Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:12][CH2:22][O:23][CH3:24])=[O:2]
Reactant: COCCl
Reactant: O=Cc1ccc(C(=O)O)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C(=O)O)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
4-Formyl-3-hydroxybenzoic acid (2.20 g, 13.2 mmol) was suspended in dichloromethane (40 mL), and the suspension was added with diisopropylethylamine (9.20 mL, 52.8 mmol) and chloromethyl methyl ether (2.01 mL, 26.5 mmol) under ice-cooling. Then, the reaction mixture was warmed to room temperature and stirred for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (40 mL), and the solution was added with 2 mol/L aqueous potassium hydroxide solution (40 mL), and stirred at room temperature for 1 hour. Methanol was evaporated under reduced pressure and the residue was added with 4 mol/L hydrochloric acid and water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-formyl-3-methoxymethoxybenzoic acid (2.21 g, yield 80%).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][O:6][C:7]([C:9]1([CH2:19][CH2:20][CH2:21]Br)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=O)=[O:8].C(OC)(C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]12[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11][CH:10]1[NH:1][CH2:21][CH2:20][CH2:19]2)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1(CCCBr)C(=O)Cc2ccccc21
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C12CCCNC1Cc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
NaN3 (0.44 g) is added to a solution of 1-(3-bromo-propyl)-2-oxo-indan-1-carboxylic acid methyl ester (2.06 g) in dimethylformamide (10 mL) at room temperature. The solution is stirred at room temperature for 4 h and then tBuOMe and ethyl acetate are added. The resulting mixture is washed with water and brine and dried (MgSO4). Most of the organic solvent is evaporated and tetrahydrofuran (10 mL), acetic acid (0.5 mL), and finally 10% Pd/C (150 mg) are added to the residue. The resulting mixture is shaken in hydrogen atmosphere (1 bar) at room temperature for 14 h. Then, the mixture is filtered, the filtrate is concentrated, and the residue is taken up in tBuOMe. The organic phase is washed with aqueous Na2CO3 solution and brine and dried (MgSO4). Then, the solvent is evaporated and the residue is dissolved in methanol (10 mL). To the solution is added acetic acid (0.5 mL) and 10% Pd/C (50 mg) and the resulting mixture is shaken under hydrogen atmosphere (1 bar) at room temperature for 6 h. Then, the mixture is filtered and the filtrate is concentrated under reduced pressure to give the crude title compound that is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2nc(-c3ccccc3)[nH]c2c1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
4-Bromobenzene-1,2-diamine (0.5 g, 2.67 mmol), benzaldehyde (0.284 g, 2.67 mmol), and 4-methylbenzenesulfonic acid (0.046 g, 0.267 mmol) in DMF (8 mL) were combined and heated at 100° C. for 1 hour in a microwave reactor. The reaction mixture was subsequently diluted with EtOAc, washed with brine (4×100 mL), concentrated, and purified by CombiFlash® chromatography, eluting with a gradient of MeOH (0-30%) in DCM over 120 minutes. The product-containing fractions were combined and concentrated to give the title compound as light yellow liquid (0.48 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1coc2cccc(O)c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc2occ(C)c12

Procedure:
A solution of 3-methyl-4-hydroxybenzofuran (5.0 gm, 34.7 mmoles), acetic anhydride (50 mL) and triethylamine (25 mL) in tetrahydrofuran (150 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel. Elution with 15% ethylacetate in hexane yielded 3-methyl-4-acetoxybenzofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1>[Ni].CO.N>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10]1
Reactant: N#CC1(c2c(Cl)cccc2Cl)CCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cl
Product: NCC1(c2c(Cl)cccc2Cl)CCC1
Yield: 100 %

Procedure:
1-(2,6-dichlorophenyl)-1-cyclobutanecarbonitrile (1 g, 4.4 mmol) was reduced with Raney nickel, in methanol/NH3. The catalyst was removed and washed with methanol. The filtrate was concentrated, and diethyl ether (100 mL) was added to the residue. Concentrated HCl was added dropwise to precipitate the desired product; 1.05 g (100% yield).
Reaction SMILES: [C:1]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:25]([NH:32][C:33]([N:35]1[CH2:40][CH2:39][C:38](=[O:41])[N:37]2[C@@H:42]([CH2:58]C3C=CC(O)=CC=3)[C:43](=[O:57])[N:44]([CH2:46][C:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[CH:50]=[CH:49][CH:48]=3)[CH2:45][CH:36]12)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)(=O)CCCCCCCCCCCC>>[C:1]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:58][C@@H:42]2[N:37]3[C:38](=[O:41])[CH2:39][CH2:40][N:35]([C:33](=[O:34])[NH:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:36]3[CH2:45][N:44]([CH2:46][C:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[CH:50]=[CH:49][CH:48]=3)[C:43]2=[O:57])=[CH:23][CH:24]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Oc1ccccc1
Reactant: O=C1[C@H](Cc2ccc(O)cc2)N2C(=O)CCN(C(=O)NCc3ccccc3)C2CN1Cc1cccc2ccccc12
Agent: CCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)CC3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1

Procedure:
According to particular aspects, synthesis of 44-(46S)-1-(benzylcarbamoyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidin-6-yl)methyl)phenyl palmitate was achieved in analogy with above Example 10 except starting with a solution of (6 S)—N-benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide, and reacting with tridecanoyl chloride to obtain the title compound.
Reaction SMILES: [CH2:1]=O.[OH-].[Na+].[NH2:5][CH2:6][C:7]([OH:9])=[O:8].[P:10]([O-:15])([O:13]C)[O:11]C.Cl>O>[P:10]([CH2:1][NH:5][CH2:6][C:7]([OH:9])=[O:8])([OH:15])([OH:13])=[O:11]
Reactant: COP([O-])OC
Reactant: C=O
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
8.6 g. of 37% formaline (= 0.1 moles of formaldehyde) are added to a stirred solution of 4.0 g. (0.1 moles) of sodium hydroxide and 7.5 g. (0.1 moles) of glycine in 40 ml. of water. After 10 minutes of stirring at 0° to 5° C, 11 g. (0.1 moles) of dimethyl phosphite are added, and stirring is continued for 2 hours at 90° to 100° C. The mixture is acidified with 60 ml. of concentrated hydrochloric acid, and stirred for further 2 hours at 90° to 100° C. The obtained solution is evaporated to dryness under reduced pressure (80 to 100 mmHg.). The oily residue is boiled with 200 ml. of 90% ethanol, the mixture is cooled, the product is filtered off, and dissolved in 30 to 35 ml. of hot water. The solution is decolorized, filtered, and the product is precipitated from the filtrate with 45 ml. of acetone. 11.0-11.3 g. (65-67%) of N-phosphonomethyl-glycine are obtained: m.p.: 224°-225° C (with decomposition).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:16]1[N:17]=[C:18](N)[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:21]=12.N([O-])=[O:37].[Na+].N>O>[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:16]1[N:17]=[C:18]([OH:37])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:21]=12
Reactant: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(N)cc12
Reactant: O=N[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(O)cc12
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
The compound prepared in Example 847 was treated with a saturated sodium bicarbonate solution to obtain 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-amine. Concentrated sulfuric acid (1 ml) and water (5 ml) were added to 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-amine (50 mg, 0.13 mmol) and then sodium nitrite (43.1 mg, 0.63 mmol) was added thereto. The reaction mixture was stirred for 5 minutes at 100° C. under heating and then excess ammonia solution was added thereto. The reaction mixture was stirred for 2 minutes under heating at the same temperature and then filtered to discard insoluble matertals. A potassium hydroxide solution was added to the reaction mixture, which was then filtered to discard insoluble matertals. The reaction mixture was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 28.4 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNS(C)(=O)=O
Reaction time: 18 h
Yield: 12.2 %

Procedure:
A solution of the compound of Example 51, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.570 g, 5.50 mmol) in 40 mL of 1-methyl-2-pyrrolidinone was treated with triethylamine (1.53 mL, 11.0 mmol). With vigorous stirring, methanesulfonyl chloride (0.426 mL, 5.50 mmol) was added dropwise. After 18 h, the reaction was treated with 50 mL of water and then concentrated to yield a solid. The solid was purified by column chromatography (SiO2, 90:10:0.5 CHCl3:MeOH:NH4OH) to yield 244 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}methanesulfonamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C(C)=CC=CC=1>[CH3:9][N:10]([CH3:14])[C:11]([NH:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1)=[O:12]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1nc(N)sc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Cc1nc(NC(=O)N(C)C)sc1C
Yield: 91.5 %

Procedure:
Using 2-amino-4,5-dimethylthiazole (1.28 g), N,N-dimethylcarbamoyl chloride (1.29 g), aluminum chloride (1.60 g), and xylene (40 ml), the reaction is run as in Example 1, whereby 1,1-dimethyl-3-(4,5-dimethyl-2-thiazolyl)urea (1.82 g) is obtained. Yield is 91.5%. Melting point is 202.5° to 204° C. (after recrystallization from ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16]OC)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:19].[NH:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[NH2:21]>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH2:8].[ClH:19].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=[N:21][NH:20][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=Cc1ccc(OCc2ccccc2)cc1
Reactant: NNc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: C(Cc1ccc(OCc2ccccc2)cc1)=NNc1ccncc1
Product: O
Yield: 120.4 %

Procedure:
A mixture of 1-benzyloxy-4-(2-methoxyvinyl)benzene (16.9 g), 4-hydrazinopyridine hydrochloride (11.3 g) and p-toluenesulfonic acid (0.68 g) in ethanol (200 ml) was heated under reflux for 5 hrs, with stirring. The reaction mixture was cooled, filtered, and the filtrate was concentrated in vacuo. The residue crystallized to give 15.75 g (63%) of product, mp 203-205° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: Sc1ccccc1
Product: c1ccc(Sc2ccccc2)cc1

Procedure:
The general procedure was used to convert iodobenzene and thiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (360 mg, 98% yield). 1H NMR (300 MHz, CDCl3) δ 7.48–7.44 (m, 4H; Ha, Ha′, Hd, Hd′), 7.42–7.39 (m, 4H; Hb, Hb′, He, He′), 7.37–7.31 (m, 2H; Hc, Hc′). 13C NMR (75 MHz, CDCl3) δ 135.70 (C1), 130.94 (C2), 129.10 (C3), 126.94 (C4). Anal. Calcd. for C12H10S: C, 77.37; H, 5.41; S, 17.21; Found C, 77.50; H, 5.45; S, 17.00.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25](O)=[O:26])[CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:25]([C:17]2[CH:16]=[N:15][C:24]3[C:19]([CH:18]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:26])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Reactant: O=C(O)c1cnc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2cnc3ccccc3c2)c1
Reaction time: 17 h

Procedure:
1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (0.400 g, 2.0 mmol) was coupled with 3-quinolinecarboxylic acid (0.373 g, 2.2 mmol) in dichloromethane (35 ml) with triethylamine (1.40 ml, 10.0 mmol) and propylphosphoric acid anhydride (0.65 ml, added as a 0.65 ml ethyl acetate solution). After 17 hours, the solution was filtered through a pad of celite and the filtrate concentrated. Dichloromethane and aqueous sodium bicarbonate were added the layers separated. The aqueous layer was extracted with dichloromethane (2X) and the combined organic layers washed with aqueous sodium bicarbonate, brine, dried (Na2SO4), filtered, and concentrated. Recrystallisation from 1,2-dichloroethane gave the pure product, MP: 174°-175° C.
Reaction SMILES: [Si]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[N:20]([CH2:21][CH3:22])[C:19]2[C:18](OC3C=CC=CC=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1)(C(C)(C)C)(C)C.[CH3:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=1)[NH2:34].Cl.N1C=CC=CC=1.C1(O)C=CC=CC=1>ClCCl>[CH2:21]([N:20]1[C:19]2[C:18]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([O:38][C:39]4[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=4)=[C:31]([CH3:30])[CH:32]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=[C:12]1/[CH:11]=[CH:10]/[CH2:9][OH:8])[CH3:22]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCn1c(/C=C/CO[Si](C)(C)C(C)(C)C)cc2ncnc(Oc3ccccc3)c21
Agent: Cl
Solvent: Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1c(/C=C/CO)cc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 120 °C
Yield: 40.4 %

Procedure:
A mixture of 6-((1E)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propenyl)-5-ethyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (78 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (61.2 mg), pyridine hydrochloride (26 mg) and phenol (122 mg) was stirred with heating at 120° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with dichloromethane (30 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→80:20) to give the title compound (32 mg) as a powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:35])=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(S(=O)CCOc2ccc3ccccc3c2)cc1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid methyl ester (2.56 g) in dichloromethane (75 mL) was chilled in ice and 85 % metachloroperbenzoic acid (1.42 g) was added. The mixture was stirred cold for 1 hour, diluted with saturated sodium bicarbonate solution, and extracted with dichloromethane. The dried (Na2SO4) was filtered, evaporated and the residue was crystallized from dichloromethane-hexane to give 2.2 g of rac.-4-[[2-(2-naphthalenyloxy)ethyl]sulfinyl]-alpha-oxobenzeneacetic acid methyl ester, mp 129°-130° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[C:20]([C:21]([OH:23])=O)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:21]([C:20]3[C:11](=[O:10])[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:23])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: O=C(O)c1cc2ccccc2[nH]c1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccccc2[nH]c1=O
Temperature: 25 °C

Procedure:
DIEA (50.7 μL, 0.29 mmol) was added to 2-Oxo-1,2-dihydro-quinoline-3-carboxylic acid (50.0 mg, 0.26 mmol) and HATU (110.6 mg, 0.29 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (55.3 mg, 0.26 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give the final product: LCMS (ESI) m/z 381 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.C(O)(CC)(C)C.C(OCC)(=O)C>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([CH2:25][OH:26])[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2F)sc1N
Reactant: OCc1cccc(Br)n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: CCC(C)(C)O
Product: NC(=O)c1cc(-c2ccc(F)cc2F)sc1Nc1cccc(CO)n1

Procedure:
A suspension containing 2-amino-5-(2,4-difluorophenyl)thiophene-3-carboxamide (60 mg, 0.24 mmol), (6-bromo-pyridin-2-yl)methanol (44.4 mg, 0.24 mmol), 2-dicylohexylphosphino-2′,4′,6′-triisopropyl-1,1-biphenyl (5.62 mg, 0.012 mmol), dibenyzlideneacetone bis(triphenylphosphine) (2.161 mg, 2.36 μmol) and potassium carbonate (35.9 mg, 0.26 mmol) in tert-butanol or tert-amyl alcohol (0.5 mL) was sealed in 5 mL microwave reaction vessel and was purged of oxygen by doing 5 vacuum/argon flush cycles. After heating the reaction at 100° C. for 2 hours, the mixture was cooled, diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium bicarbonate (2×5 mL) and brine (2×5 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase HPLC (35-95% acetonitrile/water with 0.05% trifluoroacetic acid), and then the appropriate fractions were diluted with ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (15 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (15 mL) and water (2×15 mL), dried over sodium sulfate, filtered and concentrated to yield the title compound as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[C:15]2[CH2:18][N:17]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]2[CH2:18][N:17]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cc(F)cc(Br)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(c1cc(F)cc(Br)c1)C1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared from ethyl (3-bromo-5-fluorophenyl)[1-(diphenylmethyl)azetidin-3-ylidene]acetate according to the procedure described in Preparation 6 except that THF was used as the co-solvent; Mass Spectrum m/e=482 (M+1, 79Br), 484 (M+1, 81Br).
Reaction SMILES: [NH3:1].[P:2]([Cl:7])([Cl:6])(Cl)(Cl)Cl>>[N:1]1[P:2]([Cl:7])([Cl:6])=[N:1][P:2]([Cl:7])([Cl:6])=[N:1][P:2]([Cl:7])([Cl:6])=[N:1][P:2]=1([Cl:7])[Cl:6]
Reactant: N
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1

Procedure:
A two-stage cascaded continuous reaction is effected as set forth in Example I, with the exception that NH3 feed is divided equally between the two reactors, instead of the total NH3 being fed to the first reactor. Into each reactor is metered a five to ten percent excess over the one-half molar equivalent of NH3, based on the moles of PCl5 introduced. A sample of product obtained under conditions as described in Example I, was collected and filtered. The filtrate was stripped of solvent in vacuo to obtain the product polymeric phosphonitrilic chloride, which contained 87.1% hexane soluble cyclic oligomers. The hexane insoluble linear fraction was a yellow oil. The cyclic portion was analyzed by gas chromatography and the distribution of cyclic portion was as follows: