Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[O:14][CH2:15][CH2:16][OH:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([CH2:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[O:14][CH2:15][CH2:16][O:17][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1CS(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 68.7 %

Procedure:
A mixture of 2-(3-benzenesulfonylmethyl-4-nitro-phenoxy)-ethanol (8.2 g, 24 mmol), p-toluenesulfonyl chloride (9.39 g, 49.3 mmol) and triethylamine (19 mL, 140 mmol) in methylene chloride (85 mL) was stirred at ambient temperature under nitrogen for 4.5 hours. It then was solvent evaporated and partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 63° C. for 30 minutes. The residue was purified by flash chromatography with 100% chloroform and 5% methanol in chloroform. It was dried in vacuo at 65° C. for 20 minutes to yield toluene-4-sulfonic acid 2-(3-benzenesulfonylmethyl-4-nitro-phenoxy)-ethyl ester as a yellow solid (8.1 g, 69%); Mass spectrum (−EI, [M−H]−) m/z 490. 1HNMR (300 MHz, DMSO-d6): δ7.99 (d, 1H, J=9.02 Hz), 7.67-7.75 (m, 3H), 7.54-7.62 (m, 4H), 7.43 (d, 2H, J=7.93 Hz), 7.00 (dd, 1H, J=9.15 Hz and 2.80 Hz), 6.78 (d, 1H, J=2.81 Hz), 5.09 (s, 2H), 4.29-4.31 (m, 2H), 4.13-4.15 (m, 2H), 2.37 ppm (s, 3H). Elemental Analysis for C22H21NO8S 0.40 mol H2O: Calcd: C, 52.98; H, 4.41; N, 2.81; Found: C, 52.67; H, 4.26; N, 2.61.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([O:17][C:18]2[C:19]([O:30][CH3:31])=[CH:20][CH:21]=[C:22]3[C:27]=2[O:26][C:25](=[O:28])[CH:24]=[C:23]3[OH:29])[CH2:16][CH2:15][CH2:14][CH2:13]1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:29][C:23]2[C:22]3[C:27](=[C:18]([O:17][CH:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)[C:19]([O:30][CH3:31])=[CH:20][CH:21]=3)[O:26][C:25](=[O:28])[CH:24]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(O)cc(=O)oc2c1OC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(OS(=O)(=O)c3ccc(C)cc3)cc(=O)oc2c1OC1CCCC1
Reaction time: 20 h

Procedure:
4-Methylbenzene-1-sulfonyl chloride (135 mg, 0.71 mmol) was added to a solution of 8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one (175 mg, 0.63 mmol), pyridine (0.15 mL, 1.85 mmol), and anhydrous dichloromethane (4 mL) at rt under N2. After 20 h, the reaction was concentrated and purified by silica gel chromatography (1:0→7:3; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-yl 4-methylbenzenesulfonate: MS (ESI): 431.3.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH3:19].O>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][CH2:18][CH3:19])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: CCCI
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(Cl)cc(=O)n(C)c1=O

Procedure:
6-chloro-3-methyl uracil (10 g) and potassium carbonate (10.34 g) in DMF (70 ml) under nitrogen was treated with n-propyl iodide (25.4 g) and heated at reflux for 8 h. The reaction 30 was cooled and then poured into water (700 ml) and extracted with ethyl acetate. The combined organics were dried and evaporated in vacuo to afford the subtitle compound an orange oil, 17.52 g. δ 1HCDCl3 0.98 (3H, t), 1.74 (2H, sextet), 3.33 (3H, s), 4.02 (2H, t), 8.02 (1H, s).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccnc1Br
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ncccc3C)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 2-bromo-3-methylpyridine
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Si](C)(C)C)=[CH:17][C:16]=1[F:25].[Br:27]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:27])=[CH:17][C:16]=1[F:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of 2-(2-fluoro-4-trimethylsilanylphenylamino)-6-formylamino methyl-nicotinic acid methyl ester (11.6 g, 30.9 mmol) in DCM (300 mL) at −30° C. was added N-bromo succinimide (5.56 g, 30.9 mmol) portionwise. The reaction mixture was stirred at −30° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was separated and washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange gum (11.8 g, 100%). LCMS (Method B): RT=3.67 min, M+H+=382/384.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:11].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([Br:11])[CH:4]=1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c(Br)c1
Yield: 97 %

Procedure:
A mixture of 87.6 g (0.38 mole) of 95% pure 4-fluoro-3-bromo-benzoic acid, 200 ml of methanol and 3 ml of sulphuric acid was boiled under for 18 hours. The excess methanol was then distilled off in vacuo, 300 ml of toluene were added and the solution was shaken first with 50 ml of water, then with 50 ml of saturated sodium bicarbonate solution and subsequently with 50 ml of water again. Thereafter, the solvent was distilled off in vacuo and the residue was distilled in vacuo. 86 g (97% of theory) of 4-fluoro-3-bromo-benzoic acid methyl ester were obtained in this manner in the form of a colorless oil which solidified as crystals when cold and had a boiling point of 64° C./0.1 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[C:31]1=[O:38].Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:35]([CH:32]2[CH2:33][CH2:34][N:30]([CH3:29])[C:31]2=[O:38])=[O:36])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[N:9]=[C:10]([I:26])[C:11]=12
Reactant: CN1CCC(C(=O)O)C1=O
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (300.0 mg, 0.6119 mmol), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (87.59 mg, 0.6119 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (351.9 mg, 1.836 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (248.0 mg, 1.836 mmol), N-ethyl-N-isopropylpropan-2-amine (395.4 mg, 3.060 mmol) and THF (50 mL). The reaction mixture was stirred at ambient temperature overnight, and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (0.360 g, 95.6%). LRMS (APCI pos): m/e 616 (M+1). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.31 (d, 1H), 7.79 (dd, 1H), 7.36 (d, 2H), 7.29 (m, 1H), 7.20 (t, 1H), 6.83 (m, 2H), 6.20 (d, 1H), 5.61 (s, 2H), 3.78 (s, 3H), 3.42-3.50 (m, 3H), 2.94 (s, 3H), 2.50-2.61 (m, 1H), 2.35-2.48 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].COCN[C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: COCNC(=O)C1CCCC1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Product: COC(=O)c1sc(C(=O)C2CCCC2)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and cyclopentanecarboxylic acid methoxymethylamide were reacted by method Z. The product with the molecular weight of 349.33 (C15H17F2NO4S) was obtained in this way; MS (ESI): 350 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52](=[O:65])[C:53]2[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=2)=[CH:46][C:40]=1[O:41][CH2:42][C:43](O)=[O:44]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52](=[O:65])[C:53]4[CH:54]=[C:55]([O:63][CH3:64])[C:56]([O:61][CH3:62])=[C:57]([O:59][CH3:60])[CH:58]=4)[CH:48]=[CH:49][C:39]=3[O:38][CH3:37])[S:10][C:6]=2[CH:5]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 805.1 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9j) (498 mg, 80% yield)
Reaction SMILES: C(O[C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)=[O:5])C.[CH3:15][CH2:16][O:17][C:18]([CH3:20])=[O:19].C(O[K])(C)(C)C>C1(C)C=CC=CC=1>[O:5]=[C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:10]=1)[CH2:20][C:18]([O:17][CH2:16][CH3:15])=[O:19]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1nc(C(F)(F)F)cs1
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1nc(C(F)(F)F)cs1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 4-trifluoromethylthiazole-2-carboxylic acid ethylester (8.88 mmol) in toluene (50 mL) were added successively EtOAc (13.32 mmol) and tBuOK (17.76 mmol). The resulting mixture was stirred at 100° C. for 1 hr. The solvent was removed by evaporation and water and Et2O were added. The solution was neutralized with acetic acid. The extract was washed with water and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 28 as a yellow oil in 45% yield. MS (ESI, EI−): m/z=266 (MH−).
Reaction SMILES: O1CCOCC1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C(N(CC)CC)C>[C:32]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCCCCO)cc2)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 500 ml of dry dioxane in a reaction flask are added 9.0 g of 4-(6-hydroxyhexyloxy)-4'-nitrostilbene and 5 g triethylamine. The solution is heated to 50° C., and 3.7 g of methacryloyl chloride is added dropwise. The reaction is stirred at 45°-50° C. for about 6 hours and an additional 3.7 g of methacryloyl chloride is added. The reaction mixture is stirred for about 10 hours at 50° C., the dioxane is removed and the resultant residue is slurried with water in a blender. The solid is filtered, washed with water, and dried. The crude product is recrystallized from ethanol, mp 90°-95° C.
Reaction SMILES: [Cl:1]C1N=C(Cl)N=C(Cl)N=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH:18](O)[CH3:19]>CN(C)C=O.ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH:18]([Cl:1])[CH3:19]
Reactant: CC(O)c1c(Cl)cccc1Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cl)c1c(Cl)cccc1Cl
Yield: 100.3 %

Procedure:
a solution of 5 g of 2,4,6-trichloro-1,3,5-triazine in 5.5 cm3 of N,N-dimethylformamide is stirred for about 3 hours at a temperature close to 20° C. A white precipitate forms. A solution of 5 g of 1-(2,6-dichlorophenyl)-ethanol in 72 cm3 of dichloromethane is added dropwise without exceeding 25° C. After about 48 hours at a temperature close to 20° C., the suspension is solubilized by adding 150 cm3 of dichloromethane. The solution obtained is washed five times with 40 cm3 of water, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. After filtration of the residue on 100 cm3 of silica [eluent: cyclohexane/ethyl acetate (75/25 by volume)], we obtain 5.5 g of 1,3-dichloro-2-(1-chloroethyl)benzene in the form of a colorless oil, which has the following characteristics:
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:23]1
Reactant: BrCC1COc2ccccc2O1
Reactant: COc1cccc(C2CCCNC2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(C2CCCN(CC3COc4ccccc4O3)C2)c1
Temperature: 145 °C
Yield: 31.3 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (36 mg, 0.16 mmol), 3-(3-methoxyphenyl)piperidine HCl (36 mg, 0.16 mmol) and triethylamine (40 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 300 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 17 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9]([CH2:15][OH:16])=[N:10][CH:11]=[CH:12][C:13]=1Cl>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:15][OH:16])[C:8]=2[Cl:7])[CH2:2][CH2:3]1
Reactant: OCc1nccc(Cl)c1Cl
Reactant: C1COCCN1
Solvent: CCO
Product: OCc1nccc(N2CCOCC2)c1Cl

Procedure:
Morpholine (7.34 ml) and 3.4 -dichloro-2 -hydroxymethylpyridine (3.0 g) were heated together in a bomb at 180 ° for 4 hours. After cooling, the mixture was taken up in ethanol and evaporated under reduced pressure to remove excess amine. The residue was taken up in water and extracted with chloroform. After drying (K2CO3 ) and removal of solvent, the residue was chromatographed (silica gel, CHCl3) to give an oil which was crystallised from petroleum ether (60/80 ) to give 4 -morpholino-3 -chloro-2 -hydroxymethylpyridine, 3.24 g, m.p. 80°-2°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:13]1([CH2:9][C:8]2[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-acetamidobenzaldehyde (200 mg), piperidine (0.121 mL), NaBH(OAc)3 (636 mg) and DIPEA (0.617 mL) in DCM (4 mL) was stirred at RT for 4 h. DCM and sat. NaHCO3 were added. The phases were separated, the org. layer was dried (Na2SO4), filtered off and evaporated to dryness to afford 267 mg of white solid. LC-MS (B): tR=0.45 min; [M+H]+: 233.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:9](=[S:21])[NH2:10])=[CH:6][CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: NC(=S)C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-chlorophenyl)-2-(4-nitrophenyl)acetonitrile (1.000 g, 3.667 mmol, 1 equip) and phosphorus pentasulfide (1.63 g, 7.334 mmol, 2 equip) in EtOH (20 mL) was heated at reflux temperature for 20 h. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with hot ethyl ether to yield 2-(4-chlorophenyl)-2-(4-nitrophenyl)ethanethioamide as a yellow solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][C:25]([NH:29][CH2:30][CH2:31][OH:32])=[N:26][CH:27]=3)[NH:22][N:21]=2)[CH:17]=[CH:16][N:15]=1>ClCCl.CO>[CH3:12][S:13]([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][C:25]([NH:29][CH2:30][CH2:31][OH:32])=[N:26][CH:27]=3)[NH:22][N:21]=2)[CH:17]=[CH:16][N:15]=1)=[O:9]
Reactant: CSc1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 257.8 %

Procedure:
m-CPBA (797 mg, 4.62 mmol) was added slowly to a solution of 2-[3-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol (from Example 20 supra) (0.7 g, crude) in a mixture of dichloromethane and methanol (40 mL, 1:1). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was then removed under reduced pressure and the solid was purified by column chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 5:1) to afford 2-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol (Yield 1.9 g, crude). LC-MS: [M+H]+ 320.
Reaction SMILES: Cl.Cl.[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][N:21]([C:25](=[O:27])[CH3:26])[CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCC1CNCCO1)N1CCN(c2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Yield: 78.1 %

Procedure:
To a stirred solution of morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate dihydrochloride (Example 10; 0.52 g, 1.40 mmol) in pyridine (2.25 mL, 27.7 mmol) was slowly added acetyl chloride (0.15 mL, 2.10 mmol). The reaction mixture was stirred at room temperature for 1 h before the pyridine was removed in vacuo and the resulting residue diluted with sat aq NaHCO3 solution (50 mL). The organic product was extracted with EtOAc (3×50 mL). The combined organic layers were washed with sat aq NaHCO3 solution (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, 20 mL/min, gradient 0% to 5% MeOH in EtOAc). The solvents were removed in vacuo and dried in a vacuum oven overnight to afford (4-acetylmorpholin-2-yl)methyl 4-phenylpiperazine-1-carboxylate (0.38 g, 78%) as a pale brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([NH:42][CH:43]1[CH2:45][CH2:44]1)[C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([NH:42][CH:43]1[CH2:44][CH2:45]1)[C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCNCC(NC2CC2)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)C(CNCCOc2ccc(C(=O)O)cc2OC)NC2CC2)ccc1NC(=O)Nc1ccccc1C
Yield: 32.2 %

Procedure:
A mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-N-[2-cyclopropylamino]ethylamino]ethoxy]benzoate (195 mg, 0.30 mmol)) in THF:MeOH(4:1, v/v) (5 mL) and 1 N NaOH (0.756 mL) was stirred at 50° C. for 15 hr. The pH of the mixture was adjusted to 7.4 by the addition of 1 N HCl, and extracted with CHCl3:MeOH(9:1, v/v). The extract was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was crystallized with Et2O to give 57 mg (38%) 3-methoxy-4-[[2-[3-methoxy-4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-[2-cyclopropylamino]ethylamino]ethoxy]benzoic acid 264 as a white crystalline material. mp 135–140° C.; IR (KBr), 3324, 2937, 1535, 1032, 754 cm−1; 1H-NMR (CD3OD, 400 MHz) δ 0.50–0.73 (m, 4H), 2.29 (s, 3H), 2.53 (m, 1H), 2.98 (m, 1H), 3.21 (m, 1H), 3.58–3.88 (m, 11H), 3.91 (s, 1H), 4.09 (m, 1H), 4.25 (m, 1H), 6.76–6.92 (m, 3H), 7.01 (m, 1H), 7.18 (m, 2H), 7.60 (m, 3H), 8.00 (d, J=8.3 Hz, 1H); MS (FAB) m/z 591(M+H)+; Anal. Calcd. for C32H38N4O7.3.0H2O, C, 59.62; H, 6.88; N, 8.69. Found, C, 59.25; H, 6.29; N, 8.29.