmol) as a 0.1M solution in Dichloromethane, Dimethyl-amine (27 mg, 0.6 mmol) and N,N-Diisopropylethylamine (77.4 mg, 0.6 mmol). The reaction was stirred at room temperature for 30 min and then placed directly on silica and purified using a gradient of Hexane to Ethyl Acetate 0-50% over 10 CV. The relevant fractions were combined and dried in vacuo to give 108.6 mg (92%) of an off white solid; MS (ES): 394 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 7.84 (dd, J=7.8 Hz; 1.7 Hz 1H), 7.73-7.58 (m, 3H), 7.45-7.35 (m, 5H), 3.00 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47]>O1CCCC1.O>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
1.1 g (2.06 mMol) of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of water, then 570 mg (4.12 mMol) of potassium carbonate and 362 mg (2.2 mMol) of n-hexyl chloroformate were added and stirred for two hours at room temperature. The solvent was then distilled off, the residue was mixed with about 50 ml of saturated saline solution and the resulting solution was extracted three times with 20 ml of dichloromethane. The extracts were dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (100 g silica gel; dichloromethane+5% ethanol). Yield: 78% of theory, C35H42N6O5 (626.8) Rf value: 0.49 (silica gel; dichloromethane/ethanol=19:1) ##EQU61##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=O)[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.C([NH2:16])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[O:9])[NH:16][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Reactant: NC=O
Product: COc1ccc2c(c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A mixture of 4-methoxyphthalic anhydride (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 210° C. for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 4-methoxyphthalimide (21.3 g, 77%) as a pale yellow solid. 1H NMR (DMSO-d6) 11.15 (1H, br s), 7.74 (1H, d), 7.33-7.28 (2H, m), 3.92 (3H, s).
Reaction SMILES: [I:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:3]1[C:2]([I:1])=[CH:7][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1c[nH]c(=O)c(I)c1
Product: CS(=O)(=O)c1cnc(Cl)c(I)c1

Procedure:
A suspension of 9.0 g of 3-iodo-5-(methylsulfonyl)-2(1H)-pyridinone in 30 ml of phosphorus oxychloride was refluxed under nitrogen for 4 hours and gave a homogeneous mixture. This solidified on cooling and unreacted phosphorus oxychloride was removed under reduced pressure. The resulting white solid residue was dissolved in methylene chloride and extracted first with water and twice with aqueous 1N sodium hydroxide solution. The mixture was shaken until the aqueous phase remained basic. The methylene chloride solution was then dried over magnesium sulfate and concentrated to leave a white solid residue. This was recrystallized from ethyl acetate/hexane to give 2-chloro-3-iodo-5-(methylsulfonyl)pyridine as colorless needles melting at about 178.5°-180.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[CH:16][CH:15]=3)[C:4]=2[N:3]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH:24][C:35]([NH:34][C:32]4[N:31]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=4)=[O:36])=[CH:16][CH:15]=3)[C:4]=2[N:3]=1
Reactant: Nc1nc2c(Oc3ccc(N)c4ccccc34)ccnc2[nH]c1=O
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(N)nc34)c3ccccc23)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 2-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly pink solid (70 mg, 80%). 1H-NMR (DMSO-d6), δ (ppm), J (Hz): 1.29 (s, 9H, tert-Bu), 6.31 (d, 1H, Harom, J=5.5 Hz), 6.41 (s, 1H, Harom), 7.22 (d, 1H, Harom, J=8.3 Hz), 7.44 (t, 1H, J=7.0 Hz), 7.54-7.65 (m, 6H, Harom), 7.85 (d, 1H, Harom, J=8.3 Hz), 7.88-7.91 (m, 2H, Harom), 8.06 (d, 1H, Harom, J=8.6 Hz), 8.76 (s, 1H, NHurea), 9.04 (s, 1H, NHurea), 12.58 (s, 1H, NHlactame). 13C-NMR (DMSO-d6), δ (ppm), J (Hz): 30.08 (tert-Bu), 31.92 (tert-Bu), 95.69, 106.46, 116.05, 118.94, 119.36, 121.56, 122.27, 124.12 (2*C), 126.32, 126.52, 126.55, 127.11, 127.97, 129.17 (2*C), 131.22, 137.15, 138.59, 142.95, 143.56, 146.22, 151.71, 152.33, 152.72, 157.12, 160.68. HRMS (EI): m/z [M+H] calcd for C31H2O8O3: 561.2357; found: 561.2351.
Reaction SMILES: [OH:1][CH:2]([CH2:13][OH:14])[CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>O1CCCC1.CCOCC>[Si:20]([O:14][CH2:13][CH:2]([OH:1])[CH2:3][CH2:4][P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOP(=O)(CCC(O)CO)OCC
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOP(=O)(CCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of diethyl 3,4-dihydroxybutylphosphonate (8.5 g, 0.038 mol) in dry tetrahydrofuran (200 ml) was added imidazole (5.25 g, 0.077 mol). After stirring at ambient temperature for 2 minutes, t-butyldimethysilyl-chloride (5.8 g, 0.038 mol) was added. After 18 hours, the solution was filtered and the filtrate evaporated to give a colorless oil. The oil was dissolved in ether, and washed with water. The organic phase was dried (magnesium sulphate) and evaporated to give an oil which was purified by chromatography on silica gel (dichloromethane-methanol (98:2) as eluant). The title compound was obtained as an oil (8 g, 62%). IR:υmax (film), 3400, 2940, 2860, 1250, 1170, 960, 840, 780 cm-1. 1H NMR: δH (CDCl3) 0.00 (6H, s, SiMe2), 0.83 (9H, s, SiBut), 1.25 (6H, t, J=7Hz, (OCH2CH3)2), 1.5-2.0 (4H, m, CH2CH2P), 2.7 (1H, bs, D2O exchangeable, OH), 3.35-3.65 (3H, m, OCH2CH), 4.0 (4H, m, (OCH2CH3)2) Found: C, 48.66; H, 9.83%. C14H33O5SiP requires: C, 49.39; H, 9.77%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=[O:12].[CH:40]1([CH2:43][O:44][C:45]2[CH:50]=[C:49]([CH2:51]O)[CH:48]=[CH:47][C:46]=2[N:53]([S:61]([CH3:64])(=[O:63])=[O:62])C(=O)OC(C)(C)C)[CH2:42][CH2:41]1.Cl.O1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][CH2:51][C:49]1[CH:48]=[CH:47][C:46]([NH:53][S:61]([CH3:64])(=[O:63])=[O:62])=[C:45]([O:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)[CH:50]=1)=[O:12]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(COC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared in an analogous manner as described in Scheme 3, Step 1) (0.150 g, 0.256 mmol) in DCM (10 ml), DMAP (0.0156 g, 0.128 mmol) was added followed by tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl(methylsulfonyl)carbamate (0.124 g, 0.333 mmol), and the resulting mixture was stirred at RT for 3 hours. HCl 4M in dioxane (3 ml, 12 mmol) was added and the reaction was stirred at RT for additional 5 hours. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.15). A further purification by flash chromatography on silica gel column (DCM:acetone=10:1) was required to obtain (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzyloxy)carbonyloxy)ethyl)pyridine 1-oxide as a white solid (0.073 g, 0.102 mmol, 39.7% yield, MS/ESI+ 716.93 [MH]+, [αD]=−11.84, c=0.495, DCM).
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].[C:16]12([CH3:26])[C:23]([CH3:25])([CH3:24])[CH:20]([CH2:21][CH2:22]1)[CH2:19][C:17]2=O.[OH-].[K+].Cl>CO>[CH3:26][C:16]12[C:23]([CH3:25])([CH3:24])[CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:17]2[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][CH:3]1[C:4]([CH3:9])([CH3:10])[CH:5]2[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: CC(=O)C=CC1C2(C)CCC(C2)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC12CCC(C1)C(C)(C)C2CCC(=O)CC1CC2CCC1(C)C2(C)C
Temperature: 20 °C
Reaction time: 6 h

Procedure:
20.6 gm. (0.1 mole) of 1-(1,3,3-trimethylbicyclo-[2.2.1]hept-2-yl)-1-buten-3-one and 18.3 gm. (0.12 mole) of camphor is dissolved in 25 ml. methyl alcohol. A solution of 3.4 gm. of potassium hydroxide in 20 ml. of methyl alcohol is then added over a period of 15 minutes using good agitation and external cooling. The reaction mixture is maintaned at 40° C.-45° C. for 6 hours, cooled to 20° C., made slightly acid by the addition of dilute hydrochloric acid and the residue after solvent stripping under reduced pressure extracted with ether. The ether solution is washed two times with one-tenth its volume of cold water, dried over anhydrous magnesium sulfate and stripped of solvent under reduced pressure. The residual oil which contained 1-(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)-4-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)but-3-en-2-one is dissolved in 100 ml. of thiophene-free benzene and shaken under 50 psi hydrogen pressure in the presence of 3 gm. 5% palladium on carbon at 25° C. until slightly more than theoretical hydrogen uptake is observed. The catalyst is removed by filtration and the solvent stripped. The residual oil is purified by fractional distillation under reduced pressure to provide the 1-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)butan-2-one.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCCC2)ncn1
Temperature: 57.5 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 71 mg of pyrrolidine was added therein, and the mixture was stirred for 4 hours at 55-60° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 170 mg of 4-(2-butynyloxy)-6-(1-pyrrolidinyl)pyrimidine (hereinafter, referred to as Compound (17)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)CCC>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5cccs5)cc34)cc2)cc1
Yield: 59.8 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (200 mg, 0.49 mmol), 2-(tributylstannyl)thiophene (200 mg, 0.53 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (3 ml) and heated at reflux under nitrogen for 4 hr. The cooled reaction mixture was absorbed onto silica and purified by flash column chromatography (silica gel, eluting with an ethyl acetate/iso-hexane gradient). The resulting solid was triturated with iso-hexane/ethyl acetate to give the product (120 mg, 60%) as a pale yellow solid; δH [2H6]-DMSO 9.88 (1H, b, NH), 8.76 (1H, s, 5-H), 8.49 (1H, s, 2-H), 8.12 (1H, d, 7-H), 7.82-7.60 (5H, m, thiophene-3-H, thiophene-5-H, 8-H, 2′-H, 6′-H), 7.52-7.30 (5H, m, 5×Ph-H), 7.23 (1H, t, thiophene-4H), 7.18 (2H, d, 3′-H, 5′-H), 5.11 (2H, s, CH2); m/z 410 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][Cl:35])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCl)c2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N2-Butyl-8-(methyloxy)-9H-purine-2,6-diamine trifluoroacetate (701 mg, 2.001 mmol) and potassium carbonate (690 mg, 4.99 mmol) were suspended in DMF (10 ml) and the mixture heated at 50° C. under nitrogen for 2 hours. The mixture was allowed to cool and then 1-bromo-3-chloropropane (198 μl, 2.002 mmol) was added and the reaction mixture stirred at ambient temperature overnight. After 16 hours the reaction mixture was partitioned between water and DCM (25 ml of each). The aqueous phase was extracted with further DCM (2×20 ml). The combined DCM extracts were dried over magnesium sulphate and concentrated in vacuo to give the impure title compound as a pale yellow oil with some solid present (0.76 g) which was used without further purification.