Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.[Cl:24][C:25]1[C:30](C=O)=[C:29](Cl)[N:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]2[N:9]([C@H:10]3[CH2:11][CH2:12][C@@H:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:22])[CH3:23])[N:17]=4)[CH2:14][CH2:15]3)[N:8]=[CH:6][C:30]=12
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC(C)c1noc([C@H]2CC[C@@H](NNC(=O)OC(C)(C)C)CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1noc([C@H]2CC[C@@H](n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-hydrazinecarboxylic acid tert-butyl ester (Intermediate 13; 309 mg, 2.03 mmol) in tetrahydrofuran (3 mL) was added to a cooled (0° C.) solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 169 mg, 0.95 mmol) and diisopropylethylamine (337 μL, 1.9 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred at 0° C. for 30 min and then at room temperature for 5 h. The mixture was filtered, and the filtrate was washed with brine. The aqueous layer was extracted with methyl tert-butyl ether and the organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, evaporated, and held under high vacuum. Toluene (10 mL) was added and the mixture was held at 110° C. overnight. The solvent was evaporated and the residue was purified on a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (211 mg, 64%).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1F)[C:31]#[N:32]>>[C:31]([C:30]1[CH:33]=[CH:34][C:35]([O:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[C:23]3[C:18]=2[CH2:17][CH2:16][C@H:15]3[O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:26])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=2)=[C:28]([F:27])[CH:29]=1)#[N:32]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: N#Cc1ccc(F)c(F)c1
Product: N#Cc1ccc(Oc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(F)c1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,4-difluoro-benzonitrile following a procedure analogous to that described for Intermediate 12. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: N[CH:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1C(OCC)=O.Cl.[OH2:20]>>[C:8]1([N:5]2[CH2:4][CH2:3][C:2](=[O:20])[C:6]2=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Agent: Cl
Product: O=C1CCN(c2ccccc2)C1=O

Procedure:
According to the procedure of Southwick [J. Org. Chem. 21, 1087 (1956)] the ethyl ester pyrrolidinone of Example S (1.0 g, 4.0 mmol) was suspended in 75 ml of 20% HCl/H2O and refluxed for 3.5 h The reaction was cooled and filtered and the filtrate was extracted with CHCl3 (4×150 ml). Concentration of the combined extracts gave an off-white solid (358 mg). 'NMR(300 MHZ, CDCl3) δ2.92 (t, 2H), 4.17 (t, 2H), 7.32 (t, 1H), 7.98 (t, 2H), 7.84 (d, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C[OH:29]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:25][CH2:26][OH:29])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Product: O=C(OCCO)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1

Procedure:
200 mg (0.6 mmol) of 1-benzyl-3-(5-ethoxycarbonyl-2-furyl)indazole were dissolved in ethylene glycol and heated under reflux for 1.5 h. For work-up, the mixture was concentrated using a rotary evaporator and the crude product was chromatographed over silica gel using hexane/ethyl acetate (1:1). This gave 68 mg (31%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([OH:15])[CH:7]=1)[CH3:2].[OH-].[Na+:21]>C(O)C>[CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O-:12])=[O:11])=[C:8]([OH:15])[CH:7]=1)[CH3:2].[Na+:21]
Reactant: CCCCC(CC)COc1ccc(C(=O)O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(CC)COc1ccc(C(=O)[O-])c(O)c1

Procedure:
In 15 ml of ethanol was dissolved 1.24 g (4.7 mmol) of 4-(2-ethyloxy)-2-hydroxybenzoic acid (compound 14), and 0.94 ml (4.7 mmol) of a 5 mol/l NaOH aqueous solution was added thereto. The solvent was evaporated, ethanol added to the residue, and the mixture azeotropically dehydrated. The residue was dried by heating to obtain sodium 4-(2-ethylhexyloxy)-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 30). ##STR51##
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Sc1ccc(F)cc1C(N1CCN(C)CC1)C2

Procedure:
10.6 g. of 10-chloro-8-fluoro-10,11-dihydro-3-methyldibenzo[b,f]thiepin, 200 ml. of chloroform and 11.4 g. of N-methylpiperazine are heated at reflux for 30 hours. The mixture is evaporated under reduced pressure. The resulting residue is worked up via the neutral portion in essentially the same manner as described in Example 1, and there is obtained 1-{8-fluoro10,11-dihydro-3-methyl-dibenzo[b,f]thiepin-10-yl}-4-methylpiperazine, having a melting point of 117°-121° C. By treatment with methanesulfonic acid, there is obtained the dimethanesulfonate having a melting point of 176°-178° C. (from methanol/ether.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[CH2:21]([C:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:23]=[N+:24]=[N-:25])=[CH:5][CH:6]=2)[C:14]2=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1)[CH3:22]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a stirred solution of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 7, 2.8 g, 9.0 mmol) and KI (1.5 g, 9.0 mmol) in DMF (50 mL) was added sodium azide (1.2 g, 18.0 mmol), and then the resulting mixture was stirred overnight at 100° C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 2.35 g (85%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.59 (2H, t, J=7.1 Hz), 2.99 (2H, t, J=7.1 Hz), 2.83 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.52 (3H, s), 1.27 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C([O:13][C:14](=O)[CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:19]2[CH:18]=[C:17]([C:16]3[CH2:15][C:14](=[O:13])[NH:8][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[N:7]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: Nc1ccccc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccccc2N1

Procedure:
The title compound was prepared from 1,2-phenylenediamine (81 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) by refluxing in xylene according to the general procedure M. Obtained as a white solid (204 mg).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1)[CH3:8])=[O:5])C.O.[OH-].[Na+].[ClH:27]>CO.O1CCCC1>[ClH:27].[C:4]([CH2:6][CH:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1)[CH3:8])([OH:5])=[O:3]
Reactant: CCOC(=O)CC(C)c1cn(-c2cccnc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(=O)O)c1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 2.66 g of 3-(3-ethoxycarbonyl-2-propyl)-N-(3-pyridyl)indole in 15 ml of methanol and 15 ml of water containing 0.7 g of sodium hydroxide is stirred at room temperature for 18 hours, refluxed for 15 minutes, cooled and evaporated. The residue is redissolved in 25 ml of water, neutralized to pH 6 with 1.44 ml of concentrated hydrochloric acid. The resulting oil is extracted into methylene chloride and the extract is dried over sodium sulfate. Filtration and evaporation gives an oil which is redissolved in 5 ml of tetrahydrofuran and treated with 0.55 ml of concentrated hydrochloric acid. The resulting semi-solid is crystallized from methanol-ether to yield 3-(3-carboxy-2-propyl)-N-(3-pyridyl)indole hydrochloride, m.p. 205°-207°.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1[C:31]([CH:32]=O)=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])/[CH:20]=[CH:32]/[C:31]1[C:26]([CH3:25])=[N:27][CH:28]=[CH:29][C:30]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nccc(-c2ccccc2)c1C=O
Solvent: ClCCl
Product: COC(=O)/C=C/c1c(-c2ccccc2)ccnc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
Methyl (triphenylphosphoranylidene)acetate (30 g) was added to a stirred mixture of 16.0 g (0.081 mol) of 2-methyl-4-phenyl-3-pyridinecarboxaldehyde in 300 ml of methylene chloride. The resulting mixture was stirred at room temperature for 18 hours, after which the mixture was filtered through silica gel and the filtrate concentrated under vacuum. The residue was chromatographed on a silica gel column, eluting with ethyl acetate to yield 18.9 g of (E)-methyl-3-(2-methyl-4-phenyl-3-pyridinyl)-2-propenoate.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:5](=[O:20])[CH2:4][CH2:3]1.[OH-].[Na+]>O.CO>[O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:5](=[O:20])[CH2:4][CH2:3]1
Reactant: COC(=O)CCCN1C(=O)CCC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCN1C(=O)CCC(=O)c2ccccc21

Procedure:
Methyl 4-(2,5-dioxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)butanoate from step a (100 mg, 0.36 mmol) in water/methanol (0.7:2.0 ml) was treated with NaOH (1N, 0.80 ml) to obtain 63.0 mg of 4-(2,5-dioxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)butanoic acid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][CH2:17][SH:18]>CN(C=O)C>[CH2:17]([S:18][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:16]
Reactant: CCS
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccccc1C=O
Temperature: 55 °C
Yield: 72.5 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and thioethanol (17.1 mmol) were dissolved in 10.0 mL DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 55° C. for 3 days. After cooling, the mixture was added to 50 mL of saturated potassium carbonate solution and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 2:1 dichloromethane/n-hexane as eluent to give a yellow oil (1.94 g, 72%). 1H NMR (200 MHz, CDCl3): δ 1.37 (t, J=7.5, 3H), 2.99 (q, J=7.5, 2H), 7.26-7.56 (m, 3H), 7.84 (dd, J1=8.0, 1H), 10.37 (s, 1H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:21]=3)[N:16]=[C:15]([CH3:30])[CH:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][C:15]1[CH:14]=[C:13]([N:10]2[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]2)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=2)[N:16]=1
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)c2cc(Oc3ccccc3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N2CCC(N)C2)c2cc(Oc3ccccc3)ccc2n1

Procedure:
The product from step (i) above was treated with trifluoroacetic acid in dichloromethane (1:1) to give, after evaporation, the title compound as an orange oil, which was used without further purification.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]=[O:12])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH2:14][CH2:15][CH3:16]>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][CH:5]1[C:11](=[O:12])[CH2:13][CH2:14][CH2:15][CH3:16])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C=O
Reactant: CCCC[Mg]Br
Product: CCCCC(=O)C1C[C@H](C)CC[C@H]1C(C)C

Procedure:
The title compound was prepared following the general procedure of Example 1 starting from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde and butyl magnesium bromide.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:21](=[CH:22][C:11]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([O:26]CC)=[O:25].O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC(OCC)=O>>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:21](=[CH:22][C:11]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCCC4)c2ccccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCCC4)c2ccccc21

Procedure:
Following the procedure as described in Example 2, and making non-critical variations using ethyl (2-oxo-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-1(2H)-yl)acetate to replace ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained (99%): MS (ES−) m/z 348 (M−1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of N-benzyl-O-benzyl-N2-Boc-D-serinamide (3 g) and dichloromethane (15 mL), trifluoroacetic acid (15 mL) was added. The solution was stirred for 2 hours at 40° C. for completion of reaction. The solution was concentrated under vacuum to remove solvents and subsequently water was added. The aqueous layer was basified to pH 8-10 with 5% sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine solution. Organic layer was concentrated under vacuum to obtain an oily residue solidify by n-Hexane to give 1.55 g of N-benzyl-O-benzyl-D-serinamide.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)=[O:7])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][C:12]1[S:11][C:10](=[O:13])[NH:9][C:8]=1[C:6]([O:5][CH2:3][CH3:4])=[O:7]
Reactant: CCOC(=O)c1csc(=O)[nH]1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]c(=O)sc1Br
Yield: 74.7 %

Procedure:
69 g of bromine were added to a mixture of 69.2 g of 4-ethoxycarbonyl-4-thiazoline-2-one in 500 ml of chloroform and the mixture was refluxed for 20 hours. The mixture was distilled to dryness under reduced pressure and after the addition of isopropyl ether, the mixture was vacuum filtered to obtain 75.2 g of 5-bromo-4-ethoxycarbonyl-4-thiazoline-2-one melting at 121°C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:18]1[CH2:23][CH2:22][N:21]([O:24][CH3:25])[CH2:20][CH2:19]1)[NH:5][C:6](=[O:17])[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16].CC([O-])(C)C.[K+].Cl>CN(C=O)C>[OH:2][C:3]1[CH:4]([CH:18]2[CH2:19][CH2:20][N:21]([O:24][CH3:25])[CH2:22][CH2:23]2)[NH:5][C:6](=[O:17])[C:7]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16]
Reactant: COC(=O)C(NC(=O)Cc1c(C)cc(C)cc1C)C1CCN(OC)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CON1CCC(C2NC(=O)C(c3c(C)cc(C)cc3C)=C2O)CC1
Reaction time: 0.17 h

Procedure:
To a solution of (1-methoxy-piperidin-4-yl)-[2-(2,4,6-trimethyl-phenyl)-acetylamino]-acetic acid methyl ester (1.217 g, 3.36 mmol) in DMF (6 ml) at 90° C. under nitrogen was added t-BuOK (1.12 g, 10 mmol), the mixture was stirred for 10 min. Then the reaction mixture was poured into diluted hydrochloric acid and concentrated in vacuum. The crude product was purified by column chromatography on silica gel. Yield: 960 mg of 4-hydroxy-5-(1-methoxy-piperidin-4-yl)-3-(2,4,6-trimethyl-phenyl)-1,5-dihydro-pyrrol-2-one (compound P2.12) as a solid, mp 206-209° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@@H:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)O1.Br[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([F:40])[C:34]=1[C:41]1[N:45]=[C:44]([CH3:46])[O:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O.[Pd](Cl)Cl>[Cl:39][C:37]1[CH:36]=[C:35]([F:40])[C:34]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[C:33]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@@H:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)[CH:38]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2Br)no1
Reactant: CC1(C)OB(c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)C(F)(F)F)CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)C(F)(F)F)CC2)no1
Temperature: 80 °C
Yield: 54.3 %

Procedure:
1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid[(S)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]-amide (intermediate A-2) (0.145 g, 331 μmol) and 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) (106 mg, 364 μmol) were dissolved in DMSO (5.00 ml), then sodium carbonate (87.7 mg, 827 μmol), dissolved in water (0.63 ml) was added, followed by (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (12.1 mg, 16.5 μmol, eq: 0.05). This mixture was heated up to 80° C. for 2 hours, then poured into H2O (50 ml) and extracted with CH2Cl2 (2×25 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.213 g) which was purified by flash chromatography (silica gel, 20 g, 10% to 50% EtOAc in heptane) to yield the title compound (0.094 g, 54%) as light yellow solid. MS: 523.1 (MH+, 1Cl).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Br:14][C:15]1[N:19]2[CH:20]=[C:21]([Br:25])[N:22]=[C:23](Br)[C:18]2=[N:17][CH:16]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:14][C:15]1[N:19]2[CH:20]=[C:21]([Br:25])[N:22]=[C:23]([NH:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=3)[C:18]2=[N:17][CH:16]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Brc1cn2c(Br)cnc2c(Br)n1
Agent: Cl
Solvent: CC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(CNc2nc(Br)cn3c(Br)cnc23)cc1
Temperature: 108 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
4-Aminomethyl-benzenesulfonamide hydrochloride (2.22 g, 10 mmol) was added to a solution of 3,6,8-Tribromo-imidazo[1,2-a]pyrazine (2.77 g, 10 mmol) and DIPEA (3.65 ml, 21 mmol) in iBuOH (20 mL). The reaction was stirred at 108° C. for 3 h then allowed to cool to room temperature. The precipitate formed was filtered and washed with diethyl ether to give 4-[(3,6-Dibromo-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide as a pale brown solid (3.5 g, 76% yield). LC-MS m/z 462 [M+H]+.
Reaction SMILES: COC1C=C2C(=CC=1)C(=O)CCC2.C1(NC2N=CC=CC=2C(OC)=O)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39](=O)[CH:38]([C:44]([C:46]1[C:47]([NH:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[N:48][CH:49]=[CH:50][CH:51]=1)=[O:45])[CH2:37][CH2:36]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:31][O:32][C:33]1[CH:42]=[CH:41][C:40]2[C:39]3[N:52]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[C:46]([C:44](=[O:45])[C:38]=3[CH2:37][CH2:36][C:35]=2[CH:34]=1)=[CH:51][CH:50]=[CH:49][N:48]=4
Reactant: COc1ccc2c(c1)CCC(C(=O)c1cccnc1Nc1ccccc1)C2=O
Agent: COC(=O)c1cccnc1Nc1ccccc1
Agent: COc1ccc2c(c1)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1ccc2c(c1)CCc1c-2n(-c2ccccc2)c2ncccc2c1=O
Reaction time: 8 h

Procedure:
For example, with 3,4-dihydro-6-methoxy-1-naphthalenone as the ketone and methyl 2-phenylaminonicotinate as the arylaminonicotinate, the 1,3-diketone, 3,4-dihydro-6-methoxy-2-[[2-(phenylamino)-3-pyridinyl]-carbonyl]-1(2H)-napthalenone, results from the process of Example 8. To cyclize, reflux 9 g of the diketone in 400 ml of soluene containing a catalytic amount of p-toluenesulfonic acid. Collect the evolved water in a Dean-Stark trap. Remove the heat after 21/2 hours and allow the mixture to stand overnight. Distill the toluene under vacuum on a steam bath and crystallize the residue from acetonitrile, to provide the product 5,6-dihydro-3-methoxy-12-phenylnaphtho[1,2-b][1,8]naphthyridin-7(12H)-one, m.p. 234°-237.5° C., after crystallization from CH3CN.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.O1CCCC1.[OH:26][CH:27]([CH2:30][OH:31])[CH2:28][SH:29]>CO>[OH:26][CH:27]([CH2:30][OH:31])[CH2:28][S:29][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:2]([NH:3][C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH2:20])=[CH:13][CH:12]=1)=[O:1]
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Reactant: OCC(O)CS
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSCC(O)CO)cc1

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl) benzenesulfonamide in a mixture of 15 mL of methanol, and 15 mL of tetrahydrofuran and 2,3-dihydroxy-1-propanethiol. The product was washed with ether and dried in vacuo to give 0.61 g of the title compound, mp>260° C.