Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[N:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncccn5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ncccn5)cc4)CC3)n2CCS1
Yield: 62.2 %

Procedure:
A solution of the compound (397 mg, 0.78 mmol) obtained in Example 36-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (191 mg, 62%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:12]([C@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:11][CH2:10][C@H:9]([C@@H:12]([C@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:22][S:40]([CH3:39])(=[O:42])=[O:41])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:42])=[O:41]
Reactant: OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](O)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OS(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2,3,5-Tri-O-benzyl-L-xylitol (10.2 g, 24.17 nmmol) is dissolved in dry methylene chloride (100 ml) containing triethylamine (10.1 mL, 72.5 mmol). The mixture is cooled to -10° C. and methane sulfonylchloride (3.93 mL, 50.75 mmol) is added dropwise. The mixture is stirred 30 minutes at -10° C. and washed with water. The organic layer is dried over sodium sulfate, filtered and put to dryness under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 4:6 mixture of ethyl acetate and cyclohexane yield 1,4-di-O-methanesulfonyl-2,3,5-tri-O-benzyl-L-xylitol as an oil (13.9 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:27]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 69 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (443 mg, 69%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[N:17]=[C:16]2[C:11]([C:12](=[CH:18]I)[CH2:13][CH2:14][NH:15]2)=[CH:10][CH:9]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1B(O)O.C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1.C(O)C.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>[Br:7][C:8]1[N:17]=[C:16]2[C:11]([C:12](=[CH:18][C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[F:27])[CH2:13][CH2:14][NH:15]2)=[CH:10][CH:9]=1
Reactant: Brc1ccc2c(n1)NCCC2=CI
Reactant: OB(O)c1cc(F)ccc1F
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: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc(F)c(C=C2CCNc3nc(Br)ccc32)c1
Yield: 70 %

Procedure:
Na2CO3 (2N, 3.46 mL, 10.0 eq) was added to a mixture of 7-bromo-4-[1-iodomethylidene]-1,2,3,4-tetrahydro-[1,8]naphthyridine (607 mg), 2,5-difluorophenylboronic acid (328 mg, 1.2 eq), and Pd(PPh3)4 (150 mg, 0.075 eq) in toluene/ethanol (4:1 v/v). The reaction was heated at 85° C. for five (5) hours, Celite was added, and the mixture was then concentrated under reduced pressure. The dry powder was then dry loaded onto a silica gel column and a gradient of 0-20% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (70% yield). M.p. 178-179° C., LCMS: m/z=337 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.62 (t, J=5.8 Hz, 2H), 3.55-3.62 (m, 2H), 5.25 (bs, 1H), 6.26 (s, 1H), 6.45 (d, J=7.9 Hz, 1H), 6.85-6.95 (m, 1H), 6.96-7.12 (m, 3H).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH:23]([CH2:25][CH3:26])[CH3:24]>C(Cl)Cl>[CH3:21][N:22]([CH:23]([CH3:24])[CH2:25][CH3:26])[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=1)=[O:19]
Reactant: CCC(C)NC
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)nc2ccccc12

Procedure:
The procedure of Example 42 is followed using 2-phenylquinoline-4-carboxylic acid chloride hydrochloride (10.7 g) and N-methylbut-2-ylamine (10.5 g) in methylene chloride (75 ml) as the starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][CH2:15][CH3:16])[CH:7](C#N)[C:6](=[O:10])N[C:4](=[O:11])[CH:3]1C#N.[OH2:17]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH2:14][CH2:15][CH3:16])[CH2:3][C:4](=[O:11])[O:17][C:6](=[O:10])[CH2:7]1
Reactant: O
Reactant: CCCC1(C)C(C#N)C(=O)NC(=O)C1C#N
Agent: O=S(=O)(O)O
Product: CCCC1(C)CC(=O)OC(=O)C1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
Following the procedure of Vogel, A. I.; J. Chem. Soc., 1934; 1758–1765: 4-Methyl-2,6-dioxo-4-propyl-piperidine-3,5-dicarbonitrile was dissolved in 50 mL of sulfuric acid and stirred for 16 hrs. Water (50 mL) was added and the solution was refluxed for 18 hrs. Upon cooling, the crystals were collected. The crystals were suspended in 10 mL of acetic anhydride. The suspension was heated to 130° C. and stirred for 16 hrs. The solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The ether fraction was treated with anhydrous magnesium sulfate and concentrated under reduced pressure to give the productMS (ESI+) for C9H14O3 m/z 171.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O-:14])=O)=[CH:10][N:11]=2)[CH:8]=1)#[N:2].[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:28][C:29]1[C:37]2[C:36]([NH2:38])=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[N:30]=1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([NH:38][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:37]=3[C:29]([CH3:28])=[N:30][N:31]4[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=3)=[O:14])=[CH:10][N:11]=2)[CH:8]=1)#[N:2]
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: N#Cc1ccc2ncc(C(=O)[O-])n2c1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5ccc(C#N)cn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
Lithium 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (138 mg, 0.7 mmol) was dissolved in anhydrous NMP (3.6 mL) and 2,4,6-trichlorobenzoyl chloride (115 mL, 0.7 mmol) added drop-wise. The mixture was stirred at ambient temperature for 30 minutes. 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (186 mg, 0.7 mmol) was then added in one portion and the reaction heated to 80° C. in a sand bath for 6 hours. Saturated sodium bicarbonate was added until precipitate formed and allowed to stir at ambient temperature for an hour. The precipitate was filtered off and dried under high vacuum for 2 hours to give 6-cyano-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a beige solid (140 mg). MS m/z 422.3 (M+1, APCI+).
Reaction SMILES: NC1C(C(N)=[O:9])=C(N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1.[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[N:50]([CH2:64][CH2:65][N:66]4[CH2:69][CH2:68][CH2:67]4)[CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][CH:57]=[C:56]([S:60]([CH3:63])(=[O:62])=[O:61])[CH:55]=4)[N:53]=3)[CH2:45][CH2:44]2)[N:38]=[CH:37][N:36]=1>>[NH2:34][C:35]1[C:40]([C:41]([NH2:42])=[O:9])=[C:39]([N:43]2[CH2:44][CH2:45][CH:46]([C:49]3[N:50]([CH2:64][CH2:65][N:66]4[CH2:67][CH2:68][CH2:69]4)[CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][CH:57]=[C:56]([S:60]([CH3:63])(=[O:61])=[O:62])[CH:55]=4)[N:53]=3)[CH2:47][CH2:48]2)[N:38]=[CH:37][N:36]=1
Reactant: CS(=O)(=O)c1cccc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)c1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CS(=O)(=O)c1cccc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)c1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-methanesulfonyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=525, obsd.=525).
Reaction SMILES: Cl.[NH2:2][C@:3]1([C:13]([O:15][CH3:16])=[O:14])[CH2:5][C@@H:4]1[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[H][H]>[Pd].CO>[NH2:2][C@:3]1([C:13]([O:15][CH3:16])=[O:14])[CH2:5][C@@H:4]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@]1(N)C[C@@H]1c1ccc(Br)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@]1(N)C[C@@H]1c1ccccc1
Yield: 24 %

Procedure:
A mixture of (1R,2R)-methyl 1-amino-2-(4-bromophenyl)cyclopropanecarboxylate hydrochloride (120 mg) and palladium on carbon (10%) (47.3 mg) in methanol (20 mL) was stirred at 5 bar of hydrogen for 48 h. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was purified by preparative HPLC on a Phenomenex Gemini column using a 95-5% gradient of aqueous 0.1% ammonia in acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford (1R,2R)-methyl 1-amino-2-phenylcyclopropanecarboxylate (18 mg) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]I)[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1.[P:30]([O:37]CC)([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>>[CH2:32]([O:31][P:30]([CH2:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[C:15]([CH3:27])[N:14]=[C:13]3[N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:29])[CH:10]=[C:11]([CH3:28])[C:12]=23)[CH2:19][CH2:20]1)(=[O:37])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: Cc1cc(N2CCC(CCI)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCC1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1)OCC
Temperature: 160 °C

Procedure:
Under N2 atmosphere, a mixture of 1-(4-bromo-2,6-dimethyl-phenyl)-4-[4-(2-iodo-ethyl)-piperidin-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.25 g) and triethyl phosphite (10 mL) was heated at 160° C. for 4.5 hours. After the reaction was completed, excess triethyl phosphate was removed under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=1/1) to obtain a colorless oil. The oily product was crystallized from diisopropylether (10 mL) to provide (2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethyl)-phosphonic acid diethyl ester (0.16 g) as a white crystal.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([C:36]([F:39])([F:38])[F:37])([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:41]([O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[CH:48][C:49](Br)=[N:50][CH:51]=1)[CH3:42].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:41]([O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:51]=[N:50][C:49]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:4][CH3:5])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:35])([C:36]([F:37])([F:39])[F:38])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:1][CH3:2])=[CH:7][C:8]=2[CH3:21])=[CH:48][CH:47]=1)[CH3:42]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCOC(=O)Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 80.6 %

Procedure:
Degassed N,N-dimethylformamide (0.15 mL) was added to (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 14.0 mg, 0.0245 mmol), (2-bromo-pyridin-5-yl)acetic acid ethyl ester (Example 74-(1); 10.5 mg, 0.043 mmol), tetrakis(triphenylphosphine)palladium (0) (3.5 mg, 0.0030 mmol) and potassium phosphate (13.4 mg, 0.0631 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 85 to 95° C. for 10 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (12 mg, 80%).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:8]([OH:24])=[C:9]([C:21](=[O:23])[CH3:22])[CH:10]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]([C:9]1[C:8]2[O:24][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:23])[CH3:22]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
21.0 mL (258 mmol) chloroacetyl chloride are added dropwise to 60.0 g (233 mmol) 1-(3-amino-5-benzyloxy-2-hydroxyphenyl)-ethanone and 70.0 g (506 mmol) potassium carbonate while being cooled with the ice bath. Then the mixture is stirred overnight at ambient temperature and then for 6 hours at reflux temperature. The hot reaction mixture is filtered, then evaporated down to approx. 400 mL and combined with ice water. The precipitate obtained is suction filtered, dried and purified by chromatography on a short silica gel column (dichloromethane:methanol=99:1). The fractions containing the product are evaporated down, suspended in isopropanol/diisopropylether, suction filtered and washed with diisopropylether. Yield: 34.6 g (50%); mass spectroscopy [M+H]+=298.
Reaction SMILES: [NH2:1][C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:1][C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Product: C[C@H](Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1)NCc1ccccc1

Procedure:
Using a method similar to example 2, using (R)-6-[4-(2-amino-propyl)-phenoxy]-nicotinamide and benzyl bromide gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.46 minutes, Purity: 97.9%; mass spectrum (ion spray): m/z=362.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[N:13][CH:14]=1>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])[CH2:10]1
Reactant: Cc1cccc(-c2cncc(NC(=O)c3ccccc3)c2)c1C
Solvent: CCO
Product: Cc1cccc(C2CNCC(NC(=O)c3ccccc3)C2)c1C

Procedure:
A solution of 550 mg (1.82 mmol) of N-[5-(2,3-dimethylphenyl)pyridin-3-yl]benzamide in 150 ml of ethanol was reacted according to General Method 5A. The solution was concentrated under reduced pressure. The product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 760 mg (77% of theory, purity 57%)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.[N:26]1[C:27]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)=[CH:28][N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12>CN(C)C=O>[N:26]1[C:27]([C:35]2[CH:36]=[C:37]([NH:41][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:38]=[CH:39][CH:40]=2)=[CH:28][N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc12
Temperature: 25 °C

Procedure:
Diisopropylethylamine (DIEA, 0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.05 g, 0.23 mmol) and O-(7-Azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU, 0.096 g, 0.25 mmol) in 2 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (0.048 g, 0.023 mmol) was added and allowed to react for approximately 30 minutes, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 1541: 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.92 (s, 1H), 8.54 (d, J=7.0 Hz, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.73 (m, 2H), 7.60 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.44 (m, 3H), 7.26 (dd, J=5.5, 6.8 Hz, 1H), 6.90 (dd, J=5.5, 6.8 Hz, 1H), 3.96 (s, 3H); LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[H-].[Na+].Cl.[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47]Cl>>[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47][O:14][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=5)[N:29]([CH3:39])[C:28]4=[O:40])[CH2:23][CH2:22]3)=[N:8][C:9]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:10]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCCN(C)C
Yield: 31 %

Procedure:
The same procedure as in Example 48 was repeated, using 360 mg (0.66 mmol) of Compound 47 obtained in Example 47 and 2 equivalents of sodium hydride (60% in oil), except that 2-dimethylaminoethyl chloride hydrochloride was used in place of methyl iodide and reaction temperature was 60° C. in place of room temperature, to give 127 mg (yield: 31%) of Compound 53 as white crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][CH2:22][CH2:23]CN2CCCC2=O)=[O:20])=[C:13]([Cl:31])[C:12]=1[Cl:32])([CH3:3])[CH3:2].[OH:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:39]1CCN[CH2:41][CH2:40]1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:22][CH2:23][N:39]([CH2:38][CH2:37][O:36][CH2:35][CH2:34][OH:33])[CH2:40][CH2:41]2)=[O:20])=[C:13]([Cl:31])[C:12]=1[Cl:32])([CH3:2])[CH3:3]
Reactant: OCCOCCN1CCNCC1
Reactant: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)NCCCN2CCCC2=O)c(Cl)c1Cl
Product: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)N2CCN(CCOCCO)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared from the cinnamide acid of Example 331, using the procedures described in Example 340 and substituting methyl isonipecotate with N-[2-(2-hydroxyethoxy)ethyl]piperazine. 1H NMR (300 MHz, DMSO-d6) δ 1.18 (d, 6H), 3.0 (m, 3H), 3.30 (m, 2H), 3.50 (m, 10H), 3.80 (m, 2H), 4.50 (t, 1H), 6.45 (d, 1H), 7.30 (d, 1H), 7.35 (dd, 1H), 7.55 (d, 1H), 7.60 (m, 2H), 7.75 (d, 1H), 7.80 (d, 1H). MS (ESI+) m/z 523 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH3:14][N:15]([CH3:35])[C:16]([C@@H:18]1[C@H:23]([NH:24][C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH2:32])[C:26]=2[NH2:33])[C@@H:22]2[CH2:34][C@H:19]1[CH:20]=[CH:21]2)=[O:17].C([O-])(=O)C.[NH4+]>>[CH3:14][N:15]([CH3:35])[C:16]([C@@H:18]1[C@H:23]([NH:24][C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]3[NH:32][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:13][CH2:12][CH2:11][CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:33][C:26]=23)[C@@H:22]2[CH2:34][C@H:19]1[CH:20]=[CH:21]2)=[O:17]
Reactant: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1sc(N2CCCC2)nc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 5 %

Procedure:
In a similar fashion to Compound LXXXVII 4-Chloro-2-pyrrolidin-1-yl-thiazole-5-carbaldehyde (69.84 mg, 0.3223 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid dimethylamide (93.35 mg, 0.2901 mmol and Ammonium acetate (44.72 mg, 0.5802 mmol) were reacted to produce 7.35 mg (5%) of the title compound. (300 MHz, DMSO-d6) 13.50 (s, 1H), 7.94 (s, 1H), 6.67 (s, 1H), 6.38 (m, 2H), 5.12 (t, J=17 Hz, 8.5 Hz, 1H), 3.44 (m, 4H), 3.02 (d, J=9 Hz, 1H), 2.94 (s, 3H), 2.86 (m, 4H), 2.82 (s, 1H), 2.11 (d, J=8 Hz, 1H), 2.01 (m, 4H), 1.42 (d, J=8 Hz, 1H). MS=517 (M+H), HPLC: 2.96 min. (G Method)