Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][NH:21]3)=[CH:16][CH:15]=2)=[O:13])=[CH:7][C:6]=1[F:24])[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=3)(=[O:35])=[O:34])=[CH:16][CH:15]=2)=[O:13])=[CH:7][C:6]=1[F:24])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1F

Procedure:
2-Fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 473.24 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 2 was performed using 4-amino-2-fluorobenzoic acid ethyl ester and yielded 2-fluoro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester, which was reduced to 2-fluoro-4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester in step 3. Step 4 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 2-fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH2:14]([O:21][C:22](=[O:41])[C@H:23]([CH3:40])[CH2:24][C@H:25]([NH2:39])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([O:21][C:22](=[O:41])[C@H:23]([CH3:40])[CH2:24][C@H:25]([N:39]=[C:2]=[O:4])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:31][CH:32]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (6 mL) at 0° C. is added triphosgene (18 mg, 0.061 mmol). After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (Intermediate 30: 75 mg, 0.183 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid benzyl ester.
Reaction SMILES: C([O-])(O)=O.[Na+].O.O.[Sn](Cl)Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[C:28]([N+:40]([O-])=O)[CH:27]=3)=[N:22][CH:23]=2)=[CH:14][CH:13]=1.CO>CCOC(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)=[C:28]([NH2:40])[CH:27]=3)=[N:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
200 mg (2.5 mmol) NaHCO3 and 300 mg (1.1 mmol) tin-(II)-chloride dihydrate are added to a solution of 100 mg (0.22 mmol) 5-(4-chloro-phenyl)-2-[3-nitro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylethynyl]-pyridine (Example 3.13) in 10 mL EtOAc and the reaction mixture is refluxed for 2 h. To complete the reaction a further 200 mg (2.5 mmol) NaHCO3, 300 mg (1.1 mmol) tin-(II)-chloride dihydrate and 1 mL MeOH are added and the mixture is refluxed for a further 2 h. After cooling, 4 g of silica gel are added, the solvent is eliminated i.vac. and the residue is purified by chromatography (silica gel, DCM/MeOH/NH3 8:2:0.2).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:23]=1[CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:18][CH2:19][CH3:20].O>CN(C)C=O>[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](/[CH:32]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][C:36]([CH3:37])([CH3:38])[CH3:39])[C:23]=1[CH2:40][NH:41][C:42]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:48])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(C=O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.1 mL, 5.5 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.22 g, 5.5 mmol) (60% in oil), and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.45 g, 5.5 mmol) in N,N-dimethylformamide (10 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (2.03 g, 71.7%), as an amorphous.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[S:12]1[C:20]2[CH2:19][CH2:18][N:17]([C:21](Cl)=[O:22])[CH2:16][C:15]=2[CH:14]=[CH:13]1>>[S:12]1[C:20]2[CH2:19][CH2:18][N:17]([C:21]([O:11][C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([C:21]([N:17]4[CH2:18][CH2:19][C:20]5[S:12][CH:13]=[CH:14][C:15]=5[CH2:16]4)=[O:22])[N:7]=3)=[O:22])[CH2:16][C:15]=2[CH:14]=[CH:13]1
Reactant: Oc1n[nH]c2cc(F)ccc12
Reactant: O=C(Cl)N1CCc2sccc2C1
Product: O=C(Oc1nn(C(=O)N2CCc3sccc3C2)c2cc(F)ccc12)N1CCc2sccc2C1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 318 mg (1.578 mmol) of 6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carbonyl chloride. Yield: 18 mg (3%), M+H+: 483.25.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[N:10][C:9]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[N:8]1.[CH2:35]([OH:37])[CH3:36]>>[C:32]([OH:34])(=[O:33])/[CH:31]=[CH:36]/[C:35]([OH:3])=[O:37].[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:18]=2)=[N:10][C:9]([CH:30]=[N:2][OH:3])=[N:8]1.[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:18]=2)=[N:10][C:9]([CH:30]=[N:2][OH:3])=[N:8]1
Reactant: NO
Reactant: CCO
Reactant: Cn1nc(CCC(=O)O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cn1nc(C=NO)nc1NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of hydroxylamine hydrochloride (0.36 g) in ethanol (20 ml) was treated with potassium hydroxide (0.28 g). A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxaldehyde (A) (1.5 g) in ethanol (20 ml) was added. The mixture was stirred for 15 minutes and then filtered. The filtrate was evaporated and the residue was dissolved in chloroform and washed with water. The organic solution was dried, filtered and evaporated and the solid residue was dissolved in ethyl acetate/ethanol and treated with a solution of fumaric acid in ethyl acetate/ethanol, to give the title compound (0.05 g) m.p. 173°-4°.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:30][CH2:31][CH2:32][CH3:33])[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([C:4]1[N:5]=[C:6]([CH2:30][CH2:31][CH2:32][CH3:33])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2]
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A suspension of 1.78 g of 4-acetyl-2-butyl-5-cyano-1-tritylimidazole [prepared as described in step (ii) above] in 80% v/v aqueous acetic acid was stirred at 60° C. for 1 hour. The solution thus obtained was concentrated to dryness by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.66 g of the title compound as a colorless solid, melting at 77°-78° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[O:10])=[CH:5][CH:6]=1.[ClH:33].CCOC(C)=O.CCCCCCC>CCO>[Cl-:33].[CH2:7]([NH:8][C:9](=[O:10])[CH2:11][C:12]1[NH+:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH+:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1.[Cl-:33]
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Reactant: Cl
Solvent: CCO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(-c2ccc(OCC[NH+]3CCOCC3)cc2)c[nH+]1)NCc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a stirred suspension of KX2-391 (free base, 60.00 g) in absolute EtOH (600 mL) was added 170 mL of 2.5 M HCl (in ethanol), 25 mL EtOH being added to wash down the sides of the flask. The resulting homogeneous solution was stirred at room temperature (20 min) and then evaporated to near dryness (to frothing). After chasing with EtOH (2×150 mL), the residue was taken up again in EtOH (150 mL) and then was followed by the slow addition of heptane until the mixture appeared saturated (33 mL required for cloudiness to remain). After sitting overnight, two layers had formed. After adding additional heptane (250 mL) crystallization still could not be induced and so the reaction mixture was concentrated to a volume of ˜200 mL at which time the mixture was homogeneous. This thick homogeneous solution was added dropwise to very rapidly stirred (mechanical) EtOAc (2 L). After the addition was complete, a 25 mL EtOH rinse of the original flask and addition funnel was added to the rapidly stirred mixture. The rapid stirring was continued for another ˜1 h and then the mixture was filtered and the solid (partly gummy) was washed with EtOAc (300 mL) and then heptane. As soon as the heptane wash began, the solid got much gummier. The fitted Buchner funnel and its contents were covered (paper towel/rubber band) and immediately placed in the vacuum oven. After overnight vacuum at ˜45° C., the vacuum was released under nitrogen, and the Buchner funnel containing the product (foamy solid) was immediately placed in a zip-lock back and then, under nitrogen (glove bag), transferred to a bottle and the foamy solid broken up (spatula) to a powder. A second night under high vacuum (˜45° C.) resulted in only 1.3 g of additional weight loss. Constant weight was essentially attained with the third night of high vacuum (˜45° C.) where only 0.2 g of weight was lost. The final weight of material was 68.05 g (yield of 97%), containing 0.29 eq (4.8% w/w) of EtOAc, 0.035 eq (0.3% w/w) EtOH, and 0.03 eq (0.6% w/w) heptane. The purity was 99.6%.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[C:3]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NCc1ccccc1F
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Nc1cnc(Cl)nc1NCc1ccccc1F
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g (3.1 mmol) of 5-amino-2,4-dichloropyrimidine [D. T. Hurst, Heterocycl. 22, 79 (1984)], 0.35 ml (3.1 mmol) of 2-fluorobenzylamine and 0.46 ml (3.4 mmol) of triethylamine in 8 ml of 1-butanol is heated under reflux for 24 hours. The reaction mixture is then cooled to 0°. The resulting beige-coloured suspension is filtered with suction and the filter cake is washed with cyclohexane and suspended in water for 30 minutes at room temperature with stirring. The suspension is again filtered with suction and the filter cake is dried under a high vacuum at 100° over tetraphosphorus decaoxide. In this manner 5-amino-2-chloro-4-[N-(2-fluorobenzyl)amino]-pyrimidine is obtained in the form of beige-coloured crystals having a melting range of from 224° to 225°.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][SH:7])(=[O:3])[NH2:2].[CH2:8]=O.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>O>[O:13]1[CH2:14][CH2:15][N:10]([CH2:8][NH:2][C:1]([NH:4][CH2:5][CH2:6][SH:7])=[O:3])[CH2:11][CH2:12]1
Reactant: NC(=O)NCCS
Reactant: C=O
Reactant: C1COCCN1
Solvent: O
Product: O=C(NCCS)NCN1CCOCC1
Temperature: 30 °C

Procedure:
1 mol of N-carbamyl cysteamine, 1 mol of formol in an aqueous 30 % solution, 1 mol of morpholine and 10cc of distilled water are mixed while stirring. The reaction is exothermic (52°C). After cooling to about 30°C, 10cc of water is added and the mixture heated to 60°C until the reactants are completely dissolved. The mixture is then evaporated and redissolved by heating it in ethanol. This mixture is then again evaporated until dry and after washing with 50cc of ether and vacuum drying on P2O5, the result is a yellow colored paste (hygroscopic)-
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH:16]1([CH2:19][NH2:20])[CH2:18][CH2:17]1.Cl[CH2:22]Cl.CO>>[CH:16]1([CH2:19][N:20]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])[CH3:22])[CH2:18][CH2:17]1
Reactant: NCC1CC1
Reactant: ClCCl
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN(C)CC1CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.62 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 900 mg (10.57 mmol) of cyclopropylmethylamine. Yield: 0.95 g (94% of theory); C14H20N2O4 (M=280.32); calc.: molecular ion peak (M+H)+: 281; found: molecular ion peak (M+H)+: 281; Rf value: 0.4 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.I[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:19]([N:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:7]([C:5]2[S:6][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8]1)([CH3:21])[CH3:20].[CH:19]([N:8]1[C:7]([C:5]2[S:6][C:2]([F:1])=[CH:3][CH:4]=2)=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:10]=[N:9]1)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccncc2)c(-c2ccc(F)s2)n1
Product: CC(C)n1ncc(-c2ccncc2)c1-c1ccc(F)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %
Yield: 3 %

Procedure:
To a solution of 4-[3-(5-fluoro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.61 mmol) in 3 mL N,N-dimethylformamide were added 2-iodopropane (0.91 mmol) and cesium carbonate (0.67 mmol). The reaction mixture was stirred overnight at room temperature and the solvent was then evaporated. The residue was diluted with water and extracted three times with ethyl ether. The combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:ethyl acetate 20:1 to 5:1) to afford 114 mg of 4-[1-isopropyl-3-(5-fluoro-2-thienyl)-1H-pyrazol-4-yl]pyridine (64% yield) and 4 mg of 4-[1-isopropyl-5-(5-fluoro-2-thienyl)-1H-pyrazol-4-yl]pyridine (3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:12]=1.S(Cl)([Cl:32])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([Cl:32])=[O:16])[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CNc2nc(CCC(=O)O)nc3sc4c(c23)CCCC4)cc1Cl
Solvent: ClCCl
Product: COc1ccc(CNc2nc(CCC(=O)Cl)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno-[2,3-d]pyrimidine-2-yl]propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed and 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-2-yl]propionyl chloride is obtained. This is transferred to aqueous ammonia, the mixture is stirred for one hour and, after customary working up, 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-2-yl]propionamide is obtained.
Reaction SMILES: O[Li].O.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]([CH:21]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12].C1COCC1.Cl>C(OCC)(=O)C.O>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]([CH:21]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(OCc2ccccc2)c(C(=O)O)c1

Procedure:
LiOH.H2O (181 mg, 4.31 mmol) was added to a stirred solution of phenylmethyl 5-(methyloxy)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 6; 500 mg, 1.44 mmol) in a 3:1 mixture of THF:H2O (40 ml). The mixture was refluxed for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a yellow solid. 280 mg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21]>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc2CC1

Procedure:
The title compound was prepared from [2-(2,5-dichloropyrimidin-4-ylamino)-phenoxy]acetonitrile and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 927 (microwave: 120° C., 2 hours) to afford a white solid (17 mg, 22%). Mp: 153-6° C. LCMS (m/e) 449 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.46 (d, J=9 Hz, 1H), 8.10 (s, 1H), 7.63 (s, 1H), 7.35 (s, 1H), 7.23 (d. J=8 Hz, 1H), 7.15 (m, 2H), 7.06 (m, 2H), 6.94 (s, 1H), 4.90 (s, 2H), 2.92 (m, 4H), 2.71-2.55 (m, 6H), 1.14 (t. J=7 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)#[N:5].CCN(C(C)C)C(C)C>C(O)C>[OH:3][NH:2][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[NH:5]
Reactant: NO
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(C#N)CC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(C(=N)NO)CC2)cc1
Reaction time: 2 h

Procedure:
256.4 mg (3.69 mmol) Hydroxylamine hydrochloride are added to a mixture of 1.0 g (3.69 mmol) (S)-N-{1-[4-(1-cyano-piperidin-4-yl)-phenyl]ethyl}-acetamide (XXVII.1) and 0.63 mL (3.69 mmol) DIPEA in 20 mL ethanol. The mixture is refluxed for 4 h, an additional amount of 50 mg hydroxylamine hydrochloride is added and refluxing is continued for 2 h. The solvent is removed in vacuo and water is added. The mixture is then purified by HPLC (RP C18 Xbridge, water (+0.1% ammonia)/MeOH) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.C1(P(=[CH:33][C:34]#[N:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:33][C:34]#[N:35])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(C=CC#N)cc1

Procedure:
To a stirring solution of 30 in benzene (0.4 M) at room temperature under nitrogen was added (triphenylphosphoranylidene)acetonitrile (1.1 eq). The reaction was refluxed overnight. The benzene was removed under reduced pressure. The resulting oil was dissolved in ethyl acetate and washed with 1N hydrochloric acid (1×), saturated sodium bicarbonate (1×) and brine (1×) then dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (0-15% gradient methanol/dichloromethane). (98%) 1H NMR (400 MHz, CDCl3) δ 7.31-7.44 (m, 5H), 5.87 (d, 1H), 3.71 (s, 3H), 3.66 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[S:14][C:13]([C:15](OCC)=[O:16])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O>C1COCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:15]([C:13]2[S:14][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:16])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccnc(Cl)n1)c1ccc(Cl)s1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (1 eq, 46.7 mmol) and ethyl 5-chlorothiophene-2-carboxylate (1.1 eq, 51.3 mmol) in anhydrous THF (50 mL) at 0° C., under N2 was added dropwise a solution of lithium bis(trimethylsilyl)amide (1 molar solution in hexanes, 2 eq, 93.3 mmol). The mixture was stirred 2 h at 5° C. Water was then added followed by 300 mL of dichloromethane. The organic layer was separated and the yellow precipitate was then filtered and dried to afford 10.7 g (84% yield) of 2-(2-chloropyrimidin-4-yl)-1-(5-chloro-2-thienyl)ethanone.