Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=C(C)[CH:8]=[CH:9][CH:10]=1.Br.O=O.OO.[C:25]([OH:28])(=[O:27])[CH3:26]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:26]([CH:8]=[CH:9][CH:10]=1)[C:25]([OH:28])=[O:27]
Reactant: Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
Into a three liter flask is added 1.3 liters of acetic acid, 614 g. (1.90 mole) of 88.8% pure 3-(2-chloro-4-trifluoromethylphenoxy)toluene, and 32.0 g. (0.128 mole) of cobalt acetate tetrahydrate. To this stirred pink solution is added 20.0 ml (0.173 mole) of 47% aqueous hydrogen bromide whereupon the solution turns blue. The solution is then heated to 90° C. and a flow of oxygen (100%, 2.19×10-2 mole/min) is initiated. Hydrogen peroxide 10.0 ml (30%, 0.088 mole) is then added via a syringe to the solution and the exotherm raises the reaction temperature to 98° C. within 5 minutes. The reaction is monitored by thin layer chromatography and is complete within 4 hours. Isolation of the oxidation product 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid from the reaction mixture is accomplished by distillation of the acetic acid solvent, neutralization with aqueous sodium hydroxide to a pH of 11, filtration to remove the insoluble cobalt hydroxides and acidification of the filtrate with sulfuric acid to precipitate the product, which is filtered and dried to give 680.3 g of 85.1% 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid. This represents of 96.1% yield of this product based on the 3-(2-chloro-4-trifluoromethylphenoxy)toluene starting material.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1CCCCC1>[CH2:8]([S:15][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)O
Reactant: SCc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(CC(=O)O)SCc1ccccc1
Yield: 99 %

Procedure:
A solution of 3,3-dimethylacrylic acid (7 g, 70 mmol) and benzyl mercaptan (8.9 mL, 7.5 mmol) in piperidine (70 mL) was heated to reflux for 2 days. Piperidine was then evaporated and the product was partitioned between EtOAc and an aqueous solution of 1N HCl. The organic phases were washed with brine and dried over MgSO4. After evaporation of the solvent the product was distilled with a Kugelrohr apparatus under high vacuum (1 mmHg) to give 15.5 g with 99% yield.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH:30][CH2:31][CH2:32][CH3:33])[CH3:29]>C(#N)C>[CH2:28]([N:30]([CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:22]([Cl:23])[C:16]=2[O:15][CH2:14]1)[CH2:31][CH2:32][CH3:33])[CH3:29]
Reactant: CCCNCC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCN(CC)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-ethylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 347 (M+, 0.2), 101 (7), 100 (bp), 98 (5), 72 (8), 58 (9).
Reaction SMILES: [F:1]C1C=CC(C(=O)CN(CC2C=CC=CC=2)CC2C=CC=CC=2)=CC=1S(N)(=O)=O.C1(CCC(=O)C)C=CC=CC=1.[ClH:41].[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH:49]([OH:62])[CH2:50][NH:51][CH:52]([CH3:61])[CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:45][C:44]=1[S:63]([NH2:66])(=[O:65])=[O:64]>>[ClH:41].[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH:49]([OH:62])[CH2:50][NH:51][CH:52]([CH3:61])[CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([F:1])=[CH:57][CH:56]=2)=[CH:45][C:44]=1[S:63]([NH2:66])(=[O:65])=[O:64]
Reactant: NS(=O)(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1F
Reactant: CC(CCc1ccccc1)NCC(O)c1ccc(F)c(S(N)(=O)=O)c1
Agent: CC(=O)CCc1ccccc1
Agent: Cl
Product: CC(CCc1ccc(F)cc1)NCC(O)c1ccc(F)c(S(N)(=O)=O)c1

Procedure:
In a similar manner 2-fluoro-5-[[bis(phenylmethyl)amino] acetyl]-benzenesulphonamide (2.5 g) and 4-phenyl-butan-2-one (5 g) were converted into 2-fluoro-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulphonamide, hydrochloride, 0.4 g, m.p. BO°-95°.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30]O[CH2:28][CH2:27]1>C(C1C=CC([Mg]Br)=CC=1)(C)C>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:26]3[CH:30]=[CH:10][C:9]([CH:14]([CH3:15])[CH3:13])=[CH:28][CH:27]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)c1ccc([Mg]Br)cc1
Product: CC(C)c1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 4-iso-propylphenylmagnesium bromide. Yield: 52 mg of a white solid. LC-MSD, m/z for C25H21N2O2 [M+H]+=461.0, 463.0; HPLC retention time: 2.7 min.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:22]=[CH:21][C:5]3[N:6]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: Brc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(-c2ccc3c(c2)nc(-c2ccccc2)n3-c2ccccc2)cc1
Yield: 83.9 %

Procedure:
2.5 g (7.2 mmol) of 5-bromo-1,2-diphenyl-1H-benzimidazole, 1.2 g (7.9 mmol) of 4-chlorophenylboronic acid, and 0.17 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the resultant had been stood to cool, an aqueous layer was removed and an organic layer was dried with magnesium sulfate. After the solvent had been distilled off under reduced pressure, the resultant solid was purified by means of silica gel column chromatography to obtain 2.3 g of 5-(4-chlorophenyl)-1,2-diphenyl-1H-benzimidazole (83% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:10]Br>C(O)(=O)C>[Br:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: c1ccc2sccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1csc2ccccc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
Benzothiophene (2.68 g, 20.0 mmol) was dissolved in glacial acetic acid (100 mL) and cooled to 0° C. The resulting solution was treated by dropwise addition of bromine (1.08 mL, 21.0 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The crude mixture was concentrated to an oil. The residue was purified by silica gel chromatography eluting with hexane to obtain 4.02 g (94%) 3-bromobenzothiophene.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].CCCCCC>COC(C)(C)C.O1CCCC1>[CH3:2][O:3][CH:4]=[C:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC=C1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
10.4 g of methoxymethyl-triphenylphosphonium chloride were suspended in 60 ml of t-butyl methyl ether while gassing with argon in a sulphonation flask equipped with a thermometer, a mechanical stirrer, a dropping funnel and a solid substance addition tube and the suspension was treated with 3.6 g of solid potassium t-butylate at -10° C. within 10 minutes. After completion of the addition the mixture was stirred for a further 30 minutes at -10° C. to 0° C. and then the deep orange, heterogeneous reaction mixture was treated dropwise at 0° C. with a solution of 4.2 g of 4-(p-cyanophenyl)cyclohexanone in 50 ml of absolute tetrahydrofuran. The reaction mixture was subsequently stirred for a further 2 hours at room temperature, then poured into 500 ml of hexane and filtered. Low-pressure chromatography (0.5 bar) of the concentrated residue (7.1 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 4.5 g (94%) of p-[4-(methoxymethylene)cyclohexyl]benzonitrile as a colourless oil; purity 95%, Rf-value (ethyl acetate/petroleum ether vol. 1:9) 0.30.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[C:26]([OH:31])(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[C:26]([O:31][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:30])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)C(=O)O
Reactant: ON=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(C)C(=O)OC1(N=O)CCCCC1

Procedure:
1-Nitrosocyclohexyl isobutyrate was prepared from cyclohexanone oxime, lead tetraacetate and isobutyric acid using conditions of General Method 3. 1H NMR (400 MHz, chloroform-d) δ 2.68-2.79 (1H, sept, 7.0 Hz), 1.71-1.93 (8H, m), 1.48-1.62 (2H, m), 1.29 (3H, s), 1.27 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:31]=3[Cl:30])[CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CC1CC(Oc2cccc(N)c2)CCN1C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 100 %

Procedure:
Combine 4-(3-amino-phenoxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (preparation 35, 0.40 g, 1.31 mmol), 1,4-dioxane (20 mL), triethylamine (0.22 mL, 1.57 mmol) and 2-chloro-4-fluoro-benzoyl chloride (0.30 g, 1.57 mmol) with stirring. After 4 hr., partition between 4:1 hexane:ethyl acetate (100 mL) and 0.5M aqueous sodium hydroxide solution (100 mL). Separate the organic layer, dry over sodium sulfate, filter and concentrate to obtain of the title compound (0.60 g, 100%): 1H NMR (CDCl3): 7.9 (bs, 1H), 7.8 (dd, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 7.2 (dd, 1H), 7.1 (m, 1H), 7.0 (dd, 1H), 6.7 (dd, 1H), 4.7 (m, 1H), 4.35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.45 (s, 9H), 1.3 (d, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:40])([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35]C(C)C)=[CH:31][CH:30]=2)([CH3:28])[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)C(C)C.C(OC(=O)C(C)(C1C=CC(C)=CC=1)CCCCC(=O)CCCCC(C)(C1C=CC(C)=CC=1)C(OCC)=O)C.[OH-].[K+]>O.C(O)C>[CH3:28][C:24]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)([CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:39])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]([CH3:40])([C:8]1[CH:7]=[CH:6][C:5]([CH3:1])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13])[C:25]([OH:27])=[O:26]
Reactant: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccc(C)cc1)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(C)cc2)C(=O)O)cc1
Yield: 39 %

Procedure:
According to the procedure given for 210f, 209e (9.0 g, 17.2 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in water (10 mL) and ethanol (30 mL) at reflux for 6 h. After the usual extractive workup, the crude material was purified by flash chromatography (silica gel; ethyl acetate/hexanes=1/10, 1/6, 1/2) to give 210e (3.1 g, 39%) as a white solid. Mp 48-50° C. 1H NMR (CDCl3): δ 10.8-8.8 (br., 2H), 7.22 (d, 4H, J=8.1), 7.12 (d, 4H, J=8.1), 2.36 (t, 4H, J=7.5), 2.31 (s, 6H), 1.98-1.80 (m, 4H), 1.56-1.44 (m, 4H), 1.51 (s, 6H), 1.24-1.15 (m, 4H). 13C NMR (CDCl3): δ 211.63, 183.07, 140.40, 137.00, 129.58, 126.43, 50.02, 42.82, 39.10, 24.74, 24.50, 22.82, 21.39. HRMS (LSIMS, gly): Calcd for C29H39O5 (MH+): 467.2797, found: 467.2785. HPLC: 92.4% pure. Anal. (C29H38O5) C, H.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH2:14])[CH:11]=2)[CH2:6][CH2:5]1.[CH3:15][CH2:16][N:17](CC)CC>CCO>[NH2:14][CH2:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][CH:4]2[NH:3][C:16](=[NH:17])[CH3:15])=[CH:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: NCc1ccc2c(c1)C(N)CC2
Agent: Cl
Solvent: CCO
Product: CC(=N)NC1CCc2ccc(CN)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
6-Cyanoindan-1-one (prepared using the procedure of Allinger and Jones, JOC 1962, p70. vol 27 for the tetralone analogue) (3.86 g, 24.5 mmol) was converted to the 1-oxime-O-benzyl ether and reduced with BH3 -THF by the methods described in example 59 to give 1-amino-6-(aminomethyl)indane. The diamine was isolated in 31% yield as the 2 HCl salt by treatment of an ether solution with 4.0N HCl in dioxane. 1-Amino-6-aminomethylindane 2HCl (0.5 g, 2.1 mmol) was stirred in EtOH (20 ml), cooled to 0° C. and treated with NEt3 (0.59 ml, 4.2 mmol). Intermediate A (0.43 g, 2.1 mmol) was added and the mixture was allowed to warm to 20° C. and stir overnight. The white crystaline product was collected and washed with a small volume of ether and dried in vacuo to give N-(6-(Aminomethyl)-1-indanyl)acetamidine (0.27 g, 35%) as the 2 HCl salt. NMR (D2 0) 7.45-7.25 (m, 3H), 4.8 (m, 1H), 4.45 (s, 2H), 3.2-2.85 (m, 2H), 2.6)m, 1H), 2.2 (s, 3H, CH3), 2.1 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=1[O:20][CH3:21].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[N:1]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[O:20][CH3:21])[NH:10][C:3]=2[CH:4]=1
Reactant: COc1cc(C#N)ccc1C(=O)Nc1cc(Cl)c(Cl)cc1N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1cc(C#N)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Yield: 73.1 %

Procedure:
A suspension of N-(2-amino-4,5-dichlorophenyl)-2-methoxy-4-cyanobenzamide (2.9 g, 8.6 mmol) and P2O5 (2.9 g, 10 mmol) in xylene (48 ml) was refluxed for 24 h. Additional P2O5 (2.9 g, 10 mmol) was added and the mixture was refluxed for 42 h. Solvent was removed under reduced pressure. The residue was treated with 2N NaOH (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2 g of the title compound (yield 73%), mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:18](=[O:19])[N:17]3[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:18](=[O:19])[N:17]3[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[CH:11]2[OH:20])=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(N2C(=O)C3CCCCN3C2=O)c(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N2C(=O)N3CCCCC3C2O)c(F)cc1Cl
Temperature: 30 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
31.3 g (0.10 mol) of 8-(4-chloro-2-fluoro-5-methoxyphenyl)-7,9-dioxo-1,8-diazabicyclo[4.3.0]nonane were dissolved in 200 ml of methanol. 5.7 g (0.15 mol) of sodium borohydride were added in portions at a rate such that the temperature was kept at 30°-40° C. When the addition was complete, the mixture was stirred for a further 1 hour at 30° C. and poured into 500 ml of water. The precipitate which deposited was filtered off under suction and dried. 29.8 g (94% of theory) of 8-(4-chloro-2-fluoro-5-methoxyphenyl)-7-hydroxy-9-oxo-1,8-diazabicyclo[4.3.0]nonane were obtained in the form of colorless crystals having the melting point 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2cc(Cl)c3ccc(OC)cc3n2)cc1

Procedure:
The title compound, m. p. 99-101° C., MS: m/e=299 (M+), was prepared from 4-chloro-7-methoxy-quinoline and 4-bromoanisole.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH2:17][CH2:18]Br>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:18][CH2:17][O:16][CH3:15]
Reactant: Oc1ccccc1I
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccccc1I

Procedure:
To a mixture of 2-iodophenol (5.00 g, 22.7 mmol) and potassium carbonate (4.71 g, 34.1 mmol) in ACN (7 ml) was added 2-bromoethyl methyl ether (3.79 g, 27.3 mmol).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(=O)=O.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]2[S:38][C:37]3[N:39]4[C:30](=[CH:31][N:32]=[C:33]4[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)=[O:27])[CH2:21][CH2:20]1.C(N(CC)CC)C.[I-].[Na+].N12CCCNC1CCCC=C2>C(#N)C>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26]([C:28]3[S:38][C:37]4[N:39]5[C:30](=[CH:31][N:32]=[C:33]5[CH:34]=[CH:35][CH:36]=4)[CH:29]=3)=[O:27])[CH2:23][CH2:24]2)=[CH:14][CH:13]=1)#[N:16]
Reactant: CS(=O)(=O)OCCCc1ccc(C#N)cc1
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: C1=CN2CCCNC2CCC1
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(CCCN2CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC2)cc1
Yield: 62.8 %

Procedure:
3-(4-Cyanophenyl)propyl methanesulfonate (307 mg, 1.28 mmol) was added to a stirred solution of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (400 mg, 1.07 mmol), triethylamine (539 mg, 5.33 mmol), sodium iodide (192 mg, 1.28 mmol) and 1,8-diazabicyclo[5.4.0]undecene (326 mg, 2.14 mmol) in acetonitrile (20 ml) at room temperature. After refluxing under nitrogen for 14 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (20 g) with Ethyl acetate-Methanol (2:1) to give N-[1-[3-(4-cyanophenyl)propan-1-yl]piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple oil (298 mg, 63%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7](=[O:11])[O:8][C:9](=[O:10])[C:2]=12.[C:12]1([C:18]2[N:19]=[C:20]3[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]3[CH:27]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:12]1([C:18]2[N:19]=[C:20]3[N:25]=[C:24]([NH:26][C:7]([C:3]4[C:2]([C:9]([OH:8])=[O:10])=[N:1][CH:6]=[CH:5][N:4]=4)=[O:11])[CH:23]=[CH:22][N:21]3[CH:27]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1OC(=O)c2nccnc21
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)c1nccnc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 78 °C
Yield: 46.3 %

Procedure:
Furo[3,4-b]pyrazine-5,7-dione (736 mg, 4.9 mmol) and DMAP (58 mg, cat.) were added to a solution of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 1.00 g, 4.8 mmol) in DMF (25 ml). The mixture was heated to 78° C. overnight, and cooled to RT. The formed precipitate was collected by filtration, and residual solvent was removed under vacuum. The thus obtained crude product (800 mg, 47%) was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[N:29]=[C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])[N:27]=1>C(Cl)Cl>[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[OH:43])[N:27]=2)[CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of triethylamine (507 μL, 3.64 mmol) and benzyl((R)-pyrrolidin-3-yl)methylcarbamate (0.47 g, 2 mmol) in CH2Cl2 was added dropwise to a solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (0.5 g, 1.82 mmol) in CH2Cl2 (20 mL). The reaction was stirred at room temperature for 3 h. After quenching the reaction with water, the aqueous phase was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 5-10% EtOAc in CH2Cl2 yielded benzyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate. LC/MS: m/z 473.1 (M+H)+ at 2.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C(C)C)cc2)c1

Procedure:
A solution of 100 mg (0.341 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone, 44.6 μl (0.375 mmol) benzyl bromide and 32 μl (0.375 mmol) N-ethyl-diisopropylamine in 2 ml dioxane is heated at 100° for 90 h. The reaction mixture is concentrated and the residue taken up in 0.1 M sodium hydroxide solution and extracted with dichloromethane. Preparative HPLC affords (2-benzylamino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone.