Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:37][CH:38]=[CH2:39])=[C:5]([CH:30]=[CH:31][C:32]=1[C:33]([NH:35][CH3:36])=[O:34])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:26]=[CH:25][C:14]2[CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[O:18][C:13]=2[C:12]=1[CH2:27][CH2:28][CH3:29].[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH2:37][CH:38]=[CH2:39])=[C:5]([CH:30]=[CH:31][C:32]=1[C:33]([NH:35][CH3:36])=[O:34])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:26]=[CH:25][C:14]2[CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[O:18][C:13]=2[C:12]=1[CH2:27][CH2:28][CH3:29]
Reactant: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)OC)CC3)ccc(C(=O)NC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)O)CC3)ccc(C(=O)NC)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound of Example 8 (250 mg, 0.4629 mmol) was dissolved in 2.0 ml of methanol and 694 μm of 1M lithium hydroxide was added. The reaction mixture was stirred at room temperature for about two days. The solvent was removed under vacuum and 20 ml of water was added. The aqueous residue was acidified with 10% hydrochloric acid. Filtration of the resultant suspension yielded the product as white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[C:22]([C:32]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([F:43])=[CH:40][CH:41]=3)[CH2:36][CH2:35]2)=[O:33])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:43][C:39]1[CH:38]=[C:37]2[C:42](=[CH:41][CH:40]=1)[N:34]([C:32]([C:22]1[CH:23]=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=1)=[O:33])[CH2:35][CH2:36]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CN(c1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1)S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1cc(C(=O)N2CCc3cc(F)ccc32)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1)S(C)(=O)=O

Procedure:
0.25 g (0.89 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride, 0.34 g (0.89 mmol) N-[6-chloro-4-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyridin-2-yl]-N-methyl-methanesulphonamide and 0.37 g (2.7 mmol) potassium carbonate were stirred in 3 mL of NMP for 4 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and acetonitrile was eliminated by rotary evaporation. The precipitated substance was suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][C:3]=1Cl.NC1C=CC(O)=CC=1[Cl:27]>>[NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([Cl:27])[CH:3]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1
Product: NC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-amino-3-chlorophenoxy)pyridine-2-carboxamide, substituting 4-amino-2-chlorophenol for 4-amino-3-chlorophenol. 1H-NMR (DMSO-d6) 88.46 (d, J=5.7 Hz, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.08 (dd, J=2.7, 5.7 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.74 (d, J=2.7 Hz, 1H), 6.59 (dd, J=2.7, 8.7 Hz, 1H), 5.50 (s, 2H); MS LC-MS (MH)+=264.1, RT=1.76 min.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.Cl>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]

Procedure:
7.5 G. of 4-acetylamino-3-nitrobenzenesulfonamide is dissolved in 60 ml. of 6N hydrochloric acid and refluxed for 2 hours. The reaction mixture is cooled, filtered, and the solid material washed with water and dried. The dried 4-amino-3-nitrobenzenesulfonamide has a m.p. of 280°-210° C. and is of sufficient purity for use in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[NH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1F

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyano-2-fluorobenzyl bromide (Fluorochem) and tert-butyl glycinate. It was isolated as a yellow oil (1.8 g, 74%). 1H NMR (DMSO-d6, 300 MHz) δ 7.82-7.77 (m, 1H), 7.71-7.63 (m, 2H), 3.82 (s, 2H), 3.22 (s, 2H), 2.58 (br s, 1H), 1.40 (s, 9H). LC/MS (Method B): 265.0 (M+H)+. HPLC (Method A) Rt 2.23 min (Purity: 98.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:31]4[CH2:36][CH2:35][S:34][CH2:33][CH2:32]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: C1CSCCN1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCSCC1

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and thiomorpholine was converted to 48.1 mg of the title compound (free base), mass spectrum (electrospray, m/e): M+H 512.0 and 33.2 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 512.0.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([NH2:24])=[O:23])=[CH:17][CH:16]=4)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[K+].I[CH:30]([CH3:32])[CH3:31]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([C:13]3[N:14]([CH:30]([CH3:32])[CH3:31])[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([NH2:24])=[O:23])=[CH:17][CH:16]=4)[CH2:11][CH2:12]2)=[CH:25][CH:26]=1
Reactant: CC(C)I
Reactant: NC(=O)c1ccc2[nH]c(N3CCN(Cc4ccc(Cl)cc4)CC3)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)n1c(N2CCN(Cc3ccc(Cl)cc3)CC2)cc2cc(C(N)=O)ccc21
Reaction time: 20 h
Yield: 55.3 %

Procedure:
4-(4-Chlorobenzyl)piperazinyl-indole-5-carboxamide (420 mg, 1.32 mMol) was taken in acetone. Solid KOH (280 mg, 5 mMol) was added followed by the addition of 2-iodopropane (1 g, 6 mMol) and the mixture was refluxed with stirring for 20 h. Acetone was removed in vacuo and the residue was extracted from water using methylene chloride. The extract was dried and evaporated and the residue was chromatographed on a column of silica gel using ethylacetate-hexane (ethylacetate 0 to 25%, gradient) and recrystallized from ether-hexane to yield 300 mg of the product. 1HNMR (CDCl3): δ=7.6 (s, 1H); 7.3-7.1 (m, 6H); 6.5 (s, 1H); 4.65-4.55 (m, 1H); 3.8-3.5 (m, 4H); 3.4 (s, 2H); 2.4-2.5 (s, 4H); 1.5 (d, 6H). MS (ESI) m/e 395 (M+).
Reaction SMILES: [Li+].[Br-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[CH3:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH2:22][CH:23]3[CH2:25][O:24]3)[C:17]3[CH2:26][CH2:27][N:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][C:16]=3[C:15]=2[CH:14]=1>>[OH:24][CH:23]([CH2:25][NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=1)[CH2:22][N:18]1[C:19]2[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][C:15]=2[C:16]2[CH2:29][N:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][CH2:26][C:17]1=2
Reactant: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC2CO2)C1
Reactant: COc1cccc(N)c1
Agent: [Br-]
Agent: [Li+]
Product: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC(O)CNc2cccc(OC)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Following a literature procedure (Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem. 2004, 3597-3600) LiBr (0.001 g, 0.010 mmol) and m-anisidine (0.011 mL, 0.102 mmol) were added to ethyl 8-Methyl-5-(oxiran-2-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.032 g, 0.102 mmol) and stirred vigorously at ambient temperature overnight. Upon completion the reaction was partitioned between EtOAc/H2O, and the organic layer was concentrated to an orange oil. The crude residue was purified by chromatography (SiO2, 0-50% EtOAc/Hexane) to afford the desired product (30 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:16]([NH:15][CH2:13][CH3:14])=[O:17])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1
Reactant: Nc1ccc2ncc(Cl)nc2n1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
100 mg of 3-chloropyrido[2,3-b]pyrazin-6-ylamine (0.55 mmol) were initially charged in 5 ml of pyridine and 44 μl of ethyl isocyanate (0.55 mmol) were added at room temperature. The mixture was left to stir at 75° C. for 3 h and then another 132 μl in total of ethyl isocyanate (1.65 mmol) were added to the reaction mixture is small portions over 18 h. The solvent was then removed under reduced pressure. The resulting solid was purified by means of column chromatography on silica gel (dichloromethane/methanol eluent). This gave a bright yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:24]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCNC1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: OC1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)C1
Yield: 91 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (350 mg, 1.103 mmol), 3-pyrrolidinol (200 mg, 2.02 mmol), absolute ethanol (40 ml), activated 3 Å molecular sieves (350 mg), titanium (IV) isopropoxide (1.62 ml, 5.48 mmol) and STAB (2.0 g, 9.74 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to give the title compound as a white solid (390 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.87 (d, 2H), 4.10-4.01 (m, 3H), 3.81-3.68 (m, 3H), 3.55 (t, 2H), 2.67-2.48 (m, 9H), 2.28-1.61 (m, 15H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH:26]([Mg]Cl)([CH3:28])[CH3:27].[NH4+].[Cl-]>C1COCC1.CN1C(=O)CCC1>[F:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:8]([C:7]2[C:2]([CH:26]([CH3:28])[CH3:27])=[N:3][C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:5][C:6]=2[CH3:19])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NCc1cccc(F)c1
Temperature: -30 °C
Yield: 36.1 %

Procedure:
A solution of 300 mg (0.83 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF/NMP (6:1 v/v, 14 ml) was cooled to −30° C. At this temperature were successively added 58 mg (0.16 mmol) Fe(acac)3 and 6 ml (12.0 mmol, 2M in THF) iso-propyl-magnesium-chloride. The RM was then allowed to warm to 0° C. within 1 h. Then sat. aq. NH4Cl sol. was added the mixture was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 110 mg (0.30 mmol, 36%) N-[(3-Fluorophenyl)-methyl]-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 23). [M+H]+372.2.
Reaction SMILES: BrC1C=[C:4]2[CH:10]=[N:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=NC=1.[Br:18][C:19]1[CH:20]=C2NN=CC2=[N:23][CH:24]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(CC)CC>CN(C)C1C=CN=CC=1.C(#N)C>[Br:18][C:19]1[CH:20]=[C:5]2[N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[N:9]=[CH:10][C:4]2=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)cnc21
Reactant: Brc1cnc2cn[nH]c2c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1ncc2ncc(Br)cc21
Yield: 93 %

Procedure:
Analogous to the preparation of tert-butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate, 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.0 g, 10.10 mmol) was reacted with di-tert-butyl dicarbonate (2.8 g, 13.10 mmol), NEt3 (1.44 g, 2.0 mL, 14 mmol) and 4-(dimethylamino)pyridine in acetonitrile (20 mL) for 3 h. Work-up as discussed previously in the preparation of tert-butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate provided desired product of tert-butyl 6-bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate as a brown solid (2.8 g, 93%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:21][C:22]1[CH:33]=[CH:32][C:25]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[CH:24][CH:23]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=[N:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[CH:32][CH:33]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C=CCOC(=O)c1ccc(N)cc1
Product: C=CCOC(=O)c1ccc(N=Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 75.8 %

Procedure:
Starting with 3.4 g (12.6 mmoles) of 3-(1-adamantyl)-4-methoxybenzaldehyde and 2.6 g (14.4 mmoles) of allyl 4-aminobenzoate the synthesis is effected following the procedures described in Example 8. The resulting crude product is recrystallized in ethyl acetate. After filtration and drying, 4.1 g (76%) of the allylic ester whose melting point is 160°-162° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]=[N:20][OH:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C#Cc2cnccc2C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C#Cc2cnccc2C=NO)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3-(4-Methoxyphenylethynyl)-4-pyridinecarboxaldehyde (4.965 g) was dissolved in ethanol (70 ml), a solution of hydroxylamine hydrochloride (2.179 g) and sodium acetate (3.429 g) in water (18 ml) was added thereto, and then the mixture was stirred at 70° C. overnight. After cooling as it was, the reaction mixture was evaporated and partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow solid (4.724 g, yield; 96%).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6]([OH:9])=[N:5]1)(=O)C.[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:9][C:6]1[CH:7]=[CH:8][NH:4][N:5]=1)([O-:12])=[O:11]
Reactant: CC(=O)n1ccc(O)n1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccccc1COc1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A suspension of 1-acetyl-3-hydroxy-pyrazole (3.4 g, 27.0 mmol), 2-nitrobenzyl bromide (5.9 g, 27.3 mmol) and K2CO3 (4.0 g, 28.9 mmol) in 75 mL of 2-butanone was heated to reflux for 90 min. After cooling to room temperature, the precipitated salts were filtered off and rinsed with tert-butyl methyl ether (TBME). The filtrate was then concentrated under reduced pressure (50 mbar) and redissolved in a mixture of tetrahydrofuran (THF) and methanol (MeOH) (3:2, 50 mL). 2 mL of a 10% NaOH solution were added and the solution was stirred 60 min at ambient temperature. Then, all volatiles were removed under reduced pressure (50 mL). The residue was diluted with 20 mL of H2O and 30 mL of ethyl acetate (EtOAc). The aqueous phase was extracted with EtOAc (2×20 mL). The combined org. layers were washed with water and brine (both 30 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles and recrystallised from dichloromethane (15 mL) to give the product as yellowish crystals (5.0 g, 22.8 mmol, 84%).
Reaction SMILES: [I:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].[CH2:17]([O:24][C:25]1[C:30]([CH2:31]Cl)=[C:29]([CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:24][C:25]1[C:30]([CH2:31][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([I:1])[C:3]([O:13][CH3:14])=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:29]([CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: COc1ccc2c(c1I)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1I)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.6 %

Procedure:
To a solution of 8-iodo-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (53b, 2.08 mg, 5.22 mmol) in anhydrous DMF (30 mL) was added NaH (420 mg, 10.4 mmol, 60% in oil) at 0° C. under N2 atmosphere for 30 minutes. 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 1.89 g, 7.83 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 14 hours. The mixture was quenched with H2O (60 mL) and extracted with EtOAc (4×80 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep.HPLC to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-iodo-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (53c, 2.5 g, 91%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:12][N:11]([CH2:23][CH2:24][O:25][CH3:26])[C:10]1=[O:27].C1C([N+]([O-])=O)=CC=C([Cl-][C:38]([O-])=[O:39])C=1.Cl.Cl.[O:43]=[C:44]1[NH:52][C:47]2=[N:48][CH:49]=[CH:50][CH:51]=[C:46]2[N:45]1[CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH:13]1[CH2:12][N:11]([CH2:23][CH2:24][O:25][CH3:26])[C:10](=[O:27])[CH:9]([NH:8][C:38]([N:56]2[CH2:57][CH2:58][CH:53]([N:45]3[C:46]4[C:47](=[N:48][CH:49]=[CH:50][CH:51]=4)[NH:52][C:44]3=[O:43])[CH2:54][CH2:55]2)=[O:39])[CH2:14]1
Reactant: COCCN1CC(c2cccc(F)c2F)CC(N)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCN1CC(c2cccc(F)c2F)CC(NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
Triethylamine (83 μL, 0.598 mmol) was added to a solution of 3-amino-5-(2,3-difluorophenyl)-1-(2-methoxyethyl)piperidin-2-one (170 mg, 0.598 mmol) and 4-nitrophenylchloroformate (121 mg, 0.598 mmol) in tetrahydrofuran (4 mL) at 0° C. After 1 h, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (174 mg, 0.651 mmol), triethylamine (249 μL, 1.794 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (0.135 g). MS 529.2353 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.03 (dd, J=5.3, 1.1 Hz, 1H), 7.38 (dd, J=7.8, 1.2 Hz, 1H), 7.11-7.03 (m, 2H), 7.01-6.96 (m, 2H), 5.82 (d, J=3.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.34-4.30 (m, 1H), 4.23 (d, J=6.6 Hz, 2H), 3.71-3.62 (m, 3H), 3.60-3.53 (m, 3H), 3.52-3.46 (m, 1H), 3.33 (s, 3H), 2.96 (dd, J=23.4, 10.5 Hz, 2H), 2.80-2.78 (m, 1H), 2.28-2.21 (m, 2H), 1.90 (dd, J=10.5, 2.0 Hz, 2H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:17]=[C:16]([OH:23])[N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:31])C(=O)C1>C(O)(=O)C>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[C:17]([Cl:31])=[C:16]([OH:23])[N:15]=2)=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(O)cc(C3CC3)n2)s1
Solvent: CC(=O)O
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(O)c(Cl)c(C3CC3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of N-tert-butyl-5-(4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonamide (353 mg, 1.0 mmol) and NCS (139 mg, 1.05 mmol, 1.0 equiv.) in acetic acid (5 mL) was stirred at rt for 1 h. The reaction was extracted with EA, the organic layer was washed with (brine), dried (Na2SO4) and concentrated to provide N-tert-butyl-5-(5-chloro-4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonamide (341 mg, 88%). LC-MS (m/z)=388.1 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:27][CH2:28]2)[N:18]=1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Reactant: COc1ccnc(N2CCNCC2)n1
Product: COc1ccnc(N2CCN(Cc3ccc(C(C)NC(C)=O)cc3)CC2)n1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-methoxypyrimidin-2-yl)piperazine obtained in Example 98(2) instead of phenylpiperazine, the title compound was obtained as pale-yellow crystals, m.p.=113-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N+:24]([O-:27])=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][N+:24]([O-:27])=[CH:25][CH:26]=1)[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])(=[O:30])[CH3:29]
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2cc[n+]([O-])cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(S(=O)(=O)N(C(C)=O)c2ccccc2/C=C/c2cc[n+]([O-])cc2)cc1

Procedure:
Using 1.54 g of the compound obtained in Example 20, the reaction was conducted in the presence of acetic anhydride at 140° C. for 10 minutes and, then, after-treated. The crystal crop was recrystallized from ethanol to provide 0.62 g of the title compound (white granules). m.p. 235-237° C. (decomp.)