Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.CN(C=O)C.S(Cl)(Cl)=O.C(O[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]1[C:36]([OH:38])=[O:37])=[O:22])(C)(C)C>C1COCC1.CCOC(C)=O.O>[O:37]=[C:36]1[CH:24]2[CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:27][CH2:28][N:23]2[C:21](=[O:22])[O:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC(=O)C2C1
Temperature: 40 °C

Procedure:
Pyridine (1.4 mL, 17 mmol), DMF (0.29 mL, 3.7 mmol), and thionyl chloride (1.1 mL, 15 mmol) were added in succession to a suspension of 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (3.73 g, 11.3 mmol) in THF (20 mL). The reaction mixture was heated to 40° C. for 3 h. The reaction mixture was diluted with EtOAc (50 mL) and H2O (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was suspended in Et2O (10 mL) and cooled to −20° C. for 1 h. The solid was collected by filtration, washed with Et2O (2×10 mL), and air-dried. This gave 1.73 g (60%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-]>C1COCC1>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(F)cc(Br)cc1C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: Nc1c(F)cc(Br)cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2-amino-5-bromo-3-fluorobenzoic acid (14.5 g, 62.2 mmol) in THF (150 mL) at 0° C. was added borohydride in THF (1 M, 310 mL), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with methanol (150 mL), concentrated in vacuum, diluted with aqueous sodium bicarbonate (400 mL) and extracted with ethyl acetate (200 mL*3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (13.0 g, crude), which was directly used in the next step without the further purification. MS (ES+) C7H7BrFNO requires: 219, 221, found: 220, 222 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Mg].[Cl-].[NH4+].Cl>C1COCC1>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:25]4[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH3:19])=[CH:23][CH:24]=4)([OH:17])[CH2:13][CH2:12]3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: BrCCCc1ccccc1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)cc1

Procedure:
A solution of 160 g (0.67 mol) of 4-(1,4-dioxaspiro[4.5]dec-8-yl)cyclohexanone in 600 ml of THF is added to a solution of the Grignard reagent generated from 147 g (0.74 mol) of p-bromopropylbenzene and 18.0 g (0.74 mol) of magnesium turnings (400 ml of THF). When the addition is complete, the mixture is heated under reflux for 1 h, and sat. ammonium chloride soln. is added. The mixture is acidified using dil. hydrochloric acid and extracted a number of times with MTBE. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The crude product obtained after removal of the solvents is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([C:38]([N:16]2[CH2:15][CH2:14][N:13]([C:6]3[C:5]([CH3:19])=[C:4]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH:26]=4)[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[N:7]=3)[CH2:18][CH2:17]2)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=C(Cl)C1CCCC1
Product: Cc1c(N2CCN(C(=O)C3CCCC3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure R using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and cyclopentanecarbonyl chloride to give cyclopentyl(4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)methanone. 1H NMR (DMSO-d6) δ ppm 1.51-1.73 (m, 8H), 2.10 (br s, 3H), 3.00 (m, 1H), 3.00-3.07 (m, 4H), 3.24 (br s, 2H), 3.33 (br s, 4H), 3.65-3.70 (m, 6H), 6.51 (br s, 1H), 7.13-7.19 (m, 1H), 7.27-7.30 (m, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 8.37 (s, 1H). Mass Spectrum (ESI) m/e=537.4 (M+1).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:29][CH:28]3[C:26]([N:30]([CH3:32])[CH3:31])([CH2:27]3)[CH2:25]2)[N:20]=[C:19]([Cl:33])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:33][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH:28]3[C:26]([N:30]([CH3:32])[CH3:31])([CH2:27]3)[CH2:25]2)[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN(C)C12CC1CN(c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C12CC1CN(c1nc(Cl)nc(NN)c1F)C2
Reaction time: 72 h
Yield: 52.8 %

Procedure:
To a solution of racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (1.3231 g, 2.254 mmol) in MeOH (13 mL) was added 4 N HCl in dioxane (13 mL). The solution was stirred for 3 days, and was then concentrated in vacuo. The residue was partitioned between 10% aq. K2CO3 and DCM, and the aqueous phase was extracted with a fresh portion of DCM. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give racemic 3-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.3415 g, 53%) as a brown solid. LCMS: (M+H)+: 287.1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=2[C:17]#[N:18])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2C#N)CC1
Yield: 15 %

Procedure:
Title compound was prepared according to the procedure described in example G from N-Boc-piperazine and 2-Chloro-5-trifluoromethylbenzonitrile (CAS: 328-87-0)(15% yield, yellow oil, MS (m/e): 373.1 (M+NH4+, 100%).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[F:17])[C:4](=O)[CH3:5])[CH3:2]>O1CCCC1>[CH2:4]([N:3]([CH2:1][CH3:2])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[F:17])[CH3:5]
Reactant: CCN(C(C)=O)c1cc(F)c([N+](=O)[O-])cc1F
Solvent: C1CCOC1
Product: CCN(CC)c1cc(F)c([N+](=O)[O-])cc1F
Yield: 92 %

Procedure:
Following procedures similar to those employed in Step E of this Example, the reaction of 4.2 g (0.017 mole) of N-ethyl-N-(2,5-difluoro-4-nitrophenyl)acetamide with 5.1 ml of a 10M borane dimethyl sulfide complex in tetrahydrofuran in 100 ml of dry tetrahydrofuran yielded 3.6 g of N,N-diethyl-2,5-difluoro-4-nitroaniline. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH:37](=O)[CH3:38]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: CC=O
Product: CCN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-1-ethyl-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 381) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[N:6][C:5]=2[N:4]([CH3:25])[C:3]1=[O:26].Br[CH2:28][C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:37][C:33]1[CH:32]=[C:31]([C:30]#[C:29][CH2:28][N:23]2[CH:24]=[C:20]([C:7]3[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:17])[CH3:18])[C:9]4[C:10](=[O:11])[N:2]([CH3:1])[C:3](=[O:26])[N:4]([CH3:25])[C:5]=4[N:6]=3)[CH:21]=[N:22]2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(C)c1=O
Reactant: Fc1cccc(C#CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(F)c4)c3)n2COCC[Si](C)(C)C)n(C)c1=O
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 1,3-dimethyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (obtained following literature procedure U.S. Pat. No. 6,825,349) (0.100 g, 0.27 mmol), 1-(3-Bromo-prop-1-ynyl)-3-fluoro benzene (0.057 g, 0.27 mmol), K2CO3 (0.086 mg, 0.62 mmol) and acetone (5 ml) were refluxed at 80° C. for 5 hrs. The reaction mixture was cooled to room temperature and filtered off solid K2CO3 and evaporated excess of organic solvent under vacuum. The product was purified by column chromatography (2% methanol in dichloromethane) to get pure 8-{1-[3-(3-fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dimethyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.111 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]([CH:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(c1ccccc1)C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(c1ccccc1)C1CCC(O)CC1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
[1-(4-Oxo-cyclohexyl)-1-phenyl-ethyl]-carbamic acid tert-butyl ester (28) from the previous stage (2.7 g) was dissolved in THF (60 mL) and cooled to −70° C. Sodium borohydride was added (356 mg) and the reaction mixture stirred overnight with gradual warming to room temperature. Water was added and the solution extracted with t-butylmethyl ether. The organic phase was washed with brine and dried over sodium sulphate. Evaporation gave 1.24 g of a white foam as crude product. Rt=1.41 min (Method 5). Detected mass: 246.3 (M—C4H8—H2O+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]1(OB(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=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.C1(C)C=CC=CC=1>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Ic1ccc(-c2ccc(I)cc2)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: Cc1ccccc1
Product: Ic1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
The compound was prepared under Suzuki reaction conditions. 4,4′-diiodo-biphenyl (1.0 g, 2.46 mmol), phenyl boric acid (0.24 g, 1.970 mmol), tetrakis(triphenylphosphine)palladium (0.085 g, 0.074 mmol), 2M-sodium carbonate (12.3 ml) and toluene (76 ml) were simultaneously mixed, freezed under liquid nitrogen, evacuated by a vacuum pump and then warmed to room temperature to be melted. This procedure was repeated twice, followed by injection of nitrogen. The mixed solution was refluxed for 2 days and cooled to room temperature. Thereafter, a small amount of distilled water was added, and the organic layer was filtered three times with dichloromethane, dried with sodium sulfate. Then, the dichloromethane was concentrated under reduced pressure. Purification by silica gel chromatography using 1% dichloromethane in hexane gave 4″-iodo-[1,1′;4′,1″]terphenyl (Yield: 0.245 g, 35%). The structure of the product was identified through the NMR spectrum and mass spectrum. FIG. 6 shows the mass spectrum of 4″-iodo-[1,1′;4′,1″]terphenyl.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[PH2](O)=O.[OH2:13]>>[C:7]([O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: O
Agent: O=[PH2]O
Product: O=C(OCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
The reaction was run as described in Example 2 except that the initial excess of 2-phenylethyl alcohol was 10% rather than 20%, and the organic layer that co-distilled with the water of reaction was returned to the batch at the end of each hold but the last one. After 4 h at 18014 210° C., the reaction mixture was cooled to room temperature, where the acid number was 5.50 (97.8% conversion), the APHA color was 114, and the excess 2-phenylethyl alcohol was 4.8% by GLC. A 9.94-g aliquot of 50% w/w aqueous hypophosphorous acid (H PA, 0.40% w/w based on H3PO2) was added. The excess 2-phenylethyl alcohol was removed by vacuum distillation as usual. The APHA color was 39 and the residual 2-phenylethyl alcohol was 0.19% by GLC. Treatment with activated carbon as usual afforded 1100 g (88%) of 2-phenylethyl benzoate. The APHA color was 36, the acid number was 2.10 mg KOH/g, the saponification number was 244 mg KOH/g, the residual tin was 270 ppm, and the residual phosphorous was 1300 ppm.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[S:5](=[O:18])(=[O:17])[N:4]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:3]1.C(OCC)(=O)C.Cl>C1COCC1.CO.O>[CH2:1]=[C:2]1[CH2:7][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[S:5](=[O:17])(=[O:18])[N:4]([CH2:19][C:20]([OH:22])=[O:21])[CH2:3]1
Reactant: C=C1CN(CC(=O)OCC)S(=O)(=O)N(c2c(Cl)cc(Cl)cc2Cl)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CN(CC(=O)O)S(=O)(=O)N(c2c(Cl)cc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ethyl 2-(4-methylene-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetate (305 mg, 0.74 mmol) in THF (10 mL) and MeOH (10 mL), was added LiOH monohydrate (155 mg, 3.69 mmol) in water (3 mL) and agitated for 5 hr at room temperature. After addition of ethyl acetate (30 mL) and water (30 mL), pH of the resultant was adjusted to 3 with 1 N HCl and extracted to the organic layer. The resultant was dried over MgSO4, concentrated under reduced pressure, and crystallized with ethyl acetate (1 mL) and hexane (10 mL), giving the compound of interest (253 mg, 89%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.42 (s, 2H), 5.26 (s, 1H), 5.16 (s, 1H), 4.41 (s, 2H), 4.33 (s, 2H), 4.09 (s, 2H).
Reaction SMILES: [CH:1]([C:3]1([C:12](=[O:14])[CH3:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[CH2:2].[Br:15]Br>C(Cl)Cl>[Br:15][CH2:13][C:12]([C:3]1([CH:1]=[CH2:2])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[O:14]
Reactant: BrBr
Reactant: C=CC1(C(C)=O)Cc2ccccc2C1
Solvent: ClCCl
Product: C=CC1(C(=O)CBr)Cc2ccccc2C1

Procedure:
1-(2,3-Dihydro-2-vinyl-1H-inden-2-yl)-ethanone (5.0 g) was dissolved in methylene chloride (50 ml) and to the solution bromine (4.3 g) in methylene chloride (45 ml) was added dropwise at room temperature. When a gas chromatogram indicated that the starting material had reacted, the methylene chloride solution was washed with a dilute NaHCO3 -solution and then with water. The organic layer was dried with Na2SO4 and the solvent was evaporated at reduced pressure to give the desired product.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6](O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1C=CC=CC=1.N1C=CC=CC=1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([N:31]3[CH2:30][CH2:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1c2ccccc2C=Cc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
750 mg (3.60 mmol) of the compound obtained in step 1 described above was dissolved in 8 ml of benzene. 0.02 ml of pyridine was added to the obtained solution, and 3.5 ml (48.2 mmol) of thionyl chloride was added to the obtained mixture under cooling with ice. After stirring the reaction mixture at 0° C. for 1 hour and then at room temperature for 2 hours, the solvent was evaporated under reduced pressure. 10 ml of tetrahydrofuran was added to the residue. 2.5 ml (18 mmol) of triethylamine and 805 mg (4.32 mmol) of t-butyl piperazinecarboxylate were added to reaction mixture under cooling with ice. The temperature of the mixture was slowly elevated to room temperature, and it was stirred overnight. The solvent was evaporated under reduced pressure. Dichloromethane was added to the residue. After washing with water and saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduce pressure, and the residue was purified by the basic silica gel chromatography (hexane: dichloromethane=9:1) to obtain the title compound.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](Cl)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].O>CC(N(C)C)=O>[C:1]([NH:10][NH:11][C:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(Cl)c1ccccc1O
Reactant: NNC(=O)c1ccccc1O
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30.4 g of salicylic acid hydrazide are dissolved in 500 ml of dimethylacetamide and 34.8 g of salicylic acid chloride are added dropwise over the course of 70 minutes at 25° - 40° C. The yellow solution is stirred for 3 hours at room temperature and is then poured into 1 liter of water, whereupon white, fine crystals precipitate. The substance is filtered off, washed with water and dried in vacuo at 60° C. The product is purified by recrystallisation from ethylene gylcol monomethyl ether. The N,N'-bis-salicyloyl-hydrazine thus obtained (stabiliser No. 1), melts at 303° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[CH:17]=[O:18]>>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1)[CH:17]=[O:18]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluoro-3-(trifluoromethyl)phenol and 3,4-difluorobenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=NC(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[C:29]1[CH:39]=[CH:38][C:32]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[CH:31][N:30]=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:29]2[CH:39]=[CH:38][C:32]([C:33](=[O:34])[N:35]([CH3:36])[CH3:37])=[CH:31][N:30]=2)[C:8]2[CH2:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Reactant: CN(C)C(=O)c1ccc(Br)nc1
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)cn2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 6-bromo-N,N-dimethyl-nicotinamide (162a) (335 mg, 1.46 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (250 mg, 1.12 mmol) to give a white foam (200 mg, 50% yield). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=2.02 Hz, 1 H) 7.83 (dd, J=8.46, 2.40 Hz, 1 H) 7.34 (d, J=1.01 Hz, 1 H) 7.27 (s, 1 H) 6.97 (d, J=8.34 Hz, 1 H) 3.86 (s, 3 H) 3.08 (d, J=21.47 Hz, 6 H) 2.82 (s, 2 H) 1.46 (s, 6 H); LCMS for C20H22N2O5 m/z 371.20 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]=[O:13])=[C:4]([OH:14])[CH:3]=1.[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21](O)[C:17]=1[C:18]([OH:20])=[O:19].S(=O)(=O)(O)O>>[OH:15][C:16]1[CH:24]=[CH:23][C:22]2[N+:12]([O-:13])=[C:5]3[C:4](=[CH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=43)[O:14][C:21]=2[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=Nc1c(O)cc(O)c2ccccc12
Reactant: O=C(O)c1c(O)cccc1O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(O)ccc2c1oc1cc(=O)c3ccccc3c-1[n+]2[O-]

Procedure:
2.84 g. 1,3-dihydroxy-4-nitrosonaphthalene, 2.31 g. 2,6-dihydroxybenzoic acid, 1.29 g. pyrolusite and 1.6 ml. concentrated sulphuric acid are reacted analogously to Example 1a). Yield 2.8 g.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]2[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)=[O:16]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Reactant: Nc1ccccn1
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccccn3)ccc12
Yield: 28.7 %

Procedure:
This compound was prepared according to the method of Example 15, using 49 mg (0.177 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 18 mg (0.195 mmol, 1.1 equiv) 2-aminopyridine as starting materials, to give 17 mg (34%) of yellow amorphous foam: HRMS calcd for C20H22N4O+H: 335:1872. Found: 335.1874.