Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])=[CH:8][CH:7]=1
Reactant: CC(C)(CO)Oc1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C=O)Oc1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
An oven dried flask containing 350 ml dry CH2Cl2 was cooled to −78° C. under argon. The oxalyl chloride (31.0 g, 20.7 mL, 244 mmol, Eq: 1.30) was added followed by the addition of DMSO (28 mL, 394 mmol, 2.1 equiv) via dropwise addition. The mixture is stirred for 10 minutes and then a solution of 2-(6-chloropyridin-3-yloxy)-2-methylpropan-1-ol (41.17 g of 92% pure material, 188 mmol, Eq: 1.00), dissolved in 60 ml CH2Cl2, was added via slow dropwise addition. The mixture is stirred for 30 minutes at −78° C. Triethylamine (105 mL, 751 mmol, 4 equiv) was added and the cooling bath was removed and the reaction mixture was allowed to stir for 1 hour with warming to ambient temperature. The reaction mixture was diluted with saturated NaHCO3 (275 mL), shaken and the organic phase collected and washed with an equal volume of brine. The aqueous phase was back-extracted with DCM (2×150 ml). The combined organics phase was dried (MgSO4), filtered and concentrated in vacuo. This resulting residue was purified by Analogix MPLC (SF40-240G column) eluting with 2% to 30% EtOAC/Hex gradient over 60 minutes to afford the desired product (37.1 g) as a light yellow oil. (M+H)+=200 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 6 H) 7.07-7.34 (m, 2 H) 8.05 (d, J=3.02 Hz, 1 H) 9.79 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[C:46]([NH2:59])[C:47]4[C:51]([CH:52]=3)=[N:50][N:49](C3CCCCO3)[CH:48]=4)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:52]=[C:51]4[C:47]([CH:48]=[N:49][NH:50]4)=[C:46]([NH:59][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[O:10])[CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
6-Methyl-2-pyridinecarboxylic acid (8 mg, 0.06 mmol) in DMF (0.20 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) in DMF (0.20 ml) and DIPEA (0.030 ml). The reaction mixture was shaken for five minutes then treated with 6-(1H-Indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.20 ml). The reaction mixture was shaken for 5 mins then left to stand at room temperature overnight. Solvent was removed, and the product re-dissolved in methanol (1 ml) then applied to an SCX cartridge (1 g) which had been pre-rinsed with methanol. After 1 h, the cartridge was eluted with ammonia in methanol (2M, 2×3 ml). Fractions containing product were combined, dried and then further purified by Mass Directed Automated Preparative HPLC (Method D). Fractions containing product were combined and dried to give the title compound (6.6 mg) as a pale brown gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH2:20][NH:21]4)=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37](N1C=CN=C1)=[O:38].CN(C=O)C.CCOC(C)=O>O>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([C:12]3[S:13][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[C:10]([C:24]([OH:26])=[O:25])[N:11]=3)[CH:23]=2)[CH2:18][CH2:19][CH2:20]1)=[O:38]
Reactant: COc1ccc(-c2sc(-c3ccc4c(c3)NCCC4)nc2C(=O)O)cc1
Reactant: O=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc(-c3ccc4c(c3)N(C(=O)Nc3nc5ccccc5s3)CCC4)nc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
The title compound 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(4-methoxyphenyl)thiazole-4-carboxylic acid (1) was prepared by the following procedure: To 5-(4-methoxyphenyl)-2-(1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylic acid (1L) (0.070 g, 0.19 mmol) and N-(benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide (1M) (0.051 g, 0.21 mmol) was added DMF (2 mL). The reaction mixture was allowed to stir at rt overnight. To the reaction mixture was added EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to provide 0.028 g (27%) of the desired product 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(4-methoxyphenyl)thiazole-4-carboxylic acid (1): LC/MS (APCI): m/z 543.1 (M+H).
Reaction SMILES: C(OC([C:6]1[N:7]=C[O:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)=O)C>Cl>[ClH:18].[NH2:7][CH2:6][C:10](=[O:9])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1
Reactant: CCOC(=O)c1ncoc1Cc1ccc(Cl)c(F)c1
Agent: Cl
Product: NCC(=O)Cc1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 135.6 %

Procedure:
A mixture of the product of example 29 (2.5 g, 10.53 mmol) with hydrochloride acid (6 mol/l, 30 ml) was refluxed for about 3 hours and then cooled to room temperature. The solids were collected by filtration, washed with EA and dried to give the titled product (1.7 g, 81%)
Reaction SMILES: [C:1]([C:3](=[C:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[BH4-].[Na+]>C(O)C.O>[C:1]([CH:3]([C@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCC/C=C/C1CCC(=C(C#N)C(=O)OCC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC/C=C/[C@H]1CC[C@H](C(C#N)C(=O)OCC)CC1
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
A solution of 46.0 g of ethyl cyano-[4-(1E-pentenyl)cyclohexylidene]acetate in 120 ml of ethanol is added dropwise at 5°-10° C. within 40 minutes to a mixture of 6.7 g of sodium borohydride and 120 ml of ethanol. The reaction mixture is stirred at 5° C. for 45 minutes, then diluted with 750 ml of water and extracted with three 250 ml portions of diethyl ether. The extract is washed neutral with water, dried over sodium sulphate and concentrated. There is obtained crude ethyl cyano-[trans-4-(1E-pentenyl)cyclohexyl]acetate (cis content <20%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O.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>[CH3:31][O:30][C:19]1[N:20]=[N:21][C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:23][C:18]=1[C:3]1[NH:4][C:5]2[C:10]([C:2]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:9][CH:8]=[C:7]([CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]=2
Reactant: OB(O)c1ccccc1
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1-c1ccccc1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
68 mg 3-Iodo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-piperidin-1-ylmethyl-1H-indole, 17 mg phenylboronic acid, 86 mg potassium phosphate tribasic n-hydrate, and 12 mg tetrakis(triphenylphosphine)palladium(0) are dissolved in a mixture of 2.0 mL toluene and 72 μL water. Argon is bubbled through the solution for 5 minutes. The mixture is heated to 90° C. for 2.5 hours. Concentration in vacuo affords 62 mg crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([OH:40])[CH2:37][NH:38][CH3:39])=[CH:32][CH:31]=1)[CH3:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([C:33]4[CH:32]=[CH:31][C:30]([CH2:29][N:27]([CH3:26])[CH3:28])=[CH:35][CH:34]=4)[OH:40])[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(CN(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc(CN(C)C)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 7 h
Yield: 25.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-{4-[(dimethylamino)methyl]phenyl}-2-(methylamino)ethanol (Preparation 50) (89 mg, 0.43 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky mixture was concentrated to dryness. The residue was purified with a silica gel chromatotron plate to yield the title compound (36 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH2:16])=[O:15].Cl[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=[O:19]>C(#N)C.ClCCl>[C:14]([C:10]1[N:9]([NH:8][C:18]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:19])[CH:13]=[CH:12][CH:11]=1)(=[O:15])[NH2:16]
Reactant: NC(=O)c1cccn1N
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)Nn2cccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (554 μl, 4.00 mmol) is added to a suspension of 1-amino-1H-pyrrole-2-carboxylic acid amide (501 mg, 4.00 mmol) in acetonitrile (8.0 ml). Then a suspension of methyl 4-chlorocarbonylbenzoate (264 μl, 2.00 mmol) in dichloromethane (4.0 ml) is added slowly. The reaction mixture is stirred at room temperature for 18 hours. The solvents are evaporated and the residue is triturated with water. The solid is filtered off, washed with water and dried under vacuum to give methyl 4-[(2-carbamoylpyrrol-1-yl)carbamoyl]benzoate as white crystals; HPLC/MS 1.45 min (C), [M+H] 288.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)=[CH:18][N:19]=3)=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[CH3:26][C:22]1[CH:21]=[C:20]([C:17]2[O:16][C:15]([NH:14][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]4)=[N:19][CH:18]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4cccc(C)c4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: Cc1cccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)c1

Procedure:
The title compound was prepared using the procedure as described in Example 11, substituting the product of Example 15B for the product of Example 1H.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]C#N.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C[O:33]CC1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[O:33])=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: C1CCOC1
Reactant: N#CCc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: Cc1c(Cl)nnc(C(=O)c2ccccn2)c1C
Reaction time: 8 h
Yield: 44 %

Procedure:
3,6-Dichloro-4,5-dimethyl-pyridazine (1.00 g, 5.65 mmol) is added to a dry 250-ml round-bottom flask under N2 followed by THF (50 mL) and pyridin-2-yl-acetonitrile (800 mg, 7.68 mmol). The reaction is degassed for 30 min. NaHMDS (1.0 M, 14.13 mL, 14.13 mmol) is added and the reaction is stirred overnight. The reaction mixture is transferred to a beaker and air stirred vigorously for several hours. The reaction mixture is quenched with saturated sodium bicarbonate solution. The organics are extracted with dichloromethane. The combined organic layers are washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2) to afford the title compound (616 mg, 44%).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH2:28][CH3:29])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1cccc2nonc12
Reactant: CCCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCCC1=C(C(=O)OCC)C(c2cccc3nonc23)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketoheptanoate in the same manner as in Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]([CH3:24])=O>>[CH2:12]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:24][CH:22]=[CH2:21])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH:13]=[CH2:14]
Reactant: C=CCBr
Reactant: O=Cc1ccc(O)cc1O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(C=O)c(OCC=C)c1
Yield: 93 %

Procedure:
To a solution of 6.9 g (50 mmol) of 2,4dihydroxybenzaldehyde in 100 ml of acetone was added 12 ml (120 mmol) of 3-bromopropene and 40 g of potassium carbonate and the mixture was refluxed for 3 h under stirring. The mixture was filtered and the filtrate concentrated in vacuo to give 10.2 g (93%) of 2,4diprop-2-enyloxybenzaldehyde as slightly reddish crystals.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>S1C=CC=C1.[Pd]>[C:14]1([CH2:13][CH:4]2[CH2:3][CH:2]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:7][CH2:6][N:5]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)N1CCC(=O)CC1Cc1ccccc1
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CCC(NCc2ccccc2)CC1Cc1ccccc1

Procedure:
A mixture of (±)-ethyl 4-oxo-2-(phenylmethyl)-1-piperidinecarboxylate (10 g) and benzylamine (4 g) was hydrogenated at 50° C. in thiophene (4% solution; 1 ml) and methanol (150 ml) with palladium on activated carbon (10%; 3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the solvent was evaporated, yielding (±)-ethyl 2-(phenylmethyl)-4-[(phenylmethyl)amino]-1-piperidine-carboxylate (interm. 22).
Reaction SMILES: [CH3:1][C:2]1([S:5]([NH:8][C:9]([C@@:11]2([NH:16]C(=O)OC(C)(C)C)[CH2:13][C@H:12]2[CH:14]=[CH2:15])=[O:10])(=[O:7])=[O:6])[CH2:4][CH2:3]1.C([Cl:27])(=O)C>CO>[ClH:27].[NH2:16][C@:11]1([C:9]([NH:8][S:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)(=[O:7])=[O:6])=[O:10])[CH2:13][C@H:12]1[CH:14]=[CH2:15]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: CC(=O)Cl
Solvent: CO
Product: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(C)CC1
Product: Cl
Temperature: 50 °C
Yield: 102 %

Procedure:
Compound 122 (51.5 g) was suspended in methanol (150 mL). A solution of acetyl chloride (3 eq.) in methanol was added to the suspension. The reaction mixture was heated at 50° C. for 3 hrs. The reaction mixture was concentrated at 45-50° C. and co-evaporated with DCM to give compound 123 (42.4 g) as a white powder in 102% yield due to DCM.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl(O)(=O)=O.[CH2:12](O)C>>[CH2:12]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:6]=[CH:1][CH:2]=[CH2:3]
Reactant: Cc1ccccc1
Reactant: CCO
Agent: [O-][Cl+2]([O-])O
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
5 ml (50 μmol of Ti) of toluene solution in which the metallocene is dissolved was added while vigorously agitating. After agitating for 2 hours, 10 wt % of chloric acid-ethanol solution was added to terminate a reaction, the reactant was filtered, washed with ethanol and dried in a vacuum oven of 50° C. to obtain a final styrene/1,3-butadiene copolymer.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)Cl.[Si:10]([O:27][C@H:28]([CH3:44])[C@H:29]([NH:39][CH2:40][C@@H:41]([OH:43])[CH3:42])[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Si:10]([O:27][C@H:28]([CH3:44])[C@H:29]([N:39]1[CH2:40][C@H:41]([CH3:42])[O:43][C:2](=[O:3])[C:1]1=[O:5])[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1)([C:23]([CH3:25])([CH3:26])[CH3:24])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H]1CN([C@H](c2cc(F)c(F)c(F)c2)[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)C(=O)O1
Reaction time: 2 h

Procedure:
In nitrogen atmosphere, oxalyl chloride (45 μL) was dropwise added under ice-cooling to a methylene chloride solution (2 mL) of (S)-1-[(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamino]propan-2-ol (171 mg), TEA (0.17 mL), and 4-(N,N-dimethylamino)pyridine (8 mg). The resulting reaction solution was stirred at the same temperature for 2 hr, and then iced-water and ethyl acetate were added thereto. The organic layer was separated and washed with water, 1 N hydrochloric acid, water, a saturated sodium hydrogencarbonate aqueous solution, and saturated saline in this order. Then, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=9:1 to 3: 1) to give 96 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:21]1[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1)[CH2:6][CH2:5]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2c(c1)CCN2C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-fluoroindoline (1.0 g, 7.30 mmol) and N-Boc-4-piperidone (1.60 g, 7.50 mmol) in tetrahydrofuran (10.0 mL) was added sodium triacetoxyborohydride (1.80 g, 7.50 mmol). After stirring for 3 hours at room temperature, to the mixture were added saturated sodium bicarbonate water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (chloroform/methanol=98/2 to 90/10) to give a Boc derivative of the title compound. MS (ESI+) 321 (M++1, 100%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH:19]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([NH2:37])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])([CH3:21])[CH3:20].C[Si]([C:42]#[N:43])(C)C.[OH-].[NH4+]>C(O)(=O)C>[C:42]([C:6]1([NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:28]2[CH:29]=[CH:30][C:25]([S:22]([CH:19]([CH3:21])[CH3:20])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[CH2:5][CH2:4][N:3]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:2]([CH3:1])[CH2:7]1)#[N:43]
Reactant: C[Si](C)(C)C#N
Reactant: CC1CC(=O)CCN1C(=O)OCc1ccccc1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2ccccc2N)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1CC(C#N)(Nc2ccccc2-c2ccc(S(=O)(=O)C(C)C)cc2)CCN1C(=O)OCc1ccccc1

Procedure:
To a solution of benzyl 2-methyl-4-oxopiperidine-1-carboxylate (1.97 g, 7.95 mmol) and 4′-(isopropylsulfonyl)biphenyl-2-amine (2.19 g, 7.95 mmol) in acetic acid (25 mL) was added trimethylsilyl cyanide (0.79 g, 7.95 mmol). After stirring the reaction at rt overnight the reaction was poured into an icy solution of ammonium hydroxide (30 mL). The solution was extracted with chloroform (three times), dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography afforded the desired product. To enhance the cis/trans product ratio the isolated material was dissolve in methanol (20 mL) and trimethylsilyl cyanide (3.18 g, 23.9 mmol) was added. After stirring the reaction at 70° C. overnight the reaction was concentrated under vacuum. Purification by silica gel chromatography afforded the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:32]1([CH2:31][CH2:30][CH2:29][CH:28]([NH:38][C:15]([C@H:12]2[CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][CH2:13]2)=[O:17])[CH2:27][CH2:26][CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(tert-Butoxycarbonyl)-cis-4-amino-1-cyclohexanecarboxylic acid (23) (1.00 g; 4.11 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.50 g; 4.93 mmol), N,N-diisopropylethylamine (1.70 g; 13.15 mmol) and PyBOP (2.57 g; 4.93 mmol) are added sequentially. The reaction is stirred 4 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (20%<40% ethyl acetate in hexanes) affording the desired product as a solid. CIMS: MH30 493