Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[N:20]=[CH:21][C:22]([C:33](OC)=[O:34])=[N:23][C:24]=1[O:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)(=[O:17])=[O:16].C(O)(=O)C>O1CCCC1>[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:24]([O:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:23][C:22]([CH2:33][OH:34])=[CH:21][N:20]=1)(=[O:17])=[O:16]
Reactant: COC(=O)c1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ncc(CO)nc1OCc1cccnc1)c1cccc(Cl)c1Cl
Temperature: -65 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
Lithium aluminium hydride (0.85 mL of a 1M solution in tetrahydrofuran) was added dropwise to 5-(2,3-dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-carboxylic acid, methyl ester (Example 134) (0.2 g) in tetrahydrofuran (10 mL) cooled to −65° C. The reaction mixture was allowed to warm to room temperature and stirred for 1h. Aqueous acetic acid was added and the mixture extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/methanol mixtures gave the title compound (0.08 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:26]([C:29]1[S:33][CH:32]=[N:31][C:30]=1Br)(=O)[CH3:27]>>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[C:26]([CH3:27])=[C:29]3[S:33][CH:32]=[N:31][C:30]3=[N:1][C:2]=2[C:3]=1[O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:6]
Reactant: COC(=O)c1cccc(N)c1OC(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1scnc1Br
Product: COC(=O)c1ccc2c(C)c3scnc3nc2c1OC(c1ccccc1)c1ccccc1

Procedure:
For example, methyl 3-amino-2-diphenylmethoxybenzoate A27.12 is reacted with 5-acetyl-4-bromothiazole A27.13 (WO 9317681) to afford after cyclization of the initial displacement product, 5-benzhydryloxy-9-methyl-thiazolo[4,5-b]quinoline-6-carboxylic acid methyl ester A27.14. Reaction with N-bromosuccinimide in hexachloroethane then yields the bromomethyl analog A27.15, and this material is reacted with a trialkyl phosphite in an Arbuzov reaction to give the phosphonate A27.16. The product is then reacted with 3,5-dichlorobenzyl methylamine A27.17 and trimethyl aluminum to afford after deprotection the phosphonate A27.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[OH-].[K+].[NH2:14]OS(O)(=O)=O>CN(C)C=O>[NH2:14][N:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: COc1cccc2[nH]ccc12
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc2c1ccn2N
Temperature: 20 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a mixture of 4-methoxyindole (1.26 g, 8.57 mmol), powdered potassium hydroxide (10.05 g, 0.179 mol) and dry dimethylformamide (20 mL) at 15° C. under argon was added, portionwise over 0.2 h, hydroxylamine-O-sulfonic acid. Internal temperature was kept ≦30° C. by external ice bath cooling. The mixture was stirred at 20° C. for 4 h, then was extracted with toluene (4×50 mL). The combined extracts were washed with water (4×50 mL) and brine (50 mL), then dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography of the residue on silica with 5-50% ether in hexane gradient elution gave 1-amino-4-methoxyindole (0.79 g, 56%). A mixture of 1-amino-4-methoxyindole (0.78 g, 4.8 mmol), nitrobenzene (3.4 g, 27.8 mmol), and methanolic HCl (3% w/w, 180 mL) was heated at reflux for 76 h, then cooled and partitioned between 10% aqueous NaOH (50 mL) and dichloromethane (3×30 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was purified by chromatography on silica with 5-100% ether in hexane gradient elution. The resulting 5-methoxycinnoline (0.56 g, 3.5 mmol) was mixed with 48% aqueous HBr (35 mL) and the resulting solution heated at reflux for 18 h. The mixture was cooled, then evaporated in vacuo, and the residue dissolved in water (10 mL). Aqueous ammonia (d=0.880) was added until pH 6 was obtained, and the resulting mixture cooled to 0° C. The precipitated solid was collected by filtration and purified by charcoal-methanol treatment to give the title compound (0.37 g, 53%) as a yellow solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][C@H:11]1[N:16](CC2C=CC=CC=2)[CH2:15][CH2:14][N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[C:1]([NH:9][CH2:10][C@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CNC(=O)c2ccccc2)C1
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN[C@H](CNC(=O)c2ccccc2)C1
Yield: 81.6 %

Procedure:
Into a 40 mL scintillation vial was added 15U (865 mg, 2.11 mmol) and methanol (21 mL). The solution was passed through the H-Cube hydrogentator three times at 40 psi of hydrogen pressure at 50° C. The resultant solution was concentrated under vacuum and the residue was purified by column chromatography with 5% methanol in dichloromethane to give (R)-tert-butyl 3-(benzamidomethyl)piperazine-1-carboxylate (15Fb) as an oil (550 mg, 81%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:18]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCCCCCCCCBr
Reactant: O=[N+]([O-])c1cc(CCNCc2ccccc2)ccc1OCc1ccccc1
Product: O=[N+]([O-])c1cc(CCN(CCCCCCCCN(CCc2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1

Procedure:
Similarly, by employing 1,8-dibromooctane in the above condensation with N-benzyl-4-benzyloxy-3-nitrophenethyl-amine as described above there is obtained the corresponding N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-nitrophenyl)-ethyl]-octamethylenediamine which is carried through the same sequence of reactions, namely reduction with Raney nickel and hydrogenation with palladium-on-carbon, to yield N,N'-bis[2-(3-amino-4-hydroxyphenyl)-ethyl]-octamethylenediamine.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].[Li]CCCC.Cl[CH2:19][C:20](=[O:41])[CH:21]=[P:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1COCC1>[CH2:1]([N:5]([CH2:19][C:20](=[O:41])[CH:21]=[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4]
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Reactant: C=CCCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCCN(CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of tert-butyl N-but-3-enylcarbamate (3.16 g, 18.42 mmol, 1.30 Eq) in THF (20 mL), was added n-BuLi (2.5 M, 14.74 mL, 2.60 Eq) at −78° C. under N2. The mixture was stirred at −20° C. for 1 hr. Then 1-chloro-3-(triphenyl phosphoranylidene)propan-2-one (5.00 g, 14.17 mmol, 1.00 Eq) in THF (20 mL) was added to the mixture at −78° C. under N2. The mixture was stirred at −20° C. for 3 hr. The resulting mixture was poured into water (30 mL) and stirred for 20 min. The aqueous phase was extracted with EA (10 mL). The combined organic phase was washed with saturated brine (20 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=1/1) to afford tert-butyl but-3-en-1-yl(2-oxo-3-(triphenylphosphoranylidene)propyl)carbamate (5.80 g, 11.90 mmol, 83.98% yield) as yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([O:11][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])=[O:10])[CH:2]=[CH2:3]
Reactant: O=C1CCC(=O)N1O
Reactant: C=CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Yield: 54.7 %

Procedure:
A solution of 7(a) (10.00 g), N-hydroxysuccinimide (5.04 g) and DCCI (9.03 g) in dichloromethane(400 ml) was stirred at ambient temperature for 3.5 h. The white precipitate which formed was filtered off and the filtrate evaporated under reduced pressure to give a yellow oil. This was purified by flash chromatography eluting with ethyl acetate/hexane (75:25) to give 5-nitro-isophthalic acid 1-(2.5-dioxo-pyrrolidin-1-yl) ester 3-allyl ester (7(b)) as a yellow solid (7.58 g).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:3][CH2:4][C:5]#[C:6][CH2:7]O.CCOCC.P(Br)(Br)[Br:20]>N1C=CC=CC=1>[Br:20][CH2:7][C:6]#[C:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(C)=CCC#CCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC(C)=CCC#CCBr
Temperature: 25 °C

Procedure:
A mixture of 17 g. of 6-methylundec-2-yn-5-en-1-ol, 32.4 ml. of ether, and 2.07 ml. of pyridine was stirred under nitrogen in an ice-salt bath and 4.5 ml. of phosphorus tribromide was added. The ice-salt bath was then removed and the mixture was first allowed to warm to room temperature, then was heated under reflux for 2.5 hrs. The mixture was again cooled in an ice bath, and 15 ml. each of ether and water were added. The ether layer was separated, washed with aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated. The thus obtained residue was distilled, collecting 14 g. of a mixture comprising 1-bromo-6-methylundec-2-yn-5-ene at 85°-89°C./0.005 mm.
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@@H:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(#N)C.[CH3:24][N:25]=[C:26]=[O:27]>C(N(CC)CC)C>[C:1]([N:11]1[CH2:19][C@@H:18]([O:20][C:26]([NH:25][CH3:24])=[O:27])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: CN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)O[C@H]1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 86 %

Procedure:
To a stirred solution of 5.4 g. (0.019 mole) of N-carbobenzyloxy-cis-4-hydroxy-L-proline, methyl ester, in 120 ml. of acetonitrile is added 5.4 ml. of triethylamine, followed by 5.4 ml. of methyl isocyanate. After keeping overnight at room temperature and refluxing for two hours, the reaction mixture is worked up as in Example 1c to give 5.6 g (86%) of a pale yellow viscous oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@H:14](OS(C(F)(F)F)(=O)=O)[CH:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C=O)C>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: COC1O[C@H](COC(=O)c2ccccc2)C[C@@H]1OS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC1O[C@H](COC(=O)c2ccccc2)C[C@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of [(2S,4S)-5-methoxy-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]methyl benzoate (compound 32c, 400 mg, 1.04 mmol) in DMF (3 mL) was added pyrrolidine (142 mg, 2.0 mmol) at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted by water and extracted with EtOAc, the organic layers were combined and concentrated in vacuo to afford 230 mg crude product of [(2S,4R)-5-methoxy-4-pyrrolidin-1-yl-tetrahydrofuran-2-yl]methyl benzoate (compound 32d) as an oil, which was used in next step without further purification. MS obsd. (ESP) [(M+H)+]: 306.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH2:26]([SH:30])[CH2:27][CH2:28][CH3:29].[OH-].[K+].CN1CCCC1=O.Cl>>[CH2:26]([S:30][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CCCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
5-Chloro-2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole (21.2 g, 0.06 mol), n-butyl mercaptan (7.2 g, 0.08 mol), potassium hydroxide (6.7.1 g, 0.12 mol) and N-methylpyrrolidone (50 g, 0.5 mol) are charged to a reactor and heated to 150° C. The reaction mass is held at 150° C. for 4.5 hours at which time it then cooled to ambient temperature. A mixture of 15 g of concentrated hydrochloric acid aand 70 g of ice are then added to the reactor. The solids are filtered off and washed with water. Thirty gram of crude, wet, yellow crystals are obtained as the title compound. This product can be used "as is" in procedure of Example 33.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:13][CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2[nH]ccc12
Reaction time: 3 h
Yield: 94.7 %

Procedure:
1H-Indole-4-carbaldehyde (219 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to an orange solid and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.0 mg, 1.53 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (1H-indol-4-ylmethyl)-methyl-amine (229 mg, 94%) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ 11.03 (bs, 1H), 7.29-7.24 (m, 2H), 7.03-6.93 (m, 2H), 6.51-6.50 (m, 1H), 3.88 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[N:38]=[C:10]2[CH:11]=[C:12]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)[CH:13]=[C:14]([N:15]3[CH:19]=[CH:18][CH:17]=[N:16]3)[N:9]2[N:8]=1>O1CCOCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:38]=[C:10]2[CH:11]=[C:12]([C:20]3[CH:25]=[N:24][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]4)=[N:22][CH:21]=3)[CH:13]=[C:14]([N:15]3[CH:19]=[CH:18][CH:17]=[N:16]3)[N:9]2[N:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(-n4cccn4)n4nc(N)nc4c3)cn2)CC1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-n3cccn3)n2n1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
Ethyl isocyanate (143 mg, 2.01 mmol) was added to solution of ethyl 1-{5-[2-amino-5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]pyrimidin-2-yl}-4-methylpiperidine-4-carboxylate (180 mg, 0.40 mmol) in 1,4-dioxane (15 mL) and stirred at 80° C. for 22 h. LCMS showed desired product formation. The resultant black reaction mixture was concentrated in vacuo to give a brown tarry solid which was triturated with EtOAc (10 mL) to give the desired product as a grey solid (88 mg, 42%) MS: 519.23 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1B(O)O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Product: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1

Procedure:
was prepared under similar conditions as described in the preparation of Intermediate 1.4. using 2,4-dichloro-5-fluoropyrimidine (Aldrich Chemical Company Inc.) and [2-(benzyloxy)-4-fluorophenyl]boronic acid (ABCR GmbH & CO. KG). The batch was purified by column chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCCC1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1CN
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1CNc1nc(Cl)nc2ccccc12
Yield: 33.8 %

Procedure:
2,4-Dichloroquinazoline (3.0g 0.015 mol) was stirred in a mixture of water (60 ml), tetrahydrofuran (100 ml), o-methylbenzylamine (1.83 g, 0.015 mol) and sodium acetate (1.38 g, 0.017 mol) for a total of 16 hours. The reaction mixture was evaporated under reduced pressure and crystallised from ethanol to give 2-chloro-4-(2-methylbenzylamino)quinazoline (1.44 g, 30%), m.p. 215°-217°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20](O)=[O:21])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]>C1COCC1.CO>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:19][CH2:20][OH:21])[C:23]([CH3:24])([CH3:26])[CH3:25])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]
Reactant: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CCO)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
To a solution of 250 mg (0.42 mmol) of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic acid hydrochloride (Example 6.1) in 2 mL of THF are added dropwise, under argon, 1.06 mL (2.12 mmol) of a 2N borane/dimethyl sulfide complex solution in THF. The reaction medium is stirred for 16 hours at room temperature and then diluted in 10 mL of anhydrous methanol. The solution obtained is concentrated under reduced pressure and the residue is taken up in 20 mL of methanol and then concentrated again under reduced pressure. The residue obtained is then dissolved in 20 mL of a 1/1 THF/aqueous 1N HCl solution mixture and the solution is refluxed for 4 hours. After cooling and concentrating under reduced pressure, the residue is purified by reverse-phase HPLC (RP18), eluting with a 10−2N HCl/acetonitrile gradient of from 0 to 100% acetonitrile over 120 minutes. After concentrating under reduced pressure and freeze-drying, 50 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)-1-(2-hydroxyethyl)-2,2-dimethylpropyl]-5-(2-methylphenyl)pyridine-2-carboxamide hydrochloride are obtained in the form of a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1>CC(C)=O.ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][N:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1
Reactant: ClCc1cccc(Br)c1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of thiomorpholine 1,1-dioxide (0.72 g, 5.4 mmol) and potassium carbonate (0.74 g, 5.4 mmol) in acetone (10 mL) was added bromo-3-chloromethyl-benzene (0.62 mL, 4.9 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated to a waxy solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10%→100% ethyl acetate in hexane). 4-(3-Bromo-benzyl)-thiomorpholine 1,1-dioxide was isolated as a clear viscous oil that solidified to a white solid (1.0 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.49 (s, 1H), 7.41 (ddd, J=6.9, 1.9, 1.9 Hz, 1H), 7.25-7.19 (m, 2H), 3.62 (s, 2H), 3.10-2.96 (m, 8H). MS=304, 306 (MH)+. 120b) N-{3-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.046 g, 34%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (dd, J=6.7, 1.0 Hz, 1H), 8.23 (d, J=8.H Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.68 (dd, J=7.4, 0.9 Hz, 1H), 7.62-7.60 (m, 1H), 7.48 (dd, J=8.1, 1.8 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.05 (t, J=7.1 Hz, 1H), 6.97-6.93 (m, 2H), 3.70 (s, 2H), 3.13-3.01 (m, 11H). MS=512 (MH)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]([N:13]1[CH2:20][C@@H:19](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[C:5]([N:13]1[CH2:20][C@H:19]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)O)N(C(=O)c3ccccc3)C2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To a dry flask was added aluminum trichloride (58 mg, 0.435 mmole) and benzene (3 ml). While stirring under argon, (cis)-1-benzoyl-4-tosyloxy-L-proline (50 mg, 0.128 mmole) was added. After further stirring overnight, the reaction was cooled to 0° C. and quenched with 1N HCl. The resulting mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried, and concentrated in vacuo. The residue consisted of: