Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[CH2:10]([C:12]1[N:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:14]=[C:15]2[C:24]=1[C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:17][C:16]2=O)[CH3:11].[Cl:32]CCl>C(#N)C>[Cl:32][C:16]1[C:15]2=[N:14][N:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]([CH2:10][CH3:11])=[C:24]2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: ClCCl
Reactant: CCc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCc1c2c(nn1-c1ccccc1)c(Cl)nc1ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Thionyl chloride (4 mL) and DMF (4 mL) were combined and added dropwise to a mixture of 1-ethyl-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (1.29 g, 4.40 mmol) and dichloromethane (80 mL) at 0° C. The resulting suspension was stirred 5 minutes at 0° C. before warming to ambient temperature and stirring 50 minutes. The suspension was concentrated under reduced pressure to afford an oily solid that was stirred in acetonitrile and filtered to obtain 450 mg of 4-chloro-1-ethyl-2-phenyl-2H-pyrazolo[3,4-c]quinoline as white crystals, mp 207-209° C. MS (APCI) m/z 308 (M+H)+; Anal. calcd for C18H14ClN3: C, 70.24; H, 4.58; N, 13.65. Found: C, 69.94; H, 4.48; N, 13.54
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>>[OH:14][C@@H:13]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COP([O-])OC
Agent: Cl
Product: COc1ccc([C@@H](O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes at room temperature, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, p-methoxybenzaldehyde (0.40 mmol) was added thereto. After reacting for 115 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-methoxyphenyl)methylphosphonate as a final product in a yield of 88%. The chemical reaction in this Example is shown in chemical formula 30.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14](O)=[O:15])([CH3:10])[CH3:9].[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14]([NH:25][NH:26][C:27](=[S:28])[NH2:29])=[O:15])([CH3:10])[CH3:9]
Reactant: NNC(N)=S
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)NNC(N)=S)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Oxalyl chloride (11.5 g, 0.091 mole) is added dropwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid (15.0 g, 0.059 mole) in methylene chloride (120 ml) and N,N-dimethylformamide (0.5 ml). After one hour, the solvent is removed in vacuo. The residue is dissolved in tetrahydrofuran (70 ml) and added dropwise to a stirred 0° C. suspension of thiosemicarbazide (10.9 g, 0.120 mole) in tetrahydrofuran (300 ml). After the addition is complete the mixture is allowed to warm to room temperature and stir 18 hours. The mixture is concentrated in vacuo and the residue filtered through a plug of flash silica gel using a 1:1 ethyl acetate/heptane mixture as eluent. Concentration and trituration with 1:1 isopropyl ether/hexane yielded 17.6 g (19.4 g theor., 91%) of 2-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazinecarbothioamide, mp 210°-211° C.
Reaction SMILES: [CH2:1]([NH2:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])=[CH:26][C:19]=1[O:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O-:17])=[O:16]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([NH:7][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])[CH:28]=[CH:29][C:18]=1[N+:15]([O-:17])=[O:16])[CH3:25])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: NCC1CCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCC1CCCO1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Tetrahydrofurfurylamine (1.5 grams; 0.015 mole), methylene chloride (50 ml) and triethylamine (5 ml) were charged into a glass reaction vessel equipped with a stirrer, thermometer and addition funnel. The reaction mixture was cooled to -10° C. and 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (4.3 grams) dissolved in methylene chloride (50 ml) was added dropwise with stirring. After the addition was completed stirring was continued for a period of about one hour. After this time the reaction mixture was transferred into a separatory funnel and was washed with water (300 ml) and with dilute aqueous sodium bicarbonate (100 ml). The washed solution was then dried by passing it through phase separation paper and was stripped of solvent in a rotary evaporator under aspirator pressure leaving a dark brown-orange oil as the residue. The residue was then dissolved in toluene (6 ml) and charged onto 150 cc of clay for chromatography. The product was then eluted using ethyl acetate-hexane mixtures with increasing concentrations of ethyl acetate. Twelve fractions were collected. Fractions 5 and 6 were combined and stripped of solvents to yield the desired product N-tetrahydrofurfuryl-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as an orange solid melting at 102° to 104° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:9][CH:7]([OH:8])[C@@H:6]1[N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(=[O:3])[CH3:2].[Cl:32][C:33]([Cl:37])([Cl:36])[C:34]#[N:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:32][C:33]([Cl:37])([Cl:36])[C:34](=[NH:35])[O:8][C@@H:7]1[O:9][C@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]1[N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC(=N)C(Cl)(Cl)Cl)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 36 (4.0 g, 6.98 mmol) and trichloroacetonitril (4.2 ml, 14.88 mmol) in CH2Cl2 (25 ml) 18 g of finely powdered dry K2CO3 are added. After stirring for 60 min at RT the mixture is filtered through Celite®. Chromatography (silica gel, 500 g, hexane/ethyl acetate=2:1) gives 37 (β-anomer).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=1)[C:14]([NH:16][CH2:17][C:18]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15].Br[CH2:29][C:30]([NH2:32])=[O:31]>CS(C)=O.O>[C:30]([CH2:29][N:7]1[C:6](=[O:8])[CH:5]=[N:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=2)[C:14]([NH:16][CH2:17][C:18]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])[C:2]1=[O:1])(=[O:31])[NH2:32]
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Reactant: NC(=O)CBr
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-n2ncc(=O)n(CC(N)=O)c2=O)cc1C(=O)NCC1(O)CCCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide (200.0 mg, 0.537 mmol) and Cs2CO, (290.3 mg, 0.891 mmol) were stirred in DMSO (1.79 mL, 0.3 M) at ambient temperature for 15 minutes. 2-Bromoacetamide (74.1 mg, 0.537 mmol) was added and the reaction stirred at ambient temperature for 14 hours. The reaction was diluted with water (15-fold) and the aqueous extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate, and concentrated in vacuo to a tan oil. The crude was triturated from IPE/Et2O/CH2Cl2 to give the title compound as a tan solid (105 mg). LCMS (m/z) 430.5 M+1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:3]=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1>>[OH:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:43])([F:31])[F:44])=[CH:38][CH:37]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Product: CC(C)(CO)n1cc(C(=O)c2cc(NC(=O)Cc3ccc(C(F)(F)F)cc3)ccn2)c2cnccc21

Procedure:
Prepared according to Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and 4-trifluoromethylphenylacetic acid at 70° C. The residue was purified over neutral alumina eluting with 50% EtOAc in hexane followed by acid deprotection using 10% HCl in dioxane at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[N:20]1.CCN(CC)CC>CC#N.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([NH:25][CH2:24][C:21]3[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=3)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Cn1ccc(CN)n1
Reactant: Clc1nc2ccnc(Cl)c2c2cc(Br)ccc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1ccc(CNc2nc3ccnc(Cl)c3c3cc(Br)ccc23)n1
Temperature: 120 °C

Procedure:
To a solution of 9-bromo-1,6-dichloro-benzo[c][1,6]naphthyridine (0.10 g, 0.31 mMol) in anhydrous CH3CN (4.0 mL) was added C-(1-methyl-1H-pyrazol-3-yl)-methylamine (0.040 g 0.36 mMol) and anhydrous Et3N (0.22 mL, 1.6 mMol). The reaction mixture was heated in a sealed tube at 120° C. After 3 hours the solvent was removed and the solid obtained was re-dissolved in EtOAc (10 mL). The EtOAc layer was washed with water (2×5 mL), brine (1×10 mL), and dried over MgSO4. The filtrate was concentrated and the resulting residue was purified using preparative HPLC to afford 9-bromo-1-chloro-N-[(1-methyl-1H-pyrazol-3-yl)methyl]benzo[c]-1,6-naphthyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) 11.34 (br d, 1H), 10.11 (d, 1H), 8.61 (t, 1H), 8.32 (d, 1H), 7.75-7.73 (dd, 1H), 7.55 (d, 1H), 7.37 (t, 1H), 6.40 (d, 1H), 6.18 (d, 1H), 4.74 (d, 2H), 3.77 (s, 3H). LRMS calculated for C17H14BrClN5 [M+H]+, 404.0; found 403.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5](=[O:12])[C:6]2=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a stirred solution of 5-fluoroisatin (6.00 g, 36.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.60 g, 40.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h followed by the addition of bromodiphenylmethane (10.0 g, 38.0 mmol). The mixture was stirred at 60° C. for 7 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness, the residue was recrystallized from ethyl acetate and hexanes to give 1-(diphenylmethyl)-5-fluoro-1H-indole-2,3-dione (6.30 g, 52%): 1H NMR (300 MHz, CDCl3) δ7.39-7.27 (m, 11H), 7.04-6.97 (m, 2H), 6.46-6.42 (m, 1H); MS (ES+) m/z 354.2 (M+23).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
2,4-Dichloro-5,6-dimethyl-3-nitropyridine (135.0 g, 0.488 mol) and ethyl 4-aminobutyrate hydrochloride (114.0 g, 0.683 mol) were triturated in N,N-dimethylformamide (675 mL) (DMF) at 0° C. Triethylamine (272.6 mL, 1.95 mol) was added to generate a brown slurry. After 15 minutes, the reaction mixture was allowed to warm to ambient temperature and the reaction was stirred overnight. Analysis by 1H NMR indicated the reaction was incomplete. An additional amount of triethylamine (102.2 mL, 0.73 mol) and ethyl 4-aminobutyrate hydrochloride (35.28 g, 0.159 mol) in DMF (200 mL) were added to the reaction mixture and allowed to stir over an additional 24 hours. Half of the reaction mixture was added to separate flasks and deionized water (3 L) was added to each flask and were stirred for 1 hour. The resulting precipitate in each flask was harvested by filtration and dried under reduced pressure. The crude product was recrystallized from ethyl acetate and filtered to yield 86.20 g of ethyl 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butyrate as a yellow granular solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[CH:4][CH:3]=[N:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:5]3[O:1][N:2]=[CH:3][CH:4]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1cccc(-c2ccno2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccno2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(isoxazol-5-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(isoxazol-5-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 56%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24].Cl>ClCCCl>[CH3:24][O:23][C:17]1[C:16]([O:15][CH3:14])=[CH:21][C:20]([C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:12])=[C:19]([F:22])[CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(F)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(F)c(C(=O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
12.7 g (95 mmol) of aluminium trichloride in 80 ml of 1,2-dichloroethane are stirred under nitrogen and cooled to 3°. 13.35 g (95 mmol) of benzoyl chloride are added. At 3°, this red solution is added dropwise over a period of 25 minutes to a solution of 12.55 g (80.3 mmol) of 1,2-dimethoxy-4-fluorobenzene (4-fluoroveratrole) in 80 ml of 1,2-dichloroethane. The reaction mixture is stirred for a further 3 hours at 3°, then for 31/2 hours at room temperature and then poured onto a mixture of 250 ml of ice and 20 ml of concentrated hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted several times with ether. Organic phase and ether solutions are combined, washed with 1 N sodium hydroxide solution, water and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The resulting yellow oil is stirred with 50 ml of ether in an ice bath until crystallisation takes place, yielding the desired (4,5-dimethoxy-2-fluorophenyl)-phenylmethanone in the form of white crystals having a melting point of 102°-103°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13](OC=C)(=O)[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir]>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]=[CH2:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: C=COC(C)=O
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1=CCCC=CCC1
Product: C=COc1ccc(C(=O)OC)cc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
To a solution of methyl 3-bromo-4-hydroxy-benzoate (1.00 g, 4.33 mmol, 1.00 eq) in toluene (15.00 mL) were added vinyl acetate (745.54 mg, 8.66 mmol, 2.00 eq), Chloro(1,5-cyclooctadiene)iridium(I) dimer (29.08 mg, 43.30 umol, 0.01 eq) and Na2CO3 (229.47 mg, 2.17 mmol, 0.50 eq). The mixture was stirred at 100° C. for 16 hr under N2 protection. TLC detected the reaction was complete, the solvent was evaporated, the residue was purified by chromatography (silica gel, eluting with PE:EA=10:1) to afford product methyl 3-bromo-4-vinyloxy-benzoate (730.00 mg, 2.84 mmol, 65.58% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=1.76 Hz, 1H), 7.99 (dd, J=8.53, 2.01 Hz, 1H), 7.06 (d, J=8.53 Hz, 1H), 6.65 (dd, J=13.80, 6.02 Hz, 1H), 4.98 (dd, J=13.80, 2.01 Hz, 1H), 4.70 (dd, J=5.90, 1.88 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: CC(C)([S@]([NH:6][C@H:7]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:10][CH:9]=1)=O)C.[ClH:28].O1CCOCC1>>[ClH:28].[NH2:6][C@H:7]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](N[S@](=O)C(C)(C)C)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(C)(=O)c1ccc([C@H](N)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Ethyl 4-((R)—((R)-1,1-dimethylethylsulfinamido)(4-fluorophenyl)methyl)phenyl(methyl)phosphinate, 18-d, (7 g, 18 mmol) was dissolved in HCl/dioxane (50 ml) and the mixture was stirred at room temperature for about 3 h. The mixture was then concentrated under vacuum and the residue was washed with ethyl acetate to provide the product, 18-e, (4.4 g, 80%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[NH2:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][CH:44]=[CH:43]2>ClC(Cl)C>[NH:45]1[C:46]2[C:42](=[CH:41][C:40]([NH:39][C:5]3[C:4]4[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([I:1])[CH:3]=4)[N:8]=[CH:7][N:6]=3)=[CH:48][CH:47]=2)[CH:43]=[CH:44]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: COc1cc2nc[nH]c(=O)c2cc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2cc1I
Temperature: 50 °C
Yield: 27.1 %

Procedure:
In a round bottom flask 6-Iodo-7-methoxy-3H-quinazolin-4-one (500 mg, 1.65 mmol), triphenyl phosphine polymer (2.75 gm, 3 mmol/gm) and carbon tetrachloride (2.53 gm, 16.5 mmol) were combined in 3 mL of dichloroethane and heated at reflux for 5 hours. 5-Aminoindole (686 mg, 1.65 mmol) was added to the mixture and heated at 50° C. overnight. Reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel 20% MeOH/1% ammonium hydroxide (NH4OH)/CHCl3 to provide 186 mg (28%) of product as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]1[N:14]=[C:13]([C:15](OC)=[O:16])[C:12]([CH2:19][CH2:20]C(OC)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>O1CCCC1.CO>[CH2:1]([N:8]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:9]1[N:14]=[C:13]2[C:15](=[O:16])[CH2:20][CH2:19][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCc2ccc(N(Cc3ccccc3)Cc3ccccc3)nc21
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a suspension of methyl 6-(dibenzylamino)-3-(3-methoxy-3-oxopropyl)pyridine-2-carboxylate (2.02 g, 4.83 mmol) and 60% sodium hydride (386 mg, 9.65 mmol) in tetrahydrofuran (48 mL) was added methanol (1 drop), and the mixture was heated under reflux for 1.5 hr. The reaction solution was concentrated to dryness, 12M hydrochloric acid (24 mL) was added, and the mixture was stirred at 110° C. for 15 min. The reaction solution was diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate solution, and washed with saturated brine. This was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (1.17 g, yield 74%).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)([O-:5])=[O:4].CS(O[CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:18][CH2:19][CH2:20][CH3:21])(=O)=O.O>CO>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:9]1[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[N:7]=[CH:8]1
Reactant: CCCCC(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(Cn1cnc([N+](=O)[O-])c1)c1ccc(Cl)cc1Cl
Yield: 106.6 %

Procedure:
To 1.3g (0.0307 mole) of sodium hydroxide in 150 ml of methanol is added 3.5g (0.0307 mole) of 4-nitroimidazole, and the solution is heated and the methanol distilled off. To the concentrate is added 100 ml of dimethyl formamide and the solution is heated up to 120° to remove the excess methanol and water. This dimethyl formamide solution is then cooled to less than 90° and 10.0g (of 0.0307 mole) of 2-(2,4-dichlorophenyl)hexyl methane sulfonate is added. The reaction mixture is heated up to 145° for 2 hours and then cooled and poured into water. The organic material is extracted out with ether and after drying, the extract is stripped to give 11.2g of residue. The concentrate is triturated with hexane and then dissolved in 25 ml of methanol. The methanol solution is poured slowly into water and a gummy solid forms. This solid is separated by filtration, dried and recrystallized from acetone-hexane to give 4.2g (41%) of the product, m.p. 67°-69°.