Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:4][CH:3]=1.[S-:20][C:21]#[N:22].[NH4+].BrBr.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH3:18][C:16]1[CH:15]=[CH:14][N:13]2[CH:19]=[C:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:21]([NH2:22])[S:20][C:3]=4[CH:4]=3)[N:11]=[C:12]2[CH:17]=1
Reactant: N#C[S-]
Reactant: Cc1ccn2cc(CCc3ccc(N)cc3)nc2c1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccn2cc(CCc3ccc4nc(N)sc4c3)nc2c1
Yield: 14 %

Procedure:
A solution of 2-[2-(4-aminophenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (2.5 g) and ammonium thiocyanate (1.5 g) in acetic acid (25 ml) was stirred at ambient temperature for 1 hour. A solution of bromine (0.6 ml) in acetic acid (3 ml) was dropwise added thereto at 15° to 18° C. under stirring and the resulting mixture was stirred at 10° to 20° C. for 1 hour. A mixture of ethyl acetate and water was added to the reaction mixture and the mixture was adjusted to pH 7.5 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (19:1 V/V). The eluted fractions containing desired product were evaporated to give 6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-aminobenzothiazole (0.43 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:22])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH3:22])[C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: COC(=O)c1c(C)csc1N
Product: COC(=O)c1c(C)csc1NC(=O)Cc1ccc(I)cc1
Yield: 87 %

Procedure:
The title compound was synthesized in 87% yield according to protocol A from 2-(4-iodophenyl)acetic acid and methyl 2-amino-4-methylthiophene-3-carboxylate. 13C NMR (CDCl3) δ 167.5, 166.6, 149.8, 138.1, 134.8, 133.1, 131.4, 113.0, 112.3, 93.2, 51.5, 43.3, 17.8; MH+ 416.0.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH2:18]([C@H:20]1[N:29]([CH:30]([CH3:32])[CH3:31])[C:28]2[N:27]=[C:26]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([C:43](O)=[O:44])=[C:38]4[C:42]=3[O:41][CH2:40][CH2:39]4)[N:25]=[CH:24][C:23]=2[N:22]([CH3:46])[C:21]1=[O:47])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:43]([C:37]4[CH:36]=[CH:35][C:34]([NH:33][C:26]5[N:25]=[CH:24][C:23]6[N:22]([CH3:46])[C:21](=[O:47])[C@@H:20]([CH2:18][CH3:19])[N:29]([CH:30]([CH3:31])[CH3:32])[C:28]=6[N:27]=5)=[C:42]5[O:41][CH2:40][CH2:39][C:38]=45)=[O:44])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (577 mg, 2.43 mmol), 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (1 g, 2.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (780 mg, 2.43 mmol) and diisopropylethylamine (690 mg, 5.35 mmol) were dissolved in 40 mL of dichloromethane. The reaction mixture was stirred for 2 hours. The resulting solution was added with 50 mL of aqueous ammonia and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 44 (576 mg, yield: 38.0%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH:45][C@@H:46]1[CH2:50][CH2:49][NH:48][CH2:47]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:45][C@@H:46]1[CH2:50][CH2:49][N:48]([C:19]([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH:9]=2)=[O:20])[CH2:47]1
Reactant: O[C@@H]1CCNC1
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)N2CC[C@@H](O)C2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (1.50 g, 5.28 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.0 g, 10 mmol), 1-hydroxybenzotriazole hydrate (0.404 g, 2.64 mmol), and CH2Cl2 (30 mL) were added (R)-3-hydroxypyrrolidine (0.92 g, 10 mmol) and N,N-diisopropylethylamine (1.8 mL, 10 mmol). The mixture was stirred at room temperature overnight, and then diluted with CH2Cl2 (100 mL), washed with aq. NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column (100% EtOAc) to afford a white foam. LC-MS: 354.2 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.32 (s, 1H), 8.16 and 8.12 (bs, 1H), 7.92 (m, 1H), 7.53 (d, 2H, J=7.6 Hz), 7.28 (d, 2H, J=8.4 Hz), 4.63 and 4.49 (bs, 1H), 4.41 (q, 2H, J=7.2 Hz), 3.95-3.40 (m, 4H), 2.41 (s, 3H), 2.20-1.90 (m, 2H), 1.41 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:34]5[CH2:35][CH2:36][CH:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CS(=O)(=O)C1CCNC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: CS(=O)(=O)C1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)C1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (45 mg) was coupled to 3-(methylsulfonyl)pyrrolidine via General Procedure B. The product was purified via reverse phase HPLC to give 26.1 mg of 168. MS (Q1) 513.1 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])=[CH:10][CH:9]=2)[C:5]([F:28])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.[Cl-].[Li+]>[Cu]I.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.CN(C=O)C>[F:28][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])=[CH:10][CH:9]=2)=[CH:7][C:2]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:3][CH:4]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cc(Br)ncc3F)cc2)[C@H]1c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4ncccn4)ncc3F)cc2)[C@H]1c1ccccc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A microwave vial was charged with (S)-3-(4-(2-bromo-5-fluoropyridin-4-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.060 g, 0.136 mmol), 2-(tributylstannyl)pyrimidine (commercially available from Frontier Scientific, Inc., Logan Utah) (0.067 mL, 0.204 mmol), lithium chloride (0.012 g, 0.272 mmol), copper (I) iodide (2.59 mg, 0.014 mmol), and DMF (2.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol) was added, the system was purged with argon, and the tube was sealed. The resulting mixture was stirred at 120° C. in a microwave for 1 hour. The reaction mixture was then concentrated to afford an orange oil which was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-10% MeOH-EtOAc) to afford (S)-3-(4-(5-fluoro-2-(pyrimidin-2-yl)pyridin-4-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.012 g, 0.027 mmol, 20% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 3H), 1.66 (s, 3H), 5.53 (s, 1H), 7.10-7.54 (m, 6H), 7.56-7.89 (m, 5H), 8.10-9.41 (m, 3H). m/z (ESI) 441 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>ClCCl>[N+:45]([C:42]1[CH:41]=[CH:40][C:39]([O:38][C:36](=[O:37])[NH:1][C:2]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=2[O:4][CH2:5][C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:10][C@H:9]2[CH3:23])=[O:7])=[CH:44][CH:43]=1)([O-:47])=[O:46]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1N
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of (2R, 5S)-2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.150 g, 0.37 mmol) in dichloromethane (7 ml) was added pyridine (0.066 ml, 0.82 mmol) followed by 4-nitrophenyl chloroformate (0.075 g, 0.41 mmol). The reaction was stirred at ambient temperature for 3½ hours. The reaction mixture was concentrated followed by chromatography on silica gel to give the title compound (0.153 g, 74% yield).
Reaction SMILES: C([Li])CCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21]2=[O:27])=[CH:16][CH:15]=1.C(Br)C#C>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2([CH2:12][C:10]#[CH:11])[O:24][C:23]([CH3:25])([CH3:26])[O:22][C:21]2=[O:27])=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)C(c2ccc(Cl)cc2)O1
Reactant: CC(C)NC(C)C
Agent: C#CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCC1(c2ccc(Cl)cc2)OC(C)(C)OC1=O
Reaction time: 1.5 h

Procedure:
3.3 ml of butyl lithium (1.6 molar in hexane) are added under stirring to a solution of 0.8 ml diisopropylamine in 20 ml tetrahydrofurane at −78° C. under nitrogen. After stirring for 30 minutes at the same temperature, 1.13 g of 5-(4-chloro-phenyl )-2,2-dimethyl-(1,3)-dioxolan-4-one in 5 ml tetrahydrofurane are added and stirring is continued for 1.5 hours. Then the reaction mixture is treated with a solution of 0.57 ml propargyl bromide in 3 ml tetrahydrofurane. Stirring is continued at about 60° C. over the night. Then the reaction is quenched with HCl 1N (pH 6) and ice and water and extracted with diethyl ether. The extracts are dried over sodium sulfate and evaporated. The 5-(4-chloro-phenyl)-2,2-dimethyl-5-prop-2-ynyl-(1,3)dioxolan-4-one remains as a oil which is used directly for the next step.
Reaction SMILES: [O-]CC.[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[OH:13].Br[CH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18]>C(O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[O:13][CH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18]
Reactant: Cc1ccc(Br)c(O)c1
Reactant: COC(CBr)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(COc1cc(C)ccc1Br)OC
Yield: 36.4 %

Procedure:
To a solution of anhydrous ethanol (40 ml), sodium ethoxide (31.7 ml 21% wt., 86.94 mmol) and 2-bromo-5-methylphenol (Gewali, Mohan B.; Ronald, Bruce P. J. Org. Chem. 1980, 45, 2224–2229) (16.25 g, 86.94 mmol) was added 2-bromo-1,1-dimethoxy ethane (16.17 g, 95.64 mmol). The solution was heated to reflux overnight, reduced under vacuum and partitioned between water and ether. The aqueous layer was extracted with ether and the organics were passed through a silica plug and concentrated to afford 8.71 g (36%) of desired product as a pale yellow oil: 1H NMR (400 MHz, DMSO-d6): δ 2.19 (3H, s), 3.33 (6H, s), 3.96 (2H, d, J=5.1 Hz), 4.64 (1H, t, J=5.1 Hz), 6.98 (1H, d, J=8.5 Hz), 7.08 (1H, dd, J=8.4 Hz, 1.5 Hz), 7.35 (1H, d, J=1.7 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].Br[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.CCOC(C)=O>CN(C=O)C.O>[CH3:7][C:6]([CH3:9])([CH3:8])[C:5](=[O:10])[CH2:4][O:3][C:12]1[N:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: CC(C)(C)C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)COc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Dissolve sodium hydride (380 mg, 9.5 mmol) in anhydrous DMF (7 mL). Cool at 0° C., add dropwise 1-hydroxy-3,3-dimethylbutan-2-one (1.1 g, 9.5 mmol) and stir at this temperature for 30 min. Add a solution of 6-bromo-nicotinonitrile in DMF (7 mL) and heat at 70° C. overnight. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc and water. Dry the organic fraction over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (424 mg, 50%). MS (ES+) if/A: 219 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(#N)C>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21

Procedure:
A mixture of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.64 g), acetonitrile (20 ml), potassium carbonate (0.6 g) and ethyl bromoacetate (0.44 ml) is refluxed for 3 hours. The reaction solution is concentrated and water is added to the resulting residue, and the mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1), and recrystallized from ethyl acetate/petroleum ether to give 5-(N-methyl-N-ethoxycarbonylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.82 g) as colorless prisms, m.p. 167-168° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12](=O)[NH:11][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:9][C:8]=1[C:17]([OH:19])=[O:18].O>C(O)(C)(C)C>[Cl:6][C:7]1[C:8]([C:17]([OH:19])=[O:18])=[N:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:11][C:12]=1[Cl:3]
Reactant: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Phosphorus oxychloride (363 g, 221 mL, 2.37 mol) and 5-chloro-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (169 g, 0.79 mol) were added to a 1-L flask and heated at 90° C. for 5 h. The reaction mixture was cooled to 30° C. and added over 60 minutes into a 2-L jacketed reactor containing a well-stirred mixture of t-butanol (280 mL) and water (750 mL) while maintaining the temperature at 5-10° C. After the addition of the reaction mixture was about 70% complete, the aqueous t-butanol mixture was seeded to initiate crystallization, and the addition of the reaction mixture was continued. At the end of the addition, water (750 mL) was added gradually at 10-15° C., and the mixture was stirred for an additional 1 h. The resulting mixture was cooled to 5° C., filtered, and the collected solid was washed with water (3×50 mL). The resulting wet cake was dried in a vacuum-oven at 60° C. to give 156 g (85% yield) of the title compound as a solid melting at 126-127° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].[N-:31]=[N+:32]=[N-:33].[Na+].[NH4+].[Cl-]>CN(C=O)C>[F:30][C:2]([F:29])([F:1])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]4[NH:33][N:32]=[N:31][N:28]=4)=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Temperature: 120 °C

Procedure:
To a solution of Compound 5e (0.232 g, 0.56 mmol) in DMF (5 mL) were added NaN3 (0.11 g, 1.69 mmol) and NH4Cl (0.09 g, 1.68 mmol). The reaction mixture was heated at 120° C. for 14 h, and then cooled to room temperature. An insoluble material was collected by filtration and washed with DMF (5 mL). The filtrate was acidified with 2N HCl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (10 mL), dried (MgSO4), and concentrated to give the title compound 5f which was used for subsequent reactions without further purification. MS m/z (MH+) 453.9.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[C:4]([F:15])[N:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[CH2:18]([N:8]([C:7]1[C:2]([Br:1])=[N:3][C:4]([F:15])=[CH:5][CH:6]=1)[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: O=C(Nc1ccc(F)nc1Br)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCN(C(=O)C(F)(F)F)c1ccc(F)nc1Br
Yield: 86.7 %

Procedure:
A solution of N-(2-bromo-6-fluoropyridin-3-yl)-2,2,2-trifluoro-acetamide (9.16 g, 31.9 mmol), allyl bromide (6.18 g, 47.9 mmol) and sodium carbonate (8.82 g, 63.8 mmol) in CH3CN (80 mL) is stirred at 80° C. for 2 h. The reaction mixture is concentrated in vacuo and the residue is purified by silica gel chromatography eluting with 0-60% DCM in heptane to afford N-allyl-N-(2-bromo-6-fluoro-pyridin-3-yl)-2,2,2-trifluoro-acetamide (9.05 g) as an oil. 1H NMR (300 MHz, CDCl3) δ 3.68 (q, H), 5.01 (q, H), 5.17 (d, H), 5.29 (d, H), 6.85(m, H), 7.00 (dd, H), 7.64(t, H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].CC([O-])(C)C.[K+]>CN1C(=O)CCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ncc([N+](=O)[O-])cc1C#Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cnc2[nH]c(-c3ccccc3)cc2c1
Temperature: 90 °C
Yield: 45.2 %

Procedure:
A solution of 5-nitro-3-(phenylethynyl)pyridin-2-amine (356 mg, 1.0 eq.) in NMP (6 mL) was treated with KOt-Bu (2.2 eq.), and the solution was heated to 90° C. for 48 hours. The reaction mixture was purified directly by silica gel chromatography (eluting with a gradient of 100% hexanes to 40% EtOAc/hexanes) to afford 5-nitro-2-phenyl-1H-pyrrolo[2,3-b]pyridine (161 mg, 45%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:11][CH:12]([CH:15]=O)[CH:13]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[Br:11][C:12]1[CH:13]=[N:10][C:8]2[N:7]([N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)[CH:15]=1
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CC(C)(C)c1cc2ncc(Br)cn2n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
3-tert-Butyl-1H-pyrazol-5-amine (9 g, 64.7 mmol) was dissolved in BuOH (100 ml). 2-Bromomalonaldehyde (9.76 g, 64.7 mmol) and p-TsOH*H2O (615 mg, 3.23 mmol) were added at room temperature. The mixture was stirred for 16 hours at 100° C. The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel (120 gr, 0% to 40% EtOAc in heptane) and crystallization with a small volume of diisopropylether. The crystals were washed with diisopropylether and dried for 1 hour at 50° C. and <20 mbar. The desired compound was obtained as a light yellow solid (9.5 g, 58% yield), MS: m/e=256.1/254.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:9]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:22][CH2:21]2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:9]([N:20]2[CH2:21][CH2:22][CH:23]([CH2:26][C:27]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:29])[CH2:24][CH2:25]2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:6]
Reactant: O=C(O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Reactant: CN1CCCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(-c4ccccc4)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of 0.035 g (0.078 mmol) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.044 g (0.39 mmol) of 1-methyl homopiperazine, 0.032 g (0.10 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.032 mL (0.23 mmol) of triethylamine in N,N-dimethylformamide (2 mL) are stirred overnight at room temperature. The mixture is concentrated under reduced pressure and the residue is diluted with water which causes a solid to precipitate from solution. The colorless solid is collected by filtration, washed with water and dried to provide 0.032 g (75%) of 3-chloro-N-(2-{4-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]piperidin-1-yl}-5-phenylpyridin-3-yl)benzamide (124) as a colorless solid. [M+H]+=546.3.