Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[S:30]1[C:39]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34][C:33]=2[N:32]=[CH:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[S:30]1[C:39]2[CH2:38][CH2:37][N:36]([C:27]([C:23]3[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]4[CH:17]=[C:18]5[C:13](=[CH:14][CH:15]=4)[CH2:12][C:4]4([C:5]6[C:6](=[N:7][CH:8]=[CH:9][CH:10]=6)[NH:11][C:3]4=[O:2])[CH2:19]5)[CH:22]=3)=[O:29])[CH2:35][CH2:34][C:33]=2[N:32]=[CH:31]1
Reactant: c1nc2c(s1)CCNCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ncsc2CC1

Procedure:
86 mg (0.21 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 37 mg (0.24 mmol) 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine, 0.13 mL (0.72 mmol) DIPEA and 77 mg (0.24 mmol) TBTU in 1.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:9][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[N:7][CH:6]=1)=[O:4]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][NH:2][C:3](=[O:4])[C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:9][C:8]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[N:7][CH:6]=1
Reactant: CNC(=O)C1=CN=C(N2CCN(C)CC2)CC1c1ccccc1C
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 65 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A solution of 1.5 g (4.6 mmol) (RS)-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-4,5-dihydro-pyridine-3-carboxylic acid methylamide in 15 ml CHCl3 was treated with 2.3 g (23.0 mmol) MnO2. The black suspension was heated to 65° C., stirred for 3 h at 65° C. and treated again with 2.3 g (23.0 mmol) MnO2, stirred for 3 h and added an other 0.9 g (9.2 mmol) MnO2. The reaction mixture was stirred for 10.5 h at 65° C., treated with 0.9 g (9.2 mmol) MnO2, stirred for 1 h at 65° C. and cooled to r.t. After filtration of the MnO2 the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CHCl3: MeOH =4:1) to yield 1.24 g (83.2%) product as beige foam.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:7]([NH:8]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][N:5]([C:28](=[O:41])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:4]1.Cl>C(OCC)C>[NH2:8][C@H:7]1[C@H:3]([O:2][CH3:1])[CH2:4][N:5]([C:28](=[O:41])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=2)[CH2:6]1
Reactant: CO[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CO[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.8 %

Procedure:
1-((3R,4R)-3-Methoxy-4-(tritylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.65 g) was dissolved in diethyl ether (5 mL), followed by addition of 5 M hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 17 h. The layers were separated, and the aqueous layer was washed with diethyl ether, 1 M aqueous sodium hydroxide was added to make it basic, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain the title compound (0.35 g).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH2:22][C:21]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=2)=[CH:10][CH:9]=1)=[O:7].[OH-].[Li+]>O1CCCC1.O>[Cl:34][C:29]1[CH:28]=[C:27]([C:21]2([C:23]([F:25])([F:24])[F:26])[O:20][N:19]=[C:18]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:35])=[O:2])=[O:7])=[CH:9][CH:10]=3)[CH2:22]2)[CH:32]=[C:31]([Cl:33])[CH:30]=1
Reactant: COC(=O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a stirred solution of N—[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine methyl ester (i.e. the title product of Step A) (620 mg) in tetrahydrofuran (5 mL) was added an aqueous solution of lithium hydroxide (300 mg in 5 mL of water). After stirring at room temperature for 1 h, the reaction mixture was diluted with water and extracted with hexane. The aqueous layer was acidified with 6.0 N HCl to pH=2, causing a white precipitate to form. The aqueous mixture was extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, and concentrated to afford the title compound as a white solid (600 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][CH:8]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:12]([CH3:13])=[N:11][CH2:10][CH2:9]2
Reactant: COc1cccc(CCNC(C)=O)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc2c(c1)CCN=C2C

Procedure:
In close analogy to the procedure described above, N-[2-(3-methoxy-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.Cl.[NH2:12][C:13]([NH2:15])=[NH:14].C(N(CC)CC)C>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:12]=[C:13]([NH2:15])[N:14]=[CH:7][C:6]=2[CH:9]=1
Reactant: N=C(N)N
Reactant: O=Cc1cc(Br)cnc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1ncc2cc(Br)cnc2n1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
5-bromo-2-fluoronicotinaldehyde (3.0 g, 14.78 mmol), guanidine hydrochloride (1.69 g, 17.74 mmol) and triethylamine (4.48 g, 44.35 mmol) were dissolved in 1-methyl-2-pyrrolidinone (15 mL), and the reaction mixture was stirred at 180° C. for 15 min under microwave. The mixture was cooled to RT, quenched with water (200 mL) and extracted with ethyl acetate (2×300 mL). The organic layers were combined, washed with water (3×50 mL) and brine (3×50 mL), dried over sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=3:1) to afford 6-bromopyrido[2,3-d]pyrimidin-2-amine (2.0 g, 60%) as a yellow solid. MS (ES+) C7H5BrN4 requires: 224, 226. found: 225, 227 [M+H]+.
Reaction SMILES: [Br:1][CH:2]([CH:5]=[O:6])[CH:3]=[O:4].O.[C:8]1(C)[CH:13]=CC(S(O)(=O)=O)=C[CH:9]=1.CC(O)C>C1CCCCC1>[Br:1][C:2](=[CH:5][O:6][CH:8]([CH3:13])[CH3:9])[CH:3]=[O:4]
Reactant: O=CC(Br)C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Solvent: CC(C)O
Product: CC(C)OC=C(Br)C=O
Temperature: 86 °C

Procedure:
A mixture of 2-bromomalonaldehyde, para-toluenesulfonic acid monohydrate, 2-propanol and cyclohexane were stirred at 86° C. in flask with a dean-stark trap under azeotropic conditions. Further distillation removed another 40% of the original solvent volume. The mixture was cooled to 0° C., then concentrated in-vacuo, to isolate the title compound (13.2 g). 1H-NMR: 9.16 (s, 1H), 7.65 (s, 1H), 4.51 (m, 1H), 1.47 (d, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[CH2:18]([S:21][C:22]1[O:23][C:24]2[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:27][C:25]=2[N:26]=1)[CH2:19][CH3:20]>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([NH:6][S:31]([C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([S:21][CH2:18][CH2:19][CH3:20])[O:23][C:24]=2[CH:30]=1)(=[O:32])=[O:33])[CH:7]([CH3:9])[CH3:8]
Reactant: CCCSc1nc2ccc(S(=O)(=O)Cl)cc2o1
Reactant: COC(=O)[C@H](N)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)OC)C(C)C)cc2o1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
(D)-valine methylester hydrochloride (0.2 g, 1.19 mmol) was dispersed in dichloromethane (3 mL) and cooled down to 0° C., and triethylamine (0.37 mL, 3 equi.) was added. The dichloromethane solution containing 2-n-propylthiobenzoxazol-6-sulfonyl chloride (0.26 g, 1.0 equi.) prepared in the above Example and dichloromethane (2 mL) was also added while maintaining the temperature of 0° C. When starting material was exhausted after 5 hours, the organic phase was washed with 1N HCl, dried over MgSO4, distilled under reduced pressure and dried under vacuum, to give (2R)-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino] butanoic acid methylester(0.31 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:4]=1[NH2:5].[Cl-:14]>C1C=CC=CC=1.N1C=CC=CC=1.O>[Cl:14][CH2:6][CH2:4][C:3]([NH:5][C:4]1[CH:6]=[C:7]([Cl:13])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1])=[O:2]
Reactant: [Cl-]
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1N
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
17.2 g of 2 -methoxy 4 -nitro 5 -chloroaniline dissolved in 150 ml benzene are added with 11.1 g of β chloropropionly chloride dissolved in 40 ml benzene and 2 ml pyridine. The reaction mixture is kept under stirring at room temperature for two hours then diluted with 250 ml water. The benzenic phase is separated while the aqueous phase is extracted twice with benzene. The benzenic solutions are united, washed with 2N hydrochloric acid then with water, dried on sodium sulphate, filtered and evaporated to dryness. The dry residue is recristallised from isopropyl ether and 21.1 g of 1(β chloropropionylamino) 2 -methoxy 4 -nitro 5 -chlorobenzene are recovered (yield 40-50%). It melts at 101°-110° (dec)
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13](OC)=[O:14].[CH3:24][NH2:25]>>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:25][CH3:24])=[O:14]
Reactant: CN
Reactant: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Product: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C

Procedure:
WO 95/27693 discloses that a 2-substituted phenyl-N-alkylacetamide compound having an alkoxy group at the 2-position typified by 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide is useful as an agricultural fungicide, and also discloses, as a method for producing the compound; a method in which methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetate is reacted with methyl iodide to obtain methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate, and then the methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate is reacted with methylamine to obtain 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24]([OH:26])=O)=[CH:19][CH:18]=[CH:17]4)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH2:42])=[O:34])=[CH:31][CH:30]=1>>[NH2:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:35][C:33]([C:32]1[CH:43]=[CH:44][C:29]([CH2:28][NH:27][C:24]([C:20]2[C:21]3[C:16](=[CH:15][C:14]([O:13][C:7]4[C:6]5[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)[N:10]=[CH:9][CH:8]=4)=[CH:23][CH:22]=3)[CH:17]=[CH:18][CH:19]=2)=[O:26])=[CH:30][CH:31]=1)=[O:34]
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2c1
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc2c(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccccc6N)cc5)cccc4c3)ccnc2c1
Yield: 84.9 %

Procedure:
The title compound (48.3 mg, 85% yield) was prepared as a brown solid from 6-(7-methoxyquinolin-4-yloxy)-1-naphthoic acid (34.5 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.95 (s, 3H, —OCH3), 4.64 (d, J=5.6 Hz, 2H, —CH2), 4.87 (s, 2H, benzene-NH2), 6.58-6.62 (m, 2H, Ar—H), 6.78 (dd, J=1.2 and 7.8 Hz, 1H, Ar—H), 6.97 (td, J=1.4 and 8.1 Hz, 1H, Ar—H), 7.18 (d, J=7.0 Hz, 1H, Ar—H), 7.31 (dd, J=2.5 and 9.2 Hz, 1H, Ar—H), 7.44 (d, J=2.4 Hz, 1H, Ar—H), 7.53-7.56 (m, 3H, Ar—H), 7.62 (t, J=8.0 Hz, 1H, Ar—H), 7.72 (d, J=6.1 Hz, 1H, Ar—H), 7.86 (d, J=2.5 Hz, 1H, Ar—H), 7.98-8.06 (m, 3H, Ar—H), 8.24 (d, J=9.1 Hz, 1H, Ar—H), 8.39 (d, J=9.2 Hz, 1H, Ar—H), 8.64 (d, J=5.2 Hz, 1H, Ar—H), 9.21 (t, J=6.0 Hz, 1H, —CONH), 9.61 (s, 1H, benzene-NH). LC-MS (m/z) 569 (M+1).
Reaction SMILES: [NH2:1][C:2](=[O:31])[C@@H:3]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16](=[O:29])[CH:17]([NH:21][C:22]1[S:23][C:24]([CH:27]=[O:28])=[CH:25][N:26]=1)[CH:18]([CH3:20])[CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[BH4-].[Na+]>CCO.O>[NH2:1][C:2](=[O:31])[C@@H:3]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16](=[O:29])[CH:17]([NH:21][C:22]1[S:23][C:24]([CH2:27][OH:28])=[CH:25][N:26]=1)[CH:18]([CH3:19])[CH3:20])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(C)C(Nc1ncc(C=O)s1)C(=O)NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C(Nc1ncc(CO)s1)C(=O)NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of material from Example 31 in EtOH/H2O (4:1) (2.5 mL) is added sodium borohydride (25.5 mg, 0.674 mmol) in 2 equal portions over 5 min. The resulting light suspension is stirred at room temp for 2 h, quenched with MeOH (3 mL), stirred at room temp for 30 min, quenched with acetone (5 mL), and stirred at room temp for 45 min. All volatiles were evaporated off under a gentle stream of N2 to give the title compound (quantitative yield) that is used in its entirety in the macrocyclization step. LC/MS (Condition A): ret. T=1.45 min, (M+H)+ 450.20.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH2:19])=[O:9])=[CH:5][N:4]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: Nc1ccccc1N
Product: NCc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 32.4 %

Procedure:
The title compound (157 mg, 65% yield) was prepared as a grey solid from 6-cyano-nicotinic acid (296 mg, 2 mmol) and o-phenylenediamine (864 mg, 8 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 243 (M+1).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C@@H:19]([CH3:20])[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C@H:15]1[CH3:28]>CO>[NH2:3][CH2:12][CH2:13][N:14]1[C@@H:19]([CH3:20])[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:16][C@H:15]1[CH3:28]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN1C(=O)c2ccccc2C1=O
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
tert-butyl (cis)-4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3,5-dimethyl-1-piperazinecarboxylate (0.736 g) [see Preparation 6] in methanol (1.1 ml). The reaction mixture was then stirred at 50° C. for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 10% citric acid. The aqueous layer was separated, bastified with potassium carbonate, and the product extracted with tetrahydrofuran:ethyl acetate, 1:1, several times. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (cis)-4-(2-aminoethyl)-3,5-dimethyl-1-piperazinecarboxylate (0.33 g) as a oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]2[N:20]([C:23](=[O:45])[CH:24]([NH:28][C:29](=[O:44])[CH:30]([N:32]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH3:33])[CH3:31])[CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:22][CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[N:32]([CH3:33])[CH:30]([C:29](=[O:44])[NH:28][CH:24]([C:23]([N:20]1[CH2:21][CH2:22][CH:9]2[NH:8][CH2:12][CH:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]12)=[O:45])[CH:25]([CH3:27])[CH3:26])[CH3:31])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccccc3)C21
Reaction time: 1 h

Procedure:
To a solution containing 16 (370 mg, 0.59 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. After 1 h, the reaction mixture was diluted with DCM and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford crude 18 which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][CH2:9][C:10]=1[NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(#N)C>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1=C(NC(C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1NC(C)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
A solution of 4-(1-phenyl-ethyl amino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (4 g, 11.1 mmol) in acetic acid-acetonitrile (1:1, 80 mL) was treated with sodium triacetoxyborohydride (2.59 g, 12.2 mmol), and stirred for 5 h at 0° C. The reaction was cooled to 0° C. and neutralized with saturated aqueous sodium bicarbonate (5 mL). The organic layer was washed with brine (3×20 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (3.6 g). The crude product was purified by Biotage Flash 40S chromatography, eluting with 1:1 ethyl acetate-hexanes, to provide 4-(1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a white solid (2.5 g, 62.5%). MS: 363 (M+H)+
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:43]=[C:42]([NH:44][C:45]([N:47]2[CH2:51][CH2:50][N:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:48]2=[S:58])=[O:46])[CH:41]=[CH:40][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]3[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)[S:20][C:13]=12>C(Cl)Cl>[F:8][C:9]1[CH:43]=[C:42]([NH:44][C:45]([N:47]2[CH2:51][CH2:50][N:49]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:48]2=[S:58])=[O:46])[CH:41]=[CH:40][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])=[CH:25][N:26]=3)[S:20][C:13]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=S)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=S)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
TFA (1 ml, 12.98 mmol) was added to a suspension of 302 (0.093 g, 0.128 mmol) in DCM (1.000 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, the residue was dissolved in DCM, washed with 1N NaOH solution, water, dried over anhydrous sodium sulfate and concentrated affording title compound 303 (0.0714 g, 0.109 mmol, 85% yield) as white solid.
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C(OC)(=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+]>C(OCC)(=O)C.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[C:6]([C:5]1[C:4]([F:11])=[CH:3][C:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:9]([CH3:10])[CH:8]=1)#[N:7]
Reactant: Cc1cc(C#N)c(F)cc1Br
Reactant: COC(=O)CC(=O)OC
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(F)c(C#N)cc1C
Temperature: 170 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
Combined 4-bromo-2-fluoro-5-methylbenzonitrile (4 g, 18.69 mmol) and dimethyl malonate (29.9 mL, 262 mmol) and purged with nitrogen. Potassium carbonate (3.87 g, 28.0 mmol), potassium hydrogencarbonate (2.81 g, 28.0 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.119 g, 0.411 mmol), and bis(dibenzylidineacetone)palladium(0) (0.118 g, 0.206 mmol) were added. The reaction mixture was then heated in an oil bath at 170° C. After 3 hours, the reaction mixture was cooled, diluted with ethyl acetate, and filtered through Celite®. The filtrate was concentrated and the residue dissolved in EtOAc. The organic solution was washed with 1N aqueous sodium hydroxide (2×), twice with 10% aqueous sodium chloride, and then brine. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by flash chromatography to give the title compound (1.67 g, 43%) as a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.30 (s, 3 H) 3.67 (s, 2 H) 3.72 (s, 3 H) 7.10 (d, J=9.60 Hz, 1 H) 7.42 (d, J=6.32 Hz, 1 H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:39]([O:41][CH3:42])=[O:40])#N>C1COCC1>[CH3:42][O:41][C:39]([CH:23]1[CH2:24][CH:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:20][CH2:21][C:22]1=[O:25])=[O:40]
Reactant: COC(=O)C#N
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1CC(CCOCc2ccccc2)CCC1=O
Temperature: 0 °C

Procedure:
A solution of LDA (33 ml, 1.5 M in Et2O) in THF (50 mL) at −78° C. was treated with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). The mixture was warmed to 0° C. over 30 m before re-cooling to −78° C. and adding HMPA (7 mL). Methyl cyanoformate (4.1 mL, 85 mmol) was added and the mixture was stirred for 15 m before aqueous quench and work-up. The product was purified by chromatography on SiO2 with 10% EtOAc:Hx. 5-(2-Benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester was isolated, 5.8 g (49%) and reduced with an equivalent of NaBH4 in MeOH at −10° C. to provide the alcohol (Intermediate R2). Intermediate R2 was purified by chromatography on SiO2 with 30 to 50% EtOAC:Hx. (˜90% yield).