Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[CH3:47])[C:8](=[O:35])[C@@H:9]([NH:20][C:21](=[O:34])[C@@H:22]([N:24]([CH2:32][CH3:33])C(=O)OC(C)(C)C)[CH3:23])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2].[ClH:50]>O1CCOCC1.CCOCC>[ClH:50].[C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[CH3:47])[C:8](=[O:35])[C@@H:9]([NH:20][C:21](=[O:34])[C@@H:22]([NH:24][CH2:32][CH3:33])[CH3:23])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Yield: 76 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(ethyl)carbamate (104 mg, 151 μmol) in 4 M HCl in dioxane (754 μl) was stirred for 1 h. The reaction was diluted with Et2O (10 mL) and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(ethylamino)propanamide hydrochloride (72.1 mg, 76%) as a white solid. MS m/z 590 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.Br[C:29]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:29]2([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:26]=1
Reactant: COC(=O)C1(Br)CCCC1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-4-(β-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.46 g), 1-bromo-1-methoxycarbonylcyclopentane (0.87 g), potassium iodide (0.1 g) and potassium carbonate (0.5 g) in methanol (5 mL) is stirred at reflux for 16 h. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[S:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:3]=12.[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:16])[CH:7]=1
Reactant: COC(=O)c1cc2c(Br)cnc(O)c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc2c(Br)cn(C)c(=O)c2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a solution of methyl 4-bromo-7-hydroxythieno[2,3-c]pyridine-2-carboxylate (300 mg, 1.04 mmol) stirred at 0° C. in DMF (6.6 mL) under an atmosphere of nitrogen was added K2CO3 (358 mg, 2.6 mmol). After stirring at 0° C. for 15 min, methyl iodide (177 mg, 1.3 mmol) was added dropwise. The ice bath was removed, and mixture was stirred at rt for 20 min, 50° C. for 2 h, and rt for 10 h. The reaction mixture was treated with water (8 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc (10 to 100%) in DCM to afford the title compound (284 mg, 90%) as a white solid. LCMS (M+H)+=303.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:37]([NH:36][C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=5)=[O:38])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(NC(=O)NCc2ccc(Nc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)cc2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 115 mg (0.3 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine hydrate (see Step 77.5), 0.041 ml (0.318 mmol) of 3-methoxy-phenyl isocyanate and 4 ml of THF is stirred at 20° C. for 15 hours and then concentrated by evaporation in vacuo. After recrystallization of the residue from ethyl acetate/hexane, 4-(3-chloro-phenylamino)-3-{4-[(3-methoxy-phenyl-amino)-carbonylamino-methyl]-phenylamino}-1H-pyrazolo-[3,4-d]pyrimidine is obtained in the form of the monohydrate; m.p. 157-160° C.; ESI-MS: (M−H)−=513.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][C:21]([CH2:23]Br)=[CH:22][C:16]=2[CH:15]=1)=[O:13].O>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][C:21]([CH2:23][O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: COC(=O)c1cc2cc(CBr)ccc2s1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(COc3cccnc3)ccc2s1

Procedure:
3-Hydroxypyridine (0.40 g.) was dissolved in dry N,N-dimethylformamide (10 ml.) and sodium hydride (0.20 g. of 50% dispersion in mineral oil) was added portionwise with stirring and the resulting mixture was stirred at room temperature for 30 minutes. 5-(Bromomethyl)benzo[b]thiophene-2-carboxylic acid methyl ester (1.20 g.) in a few mls of dry N,N-dimethylformamide was then added and the mixture was stirred at room temperature for 30 minutes, and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with a mixture of chloroform and toluene (1:1) first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid (0.40 g.) which was crystallized from isopropanol/petrol (b.p. 60°-80°) to give 5-(3-pyridyloxymethyl)benzo[b]thiophene-2-carboxylic acid methyl ester, m.p. 106°-107° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[C:1]1([C:7]2([C:13]([Cl:19])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1(c2ccccc2)CCCCC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a solution of 1-phenylcyclohexanecarboxylic acid (E7) (0.095 g, 0.46 mmol) in dry dichloromethane (3 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.468 g, 3.68 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at room temperature for 15 minutes and at 40° C. for one hour, then concentrated under reduced pressure to give crude title compound (0.105 g, ca. 100%). The crude product was immediately utilized in the next step of the synthesis without further purification.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:12]([I:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=O.Cl>C(O)C.O>[I:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[NH:3][C:16]([C:15]([F:22])([F:21])[F:14])=[N:8][C:6]2=[O:7]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(=O)c1cccc(I)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1nc(C(F)(F)F)[nH]c2c(I)cccc12
Yield: 98.6 %

Procedure:
EDCI hydrochloride (18.4 g) and 1-hydroxybenzotriazole (9.5 g) were added to a solution of 2-amino-3-iodobenzoic acid (16.4 g) synthesized using the method described in Journal of Medicinal Chemistry, 2004, 47 (6), 1448-1464 in DMF (120 mL), and subsequently ammonia water (21.2 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-iodobenzamide (12.8 g). 60% sodium hydride (2.29 g) was added to a solution of the obtained 2-amino-3-iodobenzamide (5.0 g) in ethanol (95 ml), then ethyl trifluoroacetate (10.8 g) was added thereto, and the mixture was heated to reflux for 15 hours. After cooling, water was added thereto, and the reaction solution was rendered acidic by the addition of 6 N hydrochloric acid. Then, the deposit was filtrated and dried under reduced pressure to obtain compound (4a) (6.4 g, yield based on 2 steps: 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:12]1([C:18]#[C:19][Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: COc1ccc(F)cc1C=O
Reactant: Br[Mg]C#Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
To a stirred solution of 5-fluoro-2-methoxybenzaldehyde (933 mg, 6.05 mmol) in anhydrous THF (15 mL) at 0° C. was added phenylethynyl magnesium bromide solution (1M in THF, 9.0 mL, 9.08 mmol). The temperature was allowed to increase to RT over the course of the reaction. After 18 h, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc (20 mL). The organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 30% EtOAc in cyclohexane) to afford the title compound (1.19 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 7.42-7.32 (m, 6H), 7.16-7.09 (m, 1H), 7.06-7.02 (m, 1H), 6.16-6.13 (d, 1H), 5.78-5.75 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:17][C:11]1([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (5.0 g, 20.55 mmol) in methanol (60 mL) and toluene (100 mL) was added a 2M solution of trimethylsilyldiazomethane (20 mL) in hexanes (the addition was accompanied by effervescence and a small exotherm). The resulting pale yellow solution was allowed to stir at ambient temperature for 1 hr. The solvent was removed under reduce pressure to give the title compound as a pale yellow oil (5.28 g 20.55 mmol, 100%); 1H NMR (CDCl3) δ 1.20 (s, 3H), 1.34-1.39 (m, 2H), 1.44 (s, 9H), 2.03-2.07 (m, 2H), 2.96-3.03 (m, 2H), 3.70 (s, 3H), 3.72-3.77 (m, 2H); MS m/e MH+. 257
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3-(trifluoromethoxy)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: COc1cccc(/C(=C/C=C/C(=O)O)c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
As in Example 115, (2E,4E)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (3.2 g) and 4-nitrophenol (1.73 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (2.35 g) and the mixture was stirred at room temperature for 1.5 hours. The usual work up furnished 4.2 g of crude product which was crystallized from 2-propanol to give 3.5 g of (2E,4E)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:29])[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:25]2[CH2:26][CH2:27][N:22]([C:20](=[O:21])[CH2:19][CH:18]([CH3:17])[CH3:29])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CC(C)CC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CC(=O)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-(3-methylbutyryl)piperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-3-methylbutan-1-one (114 mg, 66%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.36 min, m/z 403.46 (35), 401.44 (M++H, 100). HPLC tr=3.39 min (96.55%) 1H NMR (270 MHz, CDCl3) δ 0.92 (6H, d, J=6.4 Hz, 2CH3), 1.23 (2H, m, CH2), 1.46 (br s, NH), 1.82 (2H, br d, J=12.9 Hz, CH2), 2.05 (1H, hept, J=6.4 Hz, CHMe2), 2.19 (2H, m, CH2), 2.65 (2H, m, CH2), 2.99 (1H, m, CHNH), 3.77 (1H, m, ½CH2), 3.79 (2H, s, CH2NH), 4.40 (1H, br d, J=13.3 Hz, ½CH2), 6.81-6.87 (3H, m, ArH), 7.11 (1H, td, ArH), 7.19-7.25 (3H, m, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 22.80 (CH2), 22.90 (CH3), 25.93 (CH), 32.30, 33.15, 40.23, 42.24, 44.44, 45.65 (CH2), 53.87 (CH), 118.93, 119.62, 124.54, 127.94, 128.71, 129.83, 130.58, 131.79, 154.34, 156.37 (ArC), and 170.91 (C═O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(Br)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and 1-methylpiperazine (100 mg, 1.02 mmol) in CH3CN (6 mL) was added Cs2CO3 (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (280 mg, 75% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C@H:22]1[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[Cl:12][C:10]1[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]2)=[C:6]([CH2:5][O:4][CH2:1][CH:2]2[CH2:3][O:41]2)[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: ClCCl
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC3CO3)cc2Cl)cc1
Temperature: 40 °C

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (463 mg, 1 mmol) in CH2Cl2 (2 mL) at 0° C., was added mCPBA (350 mg, 2 mmol). The mixture was heated to 40° C. and kept at that temperature overnight. Upon being cooled to room temperature, 10 mL of CH2Cl2 was added to dilute the solution. The solution was then washed with aqueous NaHCO3 and brine prior to drying over Na2SO4. The solvent was removed under reduced pressure and purification of the resulting mixture with preparative TLC gave two isomers with undetermined absolute configurations.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][CH3:13])[CH2:4][NH:5][C:6](=[O:11])[C:7]([O:9]C)=O.[Cl:14][C:15]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>C(Cl)Cl.Cl>[Cl:14][C:15]1[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:2]1[C@@H:3]([CH2:12][CH3:13])[CH2:4][NH:5][C:6](=[O:11])[C:7]1=[O:9]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: CC[C@H](N)CNC(=O)C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 37.7 %

Procedure:
To an ice cold solution of (S)-methyl 2-((2-aminobutyl)amino)-2-oxoacetate hydrochloride (967 mg, 4.6 mmol) and 2-chloro-3-trifluoromethylbenzaldehyde (957 mg, 4.6 mmol) in DCM (26 mL) was added sodium triacetoxyborohydride (1.46 g, 6.9 mmol). The resulting mixture was allowed to warm to rt and stirred for 13 h. Triethylamine (1.9 mL) was added, and after 2 h the reaction was diluted with 1M HCl. The organic layer was washed with sat. aq. NaHCO3 and brine, then dried (Na2SO4), and concentrated to afford a clear oil. Purification by chromatography (SiO2; hexanes—10% IPA/EtOAc) provided the desired product as a white solid (580 mg, 38%). MS (ESI): mass calcd. for C14H14ClF3N2O2, 334.1; m/z found, 335.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=4.5 Hz, 1H), 7.68 (dd, J=7.8, 1.1 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 5.28 (d, J=15.5 Hz, 1H), 4.48 (d, J=15.5 Hz, 1H), 3.70 (dd, J=13.4, 4.2 Hz, 1H), 3.44 (ddd, J=13.4, 5.5, 1.6 Hz, 1H), 3.37-3.28 (m, 1H), 1.25-1.17 (m, 2H), 0.99 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1Br.BrCC.[Mg].C[O:16][B:17](OC)[O:18]C.Cl>CCOCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[B:17]([OH:18])[OH:16]
Reactant: Clc1cc(Cl)c(Cl)c(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CCBr
Product: OB(O)c1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of 2,3,5-trichlorobromobenzene (8.60 g, 0.033 mole) in dry ether (33 ml) and bromoethane (4.73 ml, 7.31 g, 0.067 mole) was added dropwise to a suspension of magnesium turnings (2.809, 0.12 mole) in dry ether (21.50 ml) at room temperature. The mixture was refluxed for 0.50 hr and cooled to room temperature. The mixture was then added dropwise under nitrogen to a solution of trimethylborate (5.16 ml, 5.16 g, 0.05 mole) in dry ether (8.60 ml) maintaining the temperature below −60° C. This was warmed to room temperature overnight, then cooled in an ice-bath and treated with 2M hydrochloric acid (10 ml). The ether layer was separated, washed with water (2×20 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 4.57 g (61%), M.p. 257-260° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]=[CH:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(O)(C)C>[C:4]([NH:6][CH:7]=[CH:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)NC=Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)N
Solvent: CC(C)O
Product: CCOC(=O)NC=Cc1ccc(OCC(O)CNC(C)(C)C)cc1

Procedure:
Analogously to the description in Example 2, 2.5 g (0.01 mol) of 1-[p-(2-ethoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane, on reaction with 1.0 ml (0.01 mol) of tert.-butylamine in 50 ml of isopropanol, yield 1-[p-(2-carbethoxyaminovinyl)-phenoxy]-2-hydroxy-3-tertiary-butylaminopropane as an oil. Its N-cyclohexyl-sulphamate, prepared in acetone, shows a melting point of 99°-100° C. (from ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[Cl:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([S:34]([CH2:33][CH2:32][CH2:31][Cl:30])(=[O:36])=[O:35])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(=O)(=O)CCCCl)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (78 mg, 0.19 mmol) and TEA (0.52 mL, 3.78 mmol) in DCM (10 mL) was added 3-chloropropane-1-sulfonyl chloride (63 mg, 0.36 mmol, in 1 mL DCM). After stirring at rt for one hour, EtOAc (100 mL) was added. The mixture was sequentially washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica chromatography (0-100% EtOAc in hexanes gradient) to give 5-chloro-N2-(4-(1-(3-chloropropylsulfonyl)piperidin-4-yl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off white solid; ESMS m/z 552.2 (M+H+).