Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.Cl.Cl[CH2:24][CH2:25][N:26]([CH2:28][CH2:29]Cl)[CH3:27].O>O1CCCC1>[Br:11][C:12]1[CH:20]=[C:19]2[NH:18][C:17](=[O:21])[C:16]3([CH2:29][CH2:28][N:26]([CH3:27])[CH2:25][CH2:24]3)[C:15]2=[CH:14][CH:13]=1
Reactant: CN(CCCl)CCCl
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 9.40 mL, 9.40 mmol) was added dropwise to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 0.40 g, 1.89 mmol) in tetrahydrofuran (4 mL) at −78° C. The mixture was stirred for 30 minutes, then 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (0.36 g, 1.89 mmol) was added and the mixture was warmed to room temperature. After stirring overnight, water was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated. Purification of the residue by reverse phase chromatography (0% CH3CN in H2O to 100% CH3CN in H2O) gave the title compound as a yellow oil (0.17 g, 31%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH3:16])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)[CH3:2].[CH3:17]C(C)[O-].[Na+]>C(O)(C)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:14][CH:15]([CH3:17])[CH3:16])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)[CH3:2]
Reactant: CC(C)[O-]
Reactant: CCOc1cc(OCC)c2nnc(N)n2n1
Agent: [Na+]
Solvent: CC(C)O
Product: CCOc1cc(OC(C)C)c2nnc(N)n2n1
Temperature: 85 °C

Procedure:
6,8-Diethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.126; 80 mg, 0.358 mmol) was dissolved in isopropanol (10 ml), and sodium isopropoxide (297 mg) was added. The mixture was heated to 85° C. for 1 h and concentrated, the residue was dissolved in water and a pH of 6 was established by adding aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined organic phases were dried and concentrated. The remaining residue was purified by flash chromatography (dichloromethane:MeOH). Yield: 58 mg.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=[O:27])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][OH:27])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C=O)cccn34)c(C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(CO)cccn34)c(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A solution of 3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-imidazo[1,2-a]pyridine-8-carboxaldehyde (0.33 g, 0.89 mmol) in CH3OH 910 ml) is treated with NaBH4 (37 mg, 0.98 mmol), and stirred at RT for 30 min. It is quenched with sat. NH4Cl (5 mL), the organic solvent is removed in vacuo, and the residue is diluted with H2O (10 mL) ppm. The aqueous layer is extracted with EtOAC (2×30 mL); the combined organic layers is dried with Na2SO4; filtered and concentrated to give the title compound (0.29 g, 0.78 mmol, 87%). 1H NMR (CDCl3): δ. 0.90 (t, J=7.0 Hz, 3H), 0.91 (t, J=7.0 Hz, 3H), 1.78-1.98 (m, 4H), 2.42 (s, 3H), 2.43 (s, 3H), 2.45 (s, 3H), 3.36-3.42 (m, 1H), 4.39 (bs, 1H), 5.11 (s, 2H), 6.73 (d, J=5.7 Hz, 1H), 6.73 (s, 1H), 7.17 (d, J=6.6 Hz, 1H), 7.46 (d, J=6.6 Hz, 1H) ppm. ES-MS (m/z): calcd for C22H27N5O (M+H)+: 378.5. found: 378.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>COCCOC>[CH3:15][N:14]([CH3:16])[C:12](=[O:13])[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: OB(O)c1cccs1
Reactant: CN(C)C(=O)Cc1c[nH]c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)C(=O)Cc1c[nH]c2ccc(-c3cccs3)cc12
Yield: 52.5 %

Procedure:
A solution of 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 2) (227 mg, 0.81 mmol) in DME (5 mL) is degassed by sparging with argon for 10 minutes. Then thiophene-2-boronic acid (155 mg, 1.21 mmol), caesium carbonate (658 mg, 2.02 mmol), and π-allyl tri-isopropylphosphino palladium bromide (15.7 mg, 0.04 mmol) are added, and the mixture is heated under reflux. Two additional portions of caesium carbonate (103 mg, 0.81 mmol) are added after 20 hours and 24 hours to bring the reaction to completion. The black reaction mixture is poured into 2 N NaOH (10 mL), and extracted twice with ethyl acetate. After removal of the solvent, the residue is chromatographed on silica (CHCl3:MeOH 29:1 v:v) to give the title product (121 mg, 54%). 1H-NMR (CDCl3, 300 MHz) δ 2.96, 2.98 (2 s, 3H each, 2 CH3); 3.77 (s, 2H, CH2); 6.84 (d, 3J=2.2 Hz, H-2); 7.06 (dd, 3J=5.0 Hz, 3J=3.6 Hz, thiophene H-4); 7.21 (d, thiophene H-5); 7.21 (d, 3J=8.4 Hz, H-7); 7.25 (d, thiophene H-3); 7.40 (dd, 4J=1.8 Hz, H-6); 7.70 (d, H-4); 9.16 (br s, NH). 13C-NMR (CDCl3, 75 MHz) δ 31.02 (CH2); 36.00, 38.00 (2 CH3); 109.05 (C-3); 112.17 (C-7); 116.22 (C-4); 121.08 (C-6); 122.25 (thiophene C-3); 123.70 (thiophene C-5); 124.31 (C-2); 126.29 (thiophene C-2); 127.83 (C-9); 128.15 (thiophene C-4); 136.27 (C-8); 146.56 (C-5); 172.16 (CO).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)CCl>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:18]([C:17]2[C:12]([NH:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:20])=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cccnc1Nc1ccc2ncccc2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1Nc1ccc2ncccc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-(6-quinolylamino)pyridine-3-carboxylic acid (250 mg, from Step A) and 4-chloroaniline (120 mg) and DIEA (220 ul) in DMF (15 ml) was added EDC (220 mg) and HOBt (130 mg). The reaction was stirred at 50° C. for 3 h. The solution was evaporated under reduced pressure and mixed with CH2Cl2 (50 ml). The resulting solution was washed with 1N HCl, saturated NaHCO3, H2O and brine. The organic layer was dried over Na2SO4, evaporated under reduced pressure and triturated with CH2Cl2. The precipitate was filtered and washed with EtOH to give the titled compound. MS (ES+): 375 (M+H)+; (ES−): 373 (M−H)−. Calc'd for C21H15ClN4O—374.8.
Reaction SMILES: [H-].[Li+].[C:3]([NH:9][CH2:10][C:11]1([CH2:28][CH3:29])[CH:20]2[N:15]([CH2:16][CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:19]=32)[CH2:14][CH2:13][CH2:12]1)(=O)[CH2:4][CH2:5][CH2:6][CH3:7].O.ClCCl>C(OCC)C>[CH2:3]([NH:9][CH2:10][C:11]1([CH2:28][CH3:29])[CH:20]2[N:15]([CH2:16][CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:19]=32)[CH2:14][CH2:13][CH2:12]1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)NCC1(CC)CCCN2CCc3c([nH]c4ccccc34)C21
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CCCCCNCC1(CC)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
In a 500 ml three-necked flask of having a stirrer, a reflux condenser, a thermometer, and a dropping funnel there were placed 100 ml of anhydrous ethyl ether. When this had been cooled on an ice bath there were added 4 g of lithium hydride, and the contents of the flask were stirred for 15 minutes. There was then added very slowly a solution of 7.4 g of the product of Example 7 in 50 ml of anhydrous ethyl ether. The mixture was then heated under reflux for 2 hours and stirred for a further 15 hours at room temperature. It was then cooled on an ice bath and there were added dropwise 20 ml of water followed by 150 ml of dichloromethane. The mixture was then filtered over Celite, dried over sodium sulphate and concentrated by evaporation. There were obtained 7 g of an oil which could be crystallized to a product melting at 80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:21].[Na+].OO>C1COCC1>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C@@H:13]([OH:21])[CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(F)cc2)[C@@H](O)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Add borane tetrahydrofuran complex (171 mL, 171 mmol) to a solution of tert-butyl 4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (54 g, 186 mmol) in THF (544 mL) under a nitrogen atmosphere. Stir overnight at 40° C., then add 2M sodium hydroxide (36.8 g, 70.8 mmol) and stir for 12 minutes at ambient temperature. Add hydrogen peroxide (31.1 mL, 357.8 mmol) while maintaining the internal temperature at 19-21° C. through the use of an ice-water bath. After addition is complete, remove the ice bath and stir at ambient temperature for 3 hours. Dilute the reaction mixture with water (250 mL) and extract twice with methyl tert-butyl ether (500 mL). Combine organic extracts, and sequentially wash with brine, sodium bisulfate then brine again. Dry the organics over magnesium sulphate; filter; collect the filtrate; and concentrate under vacuum. Purify the crude material via flash column chromatography using hexane/ethyl acetate (4:1, then 3:1) followed by DCM/EtOAc (1:1, then 0:100). Combine product fractions and dry under vacuum to give a white solid. Separate enantiomers using chromatography conditions “L” (see below), collecting the first eluting isomer to give the title compound (20.02 g, 36.4%) as a white solid. MS (m/z): 196 (M+1-Boc).
Reaction SMILES: O1C=CC=C1[C@H](O)CNC.[CH3:11][N:12]1[CH2:16][C@H:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[O:14]C1=O.[OH-].[K+]>>[CH3:11][NH:12][CH2:16][C@H:15]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[OH:14]
Reactant: CN1C[C@H](c2cnccn2)OC1=O
Agent: CNC[C@@H](O)c1ccco1
Agent: [K+]
Agent: [OH-]
Product: CNC[C@@H](O)c1cnccn1
Yield: 78.9 %

Procedure:
As described for the preparation of (1R)-1-(2-furyl)-2-(methylamino)ethanol, the oxazolidinone (1.51 g, 8.43 mmol) is treated with 1N aq. KOH (42.1 mL, 5 equiv., 42.1 mmol ) to give (1R)-2-(methylamino)-1-pyrazin-2-ylethanol (1.02 g, 6.65 mmol) in 79% yield as a white solid. MP: 84-85° C.; Specific Rotation [α]D25+66 (c 0.94, methanol).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH2:4]1.[NH2:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([O:29][CH3:30])[CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]([C:23]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[CH2:4]2)=[O:24])=[C:21]([O:29][CH3:30])[CH:20]=1
Reactant: N#Cc1ccc(CN2CCOC(CN)C2)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(C#N)cc2)CCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-aminomethyl-4-(4-cyanobenzyl)morpholine (1.5 g) in dichloromethane (40 ml), 4-amino-5-chloro-2-methoxybenzoic acid (1.2 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.3 g) are added, and the resulting mixture is stirred at 25° C. for 3 hours. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give the title compound as an oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]4[CH2:27][CH2:28][O:29][CH2:30][CH:31]=4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([F:44])=[C:39](B(O)O)[CH:40]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([F:44])=[C:37]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:26]5[CH2:27][CH2:28][O:29][CH2:30][CH:31]=5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)[CH:36]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1ncc(C3=CCOCC3)cc12
Reactant: OB(O)c1cc(Cl)ccc1F
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: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cc(Cl)ccc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A vial was charged with (S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.050 g, 0.103 mmol), 5-chloro-2-fluorophenylboronic acid (0.054 g, 0.310 mmol), and Pd(PPh3)4 (5.97 mg, 5.17 μmol). The vial was purged with Ar (g). Then, DMF (0.517 mL) and potassium carbonate (0.259 mL, 0.517 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was sealed and stirred at 70° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-7% MeOH in DCM) to afford (S)-7-(5-chloro-2-fluorophenyl)-3-(3,6-dihydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid. Found MS: MH+=464.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15].Cl.C(N(CC)CCCN=C=NCC)C.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH2:14][C:13]([F:17])([F:16])[F:12])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 58.1 %

Procedure:
In a solution of 5.00 g of 4-bromo-2-methyl benzoic acid and 3.45 g of 2,2,2-trifluoroethylamine in 30 ml of N,N-dimethylformamide, 5.79 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added with stirring at room temperature, and stirred at the same temperature for 1.5 hour. After the completion of the reaction, 80 ml of water was added, and precipitated crystal was filtered off, washed with water and dried to obtain 4.00 g of the aimed product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:10](=[O:11])[C:6]2=[N:7][S:8][N:9]=[C:5]2[C:4](=[O:12])[CH:3]=1.[N:13]1([CH:19]=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10](=[O:11])[C:6]2=[N:7][S:8][N:9]=[C:5]2[C:4](=[O:12])[C:3]=1[N:16]1[CH2:17][CH2:18][N:13]([CH:19]=[O:20])[CH2:14][CH2:15]1
Reactant: O=C1C=C(Cl)C(=O)c2nsnc21
Reactant: O=CN1CCNCC1
Product: O=CN1CCN(C2=C(Cl)C(=O)c3nsnc3C2=O)CC1

Procedure:
A 600 mg portion of 6-chlor-2,1,3-benzothiadiazole-4,7-dione and 342 mg of 1-piperazinecarboxaldehyde were reacted as described in Example 8, giving 164 mg of the desired product, mp 191°-194°.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH2:33][NH:34][C:35]([NH:37][C:38]3[N:42]([C:43]4[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=4)[N:41]=[C:40]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:39]=3)=[O:36])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl.CC(O)C>CCO>[P:1]([O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH2:33][NH:34][C:35]([NH:37][C:38]3[N:42]([C:43]4[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=4)[N:41]=[C:40]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:39]=3)=[O:36])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)([OH:8])([OH:3])=[O:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCOP(=O)(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of di-tert-butyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethyl phosphate (3.66 g, 4.89 mmol) in EtOH (0.2M, 24 mL) was treated with SN HCl/iPrOH (2.93 mL, 14.7 mmol) at room temperature. Stirring at room temperature was continued overnight. The solvent was evaporated in vacuo, and the residue was coevaporated from toluene, and ether (2×). The beige foam was taken in MeOH and poured slowly into a beaker containing water. The precipitated solids were collected by filtration to provide 2.83 g (91%) of the desired product. MS (APCI+) m/z 637 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.00 (s, 1H), 7.71 (d, 1H, J=9 Hz), 6.88-7.37 (m, 10H), 6.24 (s, 1H), 4.61 (br, 1H), 4.28 (d, 2H, J=5.7 Hz), 4.19 (dd, 2H, J=5.2 Hz), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: Br[CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C([Mg]Cl)(C)C.[CH:15](=[O:17])[CH3:16].Cl>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:2]1([CH:15]([OH:17])[CH3:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: CC=O
Reactant: BrC1C=CCCCCC1
Agent: [Ti+4]
Agent: CC(C)[Mg]Cl
Agent: CC(C)[O-]
Solvent: CCOCC
Product: CC(O)C1C=CCCCCC1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 25.2 %

Procedure:
At −50° C., a solution of 3-bromo-cyclooctene (4.2 g, 22 mmol; prepared by reaction of cyclooctene with N-bromosuccinimide) and titanium(IV)isopropoxide (7.2 ml, 24 mmol, 1.1 eq.) in diethyl ether (100 ml) was treated with a 2M solution of isopropylmagnesium chloride in diethyl ether (49 mmol, 2.2 eq.). The resulting mixture was stirred 1.5 h at −50° C., treated with acetaldehyde (1 ml, 18 mmol, 0.8 eq.), stirred 1 h at −40° C., and treated with 2M aqueous HCl solution. After extraction with MTBE (2×100 ml), washing of the organic phases with water (2×200 ml) and aqueous NaCl solution (200 ml), and drying (MgSO4), the crude product (4.4 g) was purified by flash chromatography (hexane/MTBE 6:1) to give 0.7 g of 1-cyclooct-2-enylethanol (26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C@@H:29]1([CH2:37]O)[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:35][OH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]3[CH2:35][OH:36])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CCCC[C@@H]1CO
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OCC2CCCCC2CO)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 64 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis-1,2-cyclohexane-dimethanol (728 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (337 mg, 64%). 1H NMR (300 MHz, CDCl3): mixture of diastereoisomers: 8.08-7.93 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.58-7.54 (m, 2H, Ar—H), 7.43-7.36 (m, 2H, Ar—H), 7.23-7.11 (m, 5H, Ar—H), 4.61 and 4.25 (d: AB, J=15.0 Hz, 2H, N—CH2); and 4.59 and 4.36 (d: AB, J=15.0 Hz, 2H, N—CH2), 3.53-3.24 (m, 2H, HO—CH2), 2.87-2.61 (m, 2H, OCH2), 1.87-1.09 (m, 10H, CH). 13C NMR (75 MHz, CDCl3): mixture of diastereoisomers: 168.25, 147.42, 145.37, 145.20, 144.84, 144.76, 137.28, 137.12, 134.97, 134.88, 133.03, 131.55, 131.41, 130.15, 130.10, 129.98, 129.94, 128.81, 128.69, 127.98, 127.92, 123.91, 123.81, 123.33, 123.30, 123.10, 123.06, 95.07, 94.97, 63.91, 63.57, 63.44, 63.31, 42.50, 42.43, 40.77, 39.99, 37.18, 27.40, 27.09, 26.21, 26.16, 23.77, 23.44, 23.29. Anal.: calc. for C29H29ClN2O5+0.3 CH2Cl2+0.1 H2O: C, 64.18; H, 5.49; N, 5.11. Found: C, 64.34; H, 5.49; N, 4.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:12]OCC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])=[CH:12][NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[C:27]([F:26])([F:35])[F:36])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC=C(S(=O)(=O)c1ccc(Cl)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: CC(=O)N(C)C
Product: O=S(=O)(C(=CNc1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 50.1 %

Procedure:
A solution of 1,1-bis(4-chlorophenylsulphonyl)-2-ethoxyethene (1.26 g) and 2-(trifluoromethyl)aniline (0.48 g) in dimethylacetamide (20 ml) was heated at reflux for 2 hours, and then it was cooled and poured onto ice (50 g). The resulting white precipitate was filtered off, washed with water and recrystallised from ethanol, to give 1,1-bis(4-chlorophenylsulphonyl)-2-[2-(trifluoromethyl)anilino]ethene (0.8 g), m.p. 169°-171° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]#[CH:12].C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:12][C:11]#[CH:10])=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#CCNc1ccc(F)cc1

Procedure:
A solution of 9.47 ml (0.1 mol) of 4-fluorobenzenamine, 16.36 g (0.11 mol) of an 80% solution of 3-bromo-1-propyne in toluene, and 17.43 ml (0.11 mol) of N-ethyl-N-(1-methylethyl)-2-propanamine in 350 ml of toluene is heated at 90° C. for three hours. Ethyl acetate is added to the reaction suspension, and it is washed three times with water. The organic layer is separated, dried (magnesium sulfate), and concentrated to give 15.5 g of a dark brown liquid. This is applied to a column of 1 kg of flash silica gel packed in heptane-dichloromethane (5:1). Elution with the same solvent gives 9.09 g (61%) of the product as a yellow oil.