Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH:21]=[C:22]1[S:26][C:25](SC)=[N:24][C:23]1=[O:29])=[CH:10][CH:9]=2)(=[O:4])=[O:3].[NH3:30]>CO>[NH2:30][C:25]1[S:26]/[C:22](=[CH:21]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:14]3[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)/[C:23](=[O:29])[N:24]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncc(S(C)(=O)=O)c(-c4ccccc4)c3c2)S1
Reactant: N
Solvent: CO
Product: CS(=O)(=O)c1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1-c1ccccc1

Procedure:
Similar procedure as described in example 41c was used, starting from 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one (example 61k), and ammonia in methanol to give 2-amino-5-[1-(3-methanesulfonyl-4-phenyl-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 410 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][C:14]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][C:14]=1[OH:27])=[O:5]
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(O)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccc(Cl)nc2Cl)c(O)c1
Reaction time: 8 h

Procedure:
A solution of 8.5 g (0.0405 mol) 2,6-dichloronicotinoyl chloride in 20 ml DMF is slowly added dropwise to a suspension of 8.8 g (0.04 mol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6.9 g (0.05 mol) potassium carbonate and 50 ml DMF and it is then stirred overnight. The reaction mixture is mixed with water, then the aqueous supernatant is decanted off, the residue is washed with water again, filtered off and then purified through silica gel (eluant: ethylene chloride/ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:7])[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ncccc1N
Product: CCOc1ccccc1C(=O)Nc1cccnc1C(N)=O

Procedure:
The title compound was prepared from 2-ethoxybenzoyl chloride and 3-aminopyridine-2-carboxamide (J. Chem. Soc., 1956, 1045) following the procedure of Preparation 7 and was obtained as an off-white solid (100%), m.p. 172-177° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11][C:12]1([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4].CO[C:38](OC)([CH3:40])[CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@@H:9]1[O:33][C:38]([CH3:40])([CH3:39])[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:10]1[CH2:11][C:12]1([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(C)(C)OC
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1(CCOCc2ccccc2)CC1)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1(CCOCc2ccccc2)CC1

Procedure:
The 5(S)-tert-butoxycarbonylamino-6-[1-(2-benzyloxyethyl)cyclopropyl]-4(S)-hydroxy-2(R)-methyl-hexanoic acid (N-butyl)amide thus obtained is reacted with dimethoxypropane and p-toluenesulfonic acid hydrate in a manner analogous to that described in Example 1 d) and the product is purified by means of FC over 80 g of silica gel (mobile phase C). This gives the title compound as the pure diastereomer: Rf (A)=0.58,
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:27](O)(C)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH:14]=[CH:13][CH:12]=3)=[O:5])([CH3:27])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1cccc(Cc3ccccc3Cl)c12
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)OC(=O)c1cc2c(cn1)[nH]c1cccc(Cc3ccccc3Cl)c12

Procedure:
0.2 g (0.55 mmol) of 5-(2-chlorobenzyl)-β-carboline-3-carboxylic acid ethyl ester is refluxed for 4 hours with 0.16 g (0.57 mmol) of titaniumtetraisopropylate in 50 ml of isopropanol. The solution concentrated by evaporation to half, the isopropyl ester crystallizes out during cooling. Yield 164 mg (79% of theory), melting point 258°-260° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH2:17]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(N)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: CCc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 2.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 4-ethylaniline (0.08 mL, 0.65 mmol) to provide 244 (4 mg, 15% yield) as a dark brown solid. LC-MS (M+H (parent)=316, obsd.=316).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].O>CO>[CH3:5][O:4][C:2]([N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)=[O:3]
Reactant: c1ccncc1
Reactant: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)N1C=CC=CC1
Reaction time: 2 h

Procedure:
Methyl chloroformate (30.9 mL/400 mmol) was added via syringe to a mixture of pyridine (31.6 g/400 mmol) and sodium borohydride (16.0 g/420 mmol) in methanol (150 mL) at -78° C. Stirred for two hours then poured in to water then extracted with diethyl ether (3×300 mL). The extracts were dried over NaCl/Na2SO4 then evaporated. The residue was purified by preparative chromatography using silica gel eluting with ethyl acetate/hexanes to yield the 1-(methoxycarbonyl)-1,2-dihydropyridine, 1A (20.2 g/130 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Br.[C:15]([O:19][C:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]1[CH2:31][NH:32][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:34])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[C:15]([O:19][C:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][N:32]([CH2:12][C:5]1[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:34])=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: CC(NCC1Nc2ccccc2N1C(=O)OC(C)(C)C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C(C)c1ccccn1

Procedure:
Using General Procedure A: Reaction of 2-bromomethyl-5-cyano-benzoic acid methyl ester and 2-[(1-pyridin-2-yl-ethylamino)-methyl]-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester in CH3CN with DIPEA, KI, and DMAP gave 2-{[(4-cyano-2-methoxycarbonyl-benzyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a light yellow solid. 1H NMR (CDCl3) δ 1.56-1.59 (m, 3H), 1.71 (s, 9H), 3.86 (s, 3H), 4.23 (s, 1H), 4.28-4.30 (m, 2H), 4.40-4.47 (m, 2H), 7.10-7.16 (m, 1H), 7.24-7.32 (m, 3H), 7.42-7.46 (m, 1H), 7.51-7.66 (m, 2H), 7.71-7.76 (m, 1H), 7.82 (d, 1H, J=1.7 Hz), 7.92 (d, 1H, J=8.0 Hz), 8.53 (d, 1H, J=4.8 Hz).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](=[O:42])(=[O:41])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[N:32]2[C:40]3[C:35](=[N:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[N:33]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(Cl)Cl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][S:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([CH3:15])([CH3:16])[CH2:13][OH:12])=[CH:18][CH:19]=2)(=[O:42])=[O:41])=[C:26]([N:32]2[C:40]3[C:35](=[N:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[N:33]2)[CH:27]=1
Reactant: COC(=O)C(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(CO)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Reaction time: 1 h

Procedure:
DIBAL-H (diisobutylaluminium hydride)(0.71 mL, 1.0 M solution in CH2Cl2) was added to 2-[4-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylsulfamoyl)-phenyl]-2-methyl-propionic acid methyl ester (synthesized according to general procedures F and G, 137 mg, 0.282 mmol) in CH2Cl2 (3 mL) at −78° C. After 1 hour, LCMS indicated a 2:1 ratio of the desired product and corresponding aldehyde intermediate. 1 N HCl (2 mL) was added to the reaction mixture, the flask was warmed to room temperature, and the solution was diluted with EtOAc (30 mL). The EtOAc layer was separated, dried (Na2SO4), and evaporated in vacuo. The resultant crude residue was treated with NaBH4 (30 mg, excess) in MeOH (3 mL) at room temperature for 10 minutes and directly purified by preparative HPLC to afford the title compound as a white powder: MS (ES) M+H expected 458.1, found 458.0.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH2:3][SH:4].Cl[CH2:7][CH2:8][CH2:9][OH:10]>CO>[CH2:9]([OH:10])[CH2:8][CH2:7][S:4][CH2:3][CH2:2][S:5][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: SCCS
Reactant: OCCCCl
Agent: [Na]
Solvent: CO
Product: OCCCSCCSCCCO
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 300 ml of absolute methanol, was added 12.2 g of metallic sodium. To the resulting solution which was being stirred in an ice bath, was added dropwise 25 g of dithioglycol. After the dropwise addition, the stirring was continued for additional 30 minutes in the ice bath. Then, 52 g of 3-chloro-1-propanol was further added dropwise. At the conclusion of the dropwise addition, the temperature of the reaction system was raised to a room temperature, and the reaction system was allowed to stand for 10 hours at the room temperature. The thus produced sodium chloride was removed by filtration under reduced pressure, and the resulting filtrate was concentrated. Crystals thus obtained were recrystallized from acetone. Melting Point 52° C., Yield 20 g.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=2)=[O:12])[CH:23]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cc(Cl)ccc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cc(Cl)ccc2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 336 (125 mg, 0.21 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (3 mL, 3 mmol) and methanol (1 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (90 mg, 73%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H)+]: 586.1471. found: 586.1473.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=O.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CC(=O)OCC
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: CCOC(=O)C=Cc1ccc2ccccc2c1
Yield: 88 %

Procedure:
The procedure described in Example 28 is repeated, except that 9.55 g (0.05 mol) of 2-naphthoyl chloride and 6.25 g (0.0625 mol) of ethyl acrylate are used. After a reaction time of 2 hours at 120° C., 9.9 g (0.044 mol) of ethyl β-(2-naphthyl)-acrylate are obtained, corresponding to a yield of 88% of theory; boiling point 106°-110° C./4 Pa. Analysis for C15H14O2 (molecular weight 188): calculated C 79.62%, H 6.24%, O 14.14%; found C 79.39%, H 6.49%, O 14.08%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][C:10]([CH3:12])=O>>[CH2:12]([N:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[N:6][C:5]1=[O:8])[CH:10]=[CH2:9]
Reactant: CC(C)=O
Reactant: O=c1ncc(Br)c[nH]1
Product: C=CCn1cc(Br)cnc1=O
Yield: 40 %

Procedure:
1-Allyl-5-bromopyrimid-2-one was prepared from 5-bromopyrimid-2-one as above in 40% yield m.p. 142°-143° C. (acetone)
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[NH:62][C:63](=[O:65])[CH3:64])[CH:53]=[CH:54][CH:55]=1>CN(C=O)C>[C:63]([NH:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([NH:49][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:51]=1)(=[O:65])[CH3:64]
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 415 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:25][O:26][NH2:27].C(N(CC)CC)C>CO>[CH3:25][O:26]/[N:27]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 30 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a solution of 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (6.3 mg, 0.021 mmol) in methanol (3 mL) was added O-methylhydroxylamine hydrochloride (16.7 mg, 0.20 mmol), followed by addition of triethyl amine to adjust the pH to 5-6. The reaction mixture was stirred at 30° C. for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The resulting solution was washed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 5.3 mg (69%) of the title compound. 1H-NMR (400 MHz, CD3Cl) δ ppm 9.67 (s, 1H), 8.94 (m, 1H), 8.16 (t, 2H), 7.93 (d, 1H), 7.86 (dd, 1H), 7.53 (dd, 1H), 6.11 (s, 2H), 4.14 (s, 3H), 2.38 (s, 3H). LCMS (method A): [MH]+=334, tR=5.02 min.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)nc2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
To absolution of 1,1-dimethylethyl(4RS,5SR)-5-(6-fluoropyridin-3-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (2.40 g, 4.91 mmol) in methanol (12 ml) was added a solution of 0.5N sodium hydroxide in methanol (11.8 ml, 5.90 mmol), and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (50 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.98 g, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C@H:37](O)[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([O:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:35][CH:36]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCCC[C@@H](O)c1ccc(CC(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCC[C@H](Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butyrate (275 mg), (R)-1-(4-isobutylphenyl)pentan-1-ol (179 mg) and triphenylphosphine (213 mg) in a mixture of tetrahydrofuran and toluene (1:4, 10 ml) was added diethyl azodicarboxylate (0.13 ml) at -25° C. After stirring for 1 hour, the reaction mixture was concentrated in vacuo. The concentrate was chromatographed on silica gel using hexane and ethyl acetate (3:1) to give ethyl (S)-4-[3-[4-[1-(4-isobutylphenyl)pentyloxy]benzoyl]indol-1-yl]butyrate (279 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]([O-:12])=[O:11])=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.S(Cl)(Cl)=O.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1[C:3]([C:10]([O:12][CH3:17])=[O:11])=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1
Reactant: O=C([O-])O
Reactant: Cc1nc(C)c(C(=O)[O-])nc1C
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(C)c(C)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5,6-trimethylpyrazine-2-carboxylate (5.38 g, 30.0 mmol) in methanol (90 mL) was added thionyl chloride (3.70 mL, 51.0 mmol) was added at 0° C. After being stirred at room temperature overnight, the reaction mixture was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo to give methyl 3,5,6-trimethylpyrazine-2-carboxylate. MS (APCI): m/z 181 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[OH-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C1(C)C=CC=CC=1.O>[C:10]([C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)#[N:11]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CC#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
4-Methoxyphenylacetonitrile (7.63 g, 50 mmol) in toluene (30 mL), PEG(E)-400 (4 g, 10 mmol) and 52% aqueous sodium hydroxide (10.73 g in 12.4 mL water) were placed in a flask equipped with a magnetic stirrer. 4-Nitrobenzaldehyde (7.56 g, 50 mmol) in a minimum of toluene was added dropwise. The mixture was stirred for 1 h at 20° C. and then diluted with water (30 mL). The organic layer was separated, washed with water (3×40 mL) and dried with sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from toluene at -20° C. to give 1-cyano-1-(4-methoxyphenyl)-2-(4-nitrophenyl)ethylene (yield=0.913 g, 6.5%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:29][NH:30][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][OH:33]>CN1C(=O)CCC1>[NH2:18][C:16]1[S:17][C:12]2[C:11]([N:30]([CH3:29])[C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][OH:33])=[N:10][C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][C:13]=2[N:15]=1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reactant: CCC[C@H](CO)NC
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](CO)N(C)c1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 120 °C
Yield: 76 %

Procedure:
5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidin-2-amine (6.0 g, 19.4 mmol) was dissolved in NMP (25 mL). DIPEA (6.8 mL, 38.8 mmol) and (2R)-2-(methylamino)pentan-1-ol (3.4 g, 29.1 mmol) were added and the mixture was heated to 120° C. for 3 days. Additional (2R)-2-(methylamino)pentan-1-ol (350 mg, 2.99 mmol) and DIPEA (1 mL, 5.74 mmol) was added and the reaction mixture was heated for 6 h at 120° C. After cooling to room temperature, the mixture was poured into ice. The precipitated product was collected by filtration and purified by flash column chromatography (eluent DCM:ethyl acetate gradient) to yield the title compound (5.74 g, 76% yield).