Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:39][CH2:40][C:41]1[C:42]([OH:49])=[N:43][C:44]([CH3:48])=[CH:45][C:46]=1[CH3:47]>O.ClCCl.C(N(CC)CC)C>[OH:49][C:42]1[C:41]([CH2:40][NH:39][C:14](=[O:16])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][N:12]=2)=[C:46]([CH3:47])[CH:45]=[C:44]([CH3:48])[N:43]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cn2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
A mixture of 5-phenoxypicolinic acid (83 mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1 mmol), N-hydroxybenzotriazole (135 mg, 1 mmol), triethylamine (0.2 mL) and dichloromethane (5 mL) was stirred at 25° C. for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added to the mixture. The resultant mixture was stirred at 25° C. for 12 hours. Then water (20 ml) was added to the mixture and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-5-phenoxypicolinamide (Compound I-21) as a white solid (50 mg, 37%). LRMS (M+H+) m/z: calcd 349.15. found 349. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.53 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 8.37-8.36 (m, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.48-7.42 (m, 3H), 7.26-7.16 (m, 3H), 5.86 (s, 1H), 4.32 (d, J=6.0 Hz, 2H), 2.22 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1>>[Cl-:1].[CH2:2]([N+:9]1[CH:10]=[CH:11][N:7]([CH3:6])[CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cn1ccnc1
Reactant: CCCCCl
Product: CCCC[n+]1ccn(C)c1
Product: [Cl-]
Temperature: 60 °C
Yield: 98.3 %

Procedure:
251.4 g of 1-chlorobutane (2.7 mol) are loaded into a 1 l glass reactor. The mixture is heated to 60° C., and then 148.6 g of 1-methylimidazole (1.8 mol) are poured in dropwise, with stirring. The mixture is left to react for 24 h at 80° C. The reaction mixture is evaporated under vacuum. 309 g of 1-butyl-3-methylimidazolium chloride are obtained in the form of a yellowish solid (yield=98%). The product is used as it is without further purification.
Reaction SMILES: CC([N:5]([CH2:9][C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=[O:20])[CH3:19])=[O:11])C(=O)[O-])(C)C.[ClH:21].CCOC(C)=O.CCCCCC>C(OCC)(=O)C.C(O)(C)C>[ClH:21].[C:18]([C:14]1[N:13]([NH:12][C:10](=[O:11])[CH2:9][NH2:5])[CH:17]=[CH:16][CH:15]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccn1NC(=O)CN(C(=O)[O-])C(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1cccn1NC(=O)CN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution consisting of 1,1-dimethylethyl-[2-[(2-acetyl-1H-pyrrol-1-yl)amino]-2-oxoethyl]carbamate (5.90 g) in ethyl acetate (45 ml) and isopropanol (35 ml) was added ethereal HCl (1.7M, excess). The resulting suspension was gently heated until the reaction mixture was homogeneous. After stirring for 24 hours at room temperature, the reaction appeared complete by TLC (silica gel, 50% EtOAc/hexane). The solid product was collected by filtration under nitrogen and recrystallized from methanol/ether to afford 3.30 g of the product, m.p. 179°-182° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[C:18](OCC)(=[O:22])[C:19]([CH3:21])=O>>[CH3:21][C:19]1[C:18](=[O:22])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:17])[CH3:1])=[CH:8][CH:7]=2)[C:10]2[C:11]([N:16]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CN(C)c1ccc(Nc2ccccc2N)cc1
Reactant: CCOC(=O)C(C)=O
Product: Cc1nc2ccccc2n(-c2ccc(N(C)C)cc2)c1=O

Procedure:
Preparation as in Example 1 but using N-(4-dimethylaminophenyl)benzene-1,2-diamine and ethyl pyruvate gave the title compound mp 230°-231° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)—(S)-1-(tetrahydro-furan-2-yl)-ethyl]-amide (152 mg, 0.28 mmol) was dissolved in dichloromethane (1.4 ml) and trifluoroacetic acid (0.87 ml, 11.3 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.4 ml) and ethylenediamine (1.2 ml, 17.8 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 46 mg (40%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)—(S)-1-(tetrahydro-furan-2-yl)-ethyl]-amide as an off-white powder. MS: (M+Na)+=431; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.09 (br. s., 1H), 9.13 (s, 1H), 8.64 (dd, J=8.7, 5.3 Hz, 1H), 8.44 (s, 1H), 8.22 (d, J=9.4 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 4.32 (br. s., 1H), 4.15 (s, 3H), 3.96 (d, J=3.0 Hz, 1H), 3.52-3.68 (m, 2H), 1.86-2.00 (m, 1H), 1.52-1.84 (m, 3H), 1.33 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@@H:3]([CH2:2][N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(C[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-(Aminomethyl)-1-N-Boc-pyrrolidine (994 mg, 4.86 mmol) was added to the stock solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 13 mL, 4.42 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The resulting residue was then dissolved in dimethylformamide (8 mL) and potassium carbonate powder (670 mg, 4.86 mmol) was added. The reaction mixture was heated at 60° C. for overnight then cooled to room temperature. Water (50 mL) was added and the suspension was extracted with ethyl acetate (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo to give quantitative (S)-ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a brown sticky solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:35]1[C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([C:44]#[N:45])[C:38]=2[CH2:37][CH2:36]1.O>C1COCC1>[CH3:12][O:13]/[CH:14]=[C:35]1\[CH2:36][CH2:37][C:38]2[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][C:43]\1=2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc2c1CCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO/C=C1\CCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium bis(trimethylsilyl)amide (2 mL, 4 mmol, 2M in THF) was added to a stirred suspension of (methoxy methyl)triphenylphosphonium chloride (1.47 g, 4.29 mmol) in dry THF (20 mL) at 0° C. for 35 min and a solution of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (450 mg, 2.86 mmol) in THF (10 mL) added over 10 min. The mixture was stirred at 0° C. for 2 h and at room temperature for 1 h. Water was added and the mixture was partitioned between EtOAc and brine. The organic layer was dried and concentrated. The crude product was purified via prep-TLC (PE:EtOAc=10:1) to afford (1E)-1-[(methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J=8.3 Hz, 0.4H), 7.42 (d, J=8.3 Hz, 0.6H), 7.30-7.40 (m, 1H), 7.18-7.22 (m, 1H), 6.70 (s, 0.6H), 6.22 (s, 0.4H), 3.72 (s, 3H), 3.15 (t, J=5.7 Hz, 2H), 2.70-2.82 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N+:6]([O-:8])[CH:7]=1.[CH3:21][NH2:22]>CO>[C:9]1([C:5]2[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3][C:2]([NH:22][CH3:21])=[CH:7][N+:6]=2[O-:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN
Reactant: [O-][n+]1cc(Cl)nc(-c2ccccc2)c1-c1ccccc1
Solvent: CO
Product: CNc1c[n+]([O-])c(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
To 1.00 g of 5-chloro-2,3-diphenylpyrazine 1-oxide, 20 ml of 40% methylamine in methanol was added and the mixture was-reacted in a sealed tube at room temperature for 15 hours. The reaction solution was extracted with ethyl acetate after adding water. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting crude crystal was washed with diisopropyl ether to obtain 536 mg of the desired compound as a pale yellow crystal having a melting point of 145 to 147° C.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7]1)C.[OH-].[K+]>CO.CO.O>[CH3:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([OH:16])=[O:3])[CH:7]=1
Reactant: CCOC(=O)Cn1cc(C)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The residue, 3-methyl-indole-1-acetic acid ethyl ester, is dissolved in 900 ml of methanol, potassium hydroxide (90 g) in 400 ml of 1:1 methanol-H2O is then added. The mixture is stirred at room temperature for 11/2 hours. The methanol is evaporated under reduced pressure. The residue is diluted with water (800 ml) and extracted (3x) with ether. Acidification with 6NHCl of the aqueous phase yields 3-methyl-indole-1-acetic acid, m.p. 174°-176° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(OC)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(OC)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: O1C2(CCC(C3C4C(=CC=CC=4)NC=3)CC2)OCC1.[O:20]1[C:24]2([CH2:29][CH2:28][C:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][N:31]=3)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>>[O:23]1[C:24]2([CH2:29][CH2:28][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][N:31]=3)[CH2:26][CH2:25]2)[O:20][CH2:21][CH2:22]1
Reactant: C1=C(c2n[nH]c3ccccc23)CCC2(C1)OCCO2
Agent: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Product: c1ccc2c(C3CCC4(CC3)OCCO4)n[nH]c2c1
Yield: 66.6 %

Procedure:
This compound was prepared in the manner described above for intermediate 2a by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole (7.18 g) with 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-azaindole (4.02 g) to afford 2.7 g (67%) of the title compound as a white solid: mp 204-207° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: COc1cc2ncn(-c3nc(-c4ccc(Cl)c(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 35.3 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,4-dichlorophenylboronic acid (28.6 mg, 0.15 mmol) gave 4-(3,4-Dichloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (15.9 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.81 (br.s., 1 H); 8.85 (s, 1 H); 8.25 (d, 1 H); 7.97 (dd, 1 H); 7.81 (s, 1 H); 7.79 (d, 1 H); 7.39 (s, 1 H); 3.85 (s, 3 H); 3.87 (s, 3 H). MS m/z 450 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:32])[C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([S:19][C:20]2[N:24]4[CH:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]4=[N:22][N:21]=2)=[CH:14][CH:13]=3)[CH2:5]1.[NH2:33][O:34][CH2:35][CH2:36][OH:37]>CO.Cl>[ClH:1].[OH:37][CH2:36][CH2:35][O:34]/[N:33]=[C:29](/[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([S:19][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[N:11]=[CH:10][C:9]([N:6]3[CH2:7][CH2:8][C@H:4]([N:3]([CH3:32])[CH3:2])[CH2:5]3)=[CH:18]4)=[N:21][N:22]=2)[CH:25]=1)\[CH3:30]
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a solution of (81.3) (12 mg, 0.026 mmol) and 2-(aminooxy)ethanol (9.86 mg, 0.128 mmol) in MeOH (5 ml) was added 2 drops of HCl (2 N) by a 1-ml syringe to reach pH about 3 and the mixture was stirred in a sealed tube at 85° C. for 16 h. The mixture was evaporated to dryness and the residue was purified by preparative acid HPLC (gradient eluent NB from 20/80 to 95/5. mobile phase A: TFA/CH3CN 0.05%; mobile phase B: TFA/H2O 0.05%). The desired fractions were collected, evaporated by BUCHI under 30 mbar at 35° C. to remove CH3CN. The remained solution was lyophilized to afford title compound (11.5 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[H][H]>CC(O)C.[Ni]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(Sc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(C)O
Product: Nc1ccc(Sc2ccccc2)nc1N
Yield: 85.5 %

Procedure:
2,3-Diamino-6-(phenylmercapto)pyridine was prepared by hydrogenating 2-amino-3-nitro-6-(phenylmercapto)pyridine (107.1 g, 0.433 mol) under 5 atm of H2 in the presence of 30 g of Raney-Ni in 1200 mL of 2-propanol at 70° C. After 4 hours (29.1 L of hydrogen) the reaction mixture was cooled to 4° C. while stirring continuously. The precipitate was collected by vacuum filtration, washed with 2-propanol and dried at 50° C. under vacuum. The combined filtrates were concentrated under reduced pressure and recrystallized from 2-propanol. After washing the hydrogenation apparatus twice with 1000 mL of THF, evaporation under reduced pressure and recrystallization from 2-propanol, the precipitate was collected and dried at 50° C. under vacuum to give 80.4 g (87.1% yield) of 2,3-diamino-6-(phenylmercapto)pyridine m.p. 119-122° C.)
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][OH:19])[CH3:15]>CN(C=O)C>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][O:19][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13])[CH3:15]
Reactant: CCN(CC)CCO
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.92 g (19.2 mmol) of sodium hydride (50% in oil) is added at 0° C. under an argon atmosphere to a solution of 2.70 g (17.4 mmol) of 2-fluoro-5-nitrotoluene and 2.54 mL (19.2 mmol) of 2-diethylaminoethanol in 50 mL of DMF and the mixture is stirred for 2 hours at 0° C. and for 1 hour at ambient temperature. The solvent is removed, the residue is taken up in ethyl acetate, and extracted with water. The organic phase is dried over sodium sulfate and evaporated down in vacuo. Then it is purified by silica gel column chromatography with dichloromethane/methanol (9:1) as eluant. Yield: 3.1 g (71% of theory); C13H20N2O3 (M=252.31); calc.: molecular ion peak (M+H)+: 253; found: molecular ion peak (M+H)+: 253; Rf value: 0.60 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][C:11]2([C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])[CH2:10]1)=[O:8])(=O)C.N>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][C:11]2([C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])[CH2:10]1)=[O:8]
Reactant: CC(=O)SCCC(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Agent: N
Product: O=C(O)[C@@H]1CC2(CN1C(=O)CCS)C(=O)CCC2=O

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield (8S)-7-(3-mercapto-1-oxopropyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylic acid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:32][CH2:33]3)=[CH:26][CH:27]=2)[CH2:19][CH2:18]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 120 °C

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (300 mg, 1.368 mmol), N-cyclopropyl-4-(piperazin-1-yl)benzamide (336 mg, 1.368 mmol), (cyanomethyl)trimethylphosphonium iodide (499 mg, 2.053 mmol) and N,N-diisopropylethylamine (1195 μl, 6.84 mmol) were suspended in propionitrile (Volume: 4109 μl) and heated in a closed vial at 120° C. for 2 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC(NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (1:1, 15 mL), and then from MeOH:EtOH:water (1:1:1, 10 mL), washed with water (3 mL) and dried in vacuum to give a light green solid.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1N.SC1SC2C=CC=C(C(F)(F)F)C=2N=1.[Cl:27][C:28]1[S:29]C2C=CC(Cl)=CC=2[N:32]=1>>[Cl:27][C:28]1[S:29][C:3]2[CH:2]=[CH:8][CH:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]=2[N:32]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: FC(F)(F)c1cccc2sc(S)nc12
Product: FC(F)(F)c1cccc2sc(Cl)nc12
Temperature: 100 °C

Procedure:
The title compound was prepared from 2-fluoro-5-trifluoromethylaniline via 2-mercapto-4-trifluoromethyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 100° C. for 6 h.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)([O:22][CH2:23][C@@H:24]1O[CH2:25]1)(=O)=O>CN(C=O)C>[OH:1][C:2]1[C:7]2[O:8][CH:24]([CH2:23][OH:22])[CH2:25][O:9][C:6]=2[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CC(=O)c1ccc(O)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1O)OC(CO)CO2
Temperature: 70 °C

Procedure:
To a solution of 2′,3′,4′-trihydroxyacetophenone (10.6 g, 63.0 mmole) in DMF (75 mL) was added potassium carbonate (17.4 g, 126 mmole). After 5 minutes (R)-glycidyl tosylate (9.67 g, 42.3 mmole) was added, then the heterogeneous mixture was heated to 70° C. for 3 hours. After removal of the solvent in vacuum, the residue was taken into water (800 mL) and was then extracted with ethyl acetate (4×300 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporate to dryness in vacuum. The crude brown oil thus obtained was column chromatographed on silica gel with 40% hexane/ethyl acetate as eluant to give the (S)-enantiomer of the title compound as a yellow oil which solidifies upon standing (7.5 g, 78%). MS (ESI) m/z 223 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].[Cu](C#N)[C:21]#[N:22]>CN1C(=O)CCC1.CCOC(C)=O.O>[C:21]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17])#[N:22]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 200 °C
Yield: 89.2 %

Procedure:
A solution of N-[4-chloro-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (0.257 g, 0.875 mmol) in NMP (2.5 mL) was treated with copper cyanide (0.180 g, 2.01 mmol) and the resulting suspension was heated to 200° C. in a microwave for 14 h. The cooled reaction mixture was diluted with EtOAc and water and then filtered through a pad of celite. The filtrate was concentrated to a brown oil and then partitioned between Et2O and water. The aqueous portion was further extracted with Et2O and the combined organics were dried (Na2SO4), filtered, and concentrated to a brown foam. Trituration with hexanes/Et2O afforded the title compound (0.222 g) in good purity: MS (ES) m/z 285 (M+1).