Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#N)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl.C([O:27]CC)C>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:22](=[O:27])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=2)=[CH:5][CH:6]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCOCC
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: Cl
Agent: II
Product: CC(C)(C)c1ccc(CC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.7 of magnesium(scraped shape) and 100 mg of a chip of iodine were added to 5 ml of anhydrous diethyl ether. 10 ml of anhydrous diethyl ether solution of 5.6 g of p-bromochlorobenzene was dropwise added thereto under nitrogen stream at a rate that was just fast enough to maintain a gentle reflux. This solution was stirred at room temperature for 20 minutes to react them, a solution of 4.8 g of p-tert-butylphenyl acetonitrile in 5 ml of anhydrous diethyl ether was dropwise added thereto at a rate that was just fast enough to maintain a gentle reflux. The solution was further stirred for 30 minutes to react them. After completion of the reaction, a mixture solution of 10 g of ice and 130 ml of 6N-hydrochloric acid was added thereto and a reaction product was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The redisue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/9) to obtain 1.3 g of 4'-chloro-2-(4-tert-butylphenyl)acetophenone. (2) 1.3 g of (4.5 mmol) of 4'-chloro-2-(4-tert-butylphenyl)acetophenone was dissolved in 15 ml of ethanol, and 0.2 g (4.5 mmol) of hydrazine monohydrate was added thereto. The mixture was refluxed under heating for three hours. After completion of the reaction, ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.3 g of [4'-chloro-2-(4-tert-butylphenyl)acetophenone]hydrazone as a yellow oily substance.
Reaction SMILES: ClCCCC[C:6]([CH:8]([NH2:11])[CH:9]=C)=O.[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:6]=[C:8]([N:11]1[CH2:12][CH2:26][CH2:22][CH2:23][C:24]1=[O:25])[CH3:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=CC(N)C(=O)CCCCCl
Reactant: C1CCOC1
Agent: [Na+]
Product: C=C(C)N1CCCCC1=O
Yield: 72 %

Procedure:
To a stirred solution of 26 (2.0 g, 11 mmol) in THF (110 mL) at -78° C. was added NaN(TMS)2 (1.0M in THF, 11 mL) in a stream followed by removal of the cooling bath. After 1.5 hours the reaction mixture was diluted with ethyl acetate and then washed with water, 5% KHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica gel, 60% ethyl acetate/hexanes) gave 27 (1.1 g, 72%) as an oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:38][CH2:37][N:36]3[C:29](=[CH:30][C:31]4[CH2:32][C:33]([CH3:40])([CH3:39])[CH2:34][C:35]=43)[C:28]2=[O:41])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:38][CH2:37][N:36]3[C:35]4[CH2:34][C:33]([CH3:39])([CH3:40])[CH2:32][C:31]=4[CH:30]=[C:29]3[C:28]2=[O:41])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2cnccn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A mixture of 188a (150 mg, 0.27 mmol) and lithium hydroxide (103 mg, 2.7 mmol) in i-propanol/THF (5:3, 8 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 188 (40 mg, 35%) as a white solid. MS-ESI: [M+H]+ 512.3. 1H NMR (500 MHz, CHCl3) δ 8.73 (d, J=2.0 Hz, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.29 (s, 1H), 8.15-8.13 (m, overlap, 2H), 8.02-8.00 (m, 2H), 7.38 (d, J=5.0 Hz, 1H), 6.86 (s, 1H), 5.12 (s, 1H), 4.68-4.51 (m, 2H), 4.33-4.29 (m, 1H), 4.18 (t, J=5.5 Hz, 2H), 3.91-3.86 (m, 1H), 3.75 (s, 3H), 2.60-2.58 (m, 2H), 2.53 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: C1C=CN=CC=1.[FH:7].[Cl:8][C:9]1[CH2:10][C:11]2[C:16](=[O:17])[O:15][C:13](=[O:14])[C:12]=2[CH2:18][CH:19]=1.[Br:20]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:20][CH:19]1[CH2:18][C:12]2[C:13]([O:15][C:16](=[O:17])[C:11]=2[CH2:10][C:9]1([Cl:8])[F:7])=[O:14]
Reactant: O=C1OC(=O)C2=C1CC=C(Cl)C2
Reactant: BrBr
Reactant: F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1OC(=O)C2=C1CC(Br)C(F)(Cl)C2
Reaction time: 6 h

Procedure:
Pyridinium poly(hydrogen fluoride) was added to a solution of 4-chloro-3,6-dihydrophthalic anhydride (6.5 g) in methylene chloride (10.1 g) at room temperature. Bromine (3.1 g) was added. A violent reaction occurs. The solution was allowed to stand for 6 hours and then was poured into a two phase mixture of methylene chloride (30 ml) and solid sodium carbonate. The suspension was stirred for 10 minutes until bubbling stopped. The mixture was filtered and the methylene chloride removed under reduced pressure. The material was purified by a bulb to bulb distillation (140° C. air temperature and 2.8 torr) to give a yellowish solid, (3.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C@@H:4]([OH:8])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C@H:4]([OH:8])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)[C@H](O)c1ccccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)c1ccccc1Cl

Procedure:
In a 1 L flask, 120 g (0.643 mole) of (R)-2-chloromandelic acid, 480 ml methanol and 4.8 g concentrated sulfuric acid were added. The solution is then heated to reflux for 2 hours and excess methanol is distilled under vacuum. The oily residue was taken in 650 ml chloroform and washed with 240 gm aqueous solution of 10% potassium carbonate and concentrated under vacuum. 124.4 gm of methyl-(R)-2-hydroxy-2-(2-chlorophenyl)acetate was obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH2:21]>>[Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[N:10][C:11]([C:14]([OH:16])=[O:21])=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: Cc1ccc(-c2ncccc2Cl)cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(-c2ncccc2Cl)cn1
Temperature: 120 °C
Yield: 51 %

Procedure:
The above 3-chloro-6′-methyl-[2,3′]bipyridinyl (2.5 mmol) was added to a 5 ml microwave vessel, followed by 3 ml of water. 3.75 mmol of potassium permanganate was added and the mixture was heated at 120° C. for 600 seconds. An additional 3.75 mmol of potassium permanganate was added and the mixture was resubmitted to microwave heating (same temperature) for 600s. After completion (monitored by LC-MS), the mixture was filtered through celite and the manganese salts were washed with water. The water was evaporated to ˜10 ml and the product was purified by HPLC to give 293 mg as a white solid (51%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:16]([NH2:18])=[O:17])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C@@H:8]([OH:19])[CH2:7][C:5]=2[CH:6]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>O.ClCCl>[CH3:37][C:36]([O:19][C@@H:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]([C:16]([NH2:18])=[O:17])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:38]
Reactant: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of eslicarbazepine (18 gm), triethylamine (8.5 gm), dimethylaminopyridine (0.1 gm), acetic anhydride (8.7 gm) and dichloromethane (90 mL) was stirred at about 20-25° C. for about 4 hrs. To the resulting solution water was added and resulting solution was stirred for about 15 minutes. Organic layer was separated and washed with 1 N HCl solution followed by washing with water. The solvent was distilled out completely. Ethyl acetate was added to the resulting residue followed by stirring at about 25-30° C. for about 3 hrs. The resulting solid was filtered, washed and dried to obtain the title compound (Yield: 80%; HPLC purity: 99.8%; Chiral purity: 99.3%; d0.9 50.7 μm, d0.5 17.3 μm, d0.1 6.0 μm).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8](Cl)=[N:9][CH:10]=1>C(O)C.O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([NH:2][NH2:3])=[N:9][CH:10]=1
Reactant: Clc1ccc(Br)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(Br)cn1

Procedure:
9.3 ml (9.5 g, 190.2 mmol) hydrazine hydrate are added to a solution of 1.8 g (9.5 mmol) 5-bromo-2-chloropyridine in 25 ml ethanol at RT, while stirring, and the mixture is then stirred at 90° C. for 46 h. After concentration of the reaction mixture in vacuo, the residue is stirred in water and the solid is filtered off, washed with water and diethyl ether and dried in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>CN(C=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>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:3][C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(-c3cccnc3)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3ccccn3)cc(-c3cccnc3)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-(5-bromo-7-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.20 g, 0.53 mmol) in DMF (5 mL) was added 2-tributylstannyl pyridine (0.23 g, 0.53 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.061 g, 0.053 mmol). The reaction mixture was then again degassed and heated at 120° C. for 8 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (230-400 M) using EtOAc-Hexane (80:20) to provide the title compound as off white solid (0.012 g, 6%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:5]2.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl-].[Na+]>CN(C)C=O>[N:27]1([CH2:33][CH2:34][NH:35][C:18]([CH:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]3[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]4[C:8]=3[NH:7][C:6]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:5]4)[CH2:13][CH2:14]2)=[O:20])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(NC2CCC(C(=O)O)CC2)c2[nH]c(-c3ccccc3)cc2c1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(NC2CCC(C(=O)NCCN3CCOCC3)CC2)c2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
The compound obtained in Example 55 (30 mg, 0.09 mmol) was dissolved in N,N-dimethyl formamide 5 ml. 2-Morpholine-4-yl-ethylamine (22 mg, 0.17 mmol), EDC (25 mg, 0.19 mmol) and HOBT (18 mg, 0.19 mmol) were added. The mixture was stirred for 8 hours at room temperature. Saturated 1N aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound 40 mg (Yield 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[C:4]([CH3:11])[CH:3]=1.[CH3:12]C(C)([O-])C.[K+].IC.CC(O)=O.C[N:25]([CH:27]=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:9])[C:27]#[N:25])=[C:4]([CH3:11])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(Br)ccc1CC#N
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CI
Solvent: O
Product: Cc1cc(Br)ccc1C(C)(C)C#N
Reaction time: 0.25 h

Procedure:
To a solution of (4-bromo-2-methyl-phenyl)-acetonitrile (1.26 g, 6 mmol) from step 3 above in DMF (15 mL) cooled to −10° C. was added a potassium t-butoxide (1.62 g, 14.4 mmol). The reaction was stirred for 15 minutes, iodomethane (0.86 mL, 13.8 mmol) was added slowly. The reaction was stirred for 2 hours then quenched with HOAc (0.51 mL, 9 mmol). The reaction mixture stirred for 20 minutes and mixed with IPE (250 mL) and water (200 mL). The layers were separated, and the aqueous layer was extracted with 3×100 mL IPE. The combined organics were washed with 200 mL water, and then dried over MgSO4. After filtering off the solids, the mother liquor was concentrated to the crude product by rotary evaporation. The residue was purified by flash column chromatography (0% to 75% EtOAc in Hexane) to give the desired product. Yield: 1.28 g, 89%. 1H NMR (400 MHz, CDCl3): δ 1.77 (6H, s) 2.62 (3H, s) 7.16 (1H, d, J=8.59 Hz) 7.31-7.40 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[Cl:30]N1C(=O)CCC1=O>CN(C=O)C>[Cl:30][C:29]1[C:9]2[C:10](=[N:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:27][N:28]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3[nH]nc(Cl)c3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a solution of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.5 mmol, obtained in example 1) in DMF (5 mL), N-chlorosuccinimide (0.10 g, 0.8 mmol) was added under argon atmosphere and the mixture was heated to 60° C. for 5 h. It was washed with 1 N NaOH and extracted with CHCl3 and EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 171 mg of title compound (yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](S(C)=O)[N:3]=1.[CH3:14][C:15]1[C:16]([CH2:21][OH:22])=[N:17][CH:18]=[CH:19][CH:20]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([O:22][CH2:21][C:16]2[C:15]([CH3:14])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Reactant: Cc1cccnc1CO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1cccnc1COc1nc(N)nc(Cl)c1C#N
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a stirred suspension of 50 mg (0.23 mmol) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile in 1 ml DME were added 28 mg (0.23 mmol) 3-methyl-2-pyridinemethanol and 521l (0.35 mmol) DBU and stirring continued for 30 min at room temperature. 5 ml water was then added and the resulting crystals collected by filtration and washed with ether to afford 22 mg (35%) 2-amino-4-chloro-6-(3-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 278 (M{37Cl}+H+, 35), 276 (M{35Cl}+H+, 100).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCNC(=O)CCl)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chloroacetyl chloride (0.483 mL) was added dropwise over 10 minutes to a vigorously stirred mixture at 0° C. of tert-butyl 4-(2-aminoethyl)-4-hydroxypiperidine-1-carboxylate (example 89, step b) (1.1 g) in ethyl acetate (25 mL) and potassium carbonate (1.77 g) dissolved in water (20 mL). The mixture was then stirred at 0° C. for 45 minutes before being extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.9 g.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:20]1([C:26]2[CH:48]=[CH:47][C:29]([NH:30][C:31]3[N:36]=[C:35]([C:37]4[N:41]([CH:42]([CH3:44])[CH3:43])[C:40]([CH3:45])=[N:39][CH:38]=4)[C:34]([Cl:46])=[CH:33][N:32]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([N:23]1[CH2:24][CH2:25][N:20]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:31]3[N:36]=[C:35]([C:37]4[N:41]([CH:42]([CH3:44])[CH3:43])[C:40]([CH3:45])=[N:39][CH:38]=4)[C:34]([Cl:46])=[CH:33][N:32]=3)=[CH:47][CH:48]=2)[CH2:21][CH2:22]1)=[O:4]
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCNCC4)cc3)ncc2Cl)n1C(C)C
Reactant: CC(C)(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCN(C(=O)C(C)(C)O)CC4)cc3)ncc2Cl)n1C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Hydroxyisobutyric acid (162 mg. 1 mmol) was added to a solution of 1,1′-carbonyldiimidazole (162 mg. 1 mmol) in DCM (4 ml) and stirred at room temperature for 15 minutes. A solution of 2-[4-(piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-5-chloropyrimidine (Example 34. 400 mg. 0.97 mmol) in DCM (8 ml) was added and stirring continued for 19 hours. DCM (25 ml) was added and the organic layer was washed with 5% (v/v) acetic acid (15 ml), water (15 ml), brine (15 ml) and dried before evaporating under reduced pressure. Chromatography on silica gel with MeOH:DCM (4:96 to 8:92) gave the title compound, after ether trituration, as a solid. (67 mg 14%). NMR: (500 MHz) 1.30 (d, 6H), 1.34 (d, 6H), 2.48 (s, 3H), 3.04 (t, 4H), 3.62 (b s, 4H), 4.00 (b s, 4H), 4.79 (septuplet, 1H), 5.41 (s, 1H), 6.90 (d, 2H), 7.22 (s, 1H), 7.48 (d, 2H), 8.51 (s, 1H), 9.49 (s, 1H); m/z 498.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:29].[N:30]1[CH:35]=C[CH:33]=[CH:32][CH:31]=1.ClC(OC1C=CC=CC=1)=[O:38].C1(N)CC1>CN(C)C=O.C(OCC)C.O>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:35]([NH:30][CH:31]4[CH2:33][CH2:32]4)=[O:38])=[C:3]([Cl:29])[CH:4]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[C:17]#[N:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OCc1ccccc1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
After dissolving 4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-cyanoquinoline (8.037 g, 20.0 mmol) in dimethylformamide (40 ml) under a nitrogen atmosphere, pyridine (1.94 ml, 24.0 mmol) and phenyl chloroformate (3.01 ml, 24.0 mmol) were added dropwise at room temperature and the mixture was stirred for 1 hour. Cyclopropylamine (3.46 ml, 50 mmol) was added dropwise, and the mixture was further stirred for 3 hours. Water (400 ml) and diethyl ether (400 ml) were added to the reaction solution, and after stirring overnight, the precipitated crystals were filtered out, washed with water and diethyl ether and dried at 70° C. to obtain the title compound (8.570 g, 17.7 mmol, 88.4%) as light brown crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:19].[Na+].O>O1CCOCC1>[NH2:3][C:4]1[C:5]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:19])=[O:1]
Reactant: O=C1Cc2cccc(S(=O)c3ccccc3)c2N1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(CC(=O)O)cccc1S(=O)c1ccccc1
Yield: 42.4 %

Procedure:
A mixture of 2-oxo-7-phenylsulfinylindoline (4.3 g.), sodium hydroxide (1.2 g.), water (10 ml.) and dioxane (10 ml.) was refluxed for 6 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water and washed with diethyl ether. The aqueous solution was adjusted to pH 4 with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride twice, dried over magnesium sulfate and evaporated under reduced pressure. The residue was washed with a mixture of ethanol and diisopropyl ether to give crystals of 2-(2-amino-3-phenylsulfinylphenyl)acetic acid (1.95 g.).
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([NH2:19])=[N:14][CH:15]=3)[CH2:4][O:3]1.[ClH:21]>O1CCCC1.CO>[ClH:21].[NH2:19][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[CH2:9][CH2:8][CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:15][N:14]=1
Reactant: CC1(C)OCC(CCn2cnc3cnc(N)nc32)CO1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Reaction time: 2 h

Procedure:
To a stirred solution of 2,2-dimethyl-5-[2-(2-aminopurin-9-yl)ethyl]-1,3-dioxane (1 g) in a mixture of tetrahydrofuran (20 ml) and methanol (6 ml ) at room temperature was added concentrated hydrochloric acid (0.32 ml). The resulting mixture was stirred for 2 hours during which time a solid crystallised. The solid was collected by filtration, washed with tetrahydrofuran (2 ml ) and dried under a flow of air to give the desired product as the hydrochloride salt (800 mg, 81% yield).