Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[S:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[C:19]([CH3:21])[N:20]=2)=[CH:11][CH:10]=1>CS(C)=O>[CH3:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:18]2[S:17][C:16]([NH:15][C:12]3[CH:13]=[N:14][C:9]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][CH:11]=3)=[N:20][C:19]=2[CH3:21])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: CN1CCNCC1
Reactant: Cc1nc(Nc2ccc(Cl)nc2)sc1-c1ccc(S(C)(=O)=O)cc1
Solvent: CS(C)=O
Product: Cc1nc(Nc2ccc(N3CCN(C)CC3)nc2)sc1-c1ccc(S(C)(=O)=O)cc1
Yield: 117.6 %

Procedure:
A stirred solution of N-methyl piperazine (0.184 g, 1.84 mmol) and (6-chloro-pyridin-3-yl)-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amine (31c) (0.070 g, 0.184 mmol) in DMSO (2 ml) is heated in a microwave (PROLABO SYNTHEWAVE s402™) at 60% power (180 W) for 10 hours. The solvent is removed and the residue is purified by chromatography on silica eluting with ethyl acetate-methanol (9:1) to give the title compound as a yellow solid (0.096 g).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][C@H:27]([CH3:33])[CH2:28][NH:29][C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[CH3:34]>>[CH3:34][C:10]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][C@H:27]([CH3:33])[CH2:28][NH:29][C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1
Reactant: ClCc1nccs1
Reactant: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4nccs4)c(C)c3)c12
Yield: 25 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)-1,3-thiazole and N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting materials) to give the title compound as a light brown solid in 25% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.25 (s, 3H), 3.42 (dt, 1H), 3.60 (dt, 1H), 4.88 (m, 1H), 5.45 (s, 2H), 7.11 (d, 1H), 7.22 (d, 1H), 7.31 (d, 1H), 7.56 (d, 1H), 7.63 (dd, 1H), 7.68 (t, 1H), 7.76 (d, 1H), 7.83 (d, 1H), 8.23 (t, 1H), 8.43 (s, 1H), 9.97 (s, 1H); Mass spectrum MH+ 464.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[C:24]([O:41][CH3:42])=[C:25]([CH:39]=[O:40])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:28]=1>O>[F:22][C:23]1[C:24]([O:41][CH3:42])=[C:25]([C:39]([OH:2])=[O:40])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:28]=1
Reactant: COc1c(F)cc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Product: COc1c(F)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reaction time: 12 h
Yield: 57 %

Procedure:
Pyridinium dichromate (0.25 g, 0.67 mmol ) was added to a solution of 5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carbaldehyde (0.2 g, 0.67 mmol) DMF (2 mL) and stirred for 12 h, to complete the reaction more pyridinium dichromate (0.2 g , 0.53 mmol) was added and stirred for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc(10 mL). Solvent was removed under reduced pressure to get 5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.12 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH3:34])[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2)C1C=CC=CC=1>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH:24]1([C:23]2[C:22]3[C:17](=[CH:18][C:19]([C:30]([O:32][CH3:33])=[O:31])=[CH:20][CH:21]=3)[N:16]([CH3:34])[C:15]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)n(C)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)n(C)c2c1
Reaction time: 12 h

Procedure:
A solution of intermediate 3 (4.00 g) in MeOH (36 mL) and AcOH (4 mL) was hydrogenated in presence of palladium hydroxide as catalyst. After 12 h, the reaction mixture was filtered and the filtrate was evaporated to give methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1-methyl-1H-indole-6-carboxylate 4: m/z=364 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.[NH2:20][OH:21].[OH-].[K+].CO>C1COCC1>[OH:21][NH:20][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: NO
Reactant: COC(=O)C=CC=CCSc1ccc(N(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(SCC=CC=CC(=O)NO)cc1
Temperature: 0 °C
Yield: 43.1 %

Procedure:
To a solution of 6-(4-dimethylamino-phenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.556 g, 2.0 mmol) in distilled THF (10 mL) containing aqueous hydroxylamine (50%, 1.21 mL, 18.4 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 2.8 mL, 2.8 mmol) over a period of 30 minutes. After stirring the mixture at 0° C. for an additional hour, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The solution was then extracted with ethyl acetate (2×50 mL), and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The solid residue was recrystallised from ethyl acetate to give the title compound (0.24 g, 43%) as a white solid.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH3:23][N:24]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:26]([C:33]2[S:37][C:36]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:35][CH:34]=2)=[N:25]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:41][S:38]([C:36]2[S:37][C:33]([C:26]3[CH:27]=[C:28]([C:29]([F:31])([F:30])[F:32])[N:24]([CH3:23])[N:25]=3)=[CH:34][CH:35]=2)(=[O:40])=[O:39])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: Cn1nc(-c2ccc(S(N)(=O)=O)s2)cc1C(F)(F)F
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)n(C)n2)s1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophene-2-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 3.66 (s, 3), 4.03 (s, 3), 4.76 (s, 2), 6.50 (s, 1), 6.71 (s, 1), 7.00 (m, 2), 7.20 (m, 1), 7.25 (m, 2), 7.93 (m, 1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH:19]=[CH:20][CH:21]=O)=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26].[S:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][CH2:20][CH2:21][CH:33]2[S:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]
Reactant: O=C1CSC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=CC=O)cc1C(F)(F)F
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC2SC(=O)NC2=O)cc1C(F)(F)F
Yield: 31 %

Procedure:
According to the same manner as that described in Example 13, 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-trifluoromethylcinnamaldehyde was condensed with 2,4-thiazolidinedione, and the resulting product was subjected to catalytic hydrogenation to give 5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-trifluoromethylphenyl]propyl]-2,4-thiazolidinedione (yield: 31%). This product was recrystallized from dichloromethane-methanol. Colorless prisms, mp: 154-155° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:55]6[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCN(C)CC4)c3)ccc2OC)c1
Yield: 59.6 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1-methylpiperazine (12 mg, 13.3 uL, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid [36.2 mg (60%)]. LC-MS m/z 759.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[C:13](F)[N:12]=2)[CH:9]=1)[C:5]#[N:6].[NH2:20][CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:24][N:23]=1>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[C:13]([NH:20][CH2:21][C:22]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)[N:12]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2nc(F)c(Cl)cc2F)c1
Reactant: NCc1n[nH]c2ncccc12
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2nc(NCc3n[nH]c4ncccc34)c(Cl)cc2F)c1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A solution of 50 mg (0.166 mmol) of 1-6 and 25 mg (0.166 mmol) of 1-3 in 1.5 mL of dry NMP was heated with stirring at 90° C. under nitrogen. After 7 hours, the reaction was stopped and cooled. The reaction mixture was diluted with water, and extracted twice with EtOAc. The combined EtOAc extracts were washed with water and brine, dried, filtered, and concentrated in vacuo to give a crude oil. The crude product was purified by reversed phase preparative HPLC on a Gilson apparatus to give the title product as a white amorphous solid. MS M+1=430. 1H NMR (CDCl3): 4.77 (d, 2H), 5.60 (br m, 1H), 7.17 (q, 1H), 7.34 (m, 1H), 7.36 (m, 1H), 7.39 (m, 1H), 7.50 (d, 1H), 8.01 (dd, 1H), 8.53 (m, 1H), 10.5-11.5 (br, 1H).
Reaction SMILES: Br[C:2]1[C:19]2=[C:20]3[C:9]([C:10]4[C:21]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=5)[CH:13]=[CH:12][CH:11]=4)=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C(C1C=C(C=C(C#C)C=1)[CH:27]=[O:28])#C>>[C:2]1([CH:27]=[O:28])[C:19]2=[C:20]3[C:9]([C:10]4[C:21]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=5)[CH:13]=[CH:12][CH:11]=4)=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: C#Cc1cc(C#C)cc(C=O)c1
Reactant: Brc1ccc2cccc3c4cccc5cccc(c1c23)c54
Product: O=Cc1ccc2cccc3c4cccc5cccc(c1c23)c54
Yield: 8.9 %

Procedure:
The first route employs bromoperylene PMI-12 and 3,5-diethynylbenzaldehyde (16) as the starting materials. The reaction under copper-free conditions, similar to those employed for the Sonogashira coupling of two porphyrins (Wagner, R. W. et al., Chem. Mater. 1999, 11, 2974-2983) afforded only a small amount (8.9%) of perylene-aldehyde 18 (entry 1, Table 1). The same reaction in the presence of CuI failed to produce perylene-aldehyde 18 (entry 2). We next examined the reaction with the reverse ethyne/bromo substitution pattern on the perylene and benzaldehyde. The reaction of ethynylperylene PMI-12′ and 3,5-dibromobenzaldehyde (14) (2:1 ratio) with CuI cocatalysis afforded 18 in 31% yield (entry 3). A further increase in the amount of perylene PMI-12′ (2.4:1 ratio) gave 18 in 66% yield (entry 4). Repetition of this reaction furnished 18 in 83% yield. While of limited scope, the survey of the Sonogashira reaction of perylene PMI-12 or PMI-12′ with aldehyde 14 or 16 revealed important reactivity differences between a bromoperylene and an ethynylperylene. Unlike perylene-aldehyde 15, compound 18 proved to be very soluble, thereby enabling subsequent porphyrin-forming reactions.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:36][O:35][C:33]([C:31]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)=[C:27]([F:26])[CH:32]=1)=[O:34]
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Product: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)c(F)c1

Procedure:
In analogy to example 74, step 6, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 74, step 5) and 2-fluoro-4-(methoxycarbonyl)phenylboronic acid was prepared the title compound as a light brown oil, MS (ESI+): m/z=468.1961 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:17]Br)[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F-:20].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:17][F:20])[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(CBr)C(=O)c1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CF)C(=O)c1ccccc1
Yield: 90 %

Procedure:
Bromomethylbenzoyl-glycine t-butyl ester was fluorinated in 90% yield using tetrabutylammonium fluoride in acetonitrile. NMR (CHCl3) δ 7.84 (d, 2H, Ar-2,6, J=8.3Hz), 7.44 (d, 2H, Ar-3,5, J=7.9Hz), 6.66 (1H, NH), 5.44 (d, 2H, CH2F, J=47Hz), 4.15 (d, 2H, CH2 gly, J=5.0Hz), 1.51 (9H, Bu).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH2:8]O)=[O:6])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:13])=O>>[N:1]([CH2:4][C:5]([NH:7][CH2:8][Cl:13])=[O:6])=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [N-]=[N+]=NCC(=O)NCO
Product: [N-]=[N+]=NCC(=O)NCCl
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To 2-azido-N-(hydroxymethyl)-acetamide (650 mg, 5 mmol) at −10° C. oxalyl chloride (635 mg, 5 mmol) was added. After 10 min gas evolution had ceased. The mixture was diluted in CDCl3. NMR-Spectrum in CDCl3: 4.1 (s, 2H), 5.2 (d, 2H, J=10 Hz), 7.3 (broad signal, 1H) ppm. The NMR was consitent with 2-azido-N-(chloromethyl)-acetamide (yield 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]1[O:15][CH2:6]1
Reactant: C=Cc1cccc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Brc1cccc(C2CO2)c1
Reaction time: 18 h
Yield: 73.6 %

Procedure:
A solution of 3-bromostyrene (1.0 g, 5.46 mmol) in CH2Cl2 (10 mL) was cooled in an ice bath. 3-Chloroperoxybenzoic acid (57% pure) (1.82 g, 6.01 mmol) was added in one batch and the stirring was continued over 18 h. The reaction mixture was concentrated to a residue and diluted with CCl4 (20 mL). Precipitated m-chlorobenzoic acid was removed by filtration and the filtrate was washed with a 50:50 mixture of 5% aq. NaHCO3 and 5% aq. NaHSO3 (100 mL). The organic extract was dried over Na2SO4 and concentrated under reduced pressure to yield 0.80 g (64%) of product as a yellow oil. 1H NMR (CDCl3) δ2.74 (m, 1, CH), 3.14 (m, 1, CH--), 3.82 (m, 1, --CH--), 7.21 (m, 2, phenyl), 7.42 (m, 2, phenyl).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][C:2]([OH:1])([C:20]([F:23])([F:22])[F:21])[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
In a 3-neck round-bottomed flask, benzyl 4-oxopiperidine-1-carboxylate (1.0 g, 4.3 mmol) was dissolved in THF (10 mL). The reaction mixture was cooled to 0° C. and trimethyl(trifluoromethyl)silane (0.78 mL, 5.3 mmol) was added. Then added TBAF (1.0M solution in THF, 0.05 mL, 0.05 mmol) which caused the internal temperature to rise to 30° C. The reaction mixture was stirred at room temperature overnight. Additional TBAF (1.0M solution in THF, 4.3 mL, 4.3 mmol) was added and the reaction mixture was stirred at room temperature for 4.25 h. The reaction mixture was quenched with water and extracted with CH2Cl2 (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with toluene to afford 0.82 g (63%) of 4-hydroxy-4-trifluoromethyl-piperidine-1-carboxylic acid benzyl ester as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1C(=O)[N:19](Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[NH2:12][C:3]1[C:2]([CH2:1][NH2:19])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CN)c1N
Yield: 21.7 %

Procedure:
To a mixture of methyl 3-methyl-2-nitrobenzoate (45.0 g, 0.23 mol) and NBS (45.0 g, 0.25 mol) in CCl4 (1500 mL) was added AIBN (1.2 g, 7.3 mmol) portion-wise under reflux. The mixture was refluxed (48 hours), and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (6% to 10% Ethyl acetate gradient in petroleum ether) to obtain methyl 2-amino-3-(aminomethyl)benzoate (9.0 g, 14% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Li]C(C)(C)C.[I:21]I>C1COCC1>[I:21][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: COc1ccc(NC(=O)C(C)(C)C)cn1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(I)c(NC(=O)C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-(6-methoxypyridin-3-yl)pivalamide (Compound 1, 7.4 g, 35.6 mmol) in anhydrous THF (200 ml) at −78° C. under argon was added t-BuLi (1.7 M in pentane, 52 ml, 89.0 mmol) slowly. After stirred at −78° C. for 1 h, a solution of I2 (22.6 g, 89.0 mmol) in anhydrous THF (100 ml) at −78° C. was cannulated into the reaction over 20 min and the reaction was stirred for 15 min at −78° C. The cooling bath was then removed and the reaction stirred for 30 min, quenched cautiously with ice, extracted with CH2Cl2. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)=[CH:16][C:15]=1[O:28][CH2:29][CH3:30]>CC(N(C)C)=O>[Cl:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:2]3[N:7]=[C:6]([C:8]4[S:9][CH:10]=[CH:11][CH:12]=4)[CH:5]=[CH:4][N:3]=3)[CH2:21][CH2:20]2)=[CH:16][C:15]=1[O:28][CH2:29][CH3:30]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Clc1nccc(-c2cccs2)n1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nccc(-c4cccs4)n3)CC2)ccc1Cl
Yield: 13.3 %

Procedure:
A solution of 2-chloro-4-thiophen-2-yl-pyrimidine (49.2 mg, 0.25 mmol, 1.0 equiv; example 4/step 1) and 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (80.6 mg, 0.30 mmol, 1.2 equiv; intermediate A2) in DMAc (2 mL) was heated by microwave irradiation to 220° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 14.3 mg (13%) of the title compound. MS (ISP): 429.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.[F:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=O)=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:15]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:24][CH:23]=2)[CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCCNC1
Agent: Cl
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCCNC2)cc1

Procedure:
The title compound is prepared from 4-fluoroaniline and 3-(4-fluorobenzoyl)piperidine hydrochloride according to the procedure of Example 31.
Reaction SMILES: [CH:1]1([C:7]2[S:24][C:10]3[N:11]=[C:12]([CH3:23])[N:13]=[C:14]([CH2:15][NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[C:28](Cl)(=[O:30])[CH3:29]>O>[CH:17]1([N:16]([CH2:15][C:14]2[C:9]3[CH:8]=[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[S:24][C:10]=3[N:11]=[C:12]([CH3:23])[N:13]=2)[C:28](=[O:30])[CH3:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Cc1nc(CNC2CCCCC2)c2cc(C3CCCCC3)sc2n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(Cc1nc(C)nc2sc(C3CCCCC3)cc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]cyclohexaneamine (47 mg) and DCM (4 mL) were added dropwise acetyl chloride (20 μL) and TEA (40 μL) at 0° C., followed by stirring at room temperature for 2.5 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed sequentially with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, and then concentrated under reduced pressure to obtain N-cyclohexyl-N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]acetamide (50 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]([F:20])([F:19])[C:9](=O)[CH2:10][C:11](=O)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>CCO>[CH2:12]([C:11]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:9]([C:8]([F:7])([F:19])[F:20])[CH:10]=1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: CC(C)CCc1cc(C(F)(F)F)nc2ccnn12

Procedure:
A solution of 2.0 gm of 3-aminopyrazole (0.024 mol) in 50 ml EtOH was refluxed with 5.0 gm of 1,1,1, -trifluoro-7-methyl-2,4-octanedione (0.024 mol) for 2 hours. The mixture was evaporated and distilled to yield 1.6 gm (48%) of a slightly yellowish oil, b.p. 103°-105°/0.5 mm.