Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@:22]2([CH3:23])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:24])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[CH:14]([CH:16]=[O:17])[CH3:15])[CH2:5][C@@H:4]([OH:25])[CH2:3]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:41](Cl)(=[O:44])[O:42][CH3:43]>C(Cl)Cl>[CH3:43][O:42][C:41]([O:1][C@@H:2]1[C@@:22]2([CH3:23])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:24])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[CH:14]([CH:16]=[O:17])[CH3:15])[CH2:5][C@@H:4]([O:25][C:41]([O:42][CH3:43])=[O:44])[CH2:3]1)=[O:44]
Reactant: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C

Procedure:
In 1 ml of methylene chloride was suspended 69 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde, followed by addition of 0.3 ml of pyridine, and the mixture was stirred with ice-cooling. Then, 5 mg of dimethylaminopyridine was added and 0.15 ml of methyl chlorocarbonate was further added dropwise. After completion of the addition, the reaction mixture was stirred at ambient temperature for 10 hours. This reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was serially washed with cold 1N-HCl, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 61 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[C:14](=[O:15])[O:13][C:12]([CH3:17])([CH3:16])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH:19]([Mg]Br)=[CH2:20]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:9]2[C:10](=[O:18])[O:11][C:12]([CH3:16])([CH3:17])[O:13][C:14]2=[O:15])[CH:19]=[CH2:20])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Solvent: C1CCOC1
Product: C=CC(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.1 (6.0 g, 24.17 mmol) in THF, was added vinylmagnesium bromide (available from Aldrich) (207.2 mL, 145.0 mmol) via cannula at 0° C. The resulting heterogeneous mixture was warmed to room temperature, stirred for 30 minutes, and quenched with 1 N aq. HCl. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 15.1 as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[S:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[S:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:15]=3)=[C:9]([C:31]([C:30]3[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=3)=[O:32])[C:5]=2[CH:4]=1
Reactant: COc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)c(C(=O)c3ccc(F)cc3)c2c1

Procedure:
The title compound was prepared by essentially following the procedure detailed in Example 1, Part C, from 5-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part C) and 4-fluorobenzoyl chloride. The crude product was purified by flash chromatography (silica gel, 55:42:3 THF-hexanes-Et3N) to afford 2.11 g (4.44 mmol, 71%) of a yellow semi-solid.
Reaction SMILES: [OH:1][CH:2]([CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][Si](C)(C)C)[CH:23]=1)[CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][CH2:19][CH:2]([OH:1])[CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)#[CH:29]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CNCc1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cccc(CNCC(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To tert-butyl 3-hydroxy-1-phenyl-4-(3-((trimethylsilyl)ethynyl)benzylamino)butan-2-ylcarbamate in a mixture of THF (2 ml) and MeOH (2 ml), 1M K2CO3 (0.25 ml) was added and the reaction mixture was stirred at rt for 18 h. Then solvent was removed, crude residue was redissolved in ethyl acetate, washed with water, brine and dried. Column purification yielded tert-butyl 4-(3-ethynylbenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate in 85% yield.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([OH:12])[N:10]=[CH:11][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14]>[OH-].[Na+]>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([OH:12])[N:10]=[CH:11][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cnc2cnc(O)nc2c1Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2cnc(O)nc2c1Br
Temperature: 25 °C

Procedure:
A suspension of ethyl 8-bromo-2-hydroxypyrido[3,2-d]pyrimidine-7-carboxylate (Preparation 4, 1.49 g) and 10% aqueous sodium hydroxide solution (40 mL) is heated at reflux until ester is consumed. The mixture is allowed to cool to room temperature and is made acidic with 50% aqueous HCl solution. The resulting precipitate is collected and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[N:9]2)[CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][N:41]3[C:44]([C:47](OCC)=[O:48])=[CH:45][N:46]=[C:40]3[CH:39]=2)[CH2:31][CH2:30]1>C1COCC1>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][N:41]3[C:44]([C:47]([NH:17][C:12]4[CH:13]=[CH:14][CH:15]=[C:16]5[C:11]=4[CH:10]=[N:9][N:8]5[CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:48])=[CH:45][N:46]=[C:40]3[CH:39]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Reactant: Nc1cccc2c1cnn2Cc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4cccnc4)cnc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-(pyridin-3-ylmethyl)-1H-indazol-4-amine (0.040 g, 0.18 mmol) in THF (1.1 mL) was cooled to −10° C. in an ice/salt bath. LHMDS (0.19 mL, 0.19 mmol, 1.0M THF) was added and the mixture was stirred for 15 minutes. To this dark solution was added a THF (1.1 mL) solution of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.030 g, 0.090 mmol) at 0° C. The mixture was slowly warmed to 0° C. where it stirred for 3 hours. The reaction was quenched with a saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (1 mm, 15% MeOH/CH2Cl2 with NH3) to afford 0.028 g of 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a tan powder. This material was suspended in MeOH (4.0 mL) and HCl (0.90 mL, 1.8 mmol, 2.0M Et2O) was added. The resulting suspension was stirred for 3 hours and then concentrated. The solid was slurried in Et2O and isolated by vacuum filtration. The solid was dried under vacuum overnight to afford 0.035 g of the title compound (62%). MS (ES+APCI) m/z=511 (M+H-3HCl).
Reaction SMILES: [H-].[Na+].[Br:3][CH:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([Br:18])=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]([CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])([OH:20])[C:6]=2[CH2:5]1.[CH3:29]I.[NH4+].[OH-]>CS(C)=O.CO>[Br:3][CH:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([Br:18])=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]([CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])([O:20][CH3:29])[C:6]=2[CH2:5]1
Reactant: CI
Reactant: CCCCC(CC)CC1(O)C(=O)c2cc(Br)ccc2C2=C1CC(Br)C=C2
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CCCCC(CC)CC1(OC)C(=O)c2cc(Br)ccc2C2=C1CC(Br)C=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.3 g (81.5 mmol) of NaH (60% dispersion in mineral oil) in 30 ml of DMSO were introduced into a 500 ml four-necked flask with mechanical stirrer, condenser, thermometer and dropping funnel which had been dried by heating. 21.6 g (54.3 mmol) of 2,7-dibromo-9-keto-10-(2-ethylhexyl)-10-hydroxydihydrophenanthrene in 60 ml of DMSO were slowly added dropwise, and the mixture was stirred at room temperature for 30 min. 5.1 ml (81.5 mmol) of methyl iodide were then added dropwise over the course of 1 h with ice cooling. The mixture was stirred at room temperature for 2 days, then cooled to 5° C., 90 ml of semi-conc. NH4OH were added dropwise, 100 ml of MeOH were added dropwise, the mixture was stirred in an ice bath for 30 min, and the product was filtered off with suction, washed with MeOH and dried at 60° C. in a vacuum drying cabinet. The crude product was recrystallised a number of times from methanol. The total yield was 17.3 g (65% of theory) with a purity of >99.8%. 1H-NMR (CDCl3): [ppm]=8.16 (d, 4JHH=2.3 Hz, 1H), 7.78 (m, 4H), 7.56 (dd, 3JHH=8.7 4JHH=2.3 Hz, 2H), 3.17 (s, 3H), 1.71 (m, 2H), 1.26 (m, 1H), 1.06 (m, 8H), 0.77 (m, 3H), 0.59 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:19]=[O:20])C.P(Cl)(Cl)(Cl)=O.O>ClCCCl>[CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:19]=[O:20])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(OCc1ccccc1)c1ccc[nH]1
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Temperature: 50 °C

Procedure:
Next, To a stirred solution of 1H-pyrrole-2-carboxylic acid benzylester (2.0 g, 9.94 mmol) in 1,2-dichloroethane (15 mL) at 5° C. is sequentially added DMF (1.12 g, 15.31 mmol) and phosphoryl trichloride (2.35 g, 15.31 mmol). After the addition, the mixture is heated to 50° C. and stirred for an hour. Water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=3:1) to give 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester; HPLC Retention time 1.64 minutes (condition C): MS 230.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([OH:29])=[CH:27][C:26]=1[OH:32].Cl>C1(C)C(C)=CC=CC=1>[Cl:24][C:25]1[C:26]([OH:32])=[CH:27][C:28]([OH:29])=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH:31]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: Oc1ccc(Cl)c(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Oc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1Cl
Temperature: 80 °C
Yield: 78.5 %

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser and a nitrogen atmosphere are charged 26.8 g (100 mmol) of 2-chloro4,6-diphenyl-s-triazine, and 100 mL, of xylene (mixture of isomers). To the beige suspension are added 14.9 g (112 mmol) of aluminum chloride in one portion. The mixture is warmed to ca. 80° C. for 2 hours. 17.4 g (120 mmol) of 4-chlororesorcinol are then added in five portions over 40 minutes to the now homogeneous solution. The reaction mixture is heated at 90° C. for 42 hours and refluxed for another 24 hours. After cooling to room temperature, the contents of the flask are poured into 100 mL of 12% aqueous hydrochloric acid. The precipitate formed is removed by filtration, washed to pH 7 with water, rinsed with methanol and dried at 70° C. under vacuum. The rifle compound is obtained as a crude ocher-red product (29.5 g) and melts at 255°-265° C. It can be used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]([CH3:12])=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.O.[OH-].[Li+:21]>C1COCC1.O>[CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]([CH3:12])=[C:5]([C:7]([O-:9])=[O:8])[N:6]=1.[Li+:21]
Reactant: CCOC(=O)c1nc(C)n(-c2ccccc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)[O-])c(C)n1-c1ccccc1
Temperature: 55 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of ethyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (compound 12a, 4.97 g, 20.3 mmol) in THF/water (15/15 mL) was added lithium hydroxide monohydrate at room temperature. The reaction mixture was stirred at 55° C. for 12 hrs, then the mixture was concentrated in vacuo. The crude solid was washed with diethyl ether to provide the title compound (4.06 g, 90%) as a white solid. The obtained product was used for the next step without purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5Cl)[CH:25]=4)[N:22]=3)[N:17]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)[CH:25]=4)[N:22]=3)[N:17]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Reactant: C1CCNC1
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(N5CCCC5)c4s3)cnc21
Yield: 85.6 %

Procedure:
A solution of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (40 mg, 0.064 mmol) in pyrrolidine (5.32 ml, 64.3 mmol) was heated in a microwave reactor at 100° C. for 2 h. The reaction mixture was evaporated to dryness under vacuum. The crude residue was suspended in MeOH (0.5 mL) and the resultant solid collected by filtration, washing with MeOH, to give 36 mg (85%) 2-(7-pyrrolidin-1-yl-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19]C(=O)C)=[CH:11]1)(=[O:9])[CH3:8]>O>[C:7]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11]1)(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CC(=O)c2ccccc21
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A solution of sodium sulfite (12.6 g, 0.1 mol) in water (180 mL) was heated to 70-75° C. under stirring, and the acetic acid 1-acetyl-1H-indol-3-yl ester of Example 1c (9.0 g, 0.041 mol) was added in small portions. The mixture was stirred at 70-75° C. for 1.5 h, and then kept at room temperature overnight. The solid product was filtered off, dried, dissolved in methylene chloride (40 mL) and flash-chromatographed on aluminum oxide with methylene chloride as an eluent to give 5.25 g (71%) of light yellow product; m.p. 138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:16][N:17]([CH3:21])[C:18]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:19]
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C

Procedure:
1.3 g. (6.3 mMole) 7-amino-4,4-dimethylisoquinoline-1,3-dione was dissolved in 30 ml. pyridine, mixed, while cooling with ice, with 1.5 g. dimethylcarbamoyl chloride and the reaction mixture further stirred for 4 hours at 25° C. Subsequently, the reaction mixture was distilled to dryness, the residue was taken up in methylene chloride, washed with water, dried and the methylene chloride distilled off. The residue was recrystallised from ethanol. Yield 1.1 g. (63.6% of theory); m.p. 256°-258° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C([O-])([O-])=O.[Cs+].[Cs+].C(OC([N:37]1[CH2:42][CH2:41][O:40][CH:39]([CH2:43]Br)[CH2:38]1)=O)(C)(C)C>CC(N(C)C)=O.CCOCC.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:43][CH:39]1[O:40][CH2:41][CH2:42][NH:37][CH2:38]1)[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Reactant: CC(C)(C)OC(=O)N1CCOC(CBr)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(OCC3CNCCO3)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.035 g, 0.11 mmol) in DMA (3.5 mL) was added Cs2CO3 (0.11 g, 0.33 mmol). The mixture stirred at room temperature for 1 hour before the addition of 2-bromomethylmorpholine-4-carboxylic acid tert-butyl ester (0.062 g, 0.22 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ether and water and the layers were separated. The aqueous layer was extracted with ether (3×) and the combined organic layers were washed with water and brine, and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford the desired product. MS (APCI+) m/z 418 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 7.90 (s, 1H), 7.38 (s, 1H), 7.21 (s, 1H), 7.11 (m, 1H), 6.84 (m, 2H), 4.22 (m, 2H), 4.18 (d, 2H), 4.05 (m, 2H), 3.31 (m, 3H), 3.03 (m, 2H), 2.31 (m, 1H), 0.92 (d, 6H)
Reaction SMILES: [CH:1]([C:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[CH3:11])[N:5]=1)([CH3:3])[CH3:2].[OH-].[Ca+2].[OH-].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCOCC1>[OH:9][C:7]1[N:6]([C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([CH3:12])[CH3:11])[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:8]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cl
Reactant: CC(C)C1=NN(C(C)(C)c2ccccc2)C(=O)C1
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C(C)C)nn(C(C)(C)c2ccccc2)c1O
Temperature: 45 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
3-Isopropyl-1-(2-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (1.22 g, 5.00 mmol) and calcium hydroxide (435 mg, 7.50 mmol) were suspended in dioxane (20 mL), heated to 45° C. and stirred for 1 hour. After the stirring, the reaction solution was allowed to cool to room temperature, and after dropwise addition of ethyl chloroformate (597 mg, 5.50 mmol), stirred at 90° C. for 6 hours. After completion of the reaction, the resulting light brown suspension was poured into ice-cold 3 M hydrochloric acid and extracted with chloroform (20 mL×5). The resulting organic layer was washed with 0.06 M hydrochloric acid (50 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 40 g, ethyl acetate:hexane=1:19 to 1:9) to give 650 mg of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:4]=[CH:5][N:6]=1.[H][H]>[Pt]=O.C(O)(=O)C>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1CCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Cc1nccn1CCC1CCNCC1

Procedure:
A suspension containing 41.8 g (0.22 mol) of the compound prepared in (a) above, 450 ml of glacial acetic acid and 5.4 g of platinum oxide in a pressure bottle was affixed to a Parr Hydrogenation apparatus under 50 psi. of hydrogen and maintained at room temperature until the hydrogen uptake was completed. The reaction mixture was filtered through Celite, and the filter bed was then washed with approximately 100 ml of acetic acid. The combined filtrates were then concentrated in vacuo and the resultant residue was distilled in a Kugelrohr apparatus to yield a low melting white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][N:10]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(C2CCNC2)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-(pyrrolidin-3-yl)pyridin-2-amine (20 mg, 0.083 mmol) in DCM in ice bath was added DIEA (57.7 μl, 0.330 mmol) and methanesulfonyl chloride (7.08 μl, 0.091 mmol). The reaction mixture was stirred in ice bath 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was used for next step without purification. LCMS (m/z): 320.0/322.0 (MH+), 0.363 min.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1CCN2C(=NCCC2)CC1.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:35]([OH:41])[CH2:36][O:37][CH2:38][CH2:39]O>CN(C=O)C>[OH:41][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: OCCOCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1OCCOCCO
Temperature: 80 °C
Yield: 74 %

Procedure:
To a stirred solution of N-hydroxyphtalimide (4.3 g, 26.2 mmol) in dry DMF (mL) was added DBU (4.0 g, 26.2 mmol). To this dark red solution was added monotosylate of diethylene glycol (6.8 g, 26.2 mmol). The reaction mixture was heated at 80° C. overnight, concentrated in vacuo, dissolved in ethyl acetate (200 mL) and extracted with saturated sodium bicarbonate until the aqueous phase was colorless. The organic phase was evaporated and dried by coevaporation with toluene. The title product was obtained after purification by flash silica gel chromatography as white solid. Yield 74%.