Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:3]=1)#[N:28]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2cc(-c3ccccc3C#N)nc(N3CCOC[C@@H]3C)n2)cc1
Yield: 41.4 %

Procedure:
(S)-1-(4-(6-chloro-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)-3-ethylurea (Intermediate 2) (90 mg, 0.24 mmol), 2-cyanobenzeneboronic acid (43 mg, 0.29 mmol), cesium carbonate (235 mg, 0.72 mmol) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (10 mg, 0.01 mmol) in dioxane/water (1:3, 1 mL) were irradiated in a Biotage microwave for 40 min at 110° C. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMSO, filtered and purified by prep HPLC (low pH) to afford a green solid (44 mg, 41%).
Reaction SMILES: [CH3:1][C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2)([CH:4]1[O:8][C:7]([NH2:9])=[N:6][CH2:5]1)[CH3:3].C([O:22][C:23](=O)[CH:24]([CH:27]=O)[CH2:25][CH3:26])C>C(O)C>[CH3:3][C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2)([C@H:4]1[O:8][C:7]2=[N:9][C:23](=[O:22])[C:24]([CH2:25][CH3:26])=[CH:27][N:6]2[CH2:5]1)[CH3:1]
Reactant: CC(C)(Oc1ccc2c(c1)CCC2)C1CN=C(N)O1
Reactant: CCOC(=O)C(C=O)CC
Solvent: CCO
Product: CCc1cn2c(nc1=O)O[C@H](C(C)(C)Oc1ccc3c(c1)CCC3)C2
Yield: 17.2 %

Procedure:
To a solution of 5-(1,1-dimethyl-indan-5-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.41 g, 1.57 mmol) in ethanol (16 mL) was added 2-formyl-butyric acid ethyl ester (0.34 g, 2.23 mmol). The reaction mixture was heated at reflux for 20 hours. It was then concentrated and loaded on a silica gel column. Chromatography with (1-5%) 2-propanol/methylene chloride gave 0.092 g of the title product. [α]D25=−24.1 (c=0.76, CHCl3).
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrCCBr.II.[CH2:23]([N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:23]([N:30]1[CH2:35][CH2:34][C:33]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([OH:36])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OC1(c2ccccc2OCc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 65 °C
Yield: 86.8 %

Procedure:
To 30 mL of anhydrous tetrahydrofuran was added 940 mg (39 mmol) of magnesium powder. The one-fifth of a solution obtained by dissolving 10 g (38 mmol) of 2-benzyloxybromobenzene in 30 mL of anhydrous tetrahydrofuran was added. To the resulting mixture were added 0.1 mL of 1,2-dibromoethane and a small amount of iodine, followed by heating to 60 to 70° C. When the reaction started, the remaining portion of the anhydrous tetrahydrofuran solution of 2-benzyloxybromobenzene was added dropwise and the mixture was heated to reflux for further 30 minutes. In the resulting anhydrous tetrahydrofuran solution of Grignard reagent, 7 g (37 mmol) of 1-benzyl-4-piperidone dissolved in 30 mL of anhydrous tetrahydrofuran was added dropwise at room temperature. After heating to reflux for 30 minutes, 10 mL of a saturated aqueous solution of ammonium chloride was added dropwise and the solvent was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ether, followed by washing with water and drying. The residue obtained by concentrating the solvent under reduced pressure was purified by chromatography on a silica gel column, whereby 12 g (yield: 87.0%) of 1-benzyl-4-(2-benzyloxyphenyl)-4-piperidinol was obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:17][S:18]([CH2:21][CH2:22][CH2:23]Cl)(=[O:20])=[O:19]>C(#N)C>[CH3:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:17]1[CH2:23][CH2:22][CH2:21][S:18]1(=[O:20])=[O:19]
Reactant: Cc1cc([N+](=O)[O-])ccc1NS(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCS1(=O)=O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
11.1 g of caesium carbonate (34.0 mmol) are added to a solution of 6.50 g (22.2 mmol) of N-(2-methyl-4-nitrophenyl)-3-chloropropane-1-sulfonamide in 150 ml of acetonitrile, and the mixture is stirred at 70° C. for 18 hours. The reaction mixture is subjected to conventional work-up, and the crude product is chromatographed on a silica-gel column using ethyl acetate/petroleum ether as eluent, giving 2-(2-methyl-4-nitrophenyl)isothiazolidine 1,1-dioxide as a yellowish solid; ESI 257.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:21])[CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:21])[CH2:15][CH2:16][CH2:17][C:18]1([CH3:19])[O:24][CH2:23][CH2:22][O:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC1(CCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-8 (45 g, 156 mmol) and ethylene glycol (13.0 mL, 223 mmol) in benzene (500 mL) was added catalytic p-toluenesulfonic acid (125 mg). The resulting mixture was heated at strong reflux with azeotropic removal of water for 4 h. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give 1-9 as a yellow oil, which crystallized on standing.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:20][C:21]4[N:22]([CH:24]=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[C:27]1([C:19]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[N:23][N:22]3[CH:24]=[CH:25][N:26]=[C:21]3[CH:20]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4ccnc4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nn4ccnc4cc3-c3ccccc3)cc2)CCC1
Reaction time: 4 h
Yield: 60.7 %

Procedure:
105 mg (0.24 mmol) {1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, (intermediate example Int-2-0, slightly contaminated), were stirred with 2.3 mL 4M hydrogen chloride in dioxane for 10 days at room temperature. After evaporation of the solvent the residue was brought to pH 9 with saturated aqueous sodium bicarbonate solution. The mixture was stirred for four hours. The precipitate was sucked off and washed with water. The solid substance was dissolved in dichloromethane and purified by chromatography on silicagel (eluents: dichloromethane/methanol) resulting in 49.6 mg of the desired compound which was however yet contaminated. Due to these impurities the compound was again purified by HPLC yielding 21.1 mg (23.7%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[C:8]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([CH3:14])=[CH:10][C:11]=2[CH3:13])[NH:6][CH2:5]1.I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CCOC(C)=O>CN(C=O)C>[CH2:23]([N:6]1[C:7]2[C:12](=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=2[NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])[CH:4]([CH2:3][CH2:2][OH:1])[CH2:5]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCO
Reactant: CCCCCCCCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CC(CCO)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 70 °C
Reaction time: 10 h
Yield: 13.5 %

Procedure:
N-[3-(2—Hydroxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethyl-propanamide (1.6 g) was dissolved in DMF (15 ml) and 1-iodooctane (3.9 g) and K2 CO3 (2.3 g) were added, which was followed by stirring at 70° C for 10 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=5/1−1/2) to give 300 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCC#Cc1ccc(Cl)c(Cl)c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OCCCc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 86.4 %

Procedure:
A suspension of Compound 38-1 (3.21 g) and chlorotris(triphenylphosphine)rhodium(I) (1.60 g) in toluene (100 ml) was stirred under a hydrogen atmosphere at 60° C. for 10 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (2.83 g) as a brown oil.
Reaction SMILES: C(OC([N:8]1[C:12](=[O:13])/[C:11](=[CH:14]\N(C)C)/[CH:10]2[CH2:18][C:19]3[C:24]([CH:9]12)=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)(C)(C)C.Cl.[O:26]1CCOCC1>O>[OH:26]/[CH:14]=[C:11]1/[CH:10]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]2[NH:8][C:12]/1=[O:13]
Reactant: CN(C)/C=C1\C(=O)N(C(=O)OC(C)(C)C)C2c3ccccc3CC12
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: O=C1NC2c3ccccc3CC2/C1=C/O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[1-dimethylamino-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester D1 (1.68 g, 4.63 mmol) in dioxane (50 mL) was added HCl (37%, 8.37 mL). The solution was stirred overnight at room temperature and was then diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated to give 3-[1-Hydroxy-meth-(Z)-ylidene]-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one C1 identical to method A (0.85 g, 78%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C=O)C>[CH3:8][C:7]1[C:2]2[N:3]([N:20]=[N:21][N:22]=2)[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cnc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cn2nnnc12

Procedure:
A mixture of 2-chloro-3-methyl-5-(4-(trifluoromethoxy)phenyl)pyridine prepared as described above (58 mg, 0.20 mmol), sodium azide (21 mg, 0.30 mmol), and pyridine 4-methylbenzenesulfonate (5 mg, 0.02 mmol) in anhydrous DMF (2.0 mL) was capped in a Biotage microwave reaction vial and subjected to irradiation at 160° C. for 30 min. Cooled, pressure released by opening the cap, additional sodium azide (65 mg, 1.00 mmol) and pyridine 4-methylbenzenesulfonate (52 mg, 0.20 mmol) were added, capped, and subjected to irradiation at 200° C. for 30 min. After cooling, the mixture was concentrated in vacuo, diluted with DMF (1.0 mL) and MeOH (2.0 mL), filtered, and subjected to preparative HPLC with a gradient MeCN/H2O (5% to 98 containing 0.1% TFA to afford 8-methyl-6-(4-(trifluoromethoxy)phenyl)tetrazolo[1,5-a]pyridine
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[OH-].[K+].O.C(Cl)Cl.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][OH:24]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)CCCO
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCOc1ccc2ccc(N)nc2n1
Temperature: 60 °C

Procedure:
A suspension of 2-amino-7-chloro-1,8-naphthyridine (89.75 g) in 3-dimethylamino-1-propanol (236 cc) is preheated to approximately 30° C. Potassium hydroxide pellets (85% pure; 65.8 g) are then introduced gradually. The reaction is exothermic, and the temperature rises to 80° C. at the end of the addition. The reaction mixture is then heated for a further 30 minutes to 90° C., allowed to cool to 60° C. and then poured into water (1500 cc) in the presence of methylene chloride (500 cc). The decanted organic extracts are washed with water (2×200 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (4 kPa). The product obtained in the form of an oil is crystallized by stirring in hexane (300 cc). The crystallized solid is then separated by filtration, washed with hexane and dried at 20° C. at reduced pressure (0.07 kPa). 2-Amino-7-(3-dimethylaminopropoxy)-1,8-naphthyridine (109 g), m.p. 88° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:23]4[NH:24][C:25]([CH3:36])=[C:26]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[C:22]=4[CH3:21])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)N(C)c3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
A mixture of 4(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol), 3,5dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (85 mg, 0.34 mmol) and piperidine (2 drops) in ethanol (3 mL) was stirred at 80° C. for 1 hour. The reaction was concentrated and column chromatographed to give 46 mg (26%) of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H, NH), 9.17 (s, 1H), 8.33 (s, 1H), 7.68 (m, 1H), 7.35 (s, 1H, H-vinyl), 7.32 (m, 2H), 3.55 (m, 4H, 2×CH2), 3.30 (s, 3H, CH3), 2.40 (m, 2H, CH2), 2.31 (s, 3H, CH3), 2.30 (m, 4H, 2×CH2), 2.20 (m, 2H, CH2), 2.10 (s, 3H, CH3), 1.55 (m, 2H, CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:19][CH2:20][C:21]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][CH:16]=[C:15]([F:18])[CH:14]=2)[N:1]=1
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2cc(F)ccc2nc(CCl)n1-c1ccccc1Cl
Yield: 12.1 %

Procedure:
Prepared according to Procedure B with 1r (850 mg, 3.21 mmol) and chloroacetyl chloride (0.77 mL, 9.63 mmol) in acetic acid (15 mL). Purified by extraction from aqueous K2CO3, followed by chromatography in EtOAc/hexanes. A second chromatography in acetone/hexanes afforded 125 mg of a white solid (12%). 1H NMR (CDCl3) δ: 7.95 (dd, J=2.9, 8.2 Hz, 1H); 7.81 (dd, J=4.8, 9.0 Hz, 1H); 7.61-7.66 (m, 1H); 7.57 (dd, J=2.7, 8.6 Hz, 1H); 7.57 (dd, J=2.7, 8.6 Hz, 1H); 7.52 (dd, J=3.2, 6.9 Hz, 1H); 7.52 (br s, 2H); 4.38 (d, J=12 Hz, 1H), 4.08 (d, J=12 Hz, 1H). MS (ES): m/z 323.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:21]1([C:27]2[CH:31]=[C:30]([C:32](O)=[O:33])[NH:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[C:21]1([C:27]2[NH:28][N:29]=[C:30]([C:32]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]4)=[CH:4][CH:3]=3)=[O:33])[CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc(-c4ccccc4)[nH]n3)cc2)C1
Temperature: 60 °C
Reaction time: 16.5 h
Yield: 74.5 %

Procedure:
In a 25 mL round-bottomed flask, (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 359 μmol, Eq: 1.00), 3-phenyl-1H-pyrazole-5-carboxylic acid (87.9 mg, 467 μmol, Eq: 1.3) (CAS-1134-49-2), N-Methylmorpholine (109 mg, 118 μl, 1.08 mmol, Eq: 3) and HBTU (204 mg, 539 μmol, Eq: 1.5) were combined with DMF (3.75 ml). The reaction mixture was stirred at 60° C. for 16.5 hours. The mixture was poured into water (10 ml) and extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography. (6 g silica gel (63-200A), eluent: heptane/EtOAc 2:1) to give the title compound as a white solid (120 mg, 74.5%). MS (ISP): 449.5 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH:10]([C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:8])=[CH:18][CH:19]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(=O)NCC(=O)c2ccco2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(OC)cc1)C(=O)c1ccco1
Yield: 73 %

Procedure:
11.0 g of N-(4-methoxybenzoyl)-(2-furylcarbonyl)methylamine, 2.0 g of 61% sodium hydride and 7.8 g of ethyl bromoacetate are treated in the same manner ad described in Preparation 1-(2). 10.7 g of ethyl 3-(4-methoxybenzoylamino)-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 72.8%
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:3]1(/[CH:2]=[CH:1]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Product: C(=C/c1ccccc1)\c1ccccc1
Yield: 94 %

Procedure:
Reaction of styrene with Grubbs' second generation catalyst for 19 hours gave the title compound in 94% yield. The 1H and 13C NMR spectra agreed with those reported in the literature. 1H NMR (CDCl3): 7.11 (s, 2H), 7.25 (tt, 2H, J=7.2, 1.2 Hz), 7.34 (m, 4H), 7.50 (m, 413C NMR (CDCl3): 126.51, 127.62, 128.65, 128.68, 137.28.
Reaction SMILES: Cl.C(O)(=O)C.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([F:24])[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([O:29]CC)=[O:28])=[CH:14]2)[C:10]([CH3:32])=[CH:9][C:8]=1[F:33]>O>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([F:24])[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:32])=[CH:9][C:8]=1[F:33]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2C)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To 800 mg of the mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 160 mg of ethyl 1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 30 minutes. After adding 0.5 ml of distilled water, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 145 mg of the title compound as a pale brown powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH2:4][OH:5].[CH3:19][P:20](Cl)(Cl)=[O:21]>C(Cl)Cl.O>[CH3:19][P:20]1(=[O:21])[O:5][CH2:4][CH:3]([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:8][CH:7]=2)[CH2:2][O:1]1
Reactant: CP(=O)(Cl)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(C(CO)CO)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C2COP(C)(=O)OC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-[2-hydroxy-1-(hydroxymethyl)ethyl]benzoate (440 mg, 1.74 mmol) and TEA (510 μl, 3.66 mmol) were taken up in CH2Cl2 (20 mL) and cooled to 0° C. Methylphosphonic dichloride (193 μl, 2.09 mmol) in CH2Cl2 (10 mL) was added dropwise over 30 minutes. The reaction was then allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) allowed separation of residual starting material from the diastereomeric products, but the diastereomers coeluted. Flash chromatography of the mixed diastereomers with 25-100% EtOAc/hexanes slowly eluted the first diastereomer, and the same column was flushed with 2-10% MeOH/CH2Cl2 to push off the second diastereomer (both were obtained as colorless solids). 1H NMR (CDCl3, 600 MHz) Diastereomer 1: δ 7.95 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 4.70-4.65 (m, 2H), 4.24-4.17 (m, 2H), 3.54-3.47 (m, 1H), 1.63 (d, J=18.0 Hz, 3H), 1.56 (s, 9H). Diastereomer 2: δ 7.97 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 4.66-4.59 (m, 2H), 4.36-4.30 (m, 2H), 3.50-3.45 (m, 1H), 1.62 (d, J=17-3 Hz, 3H), 1.57 (s, 9H). MS: cal'd 313 (MH+), exp 313 (MH+).
Reaction SMILES: Br.C[N+:3]1(CC2CC2)[C@@H:13]2[CH2:14][C:15]3[CH:20]=[CH:19]C(O)=C4O[C@H:7]5[C:8]([CH2:10]C[C@:12]2([OH:23])[C@:6]5([C:16]=34)[CH2:5][CH2:4]1)=O.[Br-].C1C2C[C@H]3N(CC4CC4)CC[C@]45[C@H](C(CC[C@@]34O)=O)[O:47]C(C=25)=C(O)C=1>>[NH2:3][C@H:13]([C:12]([OH:23])=[O:47])[CH2:14][C:15]1[CH:16]=[C:6]2[C:7]([CH:8]=[CH:10][CH:4]=[CH:5]2)=[CH:19][CH:20]=1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: C[N+]1(CC2CC2)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: Br
Agent: [Br-]
Product: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O

Procedure:
The entry for Example 4 in Table 3 represents the effect of the addition of acid (0.1 equiv. HBr). Incorporation of this reagent increased the yield of the product (naltrexone methobromide) to about 77.5% and decreased the side products to about 5.1%. Addition of HBr suppresses the ionization of the C(3) hydroxide (phenolic hydroxide) of naltrexone to form Nal (see Scheme 4) and thereby reduces the chemical reactivity of the C(3) hydroxide toward MeBr. Further, addition of a strong anhydrous acid (HBr) to the reaction system permits use of partially hydrated naltrexone (Naltrexone.2H2O) as a starting material instead of anhydrous naltrexone thereby eliminating the processing costs associated with dehydration of naltrexone. Since an additional reaction step is required to prepare anhydrous naltrexone from the hydrate (Naltrexone.2H2O), addition of HBr would reduce processing costs.