Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:19]C1C=C(Br)C=CC=1N.FC1C=C(Br)C=CC=1N>>[Br:19][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(Br)cc1Br
Reactant: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: Nc1ccc(Br)cc1F
Product: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1Br

Procedure:
This compound was prepared by the method described for 2-fluoro-4-(2-aminosulfonylphenyl)aniline described in EXAMPLE 8 by starting with 2,4-dibromoaniline rather than 2-fluoro-4-bromoaniline.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: COCCN
Agent: O=C(n1ccnc1)n1ccnc1
Product: COCCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
Following the amide coupling procedure described in protocol A, 499 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 370 mg CDI (2.28 mmol) and 165.2 mg 2-methoxyethylamine (2.20 mmol) produced 6-hydroxy-N-(2-methoxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:51][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoate (360 mg, 0.49 mmol, 1.00 equiv) in dichloromethane (2 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 217.9 mg (66%) of a white solid. 1H-NMR (300 MHz, DMSO-d6+DCl, ppm): δ 9.06˜9.04 (d, J=5.7 Hz, 1H), 8.86 (s, 1H), 8.75 (s, 1H), 8.74˜8.47 (m, 1H), 8.44˜8.10 (m, 2H), 7.88 (s, 2H), 7.88˜7.84 (d, J=7.8 Hz, 2H), 7.75˜7.48 (m, 4H), 4.60 (s, 2H), 3.86 (s, 2H), 3.78 (s, 4H), 2.63˜2.58 (m, 2H), 2.31˜1.75 (m, 6H). MS (ES, m/z): 677[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[C:20]([CH3:26])[CH:19]=1.N1CCCCC1.[BH4-].[Na+]>C(O)C.CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([NH:1][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][C:20]=3[CH3:26])[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(F)ccc1C=O
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(F)ccc1CNc1[nH]nc(Nc2cccc(Cl)c2)c1C#N
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 4-fluoro-2-methylbenzaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product C29 was scraped and collected. (50 mg)
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].[CH3:39][N:40](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:41].F[P-](F)(F)(F)(F)F.CNC>ClCCl.C1COCC1>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([N:40]([CH3:41])[CH3:39])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in dichloromethane (2 mL) were added HBTU (30 mg, 0.079 mmol) and dimethylamine (0.185 mL, 0.37 mmol, 2.0M soln in THF). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (42 mg, 99%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][N:16]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCCl>[CH3:15][N:16]1[C:20]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[C:19]([CH3:21])[CH:18]=[C:17]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(F)cc2)n1C
Reaction time: 2 h
Yield: 25 %

Procedure:
A solution of 3.95 g. (0.025 mole) of p-fluorobenzoyl chloride and 3.32 g. (0.025 mole) of aluminum chloride in 20 ml. of 1,2-dichloroethane is added dropwise to a solution of 4.52 g. (0.025 mole) of ethyl 1,4-dimethylpyrrole-2-acetate in 20 ml. of 1,2-dichloroethane at room temperature. The reaction mixture is stirred for 2 hours, and then cooled and poured into ice-dilute HCl. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and a saturated solution of sodium chloride; dried over anhydrous magnesium sulfate; and the solvent evaporated. The residue is triturated with hot hexane and crystals form upon cooling. There is obtained about 1.9 g. (25% yield) of ethyl 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate as a white solid, m.p. 84-86° C. Upon recrystallization from methanol, the m.p. is 87-89° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])[N:29]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(F)c2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc(F)c3F)cc2=O)n1
Yield: 53 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,3-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 44) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,3-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.68 g, 53%); ES+-HRMS m/e calcd for C25H29N5O4F2 [M+H+] 502.2261 found 502.2260. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.24-1.77 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.47 (dd, J=4.1, J=10.7 Hz, 1H), 6.06 (d, J=2.6 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 7.30-7.38 (m, 2H), 7.40-7.51 (m, 1H), 7.52 (d, J=2.2 Hz, 1H), 8.22 (d, J=2.6 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][OH:17])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:18][CH3:19])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][O:17][S:28]([CH3:27])(=[O:30])=[O:29])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:18][CH3:19])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1[nH]n(C2CCCC2)c2nc(CO)nc(=O)c1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(COS(C)(=O)=O)nc(=O)c1-2
Reaction time: 1 h

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-6-(hydroxymethyl) pyrazolo[3,4-d]pyrimidin-4-one (1.0 g, 3.8 mmol), CH2Cl2 (25 mL) and triethylamine (0.77 g, 7.6 mmol) at -50° C. was added methanesulfonyl chloride (0.44 g, 3.8 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 1 hour, CH2Cl2 and water were added and the organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford 1.28 g of crude product. The crude product was combined with that from a similar experimental run and the mixture was recrystallized from ether (2×) to afford 1-cyclopentyl-3-ethyl-6-(methylsulfonyloxymethyl) pyrazolo[3,4-d]pyrimidin-4-one, m.p. 138-140° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:35]4[CH2:36][CH2:37][N:38](C(OC(C)(C)C)=O)[CH2:39][CH:40]=4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:48]([F:51])([F:50])[F:49])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][N:30]1[C:31](=[O:33])[C:32]2[C:28](=[C:27]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)[CH:26]=[CH:25][C:24]=2[NH:23][C:21]2[C:20]([C:48]([F:50])([F:51])[F:49])=[CH:19][N:18]=[C:17]([NH:16][C:13]3[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=3)[N:22]=2)[CH2:29]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCNCC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(7-{[2-({4-[(d iethoxyphosphoryl)methyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 246A, 180 mg, 0.25 mmol) was added methylene chloride (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour, after which, the reaction mixture was concentrated and purified by MDP. 1H NMR (400 MHz, methanol-d4) δ=1.27 (t, J=6.9 Hz, 6 H), 2.77-2.85 (m, 2 H), 3.19 (s, 3 H), 3.29 (d, J=21.5 Hz, 2 H), 3.50 (t, J=6.1 Hz, 2 H), 3.88-3.94 (m, 2 H), 4.01-4.17 (m, 4 H), 4.59 (s, 2 H), 6.02 (dt, J=3.3, 1.7 Hz, 1 H), 7.35 (dd, J=8.5, 2.4 Hz, 2 H), 7.50 (d, J=8.8 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 8.35-8.43 (m, 1 H), 8.72 (br. s., 1 H). MS (ES+): m/z 631.23 (100) [MH+]; HPLC: tR=0.68 min (UPLC, purity).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8](=[N:16][OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:21][C:22]([NH2:24])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:16][O:17][CH2:21][C:22]([NH2:24])=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: NC(=O)CCl
Reactant: ON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
Sodium hydride (0.5 g., 50% w/w suspension in mineral oil) was added gradually to a stirred solution of 4,4'-dichlorobenzophenone oxime (2.6 g.) in dry dimethylformamide (20 ml.) keeping the temperature below 30° C. After 30 minutes, chloroacetamide (0.9 g.) was added to the stirred solution keeping the temperature below 30° C. After 16 hours stirring at ambient temperature the mixture was poured into water (100 ml.) and the subsequent mixture extracted with ether. The combined extract was washed with water, dried (MgSO4) and evaporated. The residue (2.5 g.) was added to a column of dry chromatographic silica-gel [300 g., previously deactivated by addition of 10% w/w water and then equilibrated with 10% v/w of a mixture of toluene and acetone (10:1 v/w)]. The column was then eluted with the same mixture of toluene and acetone to give, after evaporation of solvent, a solid residue (1.5 g.). The solid was recrystallised from ethyl acetate/petrol giving di-(4-chlorophenyl)methyleneamino-oxyacetamide m.p. 141°-142° C. (1.1 g.) in 34% overall yield.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.N([O-])=O.[Na+].O.[BrH:18]>C(O)(=O)C.S(=O)(=O)(O)O>[Br:18][C:3]1[C:2]([Cl:1])=[C:8]([Cl:9])[CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Br
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
Substituted nitrobenzenes, not hitherto described in the chemical literature, used in the preparation of substituted anilines as hereinbefore described in Reference Example 2, were prepared as follows: (a) 2,3-Dichloro-6-nitroaniline [29 g; prepared by a modification (reaction at 125° C.) of the procedure described by Beilstein and Kurbatow, Ann., 192, 235 (1878)] was dissolved with stirring at 55°-60° C. in glacial acetic acid (350 ml). A solution of sodium nitrite (11 g) in concentrated sulphuric acid (80 ml) was then added to the solution thus obtained with stirring over 15 minutes at a temperature of 55°-60° C. maintained by intermittent cooling with water. The red solution obtained was cooled to 15° C. and poured, with stirring, into a solution of cuprous bromide (20 g) in concentrated hydrobromic acid (200 ml) and ice (500 g). The mixture was allowed to attain laboratory temperature, heated for one hour at 60° C. and then steam-distilled. The distillate obtained was extracted with diethyl ether (6×500 ml). The combined ethereal extracts were washed successively with aqueous sodium hydroxide solution (2N; 3×750 ml and water (2×500 ml), dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated to dryness to give a yellow powder, which was then crystallised from hexane (125 ml) to give 2-bromo-3,4-dichloronitrobenzene (26.7 g), m.p. 73° C., in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][OH:31].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN([CH:64]=[O:65])C>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:30]([O:65][CH3:64])=[O:31])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: CO
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2s1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (2.61 g) from Example No. 2 in DMF (33 mL) are added triethylamine (1.6 mL), methanol (9.5 mL), Pd(OAc)2(0.132 g), and dppp (0.242 g). Carbon monoxide is bubbled through the solution, and the reaction is heated to 70° C. The reaction is stirred at 70° C. for 18 h. The reaction mixture is cooled to rt, and water (25 mL) and 2 N HCl (25 mL) are added. The resulting precipitate is filtered off and purified by column chromatography (CH2Cl2; CH2Cl2/methanol, 99/1; 98/2). A mixture of starting material and desired product is isolated as a yellow solid. This material is re-subjected to the reaction conditions above. The reaction is stirred at 70° C. for 18 h. The reaction is cooled to rt and water (25 mL) and 2 N HCl (25 mL) are added. The resulting orange solid is filtered off and purified by column chromatography (CH2Cl2; CH2Cl2/methanol, 99/1; 98/2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yellow solid which is recrystallized from methanol to yield 1.337 g (60%) of the title compound as a pale yellow, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].CCO[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:28]([O:27][C:25]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][NH:14][NH:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=1[Cl:12])=[O:26])[CH3:29]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(=O)OCC

Procedure:
##STR79## 24.5 g (0.1 mol) of 2,6-dichloro-4-trifluoromethylphenyl hydrazine and 21.6 g (0.1 mol) of diethyl ethoxymethylene malonate are stirred for 24 hours at room temperature in 150 ml of ethyl alcohol, the solvent removed by vacuum, and the crystalline residue stirred with petroleum ether. Suctioning off and air-drying results in a yield of 33 g (79.5% of the theoretical) of N-[2,2-bis-(ethoxy-carbonyl)-vinyl]-N'-(2,6-dichloro-4-trifluoromethylphenyl) hydrazine with a melting point of 86° C.
Reaction SMILES: C=O.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]1)[CH2:9]2)([O-])=O.[CH3:21]C(O)=O.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH3:21][NH:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]1)[CH2:9]2
Reactant: CC(=O)O
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reaction time: 4 h

Procedure:
To a stirred mixture of formaldehyde (0.026 mL of a 37 wt % aqueous solution, 0.32 mmol), (±)-5′-amino-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 45) (50 mg, 0.23 mmol), and AcOH (0.053 mL, 0.92 mmol) in MeOH (3 mL) at ambient temperature was added sodium cyanoborohydride (0.34 mL of a 1 M solution in THF, 0.34 mmol) and the reaction mixture was stirred for 4 h, then concentrated ill vacuo. The residue was partioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was removed, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as an off-white solid. MS: m/z=232 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.Cl.[NH:12]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:12]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:13]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCN1Cc1ccc(OC)cc1
Temperature: 62 °C
Reaction time: 72 h
Yield: 51.3 %

Procedure:
4-Methoxy benzyl chloride (55 mmol, 8.61 g) was add ed t o a mixture of K2C3 (56 mmol, 7.7 4 g) and ethyl pipecolinate hydrochloride (50 mmol, 9.68 g) in DMF (55 mL). The mixture was stirred for 3 days at 62° C., and was filtered. Ice-cold HCl solution (1.5 N, 50 mL) was added to the filtrate and it was extracted with ether (3×100 mL). The aqueous phase was basified with NaOH solution (40%) and extracted with ether (5×100 mL). The combined extracts were washed with brine, dried with Na2SO4 and MgSO4 and concentrated in vacuo to give ethyl N-(4-methoxyphenylmethyl)-pipecolinate as a yellow oil (7.12 g): 1H NMR (300 MHz) δ 7.23 (d, J=8.6 Hz, 2 H), 6.84 (d, J=8.6 Hz, 2 H), 4.22 (q, J=7.1 Hz, 2 H), 3.70 (s, Me), 3.73 (d, J=13.1 Hz, 1 H), 3.34 (d, J=13.6 Hz, 1 H), 3.08 (dd, J=8.2, 4.3 Hz, 1 H), 2.93 (m, 1 H), 2.10 (m, 2 H), 1.80 (m, 2 H), 1.56 (m, 3 H), 1.30 (t, J=7.1 Hz, 3 H); 13C NMR δ 174.00, 158.68, 130.43, 130.01, 113.46, 64.55, 60.30, 59.87, 55.20, 50.15, 29.64, 25.24, 22.67, 14.33; MS (E) 277 (2, M), 204 (90), 121 (100); HRMS (EI) m/e calcd for C16H23NO3 277.1678, found 277.1682.
Reaction SMILES: [CH3:1][CH:2]([NH:5][C:6](=S)[NH:7][NH2:8])[CH2:3][CH3:4].[Cl:10][CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>C(O)C>[ClH:10].[CH3:19][C:17]1[NH:8][N:7]=[C:6]([NH:5][CH:2]([CH3:1])[CH2:3][CH3:4])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCC(C)NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NC(C)CC)n[nH]c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
A stirred solution of 5.1 g (0.035 mole) of 4-(2-butyl)-3-thiosemicarbazide in 40 mL of absolute ethanol was treated with 5.7 g (0.035 mole) of ethyl 2-chloroacetoacetate and stirred at ambient temperature for 3 hr. The mixture was treated with 20 mL of 2N ethanolic hydrogen chloride, heated at reflux for 1 hr and stirred for ~16 hr at ambient temperature. The reaction mixture after filtering and concentrating in vacuo gave a crude orange solid. A second reaction mixture was prepared with 8.0 g (0.054 mole) of crude 4-(2-butyl)-3-thiosemicarbazide, 50 mL of absolute ethanol, 8.9 g (0.054 mole) of ethyl 2-chloroacetoacetate, and 25 mL of 2N ethanolic hydrogen chloride as described above and gave a crude orange solid. The TLC of both crude products (10% methanol/benzene; silica gel) were identical. Recrystallization of the first batch from acetone/isopropyl ether gave 4 g of fine white crystals, mp 147°-148.5° C. Recrystallization of the second batch from benzene/ligroin gave 2.5 g of pale yellow crystalline product, mp 146°-148.5° C. The 2 solids were combined (6.5 g) and recrystallized from 200 mL of acetone/isopropyl ether (3:1) to give 3.6 g of white fluffy crystals, mp 147°-149° C.