Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:16][C:17]2[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=2[N+:25]([O-:27])=[O:26])[S:11][C:12]=1[C:13]([NH2:15])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:16][C:17]2[CH:22]=[C:21]([CH2:23][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[CH:20]=[CH:19][C:18]=2[N+:25]([O-:27])=[O:26])[S:11][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccccc4Cl)c(C(N)=O)s3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.1 %

Procedure:
To a mixture of 0.20 g (0.50 mmole) of 4-(2-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.20b), 0.63 g (3.0 mmole) of sodium triacetoxyborohydride and 15 mL of dichloromethane was added 0.12 mL (1.08 mmole) of 1-methylpiperazine. The mixture was stirred at room temperature for 3 days. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-15:85) to give 0.20 g of 4-(2-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.20c).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:34]([F:37])([F:36])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH2:26]4)=[O:24])=[C:19]([CH3:33])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:38][C:39]([F:44])([F:43])[CH2:40][CH2:41]I.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:34]([F:35])([F:36])[F:37])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][C:29](=[O:31])[N:28]([CH2:41][CH2:40][C:39]([F:44])([F:43])[F:38])[C:27](=[O:32])[CH2:26]4)=[O:24])=[C:19]([CH3:33])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)NC(=O)C1
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CCC(F)(F)F)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]piperazine-2,6-dione (200 mg, 0.36 mmol, 1.00 equiv), 1,1,1-trifluoro-3-iodopropane (163.5 mg, 0.73 mmol, 2.00 equiv), N,N-dimethylformamide (10 mL), potassium carbonate (100.7 mg, 0.73 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 60 mL of H2O. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4×40 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product (85 mg) was purified by Prep-HPLC. This resulted in 39.5 g (17%) of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]-1-(3,3,3-trifluoropropyl)piperazine-2,6-dione as a white solid. (ES, m/z): [M+CH3CN]+ 685.0; 1H NMR (300 MHz, CDCl3): δ 7.85 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.28-7.23 (m, 1H), 4.79 (s, 2H), 4.19-4.10 (m, 5H), 3.75 (d, J=17.4 Hz, 1H), 2.49-2.41 (m, 2H), 2.32 (s, 3H)
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)([OH:17])[CH:10]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH3:11])=[CH:5][CH:4]=1.[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C)C=O.O>[C:32]([O:17][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=1)([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[CH:10]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[CH3:11])(=[O:34])[CH3:33]
Reactant: CC(n1cncn1)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C(C)n1cncn1
Yield: 29.1 %

Procedure:
1,1-Bis-(4-trifluoromethylphenyl)-2-(1,2,4-1H- triazol-1-yl)propan-1-ol (0.5 g.) was added carefully to a suspension of sodium hydride (60 mg., freed from dispersion in oil by washing with hexane) in dry dimethylformamide (20 cm3) under a nitrogen atmosphere. After stirring the mixture for 2 hours acetyl chloride (0.1 g) was added and after a further 2 hours the mixture was diluted with water and extracted with chloroform. The chloroform layer was separated, washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure to yield a residual oil which was purified by hplc and which solidified on trituration with petroleum ether (boiling range 60°-80° C.) to yield 1,1-bis(4-trifluoromethylphenyl)-2-(1,2,4-1H-triazol1-yl)propyl acetate (160 mg.).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:3]=1[C:4]([N:6]=[S:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:5].[Cl:18][C:19]1[C:20]([N:25]2[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1>N1C=CC=CC=1>[Cl:18][C:19]1[C:20]([N:25]2[C:29]([C:30]([NH:1][C:2]3[C:3]([C:4](=[O:5])[N:6]=[S:7]([CH2:8][CH3:9])[CH2:10][CH3:11])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=3[Cl:16])=[O:31])=[CH:28][C:27]([C:33]([F:36])([F:34])[F:35])=[N:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: c1ccncc1
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (8.82 g, 25.6 mmol) in pyridine (30 mL) was added N,N-dimethylamino pyridine (312 mg, 2.56 mmol, 10.0 mol %). At 90° C., a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (10.90 g, 29.12 mmol, 1.100 equiv.) in pyridine (50 mL) was added dropwise and the mixture was stirred for 1 h. The mixture was cooled and concentrated in vacuum. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuum. Flash-chromatography on silica gel yielded the title compound (4.12 g, 28%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1>>[Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C)nc1

Procedure:
C7d was prepared in an analogous fashion to C4d from (S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoic acid C7c and 5-methylpyridin-2-amine.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19]Cl>CN(C=O)C>[CH2:1]([N:3]([CH2:19][CH2:18][CH2:17][Cl:16])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: ClCCCCl
Reactant: CCNS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCCl)S(=O)(=O)c1ccc(C)cc1
Temperature: 53 °C
Yield: 42 %

Procedure:
To N-ethyl-p-toluenesulfonamide (5.01 g, 0.0251 mol) in DMF (50 mL) in a dry flask is added sodium hydride (80% in oil, 0.93 g, 0.031 mol). After gas evolution subsides, 1,3-dichloropropane (22.48 g, 0.199 mol) is added. The mixture is heated at 53° C. for 10 h then cooled and poured into ice water (300 mL), which is extracted twice with ether. The combined extracts are washed with 1% sodium bisulfite, water (3×), and brine. Removal of solvent by rotary evaporation then Kugelrohr distillation gives crude product, which is chromatographed on silica gel (30% hexane/CHCl3) to furnish 2.91 g product (42%) NMR (CDCl3) δ 1.15 (t, 3H), 1.9-2.2 (m, 2H), 2.44 (s, 3H), 3.11-3.35 (m, 4H), 3.6 (t, 2H), 7.3 (d, 2H), 7.74 (d, 2H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.16 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/heptane) to yield the title compound as an off-white solid (0.098 g, 21%). MS (ISP) 476.0 [(M+H)+]; mp 225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-])=O)[C:14](I)=[N:15][CH:16]=1>>[NH2:18][C:13]1[C:14]([C:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[O:5])=[N:15][CH:16]=[C:11]([Cl:10])[CH:12]=1
Reactant: O=Cc1ccccc1Cl
Reactant: O=[N+]([O-])c1cc(Cl)cnc1I
Product: Nc1cc(Cl)cnc1C(=O)c1ccccc1Cl

Procedure:
(3-Amino-5-chloro-pyridin-2-yl)-(2-chloro-phenyl)-methanone was prepared from 2-chlorobenzaldehyde and 5-chloro-2-iodo-3-nitro-pyridine in three steps according to the general procedure for synthesis of 3-Amino-5-chloro-pyridin-2-yl aryl ketones. MS m/z: 267.0 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH2:12][OH:13])=[C:10]([CH3:14])[CH:9]=[C:8]([CH3:15])[N:7]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]1[N:7]=[C:8]([CH3:15])[CH:9]=[C:10]([CH3:14])[C:11]=1[CH:12]=[O:13]
Reactant: Cc1cc(C)c(CO)c(NCCN(C)C)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(C)c(C=O)c(NCCN(C)C)n1

Procedure:
A solution of crude 2-(2-dimethylaminoethylamino)-3-hydroxymethyl-4,6-dimethylpyridine (15.0 g, 67 mmol) in methylene chloride (300 ml) containing a suspension of activated manganese dioxide (35 g) is refluxed for 5 hours. The solution is filtered hot and the manganese dioxide re-extracted with hot methylene chloride. The combined extracts are filtered through charcoal and evaporated to give 12.0 g of crude title D product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:47]=[C:46]([CH3:48])[CH:45]=[CH:44][C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH:36]=4)=[CH:27][CH:26]=3)[CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pt](=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:47]=[C:46]([CH3:48])[CH:45]=[CH:44][C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Reaction time: 0.67 h

Procedure:
To a degassed solution of the title compound from Example 12 Step D (365 mg, 0.551 mmol) in EtOAc (10 mL) was added platinum(IV) oxide (125 mg). The reaction flask was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction mixture was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 40 min, the reaction mixture was filtered though Celite, rinsing with EtOAc. Purification by flash chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 665.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=8.0 Hz, 1 H), 8.12 (s, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.79 (br s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.19-7.16 (m, 3H), 6.97 (d, J=8.5 Hz, 1H), 5.09 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 4.30-4.18 (m, 2H), 2.82-2.78 (m, 2H), 2.67-2.62 (m, 1H), 2.35 (s, 3H), 1.83-1.80 (m, 2H), 1.66-1.57 (m, 2H), 1.49 (s, 9H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[S:28][C:27]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:24]1[S:28][C:27]([CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Yield: 47 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1, using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.4 g, 1.49 mmol), 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)morpholine (0.598 g, 1.93 mmol), Pd(PPh3)4 (0.086 g, 0.074 mmol) and Cs2CO3 (0.678 g, 2.1 mmol). The crude was purified via reverse phase chromatography with a Biotage C18 SNAP 60 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 99.9%, formic acid 0.1%) to afford the title compound (0.26 g, 48%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3scc(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][CH2:9][C@@H:10]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH2:17][C@@H:12]2[CH2:11]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][CH2:9][C@@H:10]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[N:19]=[CH:20][C:21]([F:24])=[CH:22][N:23]=3)[CH2:17][C@@H:12]2[CH2:11]1
Reactant: COC(=O)c1cccc(OC[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccc(OC[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A solution of 0.15 g (0.39 mmol) of (7S,8aS)-7-(3-(methoxycarbonyl)phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Example 11j) in 15 mL of anhydrous ethyl ether was added dropwise to an ice-cold suspension of 0.029 g (0.78 mmol) of lithium aluminum hydride in 15 mL of anhdrous ethyl ether and the mixture stirred for 30 min. The reaction was carefully quenched at 0° C. with 0.029 mL of water, 0.029 mL of 15% sodium hydroxide, and 0.087 mL of water. The precipiate which formed was filtered through Celite, the filtrate concentrated in vacuo, and purification of the residue by flash silica gel chromatography with 95:5 chloroform:methanol gave 0.099 g (72%) of the title compound. Mp (.HCl) 85-89° C. HRMS calc'd for C19H24FN4O2 (MH+): 359.1883, found: 359.1895.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:15]([I:16])=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=2[I:17])=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[OH:12][CH2:11][C:10]1[CH:9]=[C:8]([I:17])[C:7]([O:6][C:5]2[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][CH:4]=2)=[C:15]([I:16])[CH:14]=1
Reactant: O=C(O)c1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a solution of 4-(4-hydroxy-phenoxy)-3,5-diiodobenzoic acid (400 mg, 0.828 mmol) in THF (6.0 ml) under argon was added borane-THF complex (3.31 mmol, 3.31 ml of 1M solution in THF) dropwise. After addition, the reaction mixture was heated at 60° C. for 3 h, then quenched with water and extracted with ethyl acetate three times. The organic extract was washed with water, then brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound (321 mg, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 2H), 6.67 (d, j=8.8 Hz, 2H), 6.55 (d, j=8.8 Hz, 2H), 4.55 (s, 2H) MS: (M+1-H2O)=451
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[N:16]([CH3:24])[CH:15]=3)[C:11]([O-])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH2:37])(=[O:36])=[O:35].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[N:16]([CH3:24])[CH:15]=3)[C:11]([NH:37][S:34]([C:28]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=3[O:26][CH3:25])(=[O:35])=[O:36])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C)ccc1S(N)(=O)=O
Reactant: Cn1cc(C(C(=O)[O-])c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Reaction time: 20 h

Procedure:
4 -Dimethylaminopyridine (151 mg) was added to a solution of 2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl)acetate acid (the product of Example 68, 480 mg. 1.24 mmol) in anhydrous dichloromethane (10 ml) at ambient temperature. 2-Methoxy-4-methyl-1-benzenesulfonamide (from Preparation 11, 300 mg, 1.48 mmol) was added to the solution, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (355 mg. 1.85 mmol), and stirring was continued for 20 hours. The solution was washed twice with 2N hydrochloric acid, and dried (magnesium sulphate) and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and crystallised from dichloromethane and diethyl ether mixture to give the subtitle compound (535 mg).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:12].CC([O-])(C)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([O:16][C:14](=[O:15])[CH:13]([C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:11]#[N:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: Brc1cccc2sccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)C(C#N)c1cccc2sccc12
Temperature: 20 °C

Procedure:
To a solution of 4-bromobenzothiophene (1 eq.) in DME were added tert-butyl cyanoacetate (1.1 eq.) and t-BuOK (2 eq.). The reaction was refluxed for 40 min. Thereto were added dichlorobis(triphenylphosphine)palladium(II) (0.02 eq.) and triphenylphosphine (0.06 eq.). The resulting mixture was refluxed for 1.5 h under argon and then cooled to 20° C. Aqueous HCl (6N) was added dropwise until pH=1 and the reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/DCM: 9/1 to 1/1) to afford benzo[b]thiophen-4-yl-cyano-acetic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:17][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:20](=[O:21])[CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1cccc(F)c1
Reactant: CCOC(=O)c1[nH]ccc1C
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(F)c2)c1C

Procedure:
4-[2-(3-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-Fluorophenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 93%. 1H-NMR (400 MHz, CDCl3): δ 1.37 (t, 3H), 2.61 (s, 3H), 4.03 (s, 2H), 4.35 (q, 2H), 7.00 (m, 3H), 7.27 (m, 1H), 7.49 (d, 1H), 9.57 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): □ 11.76, 14.38, 46.93, 60.84, 113.64, 116.30, 125.13, 127.17, 129.94, 137.42, 161.64, 193.02 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.76, 14.38; CH2 carbons: 46.93, 60.84; CH carbons: 116.30, 125.13, 127.17, 129.94 ppm. LC/MS: 91.29%, m/z=289.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]([CH2:8][C:9]([CH3:11])=O)=O)=[O:5].[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:8][C:9]([CH3:11])=[N:14]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(C)nn1C
Yield: 43.1 %

Procedure:
Ethyl acetopyruvate (Organic Syntheses, Coll. Vol. I, 1944, p. 238) (31.6 g) was dissolved in ethanol (100 ml) and treated with methyl hydrazine (12 g) in portions. The mixture was then refluxed gently for 1 hr, whereupon most of the ethanol was removed in vacuo. The residue was poured into 5% NaCl solution and the product extracted with chloroform (3 × 100 ml). The combined extracts were washed with water, dried and the solvent evaporated. The residue was then distilled in vacuo. 1,3-dimethyl-5-ethoxycarbonylpyrazole (14.5 g 43%) was obtained as a colourless oil, b.p. 25 118-121° C. (A mixture of the two isomers (1.5 g), followed by pure 1,5-dimethyl-3-ethoxycarbonylpyrazole (10.5 g, 31%), b.p. 25 178-180° C, was obtained on continued distillation).