Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[CH:10][N:11]2[CH2:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:7][CH:6]=1)=[O:4]
Reactant: COCCCBr
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCn1cc(C)c2ccc(C(=O)OC)cc21
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-methyl-1H-indole-6-carboxylic acid methyl ester (2.5 g, 13.2 mmol) in DMF (25 mL), a solution of NaH (580 mg, 14.5 mmol, 60% dispension in grease) in DMF (25 mL) is slowly added under a N2 atmosphere. The mixture is stirred at 80° C. for 20 min, and cooled to RT before the addition of 1-bromo-3-methoxypropane (4.04 g, 26.4 mmol). The resulting mixture is stirred for 24 h. 1-Bromo-3-methoxypropane (2.02 g, 13.2 mmol) and NaH (580 mg, 14.5 mmol) are added and the mixture further stirred for 24 h to complete the reaction. The solvent is concentrated under reduced pressure and the mixture diluted with AcOEt. An aqueous saturated solution of NaHCO3 is added, the layers are separated, and the aqueous one is back-extracted with AcOEt. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 80:20) to give the title compound. MS (LC-MS): 262.0 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mumin): 5.80 min.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][C:6]1([CH3:28])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][N:21]=3)[CH:9]=[CH:8][C:7]1=2>CCOCC>[CH3:5][C:6]1([CH3:28])[CH2:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]2[CH:11]=[C:10]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([OH:27])[CH2:1][CH3:2])=[CH:22][N:21]=3)[CH:9]=[CH:8][C:7]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C=O)cn3)ccc21
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC(O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Reaction time: 1 h

Procedure:
Four ml of a 3M (12 mmol) solution of ethylmagnesium bromide in ether is placed in a 3-necked flask fitted with a mechanical stirrer, a reflux condenser protected by a drying tube and a pressure-equalizing dropping funnel protected by a drying tube. The flask is cooled in an ice-bath and a solution of 3.174 g (10 mmol) of 2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]pyridine-5-carboxaldehyde in 10 ml of dry ether is added slowly with vigorous stirring. The cooling bath is then removed and the mixture heated at reflux for 3 hours. The mixture is then cooled in an ice-salt bath and 5 ml of saturated ammonium chloride solution is added. The mixture is stirred for a further 1 hour and then filtered and the residue washed with two 10 ml portions of ether. The ether solution is then separated, dried (MgSO4) and the ether removed in vacuo. The residue is then purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH:37]([CH3:40])[O:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:39][CH2:38][CH:37]([CH3:40])[O:36]2)=[O:34])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Reactant: CC1CCC(C(=O)CBr)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)C2CCC(C)O2)cc1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
Toluene-4-sulphonic acid (3.42g, 17.98mmol) in water (8ml) was added to a solution of 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (4.12g, 10.0mmol) in dichloromethane (20ml) and acetone (20ml). After stirring for 2.5h at room temperature, the reaction mixture was diluted with dichloromethane, washed with water (x2), dried and concentrated in vacuo to yield crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate as a colourless foam. The crude thiol was dissolved in acetone (50ml) and treated with a solution of 2-bromoacetyl-5-methyltetrahydrofuran (1.67g, 8.1mmol) in acetone (5ml). After 10 min., potassium carbonate (687mg, 5.0mmol) was added, and the mixture stirred for a further 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with water (x2) and brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane to yield the title compound as a colourless foam (2.68g, 60%); vmax (CH2Cl2) 3412, 1781, 1744, 1685 and 1515cm-1. (Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Product: CC(C)C(=O)Nc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N-(1H-indol-5-yl)isobutyramide (intermediate-10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([OH:24])[CH2:11][N:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[C:25]([O:24][CH:10]([CH2:11][N:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CN(CC(O)CSc1ccc(Cl)cc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN(CC(CSc1ccc(Cl)cc1)OC(C)=O)c1ccccc1
Reaction time: 20 h

Procedure:
After 200 mg (0.00054 moles) of 1-(p-chlorophenylthio)-3-(N-carbomethoxymethyl-N-phenylamino)-2-propanol and 1 g of acetic anhydride were dissolved in 3 ml of pyridine and left to stand at room temperature for 20 hr, the reaction mixture mixture was poured into iced water and extracted with ether. The ether layer was washed with 10% hydrochloric acid and water and dried. Evaporation or ether under reduced pressure gave 190 mg (86.5%) of an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:7]2.C(=O)([O-])[O-].[K+].[K+].O.[C:34](Cl)(=[O:36])[CH3:35]>C(OCC)(=O)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:34](=[O:36])[CH3:35])[CH2:5]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN)C2
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCNC(C)=O)C2
Reaction time: 0.25 h

Procedure:
To a mixture of 8-(4,5,6,7-tetramethoxyindan-2-yl)octylamine (878 mg), potassiumcarbonate (2.54 g),water (16 ml), and ethyl acetate (16 ml) was dropwise added acetyl chloride (0.341 ml) with cooling with ice. After being stirred for 15 min, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and then with recrystallization (hexane-ethyl acetate) to give the entitled compound (0.830 g) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:13]([OH:16])[CH:14]=[CH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(C)[CH:26]=CC(S(O)(=O)=O)=C[CH:22]=1.C(OCC)(=O)C>COC(OC)(C)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:13]([CH:14]=[CH2:15])[O:16][C:21]1([CH3:26])[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CC(O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 1369.8 %

Procedure:
124 mg of (3RS,4S)-4-(benzyloxycarbonyl)amino-6-methylhepten-3-ol was dissolved in 0.33 ml of 2,2-dimethoxypropane, and 4 mg of dry p-toluenesulfonic acid was added thereto. The mixture was stirred at room temperature overnight. Then, 20 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography-(n-hexane/ethyl acetate=10/1) to obtain 101 mg of (4S,5RS)-3-benzyloxycarbonyl-2,2-dimethyl-5-ethenyl-4-isobutyloxazolidine as colorless oily substance.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:10]1[CH:19]=[CH:20][C:7]([C:21]([OH:23])=[O:22])=[CH:8][CH:9]=1
Reactant: O=C=O
Reactant: Brc1ccc(COc2ccccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M in hexane, 11.4 ml) was added to a solution of 2-(4-bromobenzyloxy)pyridine (4.2 g) in THF (120 ml) at −78° C. After 15 minutes, dry ice (7 g) was added. After warming to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The aqueous phase was acidified and again extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 229.24 (C13H11NO3); MS (ESI): 230 (M+H+) was obtained in this way.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]3[N:38]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=5)=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:37][S:34]([C:31]1[CH:30]=[CH:29][C:28]([C:24]2[C:23]3[N:22]([N:21]=[C:20]([NH:19][C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:18]=4)[N:38]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:33][CH:32]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cnn(C5CCNCC5)c4)nc23)cc1
Reaction time: 1 h

Procedure:
To a well stirred solution of 4-{4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-pyrazol-1-yl}-piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.186 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.65 mL, 8.77 mmol) dropwise at room temperature. After 1 h, the reaction mixture was evaporated in vacuo and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The crude product was crystallized from a mixture of dichloromethane, methanol, ether and hexane. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-piperidin-4-yl-1H-pyrazol-4-yl)-amine was isolated as a greenish-yellow solid (58 mg, 71%). MP=Softened at 154-159° C. then melted at 211-213° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.79 (d, J=6.48 Hz, 1H), 8.42 (d, J=7.96 Hz, 2H), 8.06 (d, J=7.97 Hz, 2H), 7.94 (d, J=7.45 Hz, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.12 (t, J=7.04 Hz, 1H), 4.14 (t, J=11.29 Hz, 1H), 3.29 (s, 3H), 3.035 (d, J=12.28 Hz, 2H), 2.58 (t, J=12.16 Hz, 2H), 1.935 (d, J=11.41 Hz), 1.68-182 (m, 2H). MS=438 (MH)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH2:19])[C:6]([NH:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:7][CH:8]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].O>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])[C:20](=[O:21])[NH:19][C:5]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1Nc1ccc(Cl)cc1N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-n1c(=O)[nH]c2cc(Cl)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Chloro-N1-(5-chloro-2-methoxy-phenyl)-benzene-1,2-diamine hydrochloride (6.3 g, 20 mmol) in tetrahydrofurane (70 ml) was added carbonyldiimidazole (9 g 55 mmol). The reaction mixture was stirred at 60° C. overnight, poured into water (app. 200 ml) and extracted with ethylacetate, and the organic phase was washed with brine and evaporated to an oil. The title compound was crystallized from toluene.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].CN(C=O)C.Br[CH2:26][CH2:27][Cl:28]>O>[Cl:28][CH2:27][CH2:26][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:11]1=[O:19]
Reactant: O=c1[nH]c2ccccc2n1CCOC1CCCCO1
Reactant: ClCCBr
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(CCCl)c2ccccc2n1CCOC1CCCCO1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
Into a stirred solution of 1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (6.5 g, 25 mmoles) in DMF (40 ml) 80% sodium hydride (0.9 g, 30 mmoles) was added. After 30 minutes of stirring and heating to 35° C., 1-bromo-2-chloroethane (6.2 g, 48 mmoles) was added, the reaction temperature was increased to 90° C. and kept for 6 hours then cooled at room temperature. The reaction mixture was poured into water, extracted with diethyl ether, and the organic layer was taken to dryness. The residue was purified by flash chromatography (cyclohexane-ethyl acetate 50-50) to give 2.8 g of the title compound as a thick oil which was used without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(O)cccc3C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OCc4ccccc4)cccc3C2C1
Temperature: 80 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one (30 mg, 0.10 mmol) from Example 72, Step B, in N,N-dimethylformamide (1.5 mL) was added benzyl bromide (0.017 L, 0.15 mmol) and potassium carbonate (41 mg, 0.29 mmol). The resulting mixture was warmed to 80° C. After 4 h the reaction was cooled to room temperature, diluted with ethyl acetate, washed with 50% saturated aqueous sodium chloride, and the the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by radial chromatography (30% ethyl acetate in hexanes) to give the desired product as a clear residue (31 mg, 80%). MS (ESI) 395.4 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH2:5][OH:6].[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12]Br>CN(C)C=O>[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12][O:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][OH:6]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: OCC=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC/C=C\COCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
In a 500 ml flask, 1,4dihydroxybut-2-ene (6.13 ml, 74.5 mmol) was dissolved in N,N-dimethylformamide (150 ml) under a nitrogen atmosphere. Sodium hydride (60%, 2.98 g, 74.5 mmol) was added and the resulting mixture was stirred at ambient temperature for thirty minutes. The reaction mixture was cooled to 0° C. and 2-fluoro-5-bromobenzyl bromide (3.99 g, 14.9 mmol) was added dropwise. The resulting mixture was warmed to ambient temperature and stirred for four hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)[CH3:2].Br[C:17]1[CH:22]=[CH:21][N:20]=[N:19][CH:18]=1.C1(C)C=CC=CC=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.C(O)C>[N:19]1[CH:18]=[CH:17][C:22]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:7][CH:8]=2)=[CH:21][N:20]=1
Reactant: Brc1ccnnc1
Reactant: CCOC(=O)Cc1ccc(B(O)O)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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccnnc2)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 4-(2-ethoxy-2-oxoethyl)phenylboronic acid 37-2 (310 mg, 1.5 mmol), 4-bromopyridazine 37-1 (158 mg, 1 mmol), Pd(PPh3)4 (70 mg, 0.1 mmol), toluene (4 mL), ethanol (1 mL) and 2M Na2CO3 (1.5 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooled down to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution and brine. The organic phase was dried over Na2SO4 and then concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give ethyl 2-(4-(pyridazin-4-yl)phenyl)acetate 37-3 as pale yellow solid. MS m/z 243.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[I:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](=O)[C:25]([F:28])([F:27])[F:26])[C:20](=O)[C:19]2=[O:31])=[CH:14][CH:13]=1.C(O)C.Cl>C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:20]3[C:19](=[O:31])[N:18]([C:15]4[CH:16]=[CH:17][C:12]([I:11])=[CH:13][CH:14]=4)[CH2:23][CH2:22][C:21]=3[C:24]([C:25]([F:28])([F:26])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1C(=O)N(c2ccc(I)cc2)CCC1C(=O)C(F)(F)F
Reactant: NNc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2c(c(C(F)(F)F)nn2-c2ccc(F)c(Cl)c2)CCN1c1ccc(I)cc1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Part A. 3-chloro-4-fluorophenyl hydrazine (5.00 g, 31.14 mmol) and 1-(4-iodophenyl)-4-(trifluoroacetyl)-2,3-piperidinedione (12.8 g, 31.14 mmol) were added together with 120 mL of ethanol and 4 mL of hydrochloric acid (12 M). The mixture was stirred at reflux under N2 for overnight. The reaction was cooled down to rt. The solvents were removed, and the residue was dissolved in EtOAc (200 mL) and washed with water (100 mL×2) and brine (50 mL). It was then dried over Na2SO4 and concentrated. The residue was purified via flash chromatography on silica gel using 4:1 hexane:ethylacetate to give 1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one as a brown solid (12.5 g, 75% yield). LRMS (AP+): 536.1 (M+H)+. 1H NMR (CDCl3) δ 7.72 (d, 2H), 7.67-7.64 (m, 1H), 7.49-7.44 (m, 1H), 7.19 (t, 3H), 7.06 (d, 2H), 4.12 (t, 2H), 3.17 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: O=C(Cl)CCl
Product: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(=O)CCl)c1

Procedure:
The title compound was prepared, according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methylpyridine-2-carbonyl)indole (Example 70) and chloroacetyl chloride. m.p.: 224-225° C.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]1([N:20]2[C:28]3[CH2:27][CH2:26][CH2:25][C:24](=[CH:29][C:30]([OH:32])=O)[C:23]=3[CH:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl>[C:14]1([N:20]2[C:28]3[CH2:27][CH2:26][CH2:25][C:24](=[CH:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[C:23]=3[CH:22]=[N:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C=C1CCCc2c1cnn2-c1ccccc1
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=C1CCCc2c1cnn2-c1ccccc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 30.8 %

Procedure:
Triethylamine (0.054 mL, 0.39 mmol) and ethyl chloroformate (0.037 mL, 0.30 mmol) are added to a solution of a mixture of E/Z of 2-(1,5,6,7-tetrahydro-1-phenyl-4H-indazol-4-ylidene)acetic acid (100 mg, 0.39 mmol) in CH2Cl2 (5 mL) cooled to 0° C. and is stirred for 45 minutes at 0° C. Then morpholine (0.034 mL, 0.39 mmol) is added following the reaction by means of TLC. The solution is washed with diluted NaOH, the organic phase is separated, dried and evaporated under reduced pressure. The resulting crude product is purified by means of silica gel chromatography giving an E/Z mixture (80/20) of 4-(2-(1-phenyl-6,7-dihydro-1H-indazol-4(5H)-ylidene)acetyl)morpholine (40 mg, 0.12 mmol, 32%).