Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CC=CC=1.Cl>>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: OCCCCCCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCCCCCCCCCl)c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of 2-furoyl chloride (6.5 g; 50 mmol) was added dropwise at 0° C. to a solution of 8-chloro-1-octanol (6.6 g; 40 mmol) and pyridine (20 g; 253 mmol) and stirred at room temperature for 2 h. The resulting mixture was added to a mixture of 1N-hydrochloric acid and ice (200 ml) and extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with saturated sodium chloride solution (2×80 ml), dried over magnesium sulphate and filtered. The organic solvent was removed in vacuo to give 8-chlorooctyl-2-furancarboxylate (9.7 g) (94%) as an oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:34])=[CH:31][CH:30]=1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, white solid (111 mg, 95%), MS (ISP) m/z=469.4 [(M+H)+], mp 251.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-chloro-benzoic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]3=O)=[CH:9][C:4]=2[O:3][CH2:2]1>C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1C(Cc2ccc3c(c2)OCO3)CCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC(Cc3ccc4c(c3)OCO4)C2)cc1
Temperature: 25 °C

Procedure:
To a solution of (−)-3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one (1.73 g, 5.3 mmol) in THF (21 ml), LiAlH4 (6.5 ml of a 1 M solution in THF, 6.5 mmol) is added dropwise at rt. The mixture is refluxed for 2.5 h, cooled to rt, quenched with water and filtered over Celite®. The filtrate is evaporated, the residue dissolved in AcOEt, washed with water and brine, and the aq. layers are reextracted with AcOEt, the combined organic layers are dried over Na2SO4 and evaporated to give (+)-3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidine ([α]Drt=28.2° (c=0.5, EtOH)).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[O:31][CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>ClCCl>[CH3:1][N:2]1[C:6](/[C:7](=[N:14]\[O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:30](=[O:37])[O:31][CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:20]=[CH:19][CH:18]=2)/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Reactant: O=C(Cl)OCCCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nnnc1/C(=N\OCc1cccc(NC(=O)OCCCCCl)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)-methyl]pyridin-2-amine (150 mg, 0.485 mmol) in dichloromethane (5 mL), was added pyridine (0.078 mL), 4-chlorobutyl carbonochloridate (166 mg, 0.970 mmol). The reaction mixture was stirred for 5 hours at room temperature, concentrated in vacuo, and then purified by silica gel chromatography to yield to 4-chlorobutyl {6-[({[(Z)-(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate [200 mg; 90% of purity; 84% of to theory; HPLC/MS: m/z=344 (M+H); log P(HCOOH)=3.67].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[Br:12][CH2:13][CH2:14]O>>[Br:12][CH2:13][CH2:14][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: OCCBr
Reactant: Oc1ccc2ccccc2c1
Product: BrCCOc1ccc2ccccc2c1

Procedure:
This example was prepared by substituting 1-naphthol with 2-naphthol and substituting 3-bromopropanol with 2-bromoethanol in EXAMPLE 31A.
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:11])[C:4]([CH3:10])=[CH:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH:15]=[O:16].Cl>C(#N)C.O>[OH:16][CH:15]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([OH:11])=[C:4]([CH3:10])[CH:5]=1)[CH:14]([O:17][CH3:18])[O:13][CH3:12]
Reactant: Cc1ccc(C)c(O)c1
Reactant: COC(C=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(OC)C(O)c1cc(C)c(O)cc1C
Yield: 81 %

Procedure:
A suspension of an aqueous solution of 5.2% sodium hydroxide (630 g), 2,5-xylenol (100 g), an aqueous solution of 60% glyoxal dimethyacetal (213 g) and water (200 g) was heated at 55° C. for 5 hours with stirring. The reaction mixture was cooled in an ice bath, and to the mixture were added acetonitrile (90 g) and 7.4% hydrochloric acid (380 g) successively. The precipitating crystals were filtered to give 4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (150 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[Na].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1>C(OCC)(=O)C.O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: Nc1cc(Cl)ccn1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(OCCN2CCOCC2)ccn1
Temperature: 25 °C

Procedure:
2-Morpholinoethanol (2.2 g, 16.8 mmol) was treated with sodium (116 mg, 5.0 mmol) in a sealed tube and stirred at ambient temperature until homogeneous. 4-Chloropyridin-2-amine (1.1 g, 8.9 mmol) was added and the reaction mixture was heated to 145° C. and stirred in sealed tube for 10 hours. The mixture was cooled to ambient temperature before diluting with ethyl acetate and water. After separation of layers, the aqueous phase was extracted twice more with ethyl acetate. Concentration under vacuum afforded a viscous oil which required purification using a Biotage 40+Silica column eluting with 10% methanol/dichloromethane to give 4-(2-morpholinoethoxy)pyridin-2-amine as a viscous oil which solidified upon further drying under high vacuum (1.4 g).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:19]=[N:20]O)[CH:12]=[CH:11]1.C(N(CC)CC)C>C1COCC1>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:19]#[N:20])[CH:12]=[CH:11]1
Reactant: ON=Cc1cccc2cc[nH]c12
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc2cc[nH]c12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
2-chloro-1-methylpyridinium iodide (1.930 g) was added to a solution of 1H-indole-7-carbaldehyde oxime (D1) (1.1 g) in dry THF (80 mL) at RT. After stirring for 10 min, triethylamine (3.35 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at RT for 2 hours, then was heated to 50° C. and stirred at 50° C. for 2.5 hours. The solvent was evaporated. The residue was dissolved in EtOAc (100 mL) and water (100 mL) was added. The organic fraction was separated, washed with aqueous HCl (0.5 M, 50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1H-indole-7-carbonitrile (D2) as a white solid (0.95 g). δH (DMSO-d6, 400 MHz): 6.64 (1H, m), 7.16 (1H, t), 7.56 (1H, m), 7.68 (1H, d), 7.93 (1H, d), 12.02 (1H, br s). MS (ES): C9H6N2 requires 142; found 141.0 (M−H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH:19]([SH:21])[CH3:20]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:21][CH:19]([CH3:20])[CH3:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96.6 %

Procedure:
4-Bromo-1-fluoro-2-nitrobenzene (1.0 g, 4.5 mmol) [Aldrich] and potassium carbonate (1.6 g, 11 mmol) were stirred in N,N-dimethylformamide (10 mL), and 2-propanethiol (0.42 mL, 4.5 mmol) was added. The mixture was heated to 100° C. for 16 hours. The mixture was cooled to rt, diluted with water (100 mL), and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, and evaporated to give the desired compound (1.2 g, 96%). 1H NMR (300 MHz, CDCl3): δ 8.27 (s, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 3.55 (m, 1H), 1.40 (d, 6H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:25])[N:15]=1.[CH3:26][O:27][C:28]1[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=[C:32]([CH3:40])[C:29]=1[CH:30]=[O:31]>C(OCC)C.C1(C)C=CC=CC=1.O>[CH3:26][O:27][C:28]1[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=[C:32]([CH3:40])[C:29]=1[CH:30]([C:18]1[C:17]([C:21]([F:24])([F:22])[F:23])=[C:16]([Cl:25])[N:15]=[C:14]([Cl:13])[C:19]=1[Cl:20])[OH:31]
Reactant: FC(F)(F)c1cc(Cl)c(Cl)nc1Cl
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COc1cc(C)c(C(O)c2c(Cl)c(Cl)nc(Cl)c2C(F)(F)F)c(OC)c1OC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
17 ml (25 mmol) of n-butyllithium (1.5 M hexane solution) was dropwise added at 0° C. to a solution having 3.6 ml (25 mmol) of diisopropylamine dissolved in 60 ml of diethyl ether, followed by stirring for 45 minutes. The solution was cooled to −78° C., a solution having 6.0 g (24 mmol) of 2,3,6-trichloro-5-trifluoromethylpyridine dissolved in 8 ml of diethyl ether was added thereto, followed by stirring for 5 minutes, and a solution having 5.0 g (24 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 12 ml of toluene was added thereto, followed by stirring for 1 hours. 30 ml of water was added to the mixture to terminate the reaction, the aqueous layer was extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain (2,3,4-trimethoxy-6-methylphenyl)(2,3,6-trichloro-5-trifluoromethyl-4-pyridyl)methanol (m.p. 131-135° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)CCN2
Yield: 94 %

Procedure:
5-Chloroindole was reduced in the usual way with sodium cyanoborohydride in glacial acetic acid to give the title compound (D35) (0.96 g, 94%)
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:15]2[CH2:17][O:16]2)[CH:9]=[C:10]([F:12])[CH:11]=1>O1CCCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:13][C@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:15]([OH:16])[CH2:17][CH:1]=[CH2:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
Vinylmagnesium bromide was added to copper (I) bromide-dimethyl sulfide complex in tetrahydrofuran at low temperature. Tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (12) in tetrahydrofuran was added. At room temperature, the reaction was quenched with saturated ammonium chloride, extracted, and dried over sodium sulfate. A white solid (13) was obtained upon concentration.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:28][CH2:29][C:30]2[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=2)=[C:8]([C:10]2[CH:27]=[CH:26][C:13]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:12]=3[CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].Cl>O1CCOCC1>[CH3:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([CH2:29][O:28][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][C:8]=2[C:10]2[CH:27]=[CH:26][C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:12]=3[CH:11]=2)[CH:35]=1
Reactant: CC(=O)c1ccc(OCc2cc(C)ccn2)c(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(OCc2cc(C)ccn2)c(-c2ccc3c(c2)CCNCC3)c1

Procedure:
1,1-dimethylethyl 7-(5-acetyl-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (3.0 g) was dissolved in dioxane (20 ml). Gaseous hydrogen chloride was passed through the reaction mixture for 1.5 h. The reaction was monitored by TLC. On completion the solid formed was collected by filtration and washed with acetone. The solid was then dissolved in water and the mixture neutralised with aqueous sodium hydroxide (1M). Solid was obtained which was collected by filtration. This was triturated with diethyl ether to yield the title compound, 2.1 g (88%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:4][C:3]=1[NH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN1CCCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:5]4[C:6]([C:8]([NH2:10])=[O:9])=[N:7][C:2]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[C:3]([NH:31][C@@H:32]5[CH2:36][CH2:35][NH:34][CH2:33]5)[N:4]=4)=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)[CH2:25][CH2:26]1
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCNC5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCNC5)c(-c5ccccc5)nc4C(N)=O)cc3)CC2)CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
Under an argon atmosphere, to a mixture of 6-bromo-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-[(3R)-pyrrolidin-3-ylamino]pyrazine-2-carboxamide (257 mg), phenylboronic acid (196 mg), and N-methylpyrrolidone (5.14 mL) were added tetrakistriphenylphosphine palladium (0) (80 mg) and a 2 M aqueous sodium carbonate solution (805 μL), followed by stirring at 120° C. for 4 hours. After leaving to be cooled, chloroform and water were added thereto, followed by stirring, and the insoluble matter was separated by filtration. The filtrate was subjected to liquid separation, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1:0:0-150:10:1) to obtain 3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-6-phenyl-5-[(3R)-pyrrolidin-3-ylamino]pyrazine-2-carboxamide (244 mg) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH3:18][C:19]1([CH3:25])[CH2:24][O:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>C(#N)C>[CH3:18][C:19]1([CH3:25])[CH2:24][O:23][CH2:22][CH2:21][N:20]1[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: CC1(C)COCCN1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)COCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (80 mg, 0.305 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (2 mL) was added 3,3-dimethylmorpholine (46.2 mg, 0.305 mmol, commercially available, for example from Otava, Kiev, Ukraine or Tyger Scientific, Ewing, USA) and triethylamine (0.127 mL, 0.914 mmol). The reaction mixture was then heated to 120° C. for 50 min in a microwave reactor. The reaction mixture was concentrated in vacuo and the crude product was purified by MDAP. The relevant fractions were combined and concentrated in vacuo. The product was dissolved in DCM and 1N HCl in ether (110 uL) was added. The mixture was concentrated in vacuo, triturated with ether, then dried in vacuo to yield the title compound (white crystals, 40 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12](I)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:15][N:16](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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:15]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:16]
Reactant: CN(C)C=O
Reactant: COCc1cc(I)cc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COCc1cc(C#N)cc(C(=O)OC)c1
Temperature: 80 °C
Yield: 86 %

Procedure:
After bubbling argon into a solution of methyl 3-(methoxymethyl)-5-iodobenzoate (316 mg, 1.03 mmol) in N,N-dimethylformamide (3 mL) for 5 minutes, zinc cyanide (133 mg, 1.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (119 mg, 0.010 mmol) were added. The reaction mixture was heated at 80° C. for 15 minutes under argon. Following cooling, the reaction mixture was diluted with ethyl acetate and then the precipitate that formed was removed by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 10-30% ethyl acetate/hexanes afforded 184 mg (86%) of methyl 3-cyano-5-(methoxymethyl)benzoate as a colorless oil.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].[OH-].[K+:12]>>[C:6]([O-:10])(=[O:9])[CH:7]=[CH2:8].[K+:12].[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Agent: C=CC(N)=O
Agent: [K+]
Agent: [OH-]
Product: C=CC(=O)[O-]

Procedure:
A 34 gallon batch of a 19 weight percent potassium acrylate and 35 weight percent aqueous acrylamide solution was prepared as follows: 219 pounds of a 50 weight percent acrylamide solution was contacted with 38.4 pounds of acrylic acid, followed by the controlled addition of 58.2 pounds of a 50 percent by weight potassium hydroxide solution, 9.8 pounds of high molecular weight poly (acrylamide), P-250 (commercially available from American Cyanamid, Wayne, New Jersey 07470) in powder form was added in a controlled fashion to the aqueous solution to ensure that the powder was properly dispersed. The concentration of powdered polymer was 3 percent by weight. The thickened solution was mixed in a 100 gallon stainless steel tank with a mechanical stirrer at 48 RPM for 20 hours and remained unagitated for two additional days. Then its viscosity was measured using a Brookfield Viscometer and found to be 43,000 centipoise.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Br:12][C:13]1[CH:14]=[N:15][C:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[CH:26]=3)[C:21]([S:36][CH3:37])=[CH:20]2)=[N:17][CH:18]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:12][C:13]1[CH:18]=[N:17][C:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[CH:26]=3)[C:21]([S:36]([CH3:37])=[O:6])=[CH:20]2)=[N:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 2.10 g, 9.42 mmol) in dichloromethane (20 mL) was added at 0° C. to a solution of (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino) methanone (4.8 g, 11.08 mmol) in dry dichloromethane (300 mL). The mixture was stirred at room temperature for 3 h and then poured onto saturated sodium sulfite solution. The organic layer was separated after stirring for 15 min and washed with saturated sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated and the remnant was purified by flash column chromatography [dichloromethane with 2.5% methanol]. White solid. Yield: 3.2 g
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([N+:33]([O-])=O)[CH:27]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[C].[Pd].CO>[NH2:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[Cl:32])[CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:36]=[C:37]([F:41])[C:38]([F:40])=[CH:39][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (121 mg, 0.20 mmol) with a 10% palladium carbon (85 mg), ethyl acetate (10 mL) and methanol (1 mL) was stirred at room temperature under a hydrogen atmosphere for 19 hours. The palladium catalyst was removed by filtration, and the filtrate was concentrated to thereby afford 1-(3-amino-4-chlorobenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (78 mg, 68%).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:21][O:20][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:33][CH2:32][CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COC(Cc1ccc(OC(C)(C)C(=O)NCCc2cccc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(3-trifluoromethyl-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H26F3NO5 [M−H]−: 452.