Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(O[C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[Cl:26])=C(F)C(F)=C(F)C=1F.[NH2:32][O:33][CH2:34][CH2:35][OH:36].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:26][C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=1[NH:18][C:11]1[C:12]([F:17])=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9]([NH:32][O:33][CH2:34][CH2:35][OH:36])=[O:27]
Reactant: NOCCO
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Yield: 89.6 %

Procedure:
To a solution of 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid pentafluorophenyl ester (10.0 g, 17.4 mmol) in anhydrous dimethylformamide (36 mL) was added 2-(aminooxy)-ethanol (1.6 g, 20.8 mmol) and N,N-diisopropylethylamine (6.0 mL, 34.8 mmol). The resultant solution was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to 20% volume then diluted with ethyl acetate (360 mL). The resultant solution was washed with water (6×60 mL) and brine (2×60 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a white solid that was purified on silica gel. Elution with ethyl acetate-methanol (9:1) afforded 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (7.31 g, 90%) as a white solid. Recrystallization from methanol afforded analytically pure material, identical in all respects to the material prepared by method A.
Reaction SMILES: [C:1](/[C:3](=[CH:9]/OCC)/[C:4]([O:6]CC)=[O:5])#[N:2].[CH:13]([NH:16][NH2:17])([CH3:15])[CH3:14]>C(O)C>[NH2:2][C:1]1[N:16]([CH:13]([CH3:15])[CH3:14])[N:17]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCO/C=C(/C#N)C(=O)OCC
Reactant: CC(C)NN
Solvent: CCO
Product: CC(C)n1ncc(C(=O)O)c1N
Temperature: 25 °C
Yield: 26.5 %

Procedure:
To a solution of ethyl (2Z)-2-cyano-3-(ethyloxy)-2-propenoate (114.2 g, 0.67 mol) in ethanol (250 mL) was slowly added isopropylhydrazine (55 g, 0.74 mol) in a dropwise manner. The mixture was heated at reflux for 4 h, and then cooled to room temperature. The mixture was concentrated in vacuo. Approximately half of the crude 5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (50 g) was suspended in an aqueous solution of sodium hydroxide (4M, 130 mL), and stirred with heating at reflux for 2 h. The reaction mixture was then cooled to room temperature and adjusted to pH=3.5 with concentrated HCl, wherein precipitate formation ensued. The solid was collected by filtration and dried in vacuum oven overnight to afford crude 5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid (30 g). The solid was suspended in diphenyl ether (120 mL) and stirred with heating at 160-165° C. for 2 h. The solution was then cooled to room temperature and the solvent removed in vacuo. The crude product was purified by silica gel chromatography (eluent: petroleum ether/EtOAc=1:1) to afford the product as 12 g. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (d, 6H, J=6.4 Hz), 4.32 (m, 1H), 5.06 (s, 2H), 5.21 (s, 1H), 7.00 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@@H:4]([CH3:7])[CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OC(=O)CC(C)=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:8])[C@@H:4]([CH3:7])[CH2:5][O:6][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](C)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(=O)CC(C)=O
Product: COC(=O)[C@@H](C)COS(C)(=O)=O
Reaction time: 1 h
Yield: 100 %

Procedure:
3 g (25.3 mmol) of (S)-3-hydroxy-2-methyl-propionic acid methyl ester was dissolved in dichloromethane 50 mL, then 5.3 mL (37.9 mmol) of triethylamine was dropwise added thereto. Thereafter, 2.16 mL (27.9 mmol) of methanesulfonyl chloride was added to the solution at 0° C. After 1 hour, 200 mL of ethylacetoacetate was added to the solution and then the reaction solution was washed with water and then an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 4.97 g (25.3 mmol) of the title compound in a yield of 100%.
Reaction SMILES: [CH:1]1([C@H:7]([NH:28][C:29](=[O:42])[C@@H:30]([N:32]([CH2:40][CH3:41])C(=O)OC(C)(C)C)[CH3:31])[C:8](=[O:27])[N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C@H:10]2[C:18](=[O:26])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]1([NH:19][C:18]([C@H:10]2[N:9]([C:8](=[O:27])[C@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[NH:28][C:29](=[O:42])[C@@H:30]([NH:32][CH2:40][CH3:41])[CH3:31])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11]2)=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1)C1CCCCC1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl (S)-1-((S)-1-cyclohexyl-2-oxo-2-((S)-2-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethylamino)-1-oxopropan-2-yl(ethyl)carbamate (33 mg, 57.1 μmol, Eq: 1.00) was combined with DCM (3 mL) to give a colorless solution. TFA (1 mL, 13.0 mmol, Eq: 227) was added. After 30 min, the crude reaction mixture was concentrated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)-1-[(S)-2-Cyclohexyl-2-((S)-2-ethylamino-propionylamino)-acetyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid phenylamide as a white solid (23 mg), m/z=478 (M+H).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](Cl)=[O:11])[CH3:8].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:11])[NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8]
Reactant: NC1CCCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)NC1CCCC1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of cyclopentylamine (5.8 mL, 59 mmol, 1.0 eq.) in CH2Cl2 (250 mL) at room temperature was added ethylchloroformate (7.3 mL, 1.3 eq.) followed by an aqueous solution of K2CO3 (37 g in 500 mL of H2O). The mixture was stirred vigorously for 1 h. The separated aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated to give cyclopentyl-carbamic acid ethyl ester (9.6 g, 88%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[CH:25]=[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[CH:25]=[C:13]2[C:14]([C@@H:18]3[CH2:4][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1
Reactant: CCOC(=O)/C=C/c1cccn2nc(C)cc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.64 g, 41.0 mmol) in dimethyl sulfoxide (30 mi.') was added trimethylsulfoxonium iodide (9.01 g, 41.0 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methylpyrazolo[1,5-a]pyridin-4-yl)acrylate (7.86 g, 34.1 mmol) in dimethyl sulfoxide (120 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (5.10 g, yield 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].C([Li])(C)(C)C.CCCCC.CN(C)[CH:25]=[O:26]>C1COCC1>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:25]=[O:26])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCc1n[nH]c2ccc(C=O)cc12

Procedure:
A solution of 6.90 g (30.7 mmol) 5-bromo-3-ethyl-1H-indazole (Example 7A) in THF (300 ml) was cooled to −78° C. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (63.1 ml, 107 mmol) was slowly added. The mixture was stirred at −78° C. for 30 minutes before N,N-dimethylformamide (80.0 ml) was slowly added. The cooling bath was removed, and stirring was continued until room temperature was reached. Then, water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.5 g (84% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])[CH3:3].[CH:16]1[N:24]2[C:19]([C:20]3([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[OH:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:31]2[CH2:30][CH2:29][C:20]3([O:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]4[CH:16]=[CH:17][CH:18]=[C:19]34)[CH2:33][CH2:32]2)=[O:11])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)O
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-benzoic acid (120 mg, 0.573 mmol), spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (167 mg, 0.573 mmol), triethylamine (320 μL, 2.29 mmol), and EDC (110 mg, 0.573 mmol) were combined in DCM (5.8 mL). The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to provide (4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 432.0. found 433.1 (M+1)+; Retention time: 1.61 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH2:27][CH2:28][CH2:29][OH:30]>O>[OH:30][CH2:29][CH2:28][NH:27][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Reactant: NCCO
Solvent: O
Product: O=C(NCCO)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 145 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A mixture of 10.7 parts of methyl 4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzoate and 8 parts of 2-aminoethanol was stirred for 4 hours in an oil bath at 145° C. After cooling, the reaction mixture was poured into water. The oil was decanted, washed twice with water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2-oxybispropane and 2-propanol. The product was filtered off and dried yielding 8 parts (69.3%) of N-(2-hydroxyethyl)-4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzamide; mp. 161.1° C. (int. 80).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18](=[O:25])[N:19]4[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]4)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH:31]([B-](F)(F)F)=[CH2:32].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:25]=[C:18]1[N:19]2[C:24]([CH:23]=[CH:22][CH:21]=[CH:20]2)=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH:31]=[CH2:32])[CH:7]=3)[CH2:9][CH2:10]2)[CH:16]=[C:17]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C=C[B-](F)(F)F
Reactant: CCOC(=O)c1cc(CN2CCN(c3ccnc(Cl)c3)CC2)c2ccccn2c1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cc(N2CCN(Cc3cc(C(=O)OCC)c(=O)n4ccccc34)CC2)ccn1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 1-{[4-(2-chloropyridin-4-yl)piperazin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate (0.500 g, 1.17 mmol), potassium vinyltrifluoroborate (0.471 g, 3.51 mmol), and 1N cesium carbonate (2.34 mL, 2.34 mmol) in 5 mL of THF under nitrogen was added bis(tri-tert-butyl-phosphine)palladium(0) (10 mol %). The reaction mixture was stirred at 130° C. for 5 hours, then cooled to room temperature. The mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-5% MeOH in DCM to provide ethyl 4-oxo-1-{[4-(2-vinylpyridin-4-yl)piperazine-1-yl]methyl}-4H-quinolizine-3-carboxylate that gave a mass ion (ES+) of 419.0 for M+H+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH:9]=O)[CH:5]=[CH:4][N:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.[BH4-].[Na+].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][NH:14][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(C=O)ccnc1Cl
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(CNC2CC2)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 2-chloro-3-methylpyridine-4-carbaldehyde (58.35 g, 375 mmol) and cyclopropylamine (52.6 mL, 750 mmol) in MeOH (800 mL) was stirred overnight at rt. The mixture was cooled to 0° C. and NaBH4 (18.4 g, 488 mmol) was added portionwise. The mixture was stirred overnight at rt. Aq. 1M NaOH (250 mL) was added and the solvents were partially removed under reduced pressure. The aq. phase was extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification fy FC yielded the compound (54.56 g, 74%) as a pale yellow liquid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH3:14])=[CH:18][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNCc2ccc(F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (0.518 g, 2 mmol, Trans World Chemicals) in THF (10 mL) at room temperature was added (4-fluorophenyl)methanamine (1.00 g, 8.00 mmol, Aldrich) and triethylamine (0.56 mL, 4 mmol). The reaction mixture was stirred at rt for 1 h and quenched by the addition of 5 mL of saturated aq. NaHCO3 solution. The resulting mixture was extracted with DCM (3×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (ISCO system, eluting with CH2Cl2/EtOAc) to give the desired compound (0.35 g, 57%) as a white solid. 1H NMR (CD3OD) δ 7.64 (d, 1H, J=6.0 Hz), 7.60 (s, 1H), 7.40 (d, 2H, J=7.7 Hz), 7.36 (d, 1H, J=6.0 Hz), 7.08 (t, 211, J=7.7 Hz), 3.97 (s, 3H), 3.96 (s, 3H), 3.82 (s, 2H), 3.76 (s, 2H). MS (ESI): 304.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]#[N:14])=[CH:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]3[NH:27][N:26]=[N:25][N:14]=3)=[CH:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)sc2-c2ccc(F)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cc(-c3nnn[nH]3)sc2-c2ccc(F)cc2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonitrile (3.1 g), sodium azide (1.3 g) and ammonium chloride (1.5 g) in N,N-dimethylformamide (30 ml) was stirred at 120° C. for 24 hours. The mixture was poured into ice-water, and the resulting mixture was acidified. The precipitates were collected and recrystallized from ethanol to give crystals of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(5-tetrazolyl)thiophene (0.9 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[N:25]([CH3:29])[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[N:25]([CH3:29])[C:26](=[O:28])[N:27]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:23]=2[CH:22]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: Cn1c(=O)[nH]c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)n(C)c4ccc(Cl)cc43)CC2)ccc1Cl

Procedure:
33 mg of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (0.18 mmol, 1.00 equiv), 58 mg of 5-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one (0.19 mmol, 1.05 equiv), 100 mg of K2CO3 (0.72 mmol, 4.0 equiv), and 0.8 mL of NMP were combined in a 4 mL vial. The resultant mixture was heated at 60° C. in an oil bath overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1-methyl-1,3-dihydro-benzoimidazol-2-one (66): HPLC retention time=2.40 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected=449.0, found=449.1.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>>[CH3:23][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH2:18][CH2:19]1
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCN(C)CC1
Yield: 23 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.0 g, 6 mmol) was reacted with 1-(3-aminopropyl)-4-methylpiperazine (1.06 mL) to give 0.38 g (23% yield) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide using General Amidation Procedure 1. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.8 (br s, 1H, NH), 9.52 (s, 1H, CHO), 7.52 (m, 1H, CONH), 3.2 (m, 2H, CH2), 2.8 (m, 2H, CH2), 2.5 (m, 8H, 4×CH2), 2.34 (s, 3H, CH3), 2.29 (s, 3H, CH3), 1.68 (m, 2H, CH2). MS m/z 307 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:39]4[C:34]([Cl:33])=[N:35][CH:36]=[CH:37][CH:38]=4)=[O:41])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a stirred solution of 6.06 g of 10, 11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2, 1-c][1,4]benzodiazepine and 10 ml of N,N-diisopropylethylamine is added a solution of 4.0 g of 2-chloropyridine-3-carbonyl chloride in 25 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with water and the organic layer washed well with water. The organic layer is dried, filtered and evaporated in vacuo to a pale yellow product which is crystallized from 1:1 ethyl acetate:hexane to give 7.0 g of the desired product; M+ =442.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C1(N)CCCCC1N.[NH:21]1[C:25]2=[N:26][CH:27]=[N:28][C:29]([NH2:30])=[C:24]2[CH:23]=[N:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu](I)I.C(OCC)(=O)C>[N:8]1([C:4]2[CH:3]=[C:2]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([NH2:30])=[C:24]4[CH:23]=[N:22]3)[CH:7]=[CH:6][CH:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: Brc1cccc(-n2cccc2)c1
Reactant: Nc1ncnc2[nH]ncc12
Agent: I[Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(-n2cccc2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 5.2 %

Procedure:
1-(3-Bromo-phenyl)-1H-pyrrole (0.3 g, 1.0 eq, 1.35 mmol) and cyclohexane-1,2-diamine (0.03 g, 0.2 eq, 0.27 mmol) were added to a pre-stirred mixture of 1H-Pyrazolo[3,4-d]pyrimidin-4-ylamine (0.22 g, 1.2 eq, 1.62 mmol), copper iodide (0.013 g, 0.5 eq, 0.68 mmol) and potassium phosphate (0.6 g, 2.1 eq, 2.84 mmol) in DMF (8 ml) under an inert atmosphere. The reaction mixture was then stirred at 110° C. for 24 hours, and allowed to cool to room temperature. Ethyl acetate (8 ml) was then added to the reaction mixture which was then filtered through a plug of silica, which was then washed with a further portion of ethylacetate (20 ml). The filtrate was concentrated to dryness in vacuo and the resultant residue was purified by column chromatography using DCM/MeOH (95:5) as eluent to yield the title compound as an off-white solid (18 mg, 0.07 mmol, 5%). LCMS: [M+H]+=277, Rt=1.80 min, 97% purity.