Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:65]([SH:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:65]([S:72][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: Cc1c(Br)ccc2c(Cl)ccnc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(SCc2ccccc2)ccc2c(Cl)ccnc12
Temperature: 110 °C
Yield: 99.2 %

Procedure:
To a vial charged with 7-bromo-4-chloro-8-methylquinoline (0.950 g, 3.70 mmol) was added Dioxane (14.81 ml), DIEA (1.294 ml, 7.41 mmol), xantphos (0.429 g, 0.741 mmol), Pd2(dba)3 (0.339 g, 0.370 mmol) and benzyl mercaptan (0.438 ml, 3.70 mmol). The vessel was sealed and heated to 110° C. for 3 hr affording complete conversion according to LC-MS. The mixture was filtered through Celite and dried under reduced pressure and purified with a 25 g Interchim column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording product as a yellow oil as a mixture of mono and bis substituted product according to MS as one LC peak, 7-(benzylthio)-4-chloro-8-methylquinoline (1.100 g, 3.67 mmol, 99% yield). m/z (ESI) 300.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].[Cs+].[C:10]1([CH2:16][N:17]2[CH2:21][CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>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>[C:10]1([CH2:16][N:17]2[CH2:21][CH:20]=[C:19]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)C2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: C1=C(c2ncccn2)CN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 6 h
Yield: 22.8 %

Procedure:
To a solution of 2-bromopyrimidine (0.88 g) in dry tetrahydrofuran (30 mL) 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (P13, 1.21 g), tetrakis(triphenylphosphine)palladium(0) (0.25 g) and cesium fluoride (2.59 g) were added at room temperature. The resulting mixture was stirred at 80° C. for 6 hours. After cooling the solvent was evaporated under reduced pressure, the residue partitioned between ether and water and the organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with DCM/MeOH from 100% to 96%) to give 0.23 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][O:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A mixture of N-t-butoxycarbonyl-2-hydroxy-5-chloro-benzylamine (730 mg, 2.83 mmol), Cs2CO3 (923 mg, 2.83 mmol) and ethylbromoacetate (0.314 ml, 2.83 mmol) in DMF (5 ml) was stirred for 2 h. The crude reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil which was used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH3:11].CO[CH:14](OC)[CH2:15][NH2:16]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]2[C:6](=[CH:5][C:4]=1[CH3:11])[CH:7]=[N:16][CH:15]=[CH:14]2
Reactant: COc1ccc(C=O)cc1C
Reactant: COC(CN)OC
Solvent: c1ccccc1
Product: COc1cc2ccncc2cc1C
Temperature: -10 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
4-Methoxy-3-methylbenzaldehyde (3.00 g) was dissolved in benzene (30 ml) to prepare a solution. 2,2-Dimethoxy-ethylamine (2.10 g) was added to the solution, and the mixture was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure, the residue was then dissolved in tetrahydrofuran (30 ml), and the mixture was cooled to −10° C. Ethyl chloroformate (2.17 g) and trimethyl phosphite (2.97 g) were added thereto, and mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, the residue was then dissolved in dichloromethane (30 ml), titanium tetrachloride (22.7 g) was added to the solution, and the mixture was heated under reflux for 36 hr. The reaction solution was cooled to room temperature, was then neutralized with a 1 N aqueous sodium hydroxide solution, and was extracted with 3 N hydrochloric acid. The aqueous layer was made basic by the addition of a 3 N aqueous sodium hydroxide solution and was then extracted with dichloromethane. The solvent was removed by distillation under the reduced pressure to give 6-methoxy-7-methylisoquinoline (764 mg, yield 22%).
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To an acetic acid (4.1 mL) and dimethyl sulfoxide (70 mL) solution of 1-((E)-2-nitro-vinyl)-4-phenoxymethyl-benzene (4.1 g, 16.2 mmol) described in Manufacturing Example 86-1-3 was added sodium borohydride (981 mg, 25.9 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (2.11 g, 51%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:13](C=C)=[CH:12][C:11](CO)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([Br:42])(Br)(Br)Br.C(Cl)[Cl:44]>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:13]([Cl:44])=[CH:12][C:11]([CH2:38][Br:42])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cc(CO)cnc1NC(=O)OC(C)(C)C
Reactant: ClCCl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(CBr)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a stirred suspension of (5-hydroxymethyl-3-vinyl-pyridin-2-yl)carbamic acid tert-butyl ester (10.0 g, 40.0 mmol) in CH2Cl2 (150 ml) and THF (60 ml) was added triphenylphosphine (11.5 g, 44.0 mmol) followed by carbontetrabromide (19.9 g, 60.0 mmol) at 0° C. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. Acetonitrile (100 ml) was added and the mixture was kept at −20° C. overnight. The mixture was then filtered and the crystalline residue washed with cold acetonitrile. The product was purified by flash-chromatography (1% MeOH in dichloromethane) to give (5-bromomethyl-3-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (4.5 g, 36%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH:9]1[C:24](O)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][NH2:30].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:10][CH:9]1[C:24](=[O:25])[NH:30][O:29][CH3:28])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1C(=O)O
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester (0.364 g, 1 mmol) in dichloromethane (3 mL) was added O-Methyl Hydroxylamine HCl (95 mg, 1.13 mmol), EDC HCl (0.3 g, 1.57 mmol) and DIEA (0.28 g, 2.17 mmol). The resulting mixture was stirred at room temperature overnight and partitioned between dichloromethane and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/n-Hexane (30/70) to afford the title product.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]3[N:19]=[CH:20][C:21]4[CH:26]=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:24]([CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[C:22]=4[N:23]=3)=[N:15][CH:16]=1)=[O:10])[CH2:2]2.C(O[BH-]([O:46][C:47](=O)[CH3:48])OC(=O)C)(=O)C.[Na+].Cl[CH2:52]Cl>>[CH:32]1([N:24]2[C:22]3[N:23]=[C:18]([NH:17][C:14]4[CH:13]=[CH:12][C:11]([C:9]([N:3]5[CH2:4][CH:5]6[N:8]([CH:48]([CH3:52])[CH2:47][OH:46])[CH:1]([CH2:7][CH2:6]6)[CH2:2]5)=[O:10])=[CH:16][N:15]=4)[N:19]=[CH:20][C:21]=3[CH:26]=[C:25]2[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: ClCCl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Agent: [Na+]
Product: CC(CO)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Temperature: 25 °C
Yield: 33 %

Procedure:
To a solution of 2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (105 mg, 0.22 mmol) in dichloromethane (2 ml) 1-hydroxypropan-2-one (2 ml) was added and the resulting reaction mixture was stirred for 1H at room temperature. Sodium triacetoxyborohydride was added and the reaction mixture was stirred at room temperature overnight. When TLC/LCMS show completion the reaction mixture is diluted with dichloromethane, washed with sat NaHCO3 (2×) and brine. The combined aqueous layers back extracted with dichloromethane and the combined organic layers are dried over sodium sulfate, filtered, concentrated and purified by column chromatography (0-20% methanol/dichloromethane) which gave 7-cyclopentyl-2-(5-(8-(1-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (39 mg, 33% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.07 (s, 1H) 8.85 (s, 1H) 8.57 (d, J=9.09 Hz, 1H) 8.45 (s, 1H) 7.78 (dd, J=8.59, 2.53 Hz, 1H) 6.48 (s, 1H) 4.81 (dq, J=9.09, 8.93 Hz, 1H) 4.48 (br. s., 1H) 3.75-3.30 (m, 6H) 3.23-3.00 (m, 7H) 2.69-2.50 (m, 3H) 2.16-1.97 (m, 5H) 1.97-1.66 (m, 6H) 1.10 (d, J=6.06 Hz, 3H); HR-MS (m/z MH+) 547.32 RT 2.54 min.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1.[CH:14]1([C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH2:16][CH2:15]1>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2cc(I)ccc2n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(I)ccc2n1
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a suspension of 2,4-Dichloro-6-iodo-quinazoline (3.14 g, 9.66 mmol) in ethanol (200 mL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (2.14 g, 19.3 mmol) in ethanol (50 mL) and the partial solution was stirred for 4 h. Filtration afforded (2-Chloro-6-iodo-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (3.21 g, 81% yield). HNMR (500 MHz, dmso) δ 12.39 (1H, bs), 10.97 (1H, s), 9.15 (1H, s), 8.13 (1H, d), 7.45 (1H, d0, 1.99-1.90 91H, m), 0.99-0.90 (2H, m), 0.80-0.70 (2H, m).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])(OC(C)(C)C)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCCC/C=C/C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCCCC/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 45 mL trifluoroacetic acid and mL water was chilled in an ice bath while 34 g (0.132 mole) of (9) was added with stirring. The resulting solution was allowed to warm to room temperature over 1.5 h and then evaporated under a slow nitrogen stream overnight. The residue was triturated with ether. The solid was filtered, rinsed well with ether and dried to yield 21 g of the title compound (10), mp 77°-78° C. Anal. Calcd. for C10H15NO4F3 : C, 44.28; H, 5.95; N, 5.16. Found: C, 4.07; H, 5.96; N, 5.09.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:20]([CH3:21])[CH2:19][CH2:18][C:17]([C:22](O)=[O:23])=[CH:16][C:15]=3[CH:25]=2)=[CH:7][CH:6]=1)[CH3:3].S(Cl)(Cl)=O.[CH3:30][N:31]([CH3:34])[CH:32]=O>>[CH2:2]([O:4][CH2:5][CH2:6][CH2:30][N:31]([CH2:32][C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:22]([C:17]2[CH2:18][CH2:19][N:20]([CH3:21])[C:14]3[CH:13]=[CH:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH2:2][CH3:3])=[CH:10][CH:9]=4)=[CH:25][C:15]=3[CH:16]=2)=[O:23])=[CH:15][CH:25]=1)[CH3:34])[CH3:3]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOCCCN(C)Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCC)cc4)ccc3N(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In dimethylformamide (5 ml) was dissolved 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylic acid hydrochloride (0.5 g), and to the mixture was added, under ice-cooling, thionyl chloride (0.25 ml). The mixture was stirred at room temperature for 45 minutes, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the mixture was added dropwise to a suspension of 4-((N-(3-ethoxypropyl)-N-methylamino)methyl)aniline dihydrochloride (0.41 g) and triethylamine (1.2 ml) in tetrahydrofuran (10 ml), under ice-cooling. Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-((N-(3-ethoxypropyl)-N-methylamino)methyl)phenyl)-7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 319) (0.39 g) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[O:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:23]2([OH:26])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(I)cn1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2ccc(Br)nc2)CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-bromo-5-iodopyridine (2.00 g) in tetrahydrofuran (20 mL) and diethyl ether (10 mL) was added dropwise 1.6M n-butyllithium hexane solution (4.40 mL) at −78° C. The mixture was stirred at −78° C. for 30 min under argon atmosphere, and a solution of tetrahydro-4H-pyran-4-one (0.651 mL) in tetrahydrofuran (10 mL) was added dropwise thereto at −78° C. The reaction mixture was slowly warmed to −50° C., aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.932 g).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][NH:21][C:22](=[O:25])[O:23][CH3:24]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][NH:21][C:22]([O:23][CH3:24])=[O:25])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: COC(=O)NCCO
Product: COC(=O)NCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and methyl 2-hydroxyethylcarbamate, there is obtained 2-methoxycarbonylamino-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 339 (5), 308 (2), 237 (22), 194 (56), 102 (100);
Reaction SMILES: C1(C)C=CC([C@]([C@H](C(O)=O)O)(O)C(O)=O)=CC=1.[CH:18]([N:21]([CH2:25][CH2:26][CH:27]([C:34]1[CH:39]=[C:38]([Br:40])[CH:37]=[CH:36][C:35]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].[OH-].[Na+]>O>[CH:18]([N:21]([CH2:25][CH2:26][C@@H:27]([C:34]1[CH:39]=[C:38]([Br:40])[CH:37]=[CH:36][C:35]=1[O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:22]([CH3:24])[CH3:23])([CH3:19])[CH3:20]
Reactant: CC(C)N(CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: Cc1ccc([C@](O)(C(=O)O)[C@@H](O)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C

Procedure:
To the obtained p-toluyl-L-tartaric acid salt of N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine of formula (E) added 500 ml R.O. Water and 300 ml MDC reaction cooled to 0° C. to 5° C. and pH was adjusted at 9 to 10 by 10% sodium hydroxide followed by raising of temperature to 25° C. to 35° C. Layers were separated and MDC layer washed with 2×200 ml 20% brine solution and finally MDC was distilled out under vacuum below 50° C. to afford title compound (R)—N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-Phenylpropylamine compound of formula (F).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[O:8][CH2:9][CH2:10][OH:11].CC(C)([O-])C.[K+].Cl[C:24]1[C:29]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[CH3:36])=[N:28][CH:27]=[CH:26][N:25]=1>CN(C=O)C>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:24]1[C:29]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[CH3:36])=[N:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Reactant: CN(C)CCOc1ccccc1OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1ccccc1OCCN(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 2-{2-[2-(dimethylamino)ethoxy]phenoxy}ethanol (from Step 3; 0.82 g, 3.6 mmol) in dry DMF (25 mL) was added potassium tert-butoxide (0.59 g, 5.3 mmol) and the mixture was stirred at room temperature for 10 minutes. To the mixture was added 2-chloro-3-[(2R)-2-methylpiperazin-1-yl]pyrazine* (0.70 g, 3.3 mmol) in DMF (5 mL) in one portion and the reaction mixture was stirred at 55° C. for 2 h. A small spoon of silica was added, the solvent was filtered off and the solvent was evaporated under reduced pressure. The crude product was purified on a column of silica (100 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (95:5:0.2; 100 mL, followed by 90:10:0.2) as eluent to give 0.80 g (60%) of the title compound as a light brown oil. HRMS m/z calcd for C21H31N5O3 (M)+ 401.2427. found 401.2414. *Reported in WO 00/76984, Example 192, Step 2.
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1>C(O)C>[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N:1][NH2:2])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NN
Solvent: CCO
Product: NN=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 0.75 h
Yield: 91 %

Procedure:
Hydrazine (3.3 mL, 105 mmol) was dissolved in ethanol (10 mL) at room temperature. To this solution was added 4-trifluoromethoxybenzaldehyde (5.0 mL, 35 mmol) dropwise over 25 min. The reaction mixture was stirred an additional 45 min and concentrated under vacuum. The residue was dissolved in ethyl ether (20 mL) and washed with water (10 mL). The water layers were extracted with ethyl ether (3×15 mL), and the combined organic layer was dried over magnesium sulfate, filtered and concentrated to give [4-(trifluoromethoxy)-benzylidene]hydrazine (XX) as a yellow oil (6.5 g, 91% yield). 1H NMR (DMSO-d6): δ 7.69 (s, 1H); δ 7.56 (d, J=8.7 Hz, 2H) δ 7.30 (d, J=7.8 Hz, 2H); δ 6.94 (bs, 2H); GC-MS m/z 204 (M+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:41][N:42]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)[CH3:43])=[C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=2)[CH:31]=1.CCN(C(C)C)C(C)C.Cl.[CH2:67]([O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73])[CH3:68]>CCOC(C)=O.C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:41][N:42]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=3)=[CH:46][CH:45]=2)[CH3:43])=[C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([NH:73][CH2:72][CH2:71][C:70]([O:69][CH2:67][CH3:68])=[O:74])=[O:39])=[N:36][CH:37]=2)[CH:31]=1
Reactant: CN(Cc1ccc(Cl)cc1-c1ccc(C(=O)O)nc1)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 45 °C

Procedure:
Solid HATU (127 mg, 0.34 mmol) was added to a THF solution (3 mL) of 5-(5-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)(methyl)amino)methyl)phenyl)picolinic acid (155 mg, 0.34 mmol), i-Pr2NEt (0.29 mL, 1.67 mmol), and β-alanine ethyl ester hydrochloride (54 mg, 0.35) and the resulting mixture was warmed to 45° C. After 16 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.