Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[C:11]2[CH:12]=[CH:13][O:14][C:10]=2[C:9]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[S:20][CH:21]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH2:16][O:15][C:9]3[C:10]4[O:14][CH:13]=[CH:12][C:11]=4[C:6]([CH2:5][CH:4]([O:29][CH2:30][CH3:31])[C:3]([OH:32])=[O:2])=[CH:7][CH:8]=3)[N:18]=2)=[CH:23][CH:24]=1
Reactant: CCOC(Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)c2occc12)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)c2occc12)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{7-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-benzofuran-4-yl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain [rac]-3-{7-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-benzofuran-4-yl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:17][CH:16]2[C:18]([O:20][CH3:21])=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Br:22][CH2:23][CH2:24][OH:25].B(F)(F)F.CCOCC>C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH:16]([NH:15][S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[CH2:17][O:25][CH2:24][CH2:23][Br:22]
Reactant: OCCBr
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CC2C(=O)OC)cc1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)NC(COCCBr)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
To a 0° solution of 1-({[4-(2-butynyloxy)phenyl]sulfonyl}-2-aziridinecarboxylic acid, methyl ester (0.55 g, 1.78 mmol) in 2-bromoethanol (1.26 mL,17.8 mmol) was dropwise added boron trifluoride etherate (0.18 mL). The mixture was stirred at 0° C. for 30 minutes and stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate. The organic layer was washed with 1N NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (7:3) to obtain 0.2 g of 3-(2-bromo-ethoxy)-2-(4-[2-butynyloxy]-benzenesulfonylamino)-propionic acid methyl ester. Yield: 26%. mp 45-46° C. Electrospray Mass Spec 434.1.436.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][O:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>CS(C)=O>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH2:33][O:32][CH3:31])[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: COCC1CCCN1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: CS(C)=O
Product: COCC1CCCN1c1cc(C(=O)Nc2ccc(C)c(-c3ccc(C(=O)NCC4CC4)cc3)c2)ccn1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) and 2-(methoxymethyl)pyrrolidine (1 ml) in DMSO (1 ml) was heated at 140° C. for 24 h in a sealed tube. The reaction was concentrated under vacuum, the residue chromatographed on an SPE (C18) eluting with a water/acetonitrile gradient, to give, after evaporation of the solvents under vacuum N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(2-methoxymethylpyrrolidin-1-yl)isonicotinamide (16 mg). NMR; δH [2H6]—DMSO 10.29,(1H, s), 8.62,(1H, t), 8.21,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.00,(1H, d), 6.89,(1H, s), 4.23,(1H, b), 3.52-3.47,(2H, m), 3.26,(5H, m), 3.16,(2H, t), 2.20,(3H, s), 2.07-1.90,(4H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.78 min, MH+499.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2]1.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][NH:13][CH2:2][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[OH:1]
Reactant: CCCCCCC1CO1
Reactant: NCCO
Product: CCCCCCC(O)CNCCO
Yield: 93 %

Procedure:
50 g (0.39 mmole) of 1,2-epoxy-octane are added dropwise to 250 cm3 (4 moles) of ethanolamine at 100° C. Heating is maintained for 1 h after the addition is complete, then the excess ethanolamine is distilled in a vacuum. The residue is recrystallised from 600 cm3 of hexane, after filtration and drying. The solid residue obtained weighs 69 g (melting point 45° C., yield=93% Rf=0.62 silica/butanol/H2O/acetic acid/50/25/11).
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[CH:13]=[C:8]2[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[O:25])=[N:6]1)(C)(C)C>FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>[F:21][C:19]1[CH:20]=[C:15]([S:14][C:12]2[CH:13]=[C:8]3[C:7]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)=[CH:29][CH:28]=4)=[O:25])=[N:6][NH:5][C:9]3=[N:10][CH:11]=2)[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: CN1CCN(c2ccc(NC(=O)Nc3nn(C(C)(C)C)c4ncc(Sc5cc(F)cc(F)c5)cc34)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(NC(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)cc2)CC1
Yield: 81.6 %

Procedure:
A solution of 0.150 g (0.272 mmol) of 1-(1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea dissolved in 20 ml of TFA (trifluoroacetic acid) is refluxed for 3 hours. The solvent is evaporated and the crude reaction product is diluted with saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried on MgSO4, filtered and concentrated. The solid obtained is triturated in methanol, filtered and dried. 110 mg (82%) of 1-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea in the form of a beige solid is obtained.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH:9]2[C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:3][CH:2]=1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32]>C1COCC1>[CH2:32]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:9]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:10][CH2:11][CH2:12][CH:13]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=[CH:2]1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cnc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1cnc(CCN2C(c3ncccc3C)CCCC2c2ncccc2C)c1
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
To a solution of 1′-[2-(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (202 mg, 0.56 mmol) in THF (5 mL) at 0° C. was added NaH (60%, 8 mg, 0.21 mmol). After 30 min at 0° C., allyl bromide (16 mL, 0.19 mmol) was added. After 4 h, the reaction mixture was concentrated to afford an orange solid. Purification by radial chromatography on silica gel (2 mm plate; using CH2Cl2/CH3OH/NH4OH; 50:1:1→10:1:1) afforded the product as a pale yellow oil (25 mg, 33%). 1H NMR (CDCl3) δ 1.58-1.73 (m, 3H), 1.95-2.08 (m, 3H), 2.38-2.48 (m, 8H), 2.93 (s, 2H), 4.14 (d, 2H, J=9.0 Hz), 4.27 (d, 2H, J=6.0 Hz), 5.02 (d, 1H, J=18.0 Hz), 5.16 (d, 1H, J=9.0 Hz), 5.71-5.84 (m, 1H), 5.96 (s, 1H), 7.06 (dd, 2H, J=6.0, 3.0 Hz), 7.12 (s, 1H), 7.40 (d, 2H, J=9.0 Hz), 8.46 (s, 2H). 13C NMR (CDCl3) δ 19.21, 23.68, 25.45, 30.08, 31.94, 49.56, 62.43, 114.86, 118.69, 122.07, 131.27, 133.15, 136.13, 138.79, 141.84, 147.25, 160.74. ES-MS m/z 402 [M+H]+. Anal. Calcd. for C25H31N5.1.5H2O: C, 70.06; H, 8.00; N, 16.34. Found: C, 70.19; H, 7.98; N, 16.05.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([Cl:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][CH2:29][NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[N:32]=2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(C(=O)NCCn3ccc(-c4ccc(C#N)c(Cl)c4)n3)no2)cn1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (49 mg, 0.20 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off. PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 16 mg of the title compound. 1H-NMR (400 MHz; d6-DMSO): 3.70 δ (m, 2H), 3.91 (s, 3H), 4.38 (m, 2H), 6.89 (m, 1H), 6.97 (d, 1H), 7.85 (m, 1H), 7.94-8.00 (m, 3H), 8.10 (d, 1H), 8.36 (s, 1H), 8.86-9.13 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[CH:7]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-c2cncc(Br)c2)c1
Temperature: 70 °C
Yield: 26.5 %

Procedure:
A mixture of 3,5-dibromopyridine (1.2 g, 5 mmol), 3-trifluoromethylphenyl boronic acid (0.95 g, 5 mmol), tetrakis(triphenylphosphine)palladium (0) (0.23 g, 0.2 mmol), and sodium carbonate (1.1 g, 10 mmol) in EtOH (10 mL) and water (1 mL) were heated in an oil bath at 70° C. for 3 days. The mixture was cooled to RT and diluted with EtOAc (20 mL) and water (10 mL). The layers were partitioned and the organic layer was dried (Na2SO4), filtered and concentrated. Purification by chromatography (eluting with 10:1 hexanes/EtOAc) resulted in 0.4 g (26%) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 8.76 (d, 1H, J=2.1 Hz), 8.71 (d, 1H, J=2.1 Hz), 8.06 (dd, 1H, J=2.1, 2.1 Hz), 7.80 (s, 1H), 7.74-7.61 (m, 3H); APCI MS m/z 304.0, 302.0 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:24]>C(O)C>[ClH:24].[CH:16](=[C:11]1[C:12](=[O:15])[C:13](=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][N:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CN(CCc2ccccc2)CC1=Cc1ccccc1
Reaction time: 16 h

Procedure:
Twenty-five grams of 1-(2-phenylethyl)-4-piperidone and 38 g of benzaldehyde are reacted in 180 ml of ethanol in the presence of 40 ml of concentrated hydrochloric acid at reflux temperature for about 5 hours and left at room temperature for about 16 hours yielding 25.5 g of material, melting point 217°-220° C, dec. Crystallization from 50 ml of hot dimethylformamide and 100 ml of acetonitrile yields 22 g of the title compound, melting point 225°-227° C, dec.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[NH2:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1>C(=O)=O.CC(C)=O>[NH2:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:1])=[O:17])=[CH:10][CH:9]=1
Reactant: CO
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: O=C=O
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccc(N)nc1

Procedure:
To methanol (5 ml) in dry ice-acetone bath was added thionyl chloride (0.41 ml) dropwise over 5 minutes. After (E)-3-(6-Aminopyridin-3-yl)acrylic acid (700 mg) was added to the mixture, the reaction mixture was heated at reflux for 1 hour, and the solvent was removed under reduced pressure. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The precipitate was collected by vacuum filtration and washed with isopropyl ether to give methyl (E)-3-(6-aminopyridin-3-yl)acrylate (725 mg) as a solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.C([O-])(=O)C.[K+].C([BH3-])#N.[Na+]>CO>[O:17]=[C:9]1[N:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:7][CH2:6]2)[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH:10]1
Reactant: O=C1N[C@@H]2CCCC[C@@H]2N1C1CCNCC1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of cis-(+/−)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one hydrochloride salt (150 mg, 0.58 mmol) in 5 mL MeOH was added ethyl 4-oxopiperidine-1-carboxylate (119 mg, 0.69 mmol) and potassium acetate (1 eq). The mixture was stirred at room temperature for 30 min and sodium cyanoborohydride (182 mg, 2.90 mmol) was added. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in 20 mL DICHLOROMETHANE, and was washed with water. Organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by High pH prep-LCMS to afford the desired racemic mixture as white solid (102 mg, 46%). MS (M+1): 379.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:19]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:9]=3[C:8]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:7][C:6]=2[CH:19]=1
Reactant: COc1ccc2c(c1)C(=O)Nc1cc(Cl)ccc1N2
Reactant: C1CNCCN1
Product: COc1ccc2c(c1)C(N1CCNCC1)=Nc1cc(Cl)ccc1N2
Yield: 55.4 %

Procedure:
8-Chloro-2-methoxy-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (28 mg, 0.1 mmol) and piperazine (86 mg, 1.0 mmol) were reacted according to GP4 to give 19 mg of the title compound (160FE20A). MS (ESI) 342 (MH+). Purity for MH+ (UV/MS) 99/100.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.CN1C(N)=CC(C2C=CC=CC=2)=N1.[F:38][C:39]([F:49])([F:48])C1C=C(C#C)C=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:39]([F:49])([F:48])[F:38])[CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Agent: Cn1nc(-c2ccccc2)cc1N
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(-c3cccc(C(F)(F)F)c3)nnc21

Procedure:
Compound 29 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 1-methyl-3-phenyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine and 3-(trifluoromethyl)-phenylacetylene instead of phenyl acetylene in Step 4.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:27])[C@H:22]([CH:24]([CH3:26])[CH3:25])[NH2:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:27])[C@@H:22]([NH:23][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH:24]([CH3:26])[CH3:25])[CH3:19]
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(=O)CC2)cc1)C(C)C

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and L-valine ethyl ester hydrochloride according to the procedure of Example 154 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H), 2.10-2.30 (m, 1H), 2.43 (t, J=6.0 Hz, 4H), 3.72 (t, J=6.0 Hz, 4H), 4.00-4.30 (m, 4H), 4.46 (t, J=5.1 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 8.21 (d, J=7.9 Hz, 1H); MS (ES) m/z: 347.3 (MH+); HRMS Calcd. for C19H26N2O4 (M+): 346.1892. Found: 346.1896.
Reaction SMILES: [CH3:1][C:2]([NH:27]C(=O)OCC1C=CC=CC=1)([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1>CO>[CH3:26][C:2]([NH2:27])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)NC(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 66 using benzyl (2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-yl)carbamate (CB67) and methanol as solvent; isolated as a yellow gum (0.775 g, 92%): 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.13 (d, J=8.2 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.39 (dd, J=9.1, 1.0 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 2.74 (s, 2H), 2.05 (s, 2H), 1.16 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 377 ([M+H]+).
Reaction SMILES: O[C:2](=[C:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]1=O)[CH2:3][CH2:4]CC.S(=O)(=O)(O)O.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH2:7]([C:8]1[O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:26]=1[C:25]([OH:28])=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCC(O)=C1C(=O)Oc2ccc([N+](=O)[O-])cc21
Agent: O=S(=O)(O)O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)O

Procedure:
263 g of 3-(1-hydroxypentylidene)-5-nitro-3H-benzofuran-2-one, 480 g of acetic acid and 190 g of 90% concentrated sulphuric acid are charged to a three-necked round-bottomed flask.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1>CCN(C(C)C)C(C)C>[OH:15][CH:12]1[CH2:13][CH2:14][N:9]([C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=2)[CH2:10][CH2:11]1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc(N2CCC(O)CC2)n[nH]1
Temperature: 120 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 6-chloropyridazin-3(2H)-one (2.6 g, 20 mmol) in DIPEA (30 mL) was added piperidin-4-ol (2.4 g, 20 mmol) and the mixture was stirred at 120° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was further purified by silica gel chromatography (DCM/MeOH=20/1) to afford the title compound (3.9 g, 100%) as a yellow solid. [LCMS: Rt=0.77 min, m/z 196.2 (M+H)+].
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH2:5][CH3:6].Cl.Cl[CH2:16][C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[CH3:3][CH:4]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:16][C:17]2[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:12]=1)[CH2:5][CH3:6]
Reactant: Nc1ncccc1CCl
Reactant: CCC(C)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(OCc2cccnc2N)cc1
Reaction time: 0.33 h
Yield: 35.2 %

Procedure:
The solution of (2-aminopyridin-3-yl)methanol (1.0 g) in THF (dry) (10 mL) was added dropwise to a solution of thionyl chloride (0.736 mL) in THF (dry) (30 mL) at 0° C. The mixture was stirred at room temperature for 30 min and concentrated in vacuo to give 3-(chloromethyl)pyridin-2-amine hydrochloride as a yellow gum. NaH (60%, 147 mg) was added to a mixture of 4-(1-methylpropyl)phenol (503 mg) in DMF (dry) (7 mL) at 0° C. The mixture was stirred at the same temperature for 20 min, then was added with the prepared 3-(chloromethyl)pyridin-2-amine hydrochloride (300 mg) at the same temperature. The mixture was stirred at 0° C. for 20 min, room temperature for 1 hr and 60° C. for 1 hr. Silica-gel was added to the mixture and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (151 mg) as pale yellow crystals.
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[C:6]([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]([N+:20]([O-])=O)=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:20][C:13]1[CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[N:11]([C:6]2[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][N:7]=2)[N:12]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1-c1ncccc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(N)nn1-c1ncccc1Cl
Yield: 77.1 %

Procedure:
10.41 g (54.9 mmol) of tin(II) chloride were initially charged in 80 ml of ethanol, 3.20 g (11.3 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-nitro-1H-pyrazole-5-carboxylate were added and the mixture was stirred at reflux temperature for 3 hours. After cooling, the reaction mixture was poured onto ice and adjusted to pH 12 with sodium bicarbonate. The aqueous phase was extracted repeatedly with ethyl acetate and dried over magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, which gave 2.20 g (71% of theory) of methyl 3-amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate (log P: 1.09; MH+: 253.1); 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.66 (s, 3H), 5.20 (s, 2H), 6.25 (s, 1H), 7.56 (m, 1H), 8.15 (d, 1H), 8.47 (m, 1H).)
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:18][CH3:19])[C:13]([O:16][CH3:17])=[C:14]([Cl:15])[C:8]=2[CH:7]=1)=[O:5])C.O.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Cl:15][C:14]1[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=2[CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:16][CH3:17]
Reactant: CCOC(=O)c1cc2c(Cl)c(OC)c(OC)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc2sc(C(=O)O)cc2c(Cl)c1OC
Yield: 100.2 %

Procedure:
4-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (29.5 g) was suspended in a mixture of methanol (450 ml), water (75 ml) and potassium carbonate (20.4 g) under an atmosphere of nitrogen. The reaction mixture was heated at reflux for 1 hour then cooled and poured into water (2.5 liter) containing hydrochloric acid (5M, 60 ml). The resultant white solid was filtered and dried at 65° C. under vacuum to give 4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (26.8 g). A portion crystallised from dichloromethane:methanol had, m.p. 267°-270° C.