Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[NH:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[NH:33][C:32]([C:41](O)=[O:42])=[CH:31]2.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CO.Cl.O.CC(N(C)C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[N:5]([C:41]([C:32]2[NH:33][C:34]3[C:30]([CH:31]=2)=[CH:29][C:28]([O:27][CH3:26])=[C:36]([O:37][CH3:38])[C:35]=3[O:39][CH3:40])=[O:42])[CH2:4]1
Reactant: O=[N+]([O-])c1cc2c(c3ccc(S(=O)(=O)NCCO)cc13)C(CCl)CN2
Reactant: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1cc2cc(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc(S(=O)(=O)NCCO)ccc43)[nH]c2c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Amine 121 (75 mg, 0.19 mmol) was dissolved in MeOH/HCl(g) at room temperature and the solution was evaporated to dryness under reduced pressure. 5,6,7-Trimethoxyindole-2-carboxylic acid (59 mg, 0.23 mmol), EDCI (149 mg, 0.78 mmol), anhydrous TsOH (30 mg, 0.17 mmol) and dry DMA (3 mL) were then added, and the mixture was stirred at room temperature for 1 h. The mixture was poured into water and the precipitate was collected and washed with water, dried, and dissolved in the minimum volume of DMW at room temperature. The solution was diluted with EtOAc, filtered, and then diluted with hexane and refrigerated to give 33 (89 mg, 74%): mp 257-258° C.; 1H NMR [(CD3)2SO] δ 11.61 (s, 1H), 9.24 (s, 1H), 8.86 (d, J=1.6 Hz, 1H), 8.43 (d, J=8.9 Hz, 1H), 8.02 (dd, J=8.9, 1.7 Hz, 1H), 7.91 (t, J=5.7 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 6.99 (s, 1H), 4.93 (t, J=10.1 Hz, 1H), 4.70-4.58 (m, 3H), 4.18-4.07 (m, 2H), 3.94 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H, 3.39 (q, J=6.0 Hz, 2H), 2.88 (q, J=6.1 Hz, 2H). Anal. (C27H27ClN4O9S) C, H, N.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=4[NH:16][C:15]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:28]([C:30]1[CH:39]=[C:38]([CH3:40])[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29].CCN(C(C)C)C(C)C.CO.C[C:53](C)([O-:55])C.[K+]>C(O)(=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:17]2[NH:16][C:15](=[O:27])[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:6]=[N:7][C:2]([O:55][CH3:53])=[C:3]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[CH:4]=4)[CH2:9][CH2:10]3)[CH2:20][CH2:19][C:18]=2[CH:21]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(Cl)nn3)CC1)C(=O)N2
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(OC)nn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.13 g (0.11 mmol) (purity 50%) 3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]-diazepin-2-one and 0.050 mL (0.29 mmol) DIPEA were heated with 1 mL MeOH in a microwave container for 2 h at 125° C. Then potassium-tert-butoxide was added and the mixture was stirred for 48 h at RT. Next, the reaction mixture was heated for a further 6 h and then it was neutralised with acetic acid and purified by preparative HPLC-MS.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][C:12]1=[C:13]([CH3:19])[C:14]([O:16][C:17]1=O)=[O:15]>C(O)(=O)CC>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[CH:5][C:3]=1[N:4]1[C:14](=[O:15])[C:13]([CH3:19])=[C:12]([CH3:11])[C:17]1=[O:16]
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CCC(=O)O
Product: CC1=C(C)C(=O)N(c2cc(O)c(Cl)cc2F)C1=O
Reaction time: 12 h
Yield: 101.6 %

Procedure:
A mixture of 16.1 g of 2-fluoro-4-chloro-5-hydroxyaniline and 12.6 g of dimethylmaleic acid anhydride in 100 ml of propionic acid are heated to 150° and stirred for 12 hours at that temperature. The reaction mixture is then allowed to cool and concentrated. The residue is cristallized from methanol and yields 27.3 g of N-(2-fluoro-4-chloro-5-hydroxyphenyl)-2,3-dimethylmaleic acid imide melting at 170°-171°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH:25][C:33]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH3:35])=[O:34])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Product: Cc1ccccc1NC(=O)Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 71.5 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenylamine (142 mg, 0.4 mmol) and 2-tolyl isocyanate (57 μL, 0.4 mmol) and following the procedure as outlined in Example 60, 140 mg of 1-{2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenyl}-3-o-tolyl-urea was isolated as an off white powder in 98% purity @ 214 nm; LCMS (APCI): 490 [M+H]+.
Reaction SMILES: C(OCC)(=O)C.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]=[N+]=[N-])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[O:52]=[C:53]1[CH2:57][CH2:56][CH2:55][N:54]1[CH2:58][CH2:59][CH2:60][NH:61][C:62]([C@@H:64]1[CH2:68][CH2:67][CH2:66]N1)=[O:63]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]1[CH2:66][CH2:67][CH2:68][C@H:64]1[C:62]([NH:61][CH2:60][CH2:59][CH2:58][N:54]1[CH2:55][CH2:56][CH2:57][C:53]1=[O:52])=[O:63])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCCCN1CCCC1=O)[C@@H]1CCCN1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCCN1CCCC1=O)OCc1ccccc1

Procedure:
To 30 ml of a ethyl acetate solution of compound (4) prepared from 2.12 g of compound (3) by a known method was added 5 ml of a DMF solution of 1.17 g of compound (100) under ice-cooling and the reaction was maintained overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (90:10:1), 2.00 g of Nα -benzyloxycarbonyl-L-histidyl-N-[3-(2-oxo-1-pyrrolidinyl)-propyl]-L-prolinamide (101) was obtained.
Reaction SMILES: CS[C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][C:24]#[N:25])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)OCC>C(O)C>[N+:12]([C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3](=[C:23]([C:19]3[N:18]=[C:17]([C:16]([F:27])([F:15])[F:26])[CH:22]=[CH:21][N:20]=3)[C:24]#[N:25])[S:4][C:5]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: N#CCc1nccc(C(F)(F)F)n1
Reactant: CSc1nc2ccc([N+](=O)[O-])cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CC(=C1Nc2ccc([N+](=O)[O-])cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 160 °C
Yield: 95.5 %

Procedure:
To a solution of 2-(methylthio)-6-nitro-1,3-benzothiazole (226 mg, 1.0 mmol) in ethanol (3.5 mL) was added 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (187 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol). The orange mixture was heated in the microwave at 160° C. for 15 min, then cooled and poured into EA (60 mL). The organic layer was washed twice with 1N hydrochloric acid (25 mL each), brine (25 mL), and water (5 mL), then dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-(6-nitrobenzothiazol-2(3H)-ylidene)-2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (349 mg, 96% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].C(O[CH2:44][CH3:45])(=O)C>O>[CH2:9]([N:11]([CH2:44][CH2:45][O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:10])[CH2:12][CH3:13])[CH3:3]
Reactant: CCOC(C)=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cccc1F
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylaianine (1.0 mmol, 460 mg), 2-[(N,N-diethyl)aminolethyl chloride hydrochloride (8.05 mmol, 1.43 g) and potassium carbonate (8.05 mmol, 1.11 g) in ethyl acetate (5 mL) and water (5 mL) was stirred at room termperature overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×40 mL). The combined extracts were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to obtain 426 mg (76% yield) of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C29H34F2N4O5 (M+H) 557.2570, found 557.2575.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:20]1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:25](=[O:26])[CH2:24][CH:21]3[CH2:22][CH2:23][O:19][CH2:20]3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)CC1CCOC1
Product: O=C(CC1CCOC1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product from Example 1B and 2-(tetrahydrofuran-3-yl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.44-8.46 (m, 1H), 8.27-8.29 (bs, 1H), 7.89-7.94 (m, 1H), 7.80-7.86 (m, 1H), 7.74-7.79 (m, 1H), 3.91-3.98 (m, 6H), 3.70-3.82 (m, 1H), 3.57-3.61 (m, 1H), 3.21-3.23 (m, 4H), 2.77-2.81 (m, 1H), 2.51-2.54 (m, 2H), 2.15-2.30 (m, 1H), 1.68-1.78 (m, 1H); MS (APCI+) M/Z 359 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][C:3]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24].C(OCC)(=O)C>CN(C)C=O>[CH3:24][O:23][CH:22]([O:25][CH3:26])[CH2:21][N:9]1[C:10]2[C:5](=[N:4][C:3]([CH3:13])=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12]
Reactant: Cc1nc2ccc(=O)[nH]c2cc1F
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(Cn1c(=O)ccc2nc(C)c(F)cc21)OC
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To a solution of 0.74 g of 7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one in 5 mL of N,N-dimethylformamide, 2.0 g of cesium carbonate and 0.84 g of 2-bromo-1,1-dimethoxyethane were added, the temperature was increased to 90 to 100° C., and the mixture was stirred for 2 hours 30 minutes. The reaction mixture was cooled to room temperature, thereto was added ethyl acetate, the insoluble substance was filtered off, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.69 g of 1-(2,2-dimethoxyethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[C:6]([F:21])=[C:7]([C:12]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[O:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)[CH2:3][CH3:4].C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.[OH-].[Na+].O>[NH2:20][C:17]1[N:16]=[CH:15][C:14]([C:12]([C:7]2[C:8]([Cl:11])=[CH:9][CH:10]=[C:5]([C@H:2]([NH:1][CH3:24])[CH2:3][CH3:4])[C:6]=2[F:21])=[O:13])=[CH:19][CH:18]=1
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](NC)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Reaction time: 18 h
Yield: 3.2 %

Procedure:
A mixture of [3-((R)-1-Amino-propyl)-6-chloro-2-fluoro-phenyl]-(6-amino-pyridin-3-yl)-methanone (100 mg, 0.29 mmol), paraformaldehyde (26 mg, 0.87 mmol), sodium triacetoxyborohydride (92 mg, 0.44 mmol) and acetic acid (67 μL, 1.16 mmol) in DCM (0.5 mL) was stirred for 18 h. Chromatographic analysis showed mainly bis-addition peaks, but a small peak for product. Further DCM (5 mL) and water (5 mL) were added and the mixture was made basic with a few drops of 5M NaOH. Separated and aqueous extracted with further DCM (5 mL). The combined organic phase was washed with brine (4 mL), dried (MgSO4), filtered and concentrated. Purified by prep LCMS (basic 3) and concentrated to give (6-Amino-pyridin-3-yl)-[6-chloro-2-fluoro-3-((R)-1-methylamino-propyl)-phenyl]-methanone (3 mg). Dissolved in d6-DMSO (160 uL) and concentration determined by NMR—53 mM. Used as solution for assays. [MH]+ 322.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[F:17].[C:18]([CH:20]1[CH2:22][CH:21]1[C:23](N(OC)C)=[O:24])#[N:19]>CCCCCC.C1COCC1.ClCCl>[F:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[C:23]([CH:21]1[CH2:22][CH:20]1[C:18]#[N:19])=[O:24]
Reactant: CON(C)C(=O)C1CC1C#N
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: N#CC1CC1C(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.6 ml (4.12 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 1.00 g (4.12 mmol) of 1-bromo-2-fluoro-4-(trifluoromethyl)benzene in 8 ml of THF at −78° C., and the mixture was stirred for 0.5 h. Then, at −78° C., a solution of 423 mg (2.74 mmol) of the compound from Example 73A in 2 ml of THF was added, and the mixture was allowed to warm to RT and was stirred at RT for 2 h. It was diluted with dichloromethane, and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 206 mg (29% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:16]=[C:15](Br)[CH:14]=[N:13]2)[CH:6]=1)[CH3:2].[CH3:19][N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][N:22]=[CH:21]1.[F-].[K+]>O1CCOCC1.CCOC(C)=O.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>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:16]=[C:15]([C:24]3[N:20]([CH3:19])[CH:21]=[N:22][CH:23]=3)[CH:14]=[N:13]2)[CH:6]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: CCOC(=O)c1ccc(C)c(-n2cc(Br)cn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C)c(-n2cc(-c3cncn3C)cn2)c1
Temperature: 100 °C
Yield: 26.5 %

Procedure:
3-(4-Bromo-pyrazol-1-yl)-4-methyl-benzoic acid ethyl ester (Example 8) (366 mg, 1.18 mmol) was dissolved in dioxane (2 mL) and flushed with nitrogen. 1-Methyl-5-tributylstannanyl-1H-imidazole (366 mg, 0.986 mmol) was added to the reaction flask in dioxane (0.5 mL) then the flask was purged with N2. After Pd(PPh3)4 (85 mg, 0.074 mmol) was added, the reaction was heated to 100° C. in a sealed tube. The reaction mixture was stirred with a 10% KF solution for 30 min then diluted with EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by chromatography on silica gel (5% MeOH/CH2Cl2) to give the title compound (81 mg, 22%) as a colorless oil.
Reaction SMILES: [C:1]([C@@:9]1([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[O:23][C:20]([CH2:24][OH:25])([CH2:21][OH:22])[C@@H:11]([O:12][Si](C(C)(C)C)(C)C)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([C@@:9]1([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[O:23][C:20]([CH2:24][OH:25])([CH2:21][OH:22])[C@@H:11]([OH:12])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@]2(C(=O)c3ccccc3)C[C@H](O[Si](C)(C)C(C)(C)C)C(CO)(CO)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@@]2(C(=O)c3ccccc3)C[C@H](O)C(CO)(CO)O2)c(=O)[nH]c1=O
Yield: 78.2 %

Procedure:
A solution of N3 -benzoyl-3'-O-t-butyldimethylsilyl-4'-hydroxymethyl thymidine (0.5 g, 1.02 mM) in THF (3 ml) was treated with tetrabutylammonium fluoride in THF (1 M, 1.5 ml, 1.5 mM) at 24° C. for 4 hours. The solvent was removed and the residue was chromatographed on silica gel with 7% CH3OH/CH2Cl2 to give N3 -benzoyl-4'-hydroxymethyl thymidine (0.3 g, 0.83 mM).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]3[C:11](=[O:20])[NH:12][CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][C:16]=3[N:17]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.CC([O-])(C)C.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH3:18][C:14]1([CH3:19])[CH2:13][NH:12][C:11](=[O:20])[C:10]2[S:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[CH:30][CH:31]=4)[CH:7]=3)=[N:17][C:16]=2[CH2:15]1
Reactant: CC1(C)CNC(=O)c2sc(-c3ccnc(Cl)c3)nc2C1
Reactant: CNC(=O)c1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(Nc2cc(-c3nc4c(s3)C(=O)NCC(C)(C)C4)ccn2)cc1
Temperature: 25 °C
Yield: 19.4 %

Procedure:
2-(2-chloropyridin-4-yl)-5,6,7,8-tetrahydro-7,7-dimethylthiazolo[5,4-c]azepin-4-one (70 mg, 1.0 Eq.), 4-amino-N-methyl-benzamide (41 mg, 1.2 Eq.), NaOtBu (61 mg, 2.8 Eq.), Pd(OAc)2 (5 mg, 0.1 Eq.) were suspended/dissolved in dry toluene and degassed (vacuum/N2 cycles×5). 2-Di-tert-butylphosphino)biphenyl (143 mg, 0.2 Eq.) was then added. The resultant mixture was then refluxed overnight. A further portion of NaOtBu (61 mg, 2.8 Eq.), Pd(OAc)2 (5 mg, 0.1 Eq.) and 2-(di-tert-butylphosphino)biphenyl (14 mg, 0.2 Eq.) were added, followed by dry dioxane (0.5 mL). The resultant mixture was refluxed for a further night. The reaction mixture was allowed to cool to RT, partitioned between EtOAc/MeOH (3:1)/NH4Cl, and then extracted into EtOAc/MeOH (3:1) (3×50 mL). The combined organic layers were washed with brine (1×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (10% MeOH/90% DCM) to obtain the title compound as a bright yellow powder (18.6 mg, 19% yield); 1H NMR (DMSO D6) 1.0 (6H, s), 2.8 (3H, d), 3.0 (2H, s), 3.0 (2H, m), 7.3 (1H, m), 7.5 (1H, s), 7.8 (4H, s), 8.2 (1H, m), 8.3 (2H, m), 9.6 (1H, s); LC/MS M+1 (obs.) 422.20; LC/MS M−1 (obs.) 420.30.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CCCCCBr
Reactant: OCCCCc1ccccc1
Product: O=C(CCCCCBr)OCCCCc1ccccc1
Yield: 80 %

Procedure:
From 6-bromocaproic acid and 4-phenyl-1-butanol. Working up by means of distillation. Yield: 80%. Boiling point: 158° C. (0.008 mbar).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1>CO.[Pd]>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Cc1nccn1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution 2-methyl-1-(4-nitrophenyl)-1H-imidazole (12.8 g, 63 mmol) in MeOH (150 mL) was added Pd/C (3 g). The resulting mixture was stirred at room temperature for 8 hours under hydrogen. When TLC indicated the starting material was consumed, the mixture was filtered and concentrated in vacuo to give 4-(2-methyl-1H-imidazol-1-yl)aniline (10 g, yield 92%).
Reaction SMILES: [F:1][C:2]([C:5]1[C:10]([CH2:11][NH:12]C(=O)OC(C)(C)C)=[CH:9][N:8]=[CH:7][N:6]=1)([CH3:4])[CH3:3].[ClH:20]>C(Cl)Cl>[ClH:20].[ClH:20].[F:1][C:2]([C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cncnc1C(C)(C)F
Agent: Cl
Solvent: ClCCl
Product: CC(C)(F)c1ncncc1CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
tert-Butyl ((4-(2-fluoropropan-2-yl)pyrimidin-5-yl)methyl)carbamate (1.0 equiv.) was combined in DCM (1.5 M) at ambient temperature, and 4.0 M hydrogen chloride in dioxanes was added via syringe. The solution was allowed to stir at ambient temperature. After 16 h, the solution was condensed under reduced pressure to afford the title compound as a white solid (100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (d, J=1.56 Hz, 1H), 8.89 (s, 1H), 8.32 (br. s., 2H), 4.22 (dd, J=5.66, 3.32 Hz, 2H), 1.59-1.84 (m, 6H); MS(ESI) m/z [M+1]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([N:9]1C=CN=C1)=[S:8].C([O-])(=O)C.[NH4+]>C(O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([NH2:9])=[S:8]
Reactant: S=C(Nc1nccs1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=S)Nc1nccs1
Yield: 121.1 %

Procedure:
A mixture of 65 g (309.1 mmol) N-1,3-thiazole-2-yl-1H-imidazole-1-carbothioamide and 260 g of ammonium acetate were heated to 80° C. in 400 ml ethanol for 1.5 hours; after completion of reaction the solvent was distilled off and water was added to the obtained residue. After extraction with CH2Cl2 and drying of the organic phase with Na2SO4, 59.6 g of the target product were obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([OH:20])[CH3:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[CH2:21]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18](=[O:20])[CH3:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Product: CC(=O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1

Procedure:
1-[5-(Dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]ethanol (Example 53) was oxidized using manganese dioxide to provide 1-[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]ethanone following the procedure described for Example 139 using tetrahydrofuran as a solvent. Purification by Biotage chromatography provided 1-[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]ethanone (200 mg, 40%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ2.54 (3H, s), 4.76 (4H, s), 6.67 (1H, s), 6.97 (1H, s), 7.12-7.30 (10H, m), 8.50 (1H, s); ESI m/z 356 [C23H21N30+H]+; HPLC (Method A) >99% (AUC), tR=18.8 min.