Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:21](=[CH:22][CH:23]=2)[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH2:6][C:5]3=[O:24])[CH:28]=[N:27]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate (1 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (682 mg) were dissolved in dioxane in a nitrogen atmosphere, and aqueous 2 M sodium carbonate solution (3.8 mL) and tetrakis(triphenylphosphine)palladium (144 mg) were added thereto, and degassed. The reaction liquid was stirred overnight at 100° C., cooled to room temperature, then water was added thereto, and filtered through Celite. The filtrate was extracted with chloroform, and the organic layer was dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 0/100) to obtain the intended product as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[S:21]1[C:25]2[CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:30]([C:27]2[CH:28]=[CH:29][C:24]3[N:23]=[CH:22][S:21][C:25]=3[CH:26]=2)=[O:31])[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc2ncsc2c1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 1,3-benzothiazole-6-carboxylic acid (0.056 g). Title compound obtained as white solid (0.066 g).
Reaction SMILES: S(C)(C)=O.[H-].[Na+].[CH3:7][O:8][C:9]([O:26][CH3:27])([CH2:13][CH2:14][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][C:21](=[O:24])[O:20]1)[CH2:10][CH:11]=O.CO[CH2:30][CH2:31][O:32]C>O>[O:24]=[C:21]1[O:20][CH:19]([CH2:18][CH2:17][CH2:16][C:15](=[O:25])[CH2:14][CH2:13][C:9]([O:26][CH3:27])([O:8][CH3:7])[CH2:10]/[CH:11]=[CH:30]/[C:31](=[O:32])[CH2:11][CH2:10][CH2:9][CH2:13][CH3:14])[CH2:23][CH2:22]1
Reactant: COC(CC=O)(CCC(=O)CCCC1CCC(=O)O1)OC
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(=O)/C=C/CC(CCC(=O)CCCC1CCC(=O)O1)(OC)OC
Reaction time: 0.08 h

Procedure:
To a mixture of 70 parts of sulfinylbismethane with approximately 2 parts of a 50% dispersion of sodium hydride in mineral oil is added 11 parts of dimethyl (2-oxoheptyl) phosphonate. The resultant mixture is added, with stirring during 1 hour, to a solution of 10 parts of tetrahydro-β,β-dimethoxy-ε,5-dioxo-2-furannonanal in 52 parts of 1,2-dimethoxyethane at 0°-5° under nitrogen. Stirring is continued for 5 minutes longer, whereupon the reaction mixture is poured into 5 volumes of water, and the mixture thus obtained is extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in a 50:50 (by volume) mixture of ethyl acetate and hexane. The resultant solution is chromatographed on silica gel. Elution with a 75:25 (by volume) mixture of ethyl acetate and hexane affords, upon removal of solvent by vacuum distillation, (E)-1-(tetrahydro-5-oxofuran-2-yl)-7,7-dimethoxyhexadec-9-ene-4,11-dione as the residue, an oil. It has the formula ##STR11##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29].O>C(O)(=O)C>[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
In 75.3 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 9.2 g (0.11 mole) of sodium acetate was added at 20°-25° C. with stirring. After cooling to 15°-20° C., 64.8 g of an acetic acid solution containing 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride was added at the same temperature. The reaction was carried out for 2 hours with stirring at the same temperature. Thereafter 110.1 g of water was added at the same temperature and cooled to 0°-5° C. Precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 29.5 g (68.9% yield on L-phenylalanine methyl ester hydrochloride).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[C:14]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:15]=3[S:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:14]2[C:13]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]#[C:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:10][CH:9]=3)=[O:12])=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:16][C:15]=2[CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCO)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCOS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from Step 2 (195 mg, 0.46 mmol) was dissolved in 3 mL of methylene chloride and treated with 127 mL of triethylamine and methanesulfonyl chloride (53 mL, 0.68 mmol) and stirred 30 minutes at room temperature. The reaction was concentrated and extracted into ethyl acetate. The combined organic layers was washed with brine and dried over anhydrous magnesium sulfate. After filtration, concentration the title compound (205 mg) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[F:36][C:29]1[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 1.5 h

Procedure:
A solution of the product obtained in Step A above (74 mg, 0.14 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.18-1.24 (m, 2H); 1.35-1.40 (m, 2H); 2.12 (q, 1H, J=12 Hz); 2.79-2.86 (m, 1H); 2.92-2.98 (m, 1H); 3.64 (td, 1H, J=12, 6 Hz); 3.79 (t, 1H, J=12 Hz); 3.90-3.98 (m, 1H); 4.48-4.54 (m, 1H); 4.57-4.72 (m, 5H); 7.25-7.32 (m, 1H); 7.46-7.53 (m, 1H); 8.08 (s, 1H). LC-MS: 443.04 (M+1).
Reaction SMILES: [H-].[Na+].I[CH2:4][CH2:5][CH2:6][C:7]([CH3:12])([N+:9]([O-:11])=[O:10])[CH3:8].[F:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]([CH3:22])[C:19](=[O:21])[NH:20][C:16]=2[CH:15]=1>CN(C=O)C>[F:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]([CH3:22])[C:19](=[O:21])[N:20]([CH2:4][CH2:5][CH2:6][C:7]([CH3:12])([N+:9]([O-:11])=[O:10])[CH3:8])[C:16]=2[CH:15]=1
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Reactant: Cn1c(=O)[nH]c2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCC(C)(C)[N+](=O)[O-])c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First of all 0.624 g (13.9 mmol) 60% sodium hydride and then, with cooling, 4.6 g (17.8 mmol) 1-iodo-4-methyl-4-nitro-pentane in 10 mL DMF are added to a solution of 2.1 g (12.6 mmol) 5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one in DMF. The reaction mixture is stirred overnight at ambient temperature, then poured onto water and extracted with diethyl ether. The organic phases are evaporated down and the residue is recrystallised from isopropylether. Yield: 1.8 g (48%); mass spectroscopy [M+H]+=296.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.Br[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C(O)C>[OH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:10]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)COc1ccc(CO)cc1
Yield: 48.6 %

Procedure:
Mix potassium carbonate (2.764 g, 20 mmol), 4-hydroxy-benzyl alcohol (1.49 g, 12 mmol) in absolute ethanol (100 mL), add 1-bromopinacolone (1.791 g, 10 mmol) dropwise. Heat the mixture under reflux for 12 h. Add water to dissolve the solid, and remove most of the ethanol in vacuo. Extract the mixture with EtOAc three times. Combine the organic layers, wash with brine, dry over Na2SO4, filter and concentrate. Purify the residue by chromatography on silica gel eluting with EtOAc:hexane (1:2) to provide the desired intermediate as a colorless oil (1.08 g, 48%). MS (ES+) m/z: 205 M+H−H2O)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].[IH:31]>O>[I:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Reactant: I
Solvent: O
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCI)cn2)CC1

Procedure:
A solution of 2.09 g of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 57% hydriodic acid was stirred at 120° C. for 30 minutes. The reaction solution was diluted with water and extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was chromatographed over a silica gel column to afford 1.94 g of the title compound.
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10]>>[OH:5][CH2:4][C@H:3]([CH3:6])[CH2:2][N:21]1[CH2:22][CH2:23][CH:18]([C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:7])[CH3:24])[CH:17]=[CH:16][CH:15]=2)[CH2:19][CH2:20]1
Reactant: C[C@@H](CO)CCl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)CO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (2S)-3-chloro-2-methyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 319.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:10](=[O:23])[C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(O)C.[BH4-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]3[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC2=C1C(c1cccc(Cl)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc(Cl)c1)C1=C(CCCC1)N2
Yield: 104.5 %

Procedure:
To a stirred 70° C. mixture of 9-(3-chlorophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g), ethanol (120 mL) and pyridine (40 mL) was added sodium borohydride (7.5 g) in two portions over six hours. The solvent was removed; the resulting yellow solid washed well with water and dried in vacuo to provide the title compound (5.0 g) as a yellow solid. Recrystallization from ethanol returned analytically pure material, mp 249°-250° C.; NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.09-2.15 (m,4, CH2), 2.39-2.45 (m,2, CH2), 4.17 (s,1, CH), 7.09-7.15 (m,3, Ar), 7.21-7.26 (m,1, Ar), 8.43 (s,1, NH). (CI, CH4) MS: m/z=314(M+1). Analysis for C19H20ClNO: Calculated C, 72.72; H, 6.37; N, 4.46; Found: C, 72.55; H, 6.48; N, 4.49.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1.Cl>CS(C)=O.O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:42][C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8]
Reactant: ClCc1nnn[nH]1
Reactant: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3nnn[nH]3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-hydroxy-1H-indole-3-carboxylic acid amide Example 578 (148 mg, 0.283 mmol) in DMSO (3 mL) was treated with Cs2CO3 (0.28 g, 0.85 mmol). The mixture was stirred at RT for 5 min, followed by addition of 5-(chloromethyl)-1H-tetrazole (35 mg, 0.098 mmol) and stirring at RT for 36 h. The reaction mixture was neutralised by addition of 1N HCl. Water was then added to the mixture to form a precipitate. The solid material was filtered off, washed with water, and dried in vacuo to afford the title compound as a solid. MS (LC/MS): 573 [M+H]+; tR (HPLC conditions k): 2.92 min.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[N:24][C:22]([C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:23])[CH3:29]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Product: CN(C)C=NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 100 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid amide (0.561 g, 1.69 mmol) and N,N-dimethylformamide dimethyl acetal (5 mL) were combined and heated at reflux for 4 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (2×10 mL) to provide the title compound (0.655 g, 100%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 1.80-1.85 (m, 4H), 1.85-1.95 (m, 2H), 2.0-2.10 (m, 2H), 2.6-2.78 (m, 8H), 3.0 (s, 3H), 3.05 (s, 3H), 3.60 (m, 2H), 3.90 (m, 2H), 4.0 (t, 2H), 6.80 (d, 2H), 7.35 (d, 2H), 8.30 (s, 1H). LRMS APCI+ m/z 388 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:37]([O:42][CH3:43])([O:40][CH3:41])OC>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:24]=[CH:23][C:20]([CH:37]([O:40][CH3:41])[O:42][CH3:43])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1Br
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(Br)c3)no2)cc1
Yield: 96 %

Procedure:
4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (0.551 g, 1.423 mmol), molecular sieve (4A, 8-12 mesh, 130 mg) and p-toluenesulfonic acid monohydrate (0.037 g, 0.195 mmol) were added in trimethyl orthoformate (4 ml, 36.2 mmol) and methanol (6 ml), the reaction mixture was heated at 80° C. for 16 hr. The solution was cooled, the reaction mixture was concentrated to afford grey solid, which was purified via silica gel chromatography (12 g, 20% EtOAc:Heptane) to afford 3-(3-bromo-4-isopropoxyphenyl)-5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazole (0.61 g, 1.366 mmol, 96% yield) as white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH2:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[NH:1][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCc2ccccc2C1
Product: CC(=O)N[C@H]1CCc2ccccc2C1

Procedure:
was prepared by reaction of the commercially available (S)-7-amino-5,6,7,8-tetrahydro-naphthalene with acetic anhydride according to known methods.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:16][CH2:15]1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C(#N)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:19]1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6])=[O:33]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1cc(C(=O)NC2CC2)ccc1N1CCC(CCN2CCCCC2)CC1
Solvent: CC#N
Product: O=C(Nc1cc(C(=O)NC2CC2)ccc1N1CCC(CCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a stirred solution of compound 0.20 g (0.53 mmol) of 3-amino-N-cyclopropyl-4-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-benzamide in acetonitrile (5 mL) is added 0.04 mL (0.31 mmol) 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 30 minutes then volatiles are removed under reduced pressure. The residue is dissolved in dichloromethane and the mixture is washed with 5% aqueous NaOH solution followed by water and then dried over anhydrous magnesium sulfate. The mixture is concentrated under reduced pressure and the crude mass purified by flash silica gel chromatography to yield 0.040 g (15%) of 3-(3-Chloro-benzoylamino)-N-cyclopropyl-4-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-benzamide (112). [M+H]+=479.4
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:4]1.CCN(CC)CC.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([NH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH2:4]1)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
A mixture of 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 3.8 mmol), Et3N (5.7 mmol), N-tert-butoxycarbonylglycine (704 mg), EDCI (594 mg), HOBt (673 mg), and dichloromethane (20 mL) was stirred at room temperature for 15 h. Dichloromethane (50 mL) was added and the solution was washed with 2 N NaOH solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-[{N-(tert-butoxycarbonyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (1.31 g, 90%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]2=[O:22])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOC(C)=O>[CH3:28][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH:11]=[CH:10][C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: CI
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(CO)cc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ccc(Cn2cc(-c3ccc(OC)cc3)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
According to Scheme 24 Step 3: A mixture of 1-(4-(hydroxymethyl)benzyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (1 eq, 0.25 mmol, 0.08 g), NaH (55%, 1.5 eq, 0.37 mmol, 18 mg) and iodomethane (3 eq, 0.75 mmol, 0.11 g) in DMF (2 mL) was stirred at room temperature overnight. The crude was diluted with AcOEt. The organic layer washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 5 g SiO2, CH2Cl2/MeOH 99/1), yielding the title compound (0.14 mmol, 46 mg, 55%) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8]N.N[C@H:11]1CN2C3C(C(CC(OCCC)=O)=C2C[CH2:12]1)=CC=CC=3>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:12]=[CH:11]2
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Reactant: NNc1ccccc1F
Product: Fc1cccc2cc[nH]c12

Procedure:
This compound was prepared from 2-fluoro-phenylhydrazine according to the procedure outlined for propyl ([7R]-7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate.