Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH2:16](O)C>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:9][CH3:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCO
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 96 %

Procedure:
Following Example 11 but replacing the 1-(H)-tetrazolylacetic acid with 3,5-dinitrobenzoic acid, 3.39 g (1.6 cmoles) and the ethanol with methanol, 0.64 ml (1.6 cmoles), the ester was obtained with a yield of 96% (2.17 g), m.p.=108° C.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C[O-].[Na+].Br[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][C:25]3=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:14][CH:13]=1>CO>[CH2:1]([S:3][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][C:25]3=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:35][CH:36]=1)[CH3:2]
Reactant: O=C(c1ccc(OCCCBr)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethanethiol (0.125 ml) is dissolved in methanol (10 ml) and thereto is added sodium methoxide (0.11 g). The mixture is stirred at room temperature for 30 minutes. Thereto is added a solution of 1-{1-[4-(3-bromopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.59 g) in methanol (2 ml) and the mixture is stirred at room temperature overnight. The solvent is concentrated and water is added to the residue, extracted with chloroform, dried with sodium carbonate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give 1-{1-[4-(3-ethylthiopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.2 g).
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.[CH3:46][NH:47][CH3:48]>C(O)(C)C>[CH3:46][N:47]([CH3:48])[CH2:45][C@@H:43]([OH:44])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:37])([CH3:39])[CH3:38])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CNC
Solvent: CC(C)O
Product: CN(C)C[C@@H](O)COC(C)(C)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Yield: 20.1 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (0.69 g, 1.04 mmol), isopropyl alcohol (2 mL), and dimethylamine (1.04 mL, 2.08 mmol, 2 M in THF) was microwaved at 130° C. for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure. The resulting oil was purified by column chromatography (50% ethyl acetate/heptane) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((R)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl)-amide (147.2 mg, 20.05%) as a white powder. HRMS (ES+) m/z Calcd for C35H44Cl2F2N6O3S+H [(M+H)+]: 705.2893. found: 705.2893.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:34][OH:35]>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:29]3[CH2:33][CH2:32][CH2:31][C@@H:30]3[CH2:34][OH:35])[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: OC[C@H]1CCCN1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (R)-1-pyrrolidin-2-yl-methanol in direct analogy to the general procedure used in example 129. MS: 477.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:37]=1[CH:38]=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:38]/[C:37]2[C:36]([Cl:35])=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:44])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2c(Cl)cccc2Cl)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.89 g, 6.9 mmol) and Ph3P (1.82 g, 6.9 mmol) in DMF (35 mL) was heated at 100° C. for 1 h then 2,6-dichlorobenzaldehyde (1.2 g, 6.9 mmol) was added followed by K2CO3 (1.9 g, 13.75 mmol). The resulting deep-red mixture was stirred at 100° C. for 18 h then was allowed to cool to ambient temperature. To this was added water and the mixture was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography using methylene chloride as eluent to give 4-[(E)-2-(2,6-dichlorophenyl)-vinyl]-3-nitrobenzoic acid methyl ester as a pale-yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][C:6]=1[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])#[N:11]
Reactant: COC(=O)c1ccc(C#N)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
500 mg of 4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 50 ml of MeOH:water/3:1. 1 g of lithium hydroxide monohydrate was added to the added to the solution, and the reaction was stirred at RT for 16 h and 2 h at 50° C. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13](B(O)O)=[C:12]([F:20])[CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:22]1[S:23][C:24]([CH:27]=[CH2:28])=[CH:25][CH:26]=1>>[F:20][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:15]=[C:14]([F:16])[C:13]=1[C:22]1[S:23][C:24]([CH:27]=[CH2:28])=[CH:25][CH:26]=1
Reactant: C=Cc1ccc(Br)s1
Reactant: CCCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
Product: C=Cc1ccc(-c2c(F)cc(-c3ccc(CCC)cc3)cc2F)s1

Procedure:
The compound 2-(3,5-difluoro-4′-propylbiphenyl-4-yl)-5-vinylthiophene (PUS-3-V) is prepared analogously to Example 3 from 4′-propyl-3,5-difluoro-4-biphenylboronic acid and 2-bromo-5-vinylthiophene.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[CH2:2]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=1[OH:3])[CH3:1]
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
2-Methyl-6-nitro-benzoxazole (12.25 g, 68.76 mmol) was dissolved in Tetrahydrofuran (500 mL) and Acetic acid (4.00 mL, 70.4 mmol) and was cooled at 0° C. Sodium tetrahydroborate (5.20 g, 138 mmol) was added over 10 min and the reaction was stirred at 0° C. for 30 min, then warmed to room temperature and stirred an additional 2.5 h. The undissolved borohydride was removed by filtration, and the filtrate conc. in vacuo to 100 mL. The filtrate was poured into water (800 mL) and neutralized with sodium bicarbonate powder. The aq. was extracted 3×200 mL DCM; the org. extract was washed with 100 mL water and 200 mL 1:1 brine:satd. sodium bicarbonate sol., then dried over sodium sulfate before being filtered through a ½″ h×2″ diameter plug of silica gel, washing with 500 mL 1:1 DCM:EtOAc. The filtrate was conc. to give 2-Ethylamino-5-nitro-phenol as a yellow solid (11.5 g, 92%)
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:26])[NH:9][C:10]1[CH:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:13]=[CH:12][N:11]=1)([CH3:6])([CH3:5])[CH3:4]>C(OCC)(=O)C.[Pd]>[C:3]([O:7][C:8](=[O:26])[NH:9][C:10]1[CH:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:13]=[CH:12][N:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccccc1C#Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1CCc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanol (10 mL) and Pd/C (100 mg) are added to a solution of [4-(2-methoxy-phenylethynyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (146 mg, 0.450 mmol) in ethyl acetate (10 mL). The mixture is evacuated and purged with H2 (three times), and stirred at the room temperature under an atmosphere of H2 for 2 hours. The mixture is evacuated and purged with Argon, and filtered through a pad of diatomaceous earth. The filtrate is concentrated to give the crude product, which is used in the next step without purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[N:22]=1>>[NH:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:20][C:8]1[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1nc2ccccc2[nH]1
Product: CCCCN1C(=O)C(Nc2nc3ccccc3[nH]2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-amino-1H-benzimidazole in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.53 (m, 2H), 1.76-1.85 (m, 2H), 3.71 (t, 2H), 7.12-7.19 (m, 4H), 7.34-7.68 (m, 5H), 8.03-8.06 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])C.[Li+].[OH-]>C1COCC1.CO>[CH2:16]([O:15][C:6]1[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=[CH:10][C:5]=1[C:4]([OH:18])=[O:3])[CH3:17]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Yield: 88 %

Procedure:
2-Hydroxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.82 mmol) was reacted with ethyliodide (2.2 eq) and K2CO3 (1.69 g) in DMF solution. The reaction mixture was quenched by adding H2O. The mixture was extracted with ethyl acetate (40 ml×3). A combined organic layer was washed sat NaHCO3 solution (30 ml), H2O (40 ml×5), and brine, and then dried over MgSO4. The filterate was concentrated in vacuo to yield 2-ethoxy-4-trifluoromethyl benzoic acid ethyl ester. The ester obtained above was reacted with 1 N LiOH (15 ml) in THF and CH3OH cosolvent for 2 hrs as described above to yield title compound (1.20 g, 88%)
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].C(O)(=O)C1C=CC=CC=1.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1)[CH3:28]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:34]3[CH:35]=[CH:36][C:31]([C:30]([O:29][CH2:27][CH3:28])=[O:38])=[CH:32][CH:33]=3)=[CH:9][C:8]=2[CH:15]([CH3:16])[CH3:17])[CH2:6][CH2:5]1)[CH3:2]
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)C)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 28.0 mg (34%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40]>CN(C=O)C.C(N(CC)CC)C>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
4-Formylbenzoic acid (15 g, 100 mmol) was dissolved in DMF (250 mL) and 1-hydroxybenzotriazole (14.9 g, 110 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (21.1 g, 110 mmol) were added and the resulting mixture was stirred at room temperature for 30 minutes. Triethylamine (34.8 mL, 250 mmol) and β-alanine methyl ester hydrochloride (15.4 g, 110 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. More triethylamine (17.4 mL) and β-alanine methyl ester hydrochloride (7.7 g) were added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was dried (MgSO4) and concentrated to afford 16.2 g (70%) of 3-(4-formylbenzoylamino)propionic acid methyl ester as an oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(S(C)(=O)=O)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (58 mg, 61%), MS (ISN) m/z=378.4 [(M−H)+], mp 332° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (65.0 mg, 0.325 mmol).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:28]1(CN)CCCC1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH:6]([N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:14][N:15]=[C:10]3[NH:9][C:8]2=[O:26])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCC1CCCC1
Reactant: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2n1CC1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C1CCCC1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)nc21
Yield: 36 %

Procedure:
1-Cyclopentylmethyl-6-quinolin-5-yl-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one. A solution of N-bis-boc-3-bromo-5-(quinoline-5-yl)-pyrazin-2-ylamine (150 mg, 0.29 mmol), cyclopentylmethylamine hydrochloride (268 mg, 2 mmol), and triethylamine in ethanol (4 mL) was reacted and purified according to General Procedure E2 to give 25 mg (36% yield) of white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (dd, J=4.1, 1.6, 1H), 8.54-8.61 (m, 2H), 8.12 (d, J=8.2, 1H), 7.77-7.90 (m, 2H), 7.47-7.59 (m, 2H), 3.11-3.19 (m, 2H), 1.98-2.12 (m, 1H), 1.67-1.77 (m, 2H), 1.49-1.65 (m, 4H), 1.15-1.30 (m, 2H); MS (ESI) m/z 346.4 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].C([O-])=O.[NH4+].[CH:24]([NH2:26])=O>>[O:15]1[CH2:16][CH2:17][O:18][C:14]21[CH2:13][CH2:12][C:5]1[C:6]3[C:7](=[O:8])[NH:26][CH:24]=[N:1][C:2]=3[S:3][C:4]=1[CH2:19]2
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2c1CCC1(C2)OCCO1
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2sc3c(c12)CCC1(C3)OCCO1
Temperature: 140 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a stirring solution of ethyl 2-amino-4,7-dihydro-5H-spiro[1-benzothiophene-6,2′-[1,3]dioxolane]-3-carboxylate (40.0 g, 0.142 mol) in formamide (225 mL) was added ammonium formate (17.8 g, 0.282 mol). The resulting mixture was stirred with at 140° C. for 16 h, after which time the heterogeneous contents were removed from heating, and allowed to cool to rt. The contents were filtered, the solid filter cake was washed with water (2×60 mL), and suction dried overnight to afford the desired product as an off-white solid (33.0 g, 88%). 1H-NMR (DMSO-d6) δ 12.35 (broad s, 1H), 8.00 (s, 1H), 3.92 (s, 4H), 2.95 (t, 2H), 2.91 (s, 2H), 1.83 (t, 2H); LCMS RT=1.87 min; [M+H]+=265.2.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1>ClCCl.C(=O)([O-])O.[Na+]>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 20 h
Yield: 65.3 %

Procedure:
To a stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)-propan-2-ol (3.21 mmol, 1.1 g) and triethylamine (3.21 mmol, 0.448 ml, 0.325 g) in dichloromethane was added 1-(bromomethyl)-3-nitrobenzene (3.21 mmol, 0.694 g). The reaction was stirred for 20 hours then was diluted with dichloromethane and sodium hydrogen carbonate (aqueous). The organic layer was separated and poured onto a SCX column. The column was eluted with 2M ammonia in methanol and concentrated under reduced pressure to give the title compound (1 g). MS (ESI) m/z 478.1 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:44][CH2:45][O:46][Si:47]([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:44][CH2:45][O:46][Si:47]([C:60]([CH3:61])([CH3:63])[CH3:62])([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Potassium carbonate (722 mg, 5.23 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 900 mg, 1.72 mmol) in N,N-dimethylformamide (2 mL) at room temperature. The mixture was stirred for 30 min and then treated with (2-bromo-ethoxy)-tert-butyl-diphenyl-silane (658 mg, 1.81 mmol) at room temperature. The mixture was heated at 80° C. and stirred for 3 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (870 mg, 62.8%) as a white solid.
Reaction SMILES: [O-][CH2:2]C.[Na+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][C:14]2[C:15](=[O:21])[NH:16][C:17](=[S:20])[NH:18][CH:19]=2)=[CH:9][N:8]=1.CI>CCO>[CH3:5][O:6][C:7]1[N:8]=[CH:9][C:10]([CH2:13][C:14]2[C:15](=[O:21])[N:16]=[C:17]([S:20][CH3:2])[NH:18][CH:19]=2)=[CH:11][N:12]=1
Reactant: CC[O-]
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Into a stirred solution of sodium ethoxide (1.358 mmol, 2 eq) in EtOH (3 ml) was added 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.679 mmol, 1 eq) at rt. After 30 min, the reaction mixture was treated with methyl iodide (1.358 mmol, 2 eq) and was stirred at rt overnight. Solvent was evaporated and a crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of EtOAc in Cyclohexane: 0-10% in 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.568 mmol, yield=83%, purity=46%). [M+H]+=265.25 1H NMR (300 MHz, DMSO-d6) δ/ppm 2.39 (s, 1H), 3.82-3.87 (m, 3H), 7.75 (s, 1H), 8.47 (s, 2H)