Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: O=C(Cl)OCCCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)OCCCCCl)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 82 μl (2 molar equivalents) of 4-chlorobutyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 119 mg of the desired product (formula shown hereinabove) were isolated as an orange powder (yield=85%) which was characterized as follows:
Reaction SMILES: [OH:1][C:2]1([CH2:17][CH:18]=O)[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20](=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:21].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:23]([O:22][C:20]([NH:21][CH2:18][CH2:17][C:2]1([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=CCC1(O)CCCC1C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCC1(O)CCCC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
To a solution of benzyl 2-hydroxy-2-(2-oxoethyl)cyclopentanecarboxylate (from step C, 120 mg, 0.457 mmol) in acetonitrile (2 mL) was added tert-butyl carbamate (214 mg, 1.830 mmol), triethylsilane (213 mg, 1.830 mmol) and trifluoroacetic acid (0.070 mL, 0.915 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and subjected to preparative HPLC(Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM). The desired fractions were concentrated and freeze dried to yield benzyl 2-(2-(tert-butoxycarbonylamino)ethyl)-2-hydroxycyclopentanecarboxylate (70 mg, 0.193 mmol, 42.1% yield) as a solid. MS (ESI+)=386 (M+Na)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][NH:11]2)[CH:9]=1)[C:5]#[N:6].I[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([N:28]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:27])=[C:19]2[CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OC(C)=O)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O.O1CCOCC1>[C:5]([C:4]1[CH:7]=[C:8]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][N:11]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([N:28]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[CH2:29][C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[O:27])=[C:19]3[CH:18]=2)[CH:9]=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(I)cc23)cc1
Reactant: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)OC(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](F)C[C@@H]4c4cc(F)cc(C#N)c4)cc23)cc1
Temperature: 98 °C
Reaction time: 3 h

Procedure:
A 3 L flask was charged with 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15) (50 g, 240 mmol), 5-iodo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-43) (158 g, 290 mmol), Cs2CO3 (133 g, 408 mmol) and 1,4-dioxane (1125 mL). The reaction was heated to 98° C. and maintained for 30 minutes. Pd(OAc)2 (3.5 g, 15.6 mmol) and Xantphos (9.5 g, 16.4 mmol) were added and the reaction was heated to 102° C., and maintained for 3 hours. After 3 hours, additional 5-iodo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (1-43) (7 g, 13.3 mmol) was added and maintained at 102° C. for 1 hour. HPLC analysis (UV=215 nm) was used to monitor the reaction. The mixture was cooled to 20° C. and water (500 mL) and EtOAc (2 L) were added. The above procedure was repeated on the same scale and the two runs were combined. The suspension was filtered through 200 g of silica gel and concentrated to dryness under vacuum to give a dark brown sticky solid. The solids were dissolved in i-PrOAc (3 L) with heat and washed with water (500 mL). The organic layer was concentrated to dryness to give a dark brown solid. The solids were purified by column chromatography on silica gel with 50% EtOAc in heptanes as eluant to yield 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53). Melting point: 90° C. (dec.). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=7.6 Hz, 1 H), 7.78 (s, 1 H), 7.38 (s, 1 H), 7.30-7.26 (m, 1 H), 7.25-7.23 (m, 1 H), 7.22-7.16 (m, 5 H), 6.92-6.87 (m, 4 H), 6.6 (dd, J=2.4, 7.6 Hz, 1 H), 5.40 (d, J=52.4 Hz, 1 H), 5.09 (dd, J=6.8, 9.2 Hz, 1 H), 4.74 (d, J=16.0 Hz, 2 H), 4.50 (d, J=15.6 Hz, 2 H), 4.22-3.94 (m, 2 H), 3.82 (s, 6 H), 2.96-2.84 (m, 1 H), 2.18-2.05 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[C:28]1([SH:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](=[O:23])[S:38][C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:25])([F:27])[F:26])[CH:3]=1
Reactant: Sc1cccc2ccccc12
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Sc3cccc4ccccc34)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with naphthalene-1-thiol (88.0 mg). This gives, after chromatographic purification, S-1-naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (100 mg, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[NH:15][CH2:14][CH2:13][N:12]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:11]2)[CH:6]=[CH:5][CH:4]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[NH4+].[Cl-].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]>[F:33][C:32]([F:34])([F:35])[C:31]([C:28]1[CH:27]=[CH:26][C:25]([N:15]2[CH2:14][CH2:13][N:12]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH2:11][CH:10]2[CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[CH:30][CH:29]=1)([OH:40])[C:36]([F:37])([F:39])[F:38]
Reactant: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2)n1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a 50-mL round-bottomed flask was added 3-((6-methoxy-2-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (115 mg, 0.325 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (126 mg, 0.390 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (RuPhos)(62 mg, 0.13 mmol, Strem, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, Strem, Newburyport, Mass.) and sodium tert-butoxide (94 mg, 0.98 mmol, Aldrich, St. Louis, Mo.) in toluene (5 mL). The reaction mixture was stirred at 100° C. for 18 h and then allowed to cool to room temperature and then diluted with saturated NH4Cl (5 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give 1,1,1,3,3,3-hexafluoro-2-(4-(2-((6-methoxy-2-pyridinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (146 mg) as a light-yellow tar (mixture of enantiomers).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=3[N:11]=2)=[N:2]1.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:28][NH:29][C:19]([C:17]2[CH:16]=[CH:15][C:13]3[NH:14][C:10]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][N:2]=4)=[N:11][C:12]=3[CH:18]=2)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Reactant: NCC1CCCCC1
Product: O=C(NCC1CCCCC1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1

Procedure:
Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid and 18.7 ml of cyclohexylmethylamine, 16.1 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-cyclohexylmethyl)amide are obtained in the form of a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:14][C:15](=O)[NH:16][C:17]1[S:21][C:20]2[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=2[CH:18]=1)C1C=CC=CC=1>>[CH3:27][O:26][C:25]1[C:19]2[CH:18]=[C:17]([NH:16][C:15]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:14])[S:21][C:20]=2[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCCCC3)cc12

Procedure:
The title compound MS: m/e=365.1 (M−H) was obtained as a light brown solid (62% yield) by the reaction of piperidine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:28])[N:3]=1.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:10]=3)=[O:7])=[C:4]([CH3:28])[N:3]=2)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)c(C)n2)CC1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methylnicotinamide (0.17 mmol) was used in general procedure 3 with 1-acetylpiperazine (0.868 mmol). The product was purified by RP-HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methyl-nicotinamide. MS (Q1) 510.1 (M)+
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(OCC)(=O)C>CC(C)=O.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1

Procedure:
To a flask containing 4-nitrobenzyl bromide (21.6 g) in dry acetone (100 mL) is added potassium carbonate (34.5 g) and morpholine (10 mL). The mixture is heated to reflux overnight under a drying tube. The reaction is partioned between ethyl acetate and water and separated. The basic aqueous layer is extracted with two additional portions of ethyl acetate. The combined organic layers are washed with brine, dried, and concentrated under reduced pressure to afford 21.3 g of the title compound as a solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:18]1[N:19]=[C:20]2[C:25](=[C:26]3[C:31]=1[CH:30]=[CH:29][CH:28]=[CH:27]3)[CH:24]=[CH:23][CH:22]=[CH:21]2.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([O:16][C:18]2[N:19]=[C:20]3[C:25](=[C:26]4[C:31]=2[CH:30]=[CH:29][CH:28]=[CH:27]4)[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Clc1nc2ccccc2c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2nc3ccccc3c3ccccc23)C[C@H]1C(=O)O

Procedure:
(2S,4R)-N-Boc-4-hydroxyproline can be reacted with 6-chlorophenanthridine in NMP, in the presence of sodium t-butoxide, to produce (2S,4R)-1-(tert-butoxycarbonyl)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxylic acid. Methyl tertiary butyl ether (MTBE) and water can then be added. The aqueous layer is separated, washed, and then HCl is added, followed by extraction with MTBE. The extracted product can be mixed with diisopropylethylamine (DIPEA) and HATU (CAS #148893-10-1), and then reacted with (1R,2S)-ethyl-1-amino-2-vinylcyclopropanecarboxylate tosylate salt in dimethylformide (DMF) and toluene. The reaction produces (2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(phenanthridin-6-yloxy)pyrrolidine-1-carboxylate, which can be extracted with MTBE and washed with HCl, further extracted, washed, dried, and dissolved in 2-propanol.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH:5]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=O)[CH:16]=2)[NH:11][CH:10]=1)[C:6](N)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].O>O1CCCC1.C(OCC)(=O)C>[CH2:19]([NH:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:6]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CNC(=O)CC(C(N)=O)c1c[nH]c2ccc(NC(=O)c3ccccc3)cc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(NCc4ccccc4)cc23)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
To a stirred solution of N-methyl-3-(5-phenylcarbonylaminoindol-3-yl)succinamide (18.31 g, 52.71 mmol) in anhydrous tetrahydrofuran (270 mL) at 0° C. was added lithium aluminum hydride (20.01 g, 527 mmol, 10 eq) as a solid portionwise over 45 minutes. The resulting reaction mixture was stirred at room temperature under nitrogen for 24 hours. Sodium sulfate decahydrate (50 g) was then carefully added to the reaction mixture followed by water (5 mL) and ethyl acetate (100 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residual oil was column chromatographed using silica gel (approximately 500 g) and elution with ethyl acetate: methanol: triethylamine [gradient 9:0:1 to 8:1:1] to afford the title compound (7.90 g, 49%) as a pale yellow oil: 13C NMR (acetone-d6) δ142.9, 142.1, 132.3. 129.3, 128.6, 127.5, 121.9, 118.6, 112.8, 112.5, 102.0, 63.6, 57.1, 49.9, 42.8, 36.5, 33.0; FAB LRMS (m/z, relative intensity) 306 (MH+, 100), 263 (4), 248 (4), 223 (8).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=[C:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]=1[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.CO[CH:43](OC)[CH2:44][NH2:45].Cl.[OH-].[Na+]>C(O)(C)C>[CH2:1]([C:5]1[CH:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=[C:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]=1[N:11]1[CH:43]=[CH:44][N:45]=[C:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cc(-c2ccccc2)cc(CC(C)C)c1NC(=O)c1ccccc1
Reactant: COC(CN)OC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: CC(C)Cc1cc(-c2ccccc2)cc(CC(C)C)c1-n1ccnc1-c1ccccc1
Yield: 55 %

Procedure:
A mixture of N-(3,5-diisobutylbiphenyl-4-yl)benzamide (6.27 g, 16.3 mmol), phosphorus oxychloride (20 mL), and phosphorus pentachloride (3.40 g, 16.3 mmol) was stirred at reflux for 4 h. The phosphorus oxychloride was removed by vacuum distillation. To the crude imidoyl chloride was added isopropanol (40 mL) and aminoacetaldehyde dimethyl acetal (35 mL, 321 mmol). This was stirred at ambient temperature for 18 h after which time conc. HCl (75 mL) was added. This was stirred at reflux for 18 h. The mixture was neutralized with 1N NaOH to pH 9 and extracted with dichloromethane. The product was purified on a silica gel column. Elution first with dichloromethane then dichloromethane and ethyl acetate (9:1) gave the desired product which was recrystallized from hexane to give 3.64 g (55% yield) as a white solid. Structure was confirmed by LC-MS and 1H NMR.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[S:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=S.CCN(C(C)C)C(C)C>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:9]1[S:8][CH2:14][C:12](=[O:13])[N:11]=1
Reactant: NCc1cccs1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2cccs2)=N1

Procedure:
Similar procedure as described in example 15a was used, starting with thiophen-2-ylmethyl-amine, rhodanine, mercuric chloride and DIEA to give 2-(thiophen-2-ylmethyl-amino)-thiazol-4-one. LC-MS m/e 259 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NC1CCOCC1
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCOCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a suspension of 2,6-dichloro-3-nitropyridine (6 g, 31.1 mmol) in AcN (200 mL) at 0° C., TEA (9 mL, 62.2 mmol) and tetrahydro-2H-pyran-4-amine (3.15 g. 31.1 mmol) were added. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction crude was tempered and stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure, dissolved in EtOAc, and washed thrice with saturated NaHCO3 aqueous solution. The combined organic phases were dried over MgSO4 and concentrated to dryness. The crude residue was cromategraphed on a silica gel flash system (ISCO Combiflash) using hexanes/TBME mixtures of increasing polarity as eluent to afford 5.23 g of the desired product (65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.BrC1C=C(CC(=O)C)C=CC=1.[Br:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](=[O:31])[CH3:30])[CH:25]=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([CH:28]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:29]([OH:31])[CH3:30])[CH:25]=[N:26][CH:27]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)Cc1cncc(Br)c1
Agent: CC(=O)Cc1cccc(Br)c1
Product: CC(O)C(Cc1ccc(Cl)cc1)c1cncc(Br)c1

Procedure:
The title compound was prepared following the procedures described in Reference Example 40, Step B-C, substituting 2-bromomethyl-5-chloropyridine with 4-chlorobenzyl chloride and 3-bromophenylacetone with 5-bromo-3-pyridylacetone (Step A). 1H NMR (500 MHz, CD3OD): δ 8.43 (d, 1H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.17 (d, 2H), 7.07 (d, 2H), 4.04 (m, 1H), 3.16 (dd, 1H), 3.0-2.9 (m, 2H), 1.04 (d, 3H).
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=3)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[F-:23].[K+].C1OCCOCCOCCOCCOCCOC1>>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[C:4](=[O:5])[O:3][CH:2]3[F:23])[N:14]=1
Reactant: [F-]
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3F)n1

Procedure:
A mixture of 1.0 g of 3-chloro-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide (see Example 85) and 0.19 g of spray-dried potassium fluoride and a spatula tip of 18-crown-6 is heated at reflux temperature for 100 minutes. The mixture is then filtered over Celite® and is concentrated by evaporation, and the crude product is recrystallised from ethyl acetate/n-hexane to yield 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-fluoro-phthalide, m.p. 172°-174° C.