Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.S(=O)(=O)(O)O.[CH2:18]=[C:19]([CH3:21])[CH3:20].C(=O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: C=C(C)C
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
Combine 4-bromo-2-fluoro-phenyl acetic acid (15 g, 0.064 mol), dichloromethane (30 mL) and concentrated sulfuric acid (1.1 mL) in a 2 L stainless steel Parr® vessel. Cool the vessel and contents in a dry ice-acetone bath. Freshly distill isobutene (60 mL) with dry ice-acetone condenser and add the isobutene to the cooled Parr® vessel. Seal and pressurize the vessel with nitrogen (20 psig), agitate while allowing the reaction to warm to room temperature and continue agitation at room temperature for 18 hours. Cool the vessel to 10-15° C. with dry ice, vent, and carefully add 150 mL of ice-cold saturated sodium carbonate solution and mix. Decant vessel contents, rinse vessel with dichloromethane (100 mL), agitate mixture and separate the phases. Extract aqueous phase twice with 100 mL portions of dichloromethane, combine organic layers and wash with aqueous saturated sodium chloride, dry over MgSO4 and concentrate to produce 18.61 g (90%) of the title compound as a light orange oil. MS (ES) m/z 288/290, (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH3:13])[C:8]([CH3:12])([CH3:11])[C:9]#[N:10].[OH-:14].[Ba+2].[OH-]>>[CH3:6][N:7]([CH3:13])[C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:14]
Reactant: [OH-]
Reactant: CN(C)C(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Product: CN(C)C(C)(C)C(N)=O
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
Conc. Sulphuric acid (8 ml.) was added to 2-dimethylamino-2-methyl-propionitrile (2 g.), and was heated to 90°C and allowed to stand for five mins. The reaction mixture was added to ice cold water (100 ml.), barium hydroxide (32 g.) was added to neutralise the acid and the mixture was filtered (hyflo). The filtrate was evaporated under reduced pressure to give a solid residue which was crystallised from light petroleum (80°-100°C) to give 2-dimethylamino-2-methylpropionamide (1 g. 45%) m.p. 109°-111°C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[S:10])=[O:7])=[CH:4][CH:3]=1.[NH2:13][C:14]([NH2:16])=[O:15]>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][C:9]([NH:13][C:14](=[O:15])[NH2:16])=[S:10])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: NC(=O)NC(=S)NC(=O)c1ccc(Cl)cc1
Yield: 51.2 %

Procedure:
A solution of 4-Chlorobenzoylisothiocyanate (152.4 g) in THF (500 ml) is added dropwise to a stirred suspension of urea (46.3 g) in THF (750 ml). The reaction mixture is stirred over the weekend. The precipitate is filtered, washed with ether and dried leaving 101.7 g of a white solid, m.p. 155°-158° C. The filtrate is evaporated, filtered, the solid washed with ether and recrystallized from dioxane to give 7.8 g of additional white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Cc1cccnc1Br
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ncccc3C)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromo-3-methylpyridine
Reaction SMILES: [CH3:1][Mg]Cl.CON(C)[C:7](=[O:22])[CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1>C1COCC1>[O:22]=[C:7]([CH3:1])[CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
Added dropwise 3.0 M methylmagnesium chloride in THF (8.63 mL, 25.9 mmol) to a solution of tert-butyl 4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-1-carboxylate (5.93 g, 20.7 mmol) in THF (100 mL) at 0° C. Warmed to ambient temperature and stirred for 90 minutes. Partitioned between ether and 2N HCl, washed the organic layer twice with water, brine, dried, and concentrated to afford the title compound (4.95 g, 99.1% yield) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:4](=[O:27])[C:5]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C1COCC1.O>[CH3:26][S:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13]([C:5]2[C:4](=[O:27])[N:3]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=3)[C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2)=[O:14])=[CH:22][CH:21]=1)(=[O:25])=[O:24]
Reactant: CCOC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-carboxylate (0.70 g, 1.30 mmol) in THF (10 ml) and water (10 ml) was added NaOH (1M, 2 ml, 2 mmol), and the mixture was stirred for 1 h at room temperature, monitoring the progress of the reaction by LC-MS. 20% conversion was observed and another portion of NaOH (1M, 1 ml, 1 mmol) was added, and the reaction was allowed to run for another hour. This process was repeated until complete conversion of the ester was observed (normally 3-4 hours). The outcome of the reaction is two compounds with the same mass, in a 95:5 proportion. The main product is the subtitle compound, and the other is a regioisomer. The reaction mixture was evaporated in order to remove TIM, and the residual water solution was acidified and then extracted into EtOAc. The organic phase was collected and dried over Na2SO4. Filtration and evaporation gave a crude product 0.60 g (90%) of a yellowish solid, which was used further without purification. A portion of the product was purified using preparative HPLC.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]4)[CH2:50][CH2:49]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCN(C2CCNCC2)CC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-hydroxy-[1,4′]bipiperidine (ChemBridge) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C38H49N6O3Cl2 [(M+H)+] 707.3238, observed 707.3232.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([Cl:12])[C:3]=1[N+:13]([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H]>[Pt].C(OCC)(=O)C>[NH2:13][C:3]1[C:4]([Cl:12])=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: Nc1c(Cl)nc2ccccc2c1N

Procedure:
4-amino-2-chloro-3-nitroquinoline (5 g, 0.0224 mol) was combined with ethyl acetate (300 mL), magnesium sulfate (1 g), and 5% Pt/C (0.5 g). The mixture was hydrogenerated on a Parr apparatus until no further uptake of hydrogen was observed. The resulting mixture was filtered and the solvent was removed at reduced pressure to afford a tan solid product 3,4-diamino-2-chloroquinoline.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:15]=1)[CH3:7].[CH3:24][C:25]([NH2:38])([CH3:37])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1.Cl([O-])(=O)(=O)=O.[Li+]>C1(C)C=CC=CC=1>[OH:1][C@H:2]([CH2:3][NH:38][C:25]([CH3:37])([CH3:24])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[CH2:4][O:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:15]=1)[CH3:7]
Reactant: CCOC(=O)c1ccc(-c2ccccc2C(C)OC[C@H]2CO2)s1
Reactant: CC(C)(N)Cc1ccc2ccccc2c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2C(C)OC[C@H](O)CNC(C)(C)Cc2ccc3ccccc3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Ethyl 5-[2-[1-(((2R)-oxiranyl)methoxy)ethyl]phenyl]thiophene-2-carboxylate (499 mg) obtained in Step 4 was dissolved in toluene, [2-methyl-1-(naphthalen-2-yl)propan-2-yl]amine (299 mg) and lithium perchlorate (160 mg) were successively added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (770 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][C:5]([NH2:17])=[C:4]([N+:18]([O-])=O)[CH:3]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO.[Zn]>[NH2:17][C:5]1[CH:6]=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:2]([F:1])=[CH:3][C:4]=1[NH:18][C:33](=[O:34])[O:35][CH2:36][CH3:37]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(NCc2ccc(F)cc2)c(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)Nc1cc(F)c(NCc2ccc(F)cc2)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.2 %

Procedure:
To a stirred solution of compound 3 (0.400 g, 1.40 mmol, 1.00 equiv) in methanol (10 mL) was added zinc powder (0.470 g, 7.10 mmol, 5.00 equiv) followed by ammonium chloride solution (0.380 g, 9.10 mmol, 5.00 equiv) drop wise. After being stirred for 5 h at RT, DIPEA (0.155 g, 1.54 mmol, 1.10 equiv) and ethyl chloroformate (0.151 g, 1.40 mmol, 1.00 equiv) were added to reaction mixture at 0° C. and the stirring was continued for another 3 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (25 mL) and Extracted with EtOAc (2×75 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 1:4) to afford to compound 3A (0.100 g, 21.0%) as brown solid. TLC: 40% EtOAc/Hexane (Rf: 0.50); 1HNMR (400 MHz, DMSO-d6): δ 8.27 (br s, 1H), 7.39-7.34 (m, 2H), 7.12 (t, J=8.8 Hz, 2H), 6.81-6.78 (m, 1H), 5.93 (d, J=9.2 Hz, 1H), 5.79 (t, J=6.4 Hz, 1H), 4.42 (s, 2H), 4.22 (d, J=6.0 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H); LC-MS: m/z=322 (M++1) at RT 3.54 (95.8% purity); UPLC purity: 98.8%
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[C:5]([CH3:7])[N:6]=1.[C:9]1([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][SH:23])[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:30]>CN(C)C=O.CO>[ClH:30].[NH2:1][C:2]1[S:3][C:4]([S:23][CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][CH:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:20][CH2:19]2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(N)sc1Br
Reactant: SCCN1CCC(c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc(N)sc1SCCN1CCC(c2ccccc2)CC1
Temperature: 0 °C

Procedure:
9.65 g of 2-amino-5-bromo-4-methylthiazole, 11.1 g of 2-(4-phenyl-1-piperidinyl)ethyl mercaptan and 20.7 g of potassium carbonate in 50 ml of dimethylformamide were stirred at 80° C. for 30 minutes. The mixture was poured into ice-water and extracted with methylene chloride, and the organic phase was washed with water, dried and concentrated. The residue was purified by chromatography (SiO2 ; CH2Cl2, CH3OH (0-20%)). The hydrochloride was prepared by dissolving the free base in methanol and adding ethereal HCl.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[N:5][N:6]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.O.[OH-].[Na+]>CN(C)C=O>[CH2:9]([N:8]([CH2:7][C:4]1[S:3][C:2]2=[N:1][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][N:6]2[N:5]=1)[CH2:11][CH3:12])[CH3:10]
Reactant: CCN(CC)Cc1nnc(N)s1
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nn2cc(-c3ccccc3)nc2s1

Procedure:
18.6 g (0.1 mol) of 2-amino-5-diethylaminomethyl-1,3,4-thiadiazole and 19.9 g of ω-bromo-acetophenone in 70 mL of dimethylformamide are warmed at 150° C. for 3 hours. 150 ml of water are added to the cooled reaction mixture and the mixture is neutralised with 20% strength sodium hydroxide solution. The precipitate is filtered off with suction. After recrystallisation from acetonitrile, 11.5 g (40.2%) of melting point 138° C. remain.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(C#C[Si](C)(C)C)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 90 °C

Procedure:
6-(((2S,4R)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 6) (1.62 g, 4.20 mmol), ethynyltrimethylsilane (17.5 ml, 124 mmol), triethylamine (23 ml, 165 mmol), bis(triphenylphosphine)palladium(II) chloride (0.590 g, 0.841 mmol) and copper(I) iodide (0.080 g, 0.420 mmol) were mixed in DMF (18 ml) and heated at 90° C. overnight. The reaction was concentrated in vacuo, diluted with water (30 ml), and extracted with DCM (3×30 ml). The organics were combined and dried (hydrophobic frit). The solution was concentrated in vacuo, and the residue purified by chromatography on a silica cartridge (100 g) eluting with an ethylacetate/cyclohexane gradient (0-75% over 14 CVs). The appropriate fractions were collected and the solvent evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-2-methyl-6-((trimethylsilyl)ethynyl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (881 mg) as a black foam, which was used without further purification. LCMS (formate), Rt 1.24 min, MH+ 402
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([NH:13][CH2:14][CH:15]([OH:17])[CH3:16])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(#N)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CC#N
Product: CC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of N2-(tert-butoxycarbonyl)-N-(2-hydroxypropyl)-D-alaninamide (13 g, 53 mmol) in acetonitrile (800 ml) and water (320 ml), was added RuCl3 (300 mg, 1.06 mmol) and NaBrO3 (4 g, 26.5 mmol). The resulting mixture was stirred at room temperature overnight. After concentration to remove most of acetonitrile, the residue was departed between water and ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated to give 8.5 g (65.9%) of N2-(tert-butoxycarbonyl)-N-(2-oxopropyl)-D-alaninamide as solid. 1H-NMR CDCl3 δ 6.86 (br, 1H), 5.08 (br, 1H), 4.13 (s, 2H), 5.09 (s, 2H), 2.19 (s, 3H), 1.43 (s, 9H), 1.37 (s, 3H). ES-MS [M+1]+: 244.90
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C=O)C.O>[O:20]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:25])[N:19]1[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CBr)c2ccccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 85 °C
Yield: 99.7 %

Procedure:
To a stirred solution of 4-(bromomethyl)-1-naphthaldehyde (7 g, 28 mmol) in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated at 85° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with H2O (100 mL). The obtained solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192° C.; 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS m/z 316.09 ([M+H]+); IR (thin film) 1708 cm−1.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[CH3:12][S:13]([C:16]1[CH:17]=C([CH:22]=[CH:23][CH:24]=1)C(O)=O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:12][S:13]([C:16]1[CH:17]=[C:6]([CH:22]=[CH:23][CH:24]=1)[C:7]([Cl:9])=[O:8])(=[O:15])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DMF (0.4 mL) and oxalyl chloride (1.90 g) were added to a solution of 3-(methylsulfonyl)benzoic acid (2.00 g) in CHCl3 (including amylene, 40 mL) in a nitrogen gas flow under ice cooling, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to yield a crude product as a yellow solid, which was used in the subsequent reaction.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@H:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].S(=O)(=O)(O)O.II.O.O.[I:26](O)(=O)(=O)=O>C(O)(=O)C.O>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][C@H:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:26])=[CH:10][CH:9]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: C[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](Cc1ccc(I)cc1)NC(=O)C(F)(F)F
Temperature: 70 °C
Yield: 185.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(1R)-1-methyl-2-phenylethyl]acetamide (3.75 g) in acetic acid (32 ml)—water (6.5 ml)—sulfuric acid (0.97 ml) were added iodine (1.65 g) and periodic acid dihydrate (740 mg) at room temperature, and the mixture was heated to 60-80° C. for 5 hours. After being allowed to cool to room temperature, the mixture was partitioned between hexane/ethyl acetate and water. The organic layer was separated, washed successively with water, sodium sulfite solution, water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was recrystallized from diisopropyl ether (44 ml) to give 2,2,2-trifluoro-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]acetamide (2.15 g) as a colorless needle.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][OH:24])=[CH:18][CH:17]=1)#[N:15]>CN(C=O)C.CCOC(C)=O>[Si:5]([O:24][CH2:23][CH:22]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:19]1[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:21][CH:20]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)CNC(CO)c1ccc(C#N)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
t-Butyldimethyl silyl chloride (0.579 g; 3.84 mmol) and imidazole (0.261 g; 3.83 mmol) were added to a solution of tert-butyl 2-(1-(4-cyanophenyl)-2-hydroxyethylamino)acetate (0.709 g; 2.56 mmol) in DMF (10 mL). The reaction mixture was stirred at ambient temperature for 18 hours. The mixture was diluted with EtOAc and washed sequentially with water and brine. The organic phase was poured through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography eluting with iso-hexane/EtOAc (10:1) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.63-7.61 (m, 2H), 7.48 (d, J=8.4 Hz, 2H), 3.86-3.83 (m, 1H), 3.66-3.55 (m, 2H), 3.23 (d, J=16.8 Hz, 1H), 3.06 (d, J=16.8 Hz, 1H), 2.53 (br s, 1H), 1.47 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:26]=[C:27]([CH:29]1[CH2:31][CH2:30]1)[NH2:28]>>[CH:29]1([C:27]2[N:28]=[C:22]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:18][CH:19]([OH:21])[CH2:20]4)=[O:16])[CH2:12]3)[O:23][N:26]=2)[CH2:31][CH2:30]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1
Reactant: NC(=NO)C1CC1
Product: CCc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CC(O)C3)C2)cc1

Procedure:
60 mg (0.18 mmol) of the compound from Example 138A and 27 mg (0.27 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 24 mg (33% of theory)