Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25].N1C=CC=CC=1>C(Cl)(=O)C(Cl)=O.C(Cl)Cl>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[O:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:19][CH2:18]3)=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: O=C(O)c1ccc2c(c1)CCC(COCc1ccccc1)O2
Reactant: CC(=O)c1cccc(N)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CCC(COCc2ccccc2)O3)c1O
Temperature: 75 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A suspension of 2-(benzyloxymethyl)-6-chromanecarboxylic acid (0.700 g, 2.35 mmol) in oxalyl chloride (5.98 ml) was heated at 75° C. for 35 minutes. The oxalyl chloride excess was evaporated off in a nitrogen stream and the resulting residue was dissolved in the minimum amount of dry methylene chloride. This solution was added at 0° C. and under inert atmosphere to a solution of 3-amino-2-hydroxyacetophenone (0.550 g, 2.37 mmol), pyridine (7 ml) and dry methylene chloride (40 ml). The resulting mixture was left under stirring at room temperature for 18 h, then diluted with methylene chloride (40 ml), washed successively with 1M HCl and a sodium chloride saturated solution, dried and the solvent was evaporated off under reduced pressure. A crude was obtained which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform mixtures of increasing polarity. At a 40% chloroform proportion, 0.732 g of the title compound were eluted (72% yield).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:24])([F:23])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15](OC)=[O:16])[CH:9]=[CH:10][CH:11]=1>CO>[F:4][C:5]([F:24])([F:23])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([NH:2][NH2:3])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 52 %

Procedure:
Hydrazine hydrate (14 ml) is added dropwise to a solution of methyl 2-[(3-trifluoromethylphenyl)amino]-benzoate (1.463 g, 4.95 mmol) in 70 ml of methanol. The reaction solution is heated at 60° C. under an inert atmosphere for two hours and then concentrated in vacuo and chromatographed, eluting with ethyl acetate and hexane (1:1), providing 763.0 mg (52%) of a white solid, mp 134°-135° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][C:8]=2[CH3:16])=[O:6])[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:19]=[C:20]([NH2:27])[C:21]2[N:25]=[CH:24][NH:23][C:22]=2[CH:26]=1.[N+]1([O-])C=CC=CC=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:27][C:20]1[C:21]2[N:25]=[CH:24][N:23]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[C:8]([CH3:16])[CH:9]=3)[C:22]=2[CH:26]=[C:18]([Br:17])[CH:19]=1
Reactant: Cc1cc(B(O)O)ccc1C(=O)NC1CC1
Reactant: Nc1cc(Br)cc2[nH]cnc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(-n2cnc3c(N)cc(Br)cc32)ccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a stirred solution of [4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic acid (13.95 g, 63.68 mmol) in DCM (160 mL) at rt was added under a nitrogen atmosphere 6-bromo-1H-benzimidazol-4-amine (6.75 g, 31.84 mmol), copper(II)acetate (11.57 g, 63.68 mmol), pyridine N-oxide (3.33 g, 35.02 mmol) and pyridine (7.55 g, 95.53 mmol). After stirring overnight at rt, the mixture was stirred at 40° C. for 3 days. Filtration through ALLOX, extraction with water and evaporation of the organic phase gave the crude product, which was purified by flash chromatography to yield 6 g 4-(4-amino-6-bromo-1H-benzimidazol-1-yl)-N-cyclopropyl-2-methylbenzamide (50%).
Reaction SMILES: [H-].[Na+].[Cl-].[Cl:4][C:5]1[CH:6]=[C:7]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH2:32]1[O:42][C:35]2([CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[O:34][CH2:33]1.O>CS(C)=O>[Cl:11][C:9]1[CH:8]=[C:7]([CH:12]=[C:38]2[CH2:39][CH2:40][C:35]3([O:42][CH2:32][CH2:33][O:34]3)[CH2:36][CH2:37]2)[CH:6]=[C:5]([Cl:4])[CH:10]=1
Reactant: Clc1cc(Cl)cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1cc(Cl)cc(C=C2CCC3(CC2)OCCO3)c1
Temperature: 90 °C
Yield: 32.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 4.2 grams (0.11 mole) of sodium hydride (60% in mineral oil) in 200 mL of anhydrous dimethyl sulfoxide was heated to about 90° C. where it was maintained for 10 minutes. After this time the reaction mixture was cooled to 25° C., and 46.0 grams (0.10 mole) of 3,5-dichlorophenylmethyltriphenylphosphonium chloride was added, followed by 14.0 grams (0.10 mole) of 1,4-cyclohexanedione mono-ethylene ketal. Upon completion of addition the reaction mixture was again warmed to 90° C., then it was allowed to cool to ambient temperature. After this time the reaction mixture was poured into 400 mL of water, and the mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were then washed with two 100 mL portions of water. The organic layer was concentrated under reduced pressure to an oily solid residue. The oily solid was taken up in a solution of 90 mL of petroleum ether and 10 mL of diethyl ether, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using 10% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 9.7 grams of 8-(3,5-dichlorophenylmethylene)-1,4-dioxaspiro[4.5]decane, mp about 66° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17](Br)[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:23][CH:24]([OH:27])[C:25]#[CH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu](I)I.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.C(NCC)C>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:26]#[C:25][CH:24]([OH:27])[CH3:23])[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C#CC(C)O
Reactant: CCCCCCCCCCOc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CCCCCCCCCCOc1ccc2cc(C#CC(C)O)ccc2c1
Yield: 81 %

Procedure:
18.2 g (0.05 mol) of 6-decyloxy-2-bromonaphthalene (VI-59), 10.5 g (0.15 mol) of (+)-3-butyn-2-ol (VII*-59), 0.4 g of copper iodide, 0.7 g of triphenylphosphine, 0.4 g of bis(triphenylphosphine)palladium chloride and 100 ml of diethylamine were stirred under reflux for 12 hours in an atmosphere of nitrogen gas. After completion of the reaction, the reaction mixture was poured into ice/aqueous hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was further washed with water and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene-ethyl acetate as eluent to obtain 14.3 g (yield 81%) of optically active (+)-6-decyloxy-2-(3-hydroxy-1-butynyl)naphthalene (I'-59), mp 74°-75° C. [α]D20 =+16.9° (c=1, chloroform).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][N:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.O.[CH:36]([NH2:39])([CH3:38])[CH3:37]>[Cl-].[Na+].O>[CH:36]([NH:39][C:25]([C:24]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:28]([F:31])([F:29])[F:30])[CH:11]=2)=[O:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)=[O:27])([CH3:38])[CH3:37]
Reactant: CC(C)N
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a suspension of 140 mg (0.28 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5-diaza-phenanthren-4-one in 5.60 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 73 μL (0.85 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane and ethyl acetate as eluants) affords 100 mg (70%) of a white solid; LC/MS: 503/505 (M+H)+, m.p.: 225-226° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:32](OC(=O)C)(=[O:34])[CH3:33]>O.O1CCOCC1>[C:32]([N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:12]3[C:13](=[N:14][CH:15]=[N:16][C:11]=3[NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[NH:17][N:18]=2)[CH2:21][CH2:22]1)(=[O:34])[CH3:33]
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(N4CCNCC4)c23)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1

Procedure:
Analogously to Example 26, 100 mg (0.248 mmol) of 4-(3-chlorophenylamino)-3-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride and 103 mg (0.74 mmol) of potassium carbonate in 10 ml of water are reacted with 38 mg (0.37 mmol) of acetic anhydride in 10 ml of dioxane to form 3-(4-acetyl-piperazin-1-yl)-4-(3-chlorophenylamino)-1H-pyrazolo(3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=10.8; FAB-MS: (M+H)+=372.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[F:8][C:9]1[C:18]([CH2:19][C:20]2[N:24]3[N:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]3=[N:22][N:21]=2)=[C:17]([F:32])[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2>>[F:8][C:9]1[C:18]([CH2:19][C:20]2[N:24]3[N:25]=[C:26](/[C:29](=[N:1]/[N:2]4[CH2:6][CH2:5][O:4][C:3]4=[O:7])/[CH3:30])[CH:27]=[CH:28][C:23]3=[N:22][N:21]=2)=[C:17]([F:32])[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2
Reactant: CC(=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reactant: NN1CCOC1=O
Product: C/C(=N\N1CCOC1=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Yield: 86 %

Procedure:
The title compound was prepared from 3-aminooxazolidin-2-one and 1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone in 86% yield as white solid using the same procedure as described in the synthesis of example 40. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.00 (d, 1H), 8.50 (d, 1H), 8.33 (d, 1H); 7.87 (d, 1H), 7.75 (d, 1H), 7.63 (dd, 1H), 4.81 (s, 2H), 4.49 (t, 2H), 4.05 (t, 2H), 2.33 (s, 3H). LCMS (method A): [MH]+=424, tR=4.54 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1F
Reaction time: 0.05 h
Yield: 88.4 %

Procedure:
To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257°-260° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:36][CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:23][CH2:24][O:8][C:7]3[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[O:11][CH2:37][CH2:36]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCOc3ccc([N+](=O)[O-])cc3OCC2)cc1

Procedure:
To dimethylformamide (200 mL) add 4-nitrocatechol (13.8 g, 89 mmol), 4-methyl-N,N-bis[2-[[(4-methylphenyl)sulfonyl]oxy]ethyl]benzenesulfonamide (50.7 g, 89.4 mmol), and K2CO3 (27 g, 0.19 mol). Stir and heat the reaction at 110° C. Monitor the progress of the reaction by thin-layer chromatography. Upon completion remove the heat and add water (1.3 L) and methanol (300 mL). Collect the precipitate on paper by suction filtration. Wash the solid with water (2 L). Chromatograph the material on silica (300 g) with CH2Cl2 to obtain the title compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[N:15]([CH2:18][CH2:19][OH:20])=[N+:16]=[N-:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:15]([CH2:18][CH2:19][O:20][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NCCO
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCOC(=O)CCC(=O)O
Temperature: 40 °C

Procedure:
Succinic anhydride (23.0 g, 0.230 mol) was added into a three-neck round-bottom flask equipped with a condenser and a dropping funnel. Under nitrogen atmosphere and magnetic stirring, freshly distilled methylene chloride (150 mL), DMAP (2.3 g, 19 mmol) and freshly distilled Et3N (46.46 g, 0.460 mol) was sequentially added. After the flask was immersed into an ice-water bath, 2-azidoethanol (20.0 g, 0.230 mol) was added dropwise into the previous solution. The solution was later heated at 40° C. for 48 h, and the reaction mixture was washed successively with 1 M HCl solution (5×100 mL) and deionized water (2×100 mL). The organic phase was dried over anhydrous MgSO4 overnight. After filtering and removal of methylene chloride under reduced pressure, the final product was obtained as a yellow viscous liquid. The yield was: 38.4 g, 90%. 1H NMR (CDCl3, δ, ppm): 4.20 (t, 2H, N3CH2CH2), 3.42 (t, 2H, N3CH2), and 2.61 (m, 4H, CH2CH2COOH).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:25]1([C:23]([C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)([OH:24])[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][CH2:1][OH:10])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: O=CC=Cc1ccccc1
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCc2ccccc2)cc1

Procedure:
The (RR,SS; RS,SR)-isomer mixture is prepared from 13.2 g of cinnamaldehyde and 28.8 g of 4-benzyloxybenzophenone according to the procedure described in Example 9. Recrystallization is performed from toluene. The yield is 32.5 g (77%) of a product having m.p. 109°-15° C. The product contains both isomer pairs (RR,SS: RS,SR 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.Cl.[Br:24][C:25]1[C:26]([O:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35])=[N:27][C:28](Cl)=[N:29][CH:30]=1>C(#N)C.O1CCOCC1>[Br:24][C:25]1[C:26]([O:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35])=[N:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:20][CH2:21][OH:22])(=[N:10][S:11]([CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])(=[O:12])=[O:13])=[O:9])=[CH:4][CH:3]=2)=[N:29][CH:30]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(CCO)c1ccc(N)cc1
Reactant: C[C@@H](O)[C@@H](C)Oc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: C[C@@H](O)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(CCO)=NS(=O)(=O)CC[Si](C)(C)C)cc2)ncc1Br
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A solution of 205 mg (0.56 mmol) of (RS)—S-(4-aminophenyl)-S-(2-hydroxyethyl)-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide in 2 ml of acetonitrile is mixed with 0.15 ml of a 4N solution of HCl in dioxane. 175 mg (0.62 mmol) of (2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 2 ml of acetonitrile is added, and the batch is stirred for 24 hours at 70° C. Then, it is stirred for another 24 hours at 85° C. The solvent is removed, and the remaining residue is purified by chromatography (DCM/EtOH 9:1). 110 mg (0.18 mmol, corresponding to 32% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH2:76][CH3:77])([CH2:74][CH3:75])[O:72][B:71]([OH:78])[C:70]=2[CH:79]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:64][CH2:65][C:66]5[CH:67]=[CH:68][C:69]6[C:73]([CH2:74][CH3:75])([CH2:76][CH3:77])[O:72][B:71]([OH:78])[C:70]=6[CH:79]=5)=[O:25])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.24 mmol) and DIPEA (151 mg, 1.17 mmol) in DMF (5.0 mL) can be stirred at rt for 5 min and then HATU (180 mg, 0.47 mmol) was added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (63 mg, 0.25 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by column chromatography and prep-HPLC to provide the final title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11]C(OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH2:25])[CH:20]=[CH:21][CH:22]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][NH:25][CH2:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[CH:18]=1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: Cc1cccc(CCN)c1
Solvent: CO
Product: COc1ccc(CNCCc2cccc(C)c2)cc1OC
Yield: 74 %

Procedure:
A solution of methyl 3,4-dimethoxyphenylacetate (18.5 g, 0.088 mole) and 2-(3-methylphenyl) ethylamine was heated at 180° for 1 h. The crude amide was dissolved in 50 ml of methanol and precipitated as fine needles with 150 ml of hexane to give the title compound (20.4 g, 74%). The mother liquor deposited more material which was recrystallized from toluene (charcoal) to give an additional 4.7 g (17%) of amide. The total yield of N-(3,4-dimethoxyphenylacetyl)-2-(3-methylphenyl) ethylamine, mp 101-102°, was 91%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:16]N)[CH:13]=[CH:14][CH:15]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[C:7]3[C:2](=[O:1])[NH:3][CH:4]=[CH:5][C:6]=3[NH:16][C:12]=2[CH:11]=1
Reactant: NNc1cccc(Cl)c1
Reactant: Oc1ccnc(O)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc2[nH]c3cc(Cl)ccc3c12
Temperature: 175 °C
Reaction time: 3 h

Procedure:
To 2,4-dihydroxypyridine (25.0 g, 225 mmol) in phenyl ether (400 mL) in a three neck flask fitted with a Dean-Stark trap was added 3-chlorophenylhydrazine. The reaction mixture was heated to 175° C. for 1 h, and to 230° C. for 3 h. The reaction mixture was allowed to cool to room temperature and diluted with toluene. The mixture was filtered, washed with MeOH, and dried. The collected solids were ground to fine power, slurried in MeOH, and sonicated for 5 min. The slurry was filtered, washed with MeOH, and dried to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.83 (s, 1H); 11.19 (s, 1H); 8.05 (d, 1H); 7.53 (d, 1H); 7.32 (t, 1H); 7.21 (dd, 1H); 6.52 (d, 1H). LRMS (APCI) calc'd for (C11H7ClN2O) [M+H]+, 219.0. found 219.1.
Reaction SMILES: ClCl.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[CH3:4]
Reactant: Sc1ccccc1
Reactant: CCc1ccc(O)cc1
Agent: ClCl
Solvent: ClCCl
Product: CCc1ccc(O)c(Sc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chlorine gas was passed into a stirred, cooled (0° C.) solution of 4-ethylphenol (30.5g) and thiophenol (22g) in dichloromethane (100ml) for 3 hours. The solution was stirred overnight at room temperature the solvent was distilled off on a rotary evaporator and the residual oil was distilled, the product being in the higher boiling fraction (160°-180° C. at about 0.5 cm Hg). This fraction was chromatographed on a silica column, being eluted with hexane progressively enriched with chloroform to give the title compound (12.5g), as a clear liquid, nD23 =1.6130.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[CH:5][C:3]=1[NH2:4].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[CH:5][C:3]=1[N:4]1[C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=2[C:17]1=[O:22]
Reactant: CC1CCCC1Oc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: CC1CCCC1Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 97.8 %

Procedure:
2-Fluoro-4-chloro-5-(2-methylcyclopentyl)oxyaniline (660 mg, 2.71 mmol), 3,4,5,6-tetrahydrophthalic anhydride (503 mg, 3.31 mmol) and acetic acid (10 ml) were charged into a 50 cc round-bottom flask, and heated for 5 hours while refluxing. After completion of the reaction, the reaction solution was cooled to room temperature, and poured into ice-water (100 ml). The mixture was extracted with ethyl acetate (30 ml×3), and the organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, the solvent was distilled off under reduced pressure, and the resulting pale brown oily substance was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=9/1) to obtain N-{2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.65 mmol, 98% yield).