Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:6]=2.[C:29](Cl)(=O)C(Cl)=O.CN(C)C=O>CO>[CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:29])=[O:13])=[CH:9][C:8]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:7][CH:6]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc2c1C(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a suspension of 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.07 g, 9.94 mmol) at 0° C. was added oxalyl chloride (1.305 mL, 14.91 mmol) and N,N-dimethylformamide (0.1 mL). The resulting mixture was stirred at 0° C. for 1 h. Methanol (5 mL) was added, and the mixture was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the residue diluted with saturated aqueous NaHCO3. The aqueous mixture was extracted with methylene chloride, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was absorbed onto florisil and purified via column chromatography (ISCO, 5-100% ethyl acetate/hexanes) to afford methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.665 g, 60% yield). MS (m/z) 424.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([S:17][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccnc(Cl)c1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccnc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 26 h
Yield: 35.9 %

Procedure:
To a solution of 2-chloro-4-methoxypyridine (786 mg) in toluene (10 mL) were added phenylmethanethiol (683 mg), N,N-diisopropylethylamine (1.56 g), tris(dibenzylideneacetone)dipalladium(0) (202 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (256 mg), and the mixture was stirred at 80° C. for 26 hr under an argon atmosphere. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-hexane-ethyl acetate=19:1) to give the title compound as an orange oil (yield 454 mg, 38%).
Reaction SMILES: [F:1][C:2]1[S:10][C:9]2[C:4](=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[Cl:17]N1C(=O)CCC1=O>C1COCC1.C(NC(C)C)(C)C>[Cl:17][C:3]1[C:4]2=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=[C:9]2[S:10][C:2]=1[F:1]
Reactant: Cc1ccc2sc(F)cc2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc2sc(F)c(Cl)c2n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a solution of 461 mg (2.74 mmol) of 2-fluoro-5-methylthieno [3.2-b]pyridine (Example 7, Step 1) and 14 μl (0.1 mmol) of diisopropylamine in 12 mL of THF was added 2.15 mL of n-butyl lithium (1.4M in hexane) at -78° C. After stirring at -78° C. for 10 min, a solution of 585 mg (4.4 mmol) of N-chlorosuccinimide in 10 mL of THF was added at -78° C. The mixture was stirred at -78° C. for 20 min, warmed up to 0° C., stirred at 0° C. for 30 min, and then partitioned between aqueous ammonium chloride and ethyl acetate. Chromatographic purification on silica gel with hexane/ethyl acetate=8:1 gave 350 mg (63%) of the title product.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCN(Cc3ccccc3)CC2)c1

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 12 g of 3-bromoanisole and 15 ml of THF and a solution of 10 g of 1-benzyl-4-piperidone in 30 ml of THF. The product obtained is chromatographed on silica gel, eluting with a DCM/MeOH (97/3 to 95/5; v/v) mixture. This gives 13.7 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[CH:20]=[C:19]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2ccc(Cl)nn2)cn1
Temperature: 70 °C
Yield: 4631.1 %

Procedure:
A mixture of 3,6-dichloro-pyridazine (1.06 g, 6.98 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.47 g, 5.0 mmol) in 2.0 M potassium carbonate (10 mL, 20 mmol) and 1,4-dioxane (40 mL) was degassed by house vacuum for 15 min followed by bubbling with argon for ˜10 min, Peppsi-ipr (340 mg, 0.5 mmol) was then added. After flushing with argon for another ˜10 min, the mixture was heated at 70° C. for 4 h and allowed to cool to room temperature. The solid was removed by filtration through Celite, and the filtrate was separated. The aqueous solution was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, concentrated, and purified by column to provide o.65 g desired product (46%). 1H NMR(DMSO) δ 9.08(s, 1H), 8.47 (s, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 1.59 (s, 3H); MS (ES) m/z 280.8 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: Clc1ccc(CN[C@H]2CCCc3ccccc32)c(Cl)c1

Procedure:
2,4-Dichlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:31]1[C:36]([C:37]2[N:42]=[C:41]([CH3:43])[N:40]=[C:39]([N:44]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=3)[CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[N:38]=2)=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([CH2:54][N:44]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)[C:39]2[N:40]=[C:41]([CH3:43])[N:42]=[C:37]([C:36]3[C:31]([NH:1][C:2]4[CH:3]=[C:4]([NH:9][S:10]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)(=[O:11])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=4)=[N:32][CH:33]=[CH:34][CH:35]=3)[N:38]=2)=[CH:60][CH:59]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A mixture of N-(5-amino-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.08 g, 0.265 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.795 mL, 0.795 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min before 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.142 g, 0.318 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min then removed from the ice bath and stirred for 3 h. The reaction mixture was quenched with water. The resulting mixture was partitioned between EtOAc and sat. NH4Cl. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 20% to 30% acetone in hexanes) to give the product as a yellow solid (0.090 g). m/z (ESI, +ve ion) 727.1 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 12.48 (s, 1H); 8.78-8.95 (m, 2H); 8.41 (d, J=3.51Hz, 1H); 8.27 (s, 1H); 7.93 (dd, J=8.62, 4.97 Hz, 2H); 7.22 (d, J=6.58 Hz, 4H); 7.14 (t, J=8.48 Hz, 2H); 6.77-6.97 (m, 6H); 4.85 (d, J=3.36 Hz, 4H); 3.81 (d, J=5.12 Hz, 6H); 2.61 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(OCCBr)c(Cl)c1
Yield: 61.4 %

Procedure:
A mixture of 2,4-dichlorophenol (105 g, 0.64 mol), 1,2-dibromoethane (157 g, 0.84 mol) and water (500 mL) was heated at reflux, during which time a solution of sodium hydroxide (28.0 g, 0.70 mol) in water (125 mL) was added to the mixture over a period of one hour. The solution was allowed to reflux for 10 hours, cooled and the separated organic layer was distilled to give 1-bromo-2-(2,4-dichlorophenoxy)ethane (106 g, yield 62%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.F[C:17]1[C:18]([C:24]#[N:25])=[N:19][C:20]([F:23])=[CH:21][N:22]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:17]1[C:18]([C:24]#[N:25])=[N:19][C:20]([F:23])=[CH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1nc(F)cnc1F
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1nc(F)cnc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In 5 ml of toluene was dissolved 0.5 g f 3,6-difluoro-2-pyrazinecarbonitrile. After adding 0.41 mL of benzyl alcohol and 0.74 mL of triethylamine successively, the mixture thus obtained was stirred at 80° C. for one hour. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 0.58 g of 3-(benzyloxy)-6-fluoro-2-pyrazinecarbonitrile as a white-colored solid product.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27].Cl>CN(C)C=O.O>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:6]2[N:7]=[C:3]([CH3:2])[S:4][CH:5]=2)[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: COC(CCBr)OC
Reactant: Cc1nc(-c2c[nH]c(=O)[nH]c2=O)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2csc(C)n2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
5-(2-methyl-1,3-thiazol-4-yl)-2,4(1H,3H)-pyrimidinedione hydrochloride (Prep20, 287 mg, 1.110 mmol) was dissolved in N,N-Dimethylformamide (DMF) (4 ml). K2CO3(460 mg, 3.33 mmol) were added and the reaction mixture stirred at room temperature for 1 h. 3-bromo-1,1-bis(methyloxy)propane (0.185 ml, 1.221 mmol) was added. The obtained mixture was then stirred at room temperature. After 4 days it was diluted with water, neutralized with HCl, and extracted by EtOAc. The organic phase was washed with water (3 times), brine, dried over Na2SO4, filtered and the solvent evaporated. The obtained crude was purified by preparative LC-MS. 58.5 mg of the title compound were isolated as a white solid.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=2)[CH:11]=[C:10]([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:9]=1.[O:28]1[CH2:33][CH2:32][CH:31]([CH:34]=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH:18]=[CH:17][N:16]=2)[C:21]#[N:22])[CH:11]=[C:10]([CH:23]2[CH2:27][CH2:26][N:25]([CH2:34][CH:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)[CH2:24]2)[CH:9]=1
Reactant: C[C@@H]1CCCN1c1cc(C2CCNC2)cc(Nc2cc(C#N)ccn2)n1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CCCN1c1cc(C2CCN(CC3CCOCC3)C2)cc(Nc2cc(C#N)ccn2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 8.4 %

Procedure:
To a solution of 2-[[6-[(2R)-2-methylpyrrolidin-1-yl]-4-pyrrolidin-3-yl-2-pyridyl]amino]pyridine-4-carbonitrile hydrochloride (160 mg, 0.415 mmol) in methanol (3.0 mL) was added tetrahydropyran-4-carbaldehyde (0.086 mL, 0.831 mmol, 2.0 equiv.). It was heated @ 50° C. overnight. After cooling to room temperature, sodium triacetoxyborohydride (278.2 mg, 1.247 mmol, 3.0 equiv.) was added in portions. After 3 h, more sodium triacetoxyborohydride (278.2 mg, 1.247 mmol, 3.0 equiv.) was added, stirred @ rt for another o/n. It was quenched with 1N NaHCO3, extracted with EtOAc (2×20 mL), dried over Na2SO4, filtered, concentrated in vacuo, and purified by HPLC to afford 15.5 mg (8.3%) of product as yellow gum. LC-MS: m/z=447 (M+H+).
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:14]([CH:17]([CH2:29][CH2:30][CH3:31])[CH2:18][O:19][C:20]1[O:24][C:23]([C:25](OC)=[O:26])=[CH:22][CH:21]=1)[CH2:15][CH3:16]>C1COCC1>[O:26]=[C:25]([C:23]1[O:24][C:20]([O:19][CH2:18][CH:17]([CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH3:16])=[CH:21][CH:22]=1)[CH2:1][C:2]#[N:3]
Reactant: CCCC(CCC)COc1ccc(C(=O)OC)o1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(CCC)COc1ccc(C(=O)CC#N)o1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Anhydrous CH3CN (0.15 mL, 2.87 mmol) was added to a solution of LiHMDS (1M/THF, 3.0 mL, 3.0 mmol) at −75° C. under inert atmosphere and the reaction mixture was stirred for 5 min. A solution of methyl 5-((2-propylpentyl)oxy)furan-2-carboxylate (1.337 mmol) in anhydrous THF (7 mL) was added to the reaction mixture and the reaction mixture was stirred under inert atmosphere while slowly warming to 0° C. for over 75 min. The reaction mixture was partitioned between aqueous NaHSO4 (10%) and EtOAc. Organic layer was washed with brine, concentrated under reduced pressure. Flash chromatography purification (10%-50% EtOAc—hexanes gradient) gave 3-oxo-3-(5-((2-propylpentyl)oxy)furan-2-yl)propanenitrile as an off-white solid. Yield (0.23 g, 66%); 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J=3.8 Hz, 1H), 5.78 (d, J=3.8 Hz, 1H), 4.30 (s, 2H), 4.08 (d, J=5.6 Hz, 2H), 1.69-1.79 (m, 1H), 1.23-1.35 (m, 8H), 0.80-0.88 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:12]([OH:15])(=[O:14])C>[Pd]>[C:4]([O:15][C:12]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1)=[O:14])([CH3:7])([CH3:5])[CH3:3]
Reactant: O=C(O)C=Cc1ccncc1
Reactant: CC(=O)O
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(4-pyridyl)-2-propenoic acid (10 g) , 10% Pd—C (1 g) in acetic acid (40 ml) was hydrogenated (3.0 kg/cm2) at 65° C. for 8 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was resolved in toluene (30 ml) and concentrated in vacuo. The residue was resolved in water (30 ml) and tetrahydrofuran (50 ml), cooled to 0° C., and triethylamine (33 g) was added dropwise at 5° C. Di-t-butyl dicarbonate (18.3 g) was added to the mixture at 20° C. and stirred overnight. PH was adjusted to 7 with HCl, organic layer was washed with 10% aqueous citric acid (40 ml), 5% aqueous sodium chloride (40 ml), dried over magnesium sulfate (5 g) and concentrated in vacuo. The residue was resolved in toluene (20 ml), concentrated in vacuo to 25 ml. The mixture was stirred at 40° C. for 3 hours, n-heptane (20 ml) was added to the mixture and stirred at 0° C. overnight. The precipitate was separated and dried to give 3-(1-tert-butoxycarbonyl-4-piperidyl)propionic acid as white solid (12.8 g).
Reaction SMILES: CN1[C:10]2[C:5](=[CH:6][C:7](S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4](=O)C1=O.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2[S:42]([C:45]2[CH:46]=[C:47]3[C:51](=[CH:52][CH:53]=2)[NH:50][C:49](=[O:54])[C:48]3=[O:55])(=[O:44])=[O:43])[CH:30]=1.C(Br)C1C=CC=CC=1>>[CH2:4]([N:50]1[C:51]2[C:47](=[CH:46][C:45]([S:42]([N:38]3[CH2:39][CH2:40][CH2:41][CH:37]3[CH2:36][O:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)(=[O:44])=[O:43])=[CH:53][CH:52]=2)[C:48](=[O:55])[C:49]1=[O:54])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc2C1=O
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Agent: BrCc1ccccc1
Product: O=C1C(=O)N(Cc2ccccc2)c2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc21
Yield: 51 %

Procedure:
1-Benzyl-5-(2-(pyridin-3-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (21b) was prepared according to the same procedure for compound 11a, except using compound 20 and benzyl bromide, and the crude product was purified with ether to afford 61 mg (51%) of 21b as a yellow solid, mp 79.6-80.7° C. 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 8.22 (t, J=2.7 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.98 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.36 (m, 5H), 7.22 (m, 2H), 6.91 (d, J=8.8 Hz, 1H), 4.97 (s, 2H), 4.25 (m, 1H), 3.99-3.94 (m, 2H), 3.55-3.48 (m, 1H), 3.21-3.15 (m, 1H), 2.10-1.97 (m, 2H), 1.84-1.75 (m, 2H). LRMS (FAB) m/e: 484.1 (M+Li, 100); HRMS (FAB) m/e calcd for C25H23N3O5SLi (M+Li) 484.1518, found 484.1539.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:25][C@@H:26]2[O:31][C@@H:30]([CH2:32]O)[C@H:29](O)[C@@H:28](O)[C@@H:27]2[NH:36]C)[C@@]1(O)C=O.C1[C@H]([NH2:47])[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N>>[NH2:36][C@H:27]([C:26]([OH:31])=[O:25])[CH2:28][CH2:29][CH2:30][CH2:32][NH2:47]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
pAET7 was introduced into V12Sα obtained in Example 16, and the pMIV-FRTKmFRT-EABDAS#10 plasmid was also introduced to obtain the V12Sα strains where the lysE, dapA, dapB, asd, lysA, and ddh genes were introduced into the chromosome by the method described in Example 16. Randomly selected 200 strains were cultured in an SEII production medium containing 50 mg/L streptomycin and 20 mg/L kanamycin to select a strain which produced the most L-lysine, and was designated as Vmac1. A streptomycin-sensitive strain was selected form the Vmac1 strains to obtain a strain where pAET7 was eliminated. The pFLP31 plasmid shown in Example 9 was introduced into the strain, and a kanamycin-resistant gene region was eliminated from the mini-Mu cassette on the chromosome by the method described in Example 9. The kanamycin-sensitive strains obtained by the procedure were designated as Vmac1S strain. A streptomycin-sensitive strain was selected from the Vmac1S strain to obtain a strain where the pFLP31 plasmid was eliminated. The pAET7 plasmid was introduced again into this strain, and the plasmid pMIV-FRTKmFRT-EABDAS#10 was also introduced again. Then, the strain which produced the most L-lysine was selected and designated as the Vmac2 strain. In the same way as described above, the Vmac2S strain, Vmac3 strain, and Vmac3S strain were obtained. The amount of Lys produced by V12 was defined as 100, and the relative value of the amount of Lys produced by the Vmac3S strain was calculated and shown in Table 10.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH3:22])[CH2:17][CH2:16]2)=[CH:10][N:9]=1)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[CH2:21]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=2)[CH2:20][CH2:19]1)[CH3:22]
Reactant: CCN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCN1CCN(Cc2ccc(N)nc2)CC1

Procedure:
A mixture of [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 26.2) (0.75 g, 2.8 mmol) and a 4 N solution of HCl in dioxane (20 mL) was stirred for 72 h at rt and concentrated to afford 660 mg of the title compound as a white solid: ESI-MS: 221.1 [M+H]+; tR=0.80 min (System 1).
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]([C:8]1[N:9](S(C)(=O)=O)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]#[N:18])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)([OH:7])[CH3:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([S:3][CH2:4][C:5]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]#[N:18])=[C:12]([C:19]([F:21])([F:20])[F:22])[CH:11]=2)([OH:7])[CH3:6])[CH3:2]
Reactant: CCSCC(C)(O)c1cc2cc(C#N)c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCSCC(C)(O)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the general de-protection procedure as describe in General Procedures Example B, reacting 2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-1-methanesulfonyl-6-trifluoromethyl-1H-indole-5-carbonitrile (219 mg, 0.54 mmol) and using 4M sodium hydroxide (0.40 mL, 1.62 mmol) as the base, to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][CH:25]=O)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.[OH-].[NH4+:38].II>O>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:38])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC=O)C4CCCC4)c3)ncnc21
Reactant: [NH4+]
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 86.8 %

Procedure:
Method B. A solution of (1R)-(4-(1-(1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-37, 169 mg, 0.399 mmol) in tetrahydrofuran (THF, 1.2 mL, 15 mmol) at room temperature was added a 14.3 M solution of ammonium hydroxide (NH4OH) in water (1.2 mL), followed by iodine (I2, 112 mg, 0.439 mmol, 1.1 equiv). The resulting reaction mixture was stirred at room temperature for 25 min. When LCMS showed that the reaction was deemed complete, the reaction mixture was quenched with 10% aqueous Na2S2O3 (10 mL) before being extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-60% EtOAc/hexane gradient elution to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-12, 145.6 mg, 167.8 mg theoretical, 86.8% yield) as a colorless foam.