Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH3:13][CH:14]([NH2:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][CH:14]([N:23]1[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:12])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(N)CCc1ccccc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CCc1ccccc1)N1Cc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 1-methyl-3-phenyl-propylamine (0.090 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(1-methyl-3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.072 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.32 (d, 3H), 1.92 (m, 2H), 2.64 (m, 2H), 4.34 (dd, 2H), 4.62 (m, 1H), 7.14-7.58 (m, 8H), 7.89 (d, 1H). GC-MS: m/z 265 (M)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[CH:15].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1I>N1C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[CH:15]=1
Reactant: O=Cc1ccc(O)c(I)c1
Reactant: C#CCc1nc(-c2ccccc2)oc1C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=O)ccc2o1

Procedure:
To a slurry of cuprous oxide (12 g, 84 mmol) in pyridine (150 ml) were added a solution of 5-methyl-2-phenyl-4-(2-propynyl) oxazole in pyridine (150 ml) followed by a solution of 4-hydroxy-3-iodobenzaldehyde (35 g, 0.14 mol) in pyridine (100 ml). Bis(triphenyl-phosphine) palladium (II) chloride (0.50 g, 0.7 mmol) was then added as a solid and the mixture was heated to reflux overnight. The mixture was cooled and concentrated. The residue was taken up in ethyl acetate (250 ml+3×50 ml). The ethyl acetate solution was concentrated and the residue was extracted with hot cyclohexane. The hot solution was filtered and cooled and the solid was collected (29 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: [O-][n+]1cccc(-c2ccccc2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncccc1-c1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
Dissolve 3-phenyl-pyridine 1-oxide (1.0 g, 5.84 mmol) in phosphorus oxychloride (14 mL, 153 mmol). Heat the reaction to 105° C. for 6 hours, cool to ambient temperature and pour reaction mixture slowly onto ice with stirring to quench the excess phosphorus oxychloride. Basify with concentrated ammonium hydroxide and extract with dichloromethane. Wash the organic extract with brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (eluent: ethyl acetate-hexanes) to give 315 mg (28%) of 2-chloro-3-phenyl-pyridine as a yellow liquid. MS (m/z): 190 (M+1, 100), 192 (M+1, 60). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, 1H, J=4.6, 2.0 Hz), 7.87 (dd, 1H, J=7.5, 1.8 Hz), 7.54-7.41 (m, 6H). 1-(3-phenyl-pyridin-2-yl)-piperazine: Heat a mixture of 2-chloro-3-phenyl-pyridine (1.12 g, 5.9 mmol) and piperazine (5.08 g, 59.0 mmol) in a sealed tube at 165° C. for 23 hours. Cool to ambient temperature. Dissolve the reaction mixture in water and ethyl acetate. Extract the aqueous layer with ethyl acetate (3×). Wash the organic extracts with water (2×) and brine. Re-extract the water washes with ethyl acetate. Combine all ethyl acetate extracts, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (eluent: 2N ammonia in methanol-dichloromethane) to give 1.36 g (96%) of the title preparation as a yellow oil. HRMS-FAB (m/z): [M+H]+ calc'd for C15H18N3, 240.1500; found, 240.1492.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[CH3:36][N:37]1[CH:41]=[C:40]([CH2:42][C:43](O)=[O:44])[N:39]=[CH:38]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:40]4[N:39]=[CH:38][N:37]([CH3:36])[CH:41]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Cn1cnc(CC(=O)O)c1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(CC(=O)N2CCC(c3ccc(NC(=O)c4nc(C#N)c[nH]4)c(C4=CCCCC4)c3)CC2)c1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using (1-methyl-1H-imidazol-4-yl)-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.82 (s; 1H), 8.10 (d, 1H), 8.00 (s, 1H), 7.42 (s, 1H), 7.16 (dd, 1H), 7.06 (d, 1H), 5.80 (m, 1H), 4.66 (m, 1H), 4.12 (m, 1H), 4.04 (m, 2H), 3.92 (s, 3H), 3.28 (m, 1H), 2.82 (m, 2H), 2.26 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C28H31N7O2, 498.2 (M+H), found 498.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1.O>ClCCl>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([O:30][C:27]2[CH:26]=[CH:25][C:24]([N:10]3[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:15])[N:13]=[C:9]3[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[CH:29][CH:28]=2)(=[O:46])=[O:45])[CH:39]=1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (100 mg, 0.22 mmol) and triethylamine (0.31 ml, 2.25 mmol) in dichloromethane (5.0 ml) were cooled to −78° C. 3-Pyridinesulfonyl chloride (144 mg, 0.67 mmol) was added in small portions to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase washed with water and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (110 mg, 84%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH:33]=O)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH2:33][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Product: Cc1cccc(N2CCN(CCNCc3cc(CC(C)C)n(-c4ccccc4)n3)CC2)c1C
Yield: 96.5 %

Procedure:
Compound 18 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>CN(C=O)C>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil, 0.650 g, 16.4 mmol) in DMF (40 mL) was added tert-butyl ethyl propanedioate (2.8 g, 15.1 mmol) at room temperature. The mixture was stirred for 30 min. A solution of 5-chloro-2-nitropyridine (2.00 g, 12.6 mmol) in DMF (10 mL) was added. The mixture was heated to 80° C. and stirred for 4 hours. The solvent was removed under reduce pressure. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography with silca gel to give tert-butyl ethyl (6-nitropyridin-3-yl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.20˜8.27 (m, 2H), 4.69 (s, 1H), 4.21˜4.26 (m, 2H), 1.45 (s, 9H), 1.28 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][C:6]([OH:8])=[O:7])=[O:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29]>C(O)(=O)C>[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:9](=[O:11])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: O=CN[C@@H](CC(=O)O)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Reaction time: 5 h

Procedure:
In 28.6 g of acetic acid, 16.1 g (0.1 mole) of N-formyl L-aspartic acid was suspended and 10.2 g (0.1 mole) of acetic anhydride was added. The mixture was warmed to 50°-55° C. and stirred for 5 hours at the same temperature. After finishing the reaction, the resulting mixture was cooled to 15°-20° C. and then 9.2 g (0.11 mole) of sodium acetate and 20.5 g (0.095 mole) of L-phenylalanine methyl ester hydrochloride were successively added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. The reaction mixture was then concentrated and 57.2 g of water was added and cooled to 10°-15° C. Precipitated crystals were filtered, washed and dried. Crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester thus obtained were 28.2 g. The crystals were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 81.0:19.0. The crystals were purified with a conventional method to give high purity crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester. The yield was 20.8 g (68.0% yield on L-phenylalanine methyl ester hydrochloride).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([OH:8])[CH:3]([CH2:4]2)[CH2:2]1.[CH3:9]N(C=O)C.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH3:9][C:7]1([O:8][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:6][CH:5]2[CH2:4][CH:3]1[CH2:2][CH2:1]2
Reactant: OC1CC2CCC1C2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1(Oc2ccc([N+](=O)[O-])cc2)CC2CCC1C2
Reaction time: 0.5 h

Procedure:
To a solution of 15.6 g. (0.10 mole) of the crude norborneol in 80 ml. DMF and 160 ml. C6H6 there was added 4.21 g. of 56% NaH dispersion. Following 30 minutes heating at reflux, there was added 14.1 g. of p-fluoronitrobenzene. The mixture was then heated for an additional 6 hours, cooled and washed thoroughly with H2O and brine. The residue was chromatographed on 2 L silica gel (elution with 1:1 SSB:C6H6). Those fractions which showed a single spot on tlc were combined to afford 13.5 g. of product as a yellow oil; the NMR is in agreement with the structure.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:31])[C:28]([F:32])=[CH:27][C:26]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([N:21]1[CH2:22][C@H:18]2[C@H:17]([C:25]3[CH:30]=[C:29]([I:31])[C:28]([F:32])=[CH:27][C:26]=3[CH3:33])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=3)[CH3:14])[O:24][CH2:23][C@@H:19]2[CH2:20]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)c(I)cc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Product: CC(=O)N1C[C@H]2CO[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3cc(I)c(F)cc3C)[C@@H]2C1

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-5-iodo-2-methylphenyl)octahydropyrano[3,4-c]pyrrole and acetic anhydride according to the procedures used for example 19. MS: (MH)+660.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]([CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[C:7](=[O:18])[CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])C.[OH-].[Li+].Cl>C1COCC1.O>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:22]([NH:21][CH2:20][CH2:19][N:6]([C:7](=[O:18])[CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])[CH2:5][C:4]([OH:34])=[O:3])(=[O:24])=[O:23])([O-:33])=[O:32]
Reactant: CCOC(=O)CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(CC(=O)N(CCNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC(=O)O)c(=O)[nH]c1=O
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To a solution of N-[2-(2-Nitro-benzenesulfonylamino)-ethyl]-N-[(thymin-1-yl)-acetyl]-glycine ethyl ester (1.00 g, 2.0 mmol) in THF (10 ml,) was added a solution of lithium hydroxide (210 mg, 5 mmol) in water (10 mL) at 10° C. After stirring for 1.5 h, the reaction mixture was acidified to pH=2˜3 by adding 1 N HCl solution. The precipitated solid was filtered off, washed with water, and dried in vacuo to give the tilted product as a white solid (896 mg, 95%). 1H-NMR (500 MHz; DMSO-d6) δ 11.30 (s, 0.6H), 11.27 (s, 0.4H), 8.22˜7.85 (m, 5H), 7.31 (d, 0.6H), 7.23 (d, 0.4H), 4.63 (s, 1.2H), 4.45 (s, 0.8H), 4.19 (s, 0.8H), 4.16 (q. 0.8H), 3.93 (s, 1.2H), 3.47 (t, 1.2H), 3.34 (t, 0.8H), 3.20 (q, 1.2H), 3.04 (q. 0.8H), 1.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[C:32]1([S:38]([CH2:41][CH2:42][C:43](O)=[O:44])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:43](=[O:44])[CH2:42][CH2:41][S:38]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:40])=[O:39]
Reactant: O=C(O)CCS(=O)(=O)c1ccccc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCS(=O)(=O)c1ccccc1)O[C@@H](Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 68.6 %

Procedure:
((S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide) (150 mg, 0.357 mmol), EDC (103 mg, 0.535 mmol), 3-(phenylsulfonyl)propanoic acid (84 mg, 0.393 mmol), and DMAP (65.4 mg, 0.535 mmol) in DCM (30 ml) were stirred at RT for 4 hours. The reaction mixture was washed with HCl 1N (2×) and NaHCO3 sat. sol. (2×); the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by trituration with iPr2O (10 ml). Further triturations with petroleum ether (15 ml) and Et2O (20 ml) were performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(phenylsulfonyl)propanoyloxy)ethyl)pyridine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[C:26](OC(=O)C)(=O)[CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[C:26]2[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2ncnc3c2c(c1OC)N=C(C)N3c1cccc(Br)c1

Procedure:
A solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (120 mg, 0.32 mmol) (from Example 6, Step B, supra) in acetic anhydride (3 mL) was heated at 150° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was extracted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.05) as eluent to give the desired 3-(3-bromo-phenyl)-8,9-dimethoxy-2-methyl-3H-1,3,4,6-tetraaza-phenalene as a brown solid. (Yield 60 mg, 47%).
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][CH2:7][CH2:8][C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][N:11]([CH3:19])[C:10]=2[C:20]\1=O)C.C(=O)(O)O.[NH2:26][C:27]([NH2:29])=[NH:28]>CCO>[NH2:28][C:27]1[N:29]=[C:20]2[C:10]3[N:11]([CH3:19])[N:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=3[CH2:8][CH2:7][CH2:6][C:5]2=[CH:4][N:26]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1nn(C)c2c1CCC/C(=C\N(C)C)C2=O
Agent: O=C(O)O
Solvent: CCO
Product: CCOC(=O)c1nn(C)c2c1CCCc1cnc(N)nc1-2
Yield: 62.2 %

Procedure:
To a solution of ethyl (7E)-7-[(dimethylamino)methylidene]-1-methyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (240 mg, 0.86 mmol) in EtOH (7.5 mL), guanidine carbonate (86 mg, 0.47 mmol) was added. The reaction mixture was stirred under reflux for 24 h. The solvent was removed under reduced pressure, the crude was triturated with hexane and EtOH and collected by filtration to give 84 mg of a white solid (79% yield).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13][O:12]2)=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].[OH-].[Na+].C(O)C.P(=O)(O)(O)O>O>[CH:18]1([O:17][CH2:16][CH:15]2[CH2:14][CH2:13][O:12][N:11]2[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(CN2OCCC2COC2CCCCC2)cc1-c1ccccc1C
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1cc(CN2OCCC2COC2CCCCC2)ccc1C(=O)O
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A mixture of example 1130C (355 mg, 0.84 mmol) and sodium hydroxide (1 mL of a 4N aqueous solution, 4 mmol) in 4 mnL of ethanol was heated to reflux for 6 hours and then cooled to room temperature. The mixture was diluted with water and the pH adjusted to 5 with aqueuos phosphoric acid. The mixture was extracted with 3 portions of ethyl acetate and the combined organic fractions were washed with water and brine, dried, filtered and concentrated to provide 270 mg (78%) of the title compound. MS (ESI+): 410 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][N:11]=[C:5]2[S:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([Br:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(#N)C>[Br-:34].[CH2:33]([N:11]1[CH2:10][CH2:9][CH2:8][CH2:7][N+:6]2[C:2]([CH3:1])=[CH:3][S:4][C:5]1=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CC1=CSC2=NCCCCN12
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCN1CCCC[n+]2c(C)csc21
Product: [Br-]
Yield: 82.3 %

Procedure:
3-Methyl-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepine (1.68 g., 0.01 mole) (prepared by basification of the hydrochloride salt with sodium carbonate in acetonitrile solution) was dissolved in dry acetonitrile and refluxed for 36 hours with cetyl bromide (3.4 g., 0.011 mole). The solvent was evaporated and the residue washed with toluene and dried. Recrystallization from a mixture of acetonitrile and dry ether gave 9-cetyl-3-methyl-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepinium bromide (3.9 g., 81%) m.p. 120°-121°. (Found: C, 60.5; H, 9.5; N, 6.2. C24H45N2SBr requires C, 60.8; H, 9.5; N, 5.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[C:28]([S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[C:28]([S:33]([CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:35])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)c1ncccc1Br
Product: CC(C)S(=O)(=O)c1ncccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared as described in step D of Example 803 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 3-bromo-2-(isopropylsulfonyl)pyridine. MS (ESI): mass calcd. for C21H18FN4O2S, 395.11; m/z found, 396.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.70 (dd, J=4.6, 1.6, 2H), 8.25-8.17 (m, 1H), 7.84 (dd, J=7.8, 1.7, 1H), 7.64-7.54 (m, 2H), 7.46-7.32 (m, 3H), 6.61 (s, 1H), 4.26 (hept, J=6.8, 1H), 1.34 (d, J=6.9, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:23]>CC(N(C)C)=O.C(OCC)(=O)C.O>[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:25]=1)=[O:23]
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3cc(OC)ccc23)c2ccccc12
Temperature: 140 °C
Reaction time: 20 h

Procedure:
3.46 g (25 mmol) of potassium carbonate and 1.94 g (10 mmol) of 4-chloro-7-methoxyquinoline are added to 1.75 g (10 mmol) of 3-methoxycarbonyl-1H-indole in 50 cm3 of dimethylacetamide under an argon atmosphere. After stirring at a temperature in the region of 140° C. for 20 hours, the reaction mixture is cooled and diluted with 300 cm3 of ethyl acetate and 300 cm3 of water. The organic phase is separated off by settling and washed with three times 300 cm3 of water and 300 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 and then 7/3 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), 1.7 g of 3-methoxycarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole are obtained in the form of a yellow foam. Mass spectrum (EI): m/e 332 (M+•), m/e 301.