Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([OH:7])[CH2:4]1.[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=12.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-]>C(Cl)Cl.[OH-].[Na+].CO>[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:2][C@H:3]3[CH2:6][C@H:5]([OH:7])[CH2:4]3)[C:12]=12
Reactant: N[C@H]1C[C@H](O)C1
Reactant: O=Cc1cccn2ccnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O[C@H]1C[C@H](NCc2cccn3ccnc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
To an emulsion of trans-3-aminocyclobutanol hydrochloride (287 mg, 2.322 mmol) in DCM (5 mL) was added methanol (20 mL), imidazo[1,2-a]pyridine-8-carbaldehyde (340 mg, 2.326 mmol) and diisopropylethylamine (0.446 mL, 2.55 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 10 min. Sodium triacetoxyborohydride (1000 mg, 4.72 mmol) was then added and the reaction mixture was stirred under nitrogen for 2 hours when LCMS indicated the reaction to be complete. The reaction mixture was then concentrated in vacuo and the residue was taken up in DCM (200 mL) and aqueous 2M sodium hydroxide (200 mL) was added and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed with water (2×200 mL) and the aqueous phase was back extracted using 3:1 chloroform:isopropanol (2×250 mL). The combined organic layers were dried using a hydrophobic frit and the solvent evaporated in vacuo. The residue was pre-absorbed on florosil and purified on a silica cartridge (100 g) using a 0-25% methanol-dichloromethane gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give crude product still containing some borohydride residues. This material was dissolved in aqueous 2M sodium hydroxide (100 mL) and left at room temperature for 5 hours when sodium hydroxide pellets (ca. 0.5 g) was added and the mixture left at room temperature for a further 15 hours. The mixture was then extracted with 3:1 chloroform:isopropanol (2×300 mL) and the organic layer was separated, dried using a hydrophobic frit and the solvent evaporated in vacuo. The residue was dried on a high vacuum line for 2 hours to give the title compound as an orange oil (305 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C@@H:9](CC)C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C(NC([C@H]1N2C(=O)[C@@H](N)CCC(=O)N2CCC1)=O)CC1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)NCCc3ccccc3)N2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 267.3 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl-methyl-amino)-butyric acid (167 mg, 0.77 mmol) in DMF (5 mL) at room temperature, is added diisopropylethylamine (0.48 mL) slowly. After stirring at room temperature for 20 minutes, the solution is transferred to another flask contained (1S,9S)-9-amino-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide (240 mg, 0.70 mmol), and then a solution of HOBT (125 mg, 0.92 mmol) and HBTU (350 mg, 0.92 mmol) in DMF (5 mL) is added to the reaction mixture. After stirring for 1.5 hours, the reaction solution is diluted with ether (20 mL), and washed with water (2×10 mL). The combined organic layers is concentrated. The crude product is diluted with CH2Cl2 (10 mL) and dried over Na2SO4, and purified by chromatography (CH2Cl2/MeOH:97/3) to give (S)-1-((4S,7S)-6,10-dioxo-4-phenethylcarbamoyl-octahydro-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamoyl)-propyl]-methyl-carbamic acid tert-butyl ester (270 mg, 71.3%) as pale solid. (NMR and MS data confirmed, U-3133-69).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially available available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:15][CH2:14]1>CC1C=CC=CC=1>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Reactant: c1ccc2oc(NC3CCNCC3)nc2c1
Solvent: Cc1ccccc1
Product: O=C(NCCN1CCC(Nc2nc3ccccc3o2)CC1)c1ccc(F)cc1
Yield: 34 %

Procedure:
A mixture of 1.65 parts of 1-(4-fluorobenzoyl)aziridine (solution in benzene 1.2M), 2.1 parts of N-(4-piperidinyl)-2-benzoxazolamine and 90 parts of methylbenzene was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The product was filtered off and recrystallized from 2-propanone, yielding 1.3 parts (34%) of N-[2-[4-[(2-benzoxazolyl)amino]-1-piperidinyl]ethyl]-4-fluorobenzamide; mp. 173.3° C. (448).
Reaction SMILES: [N:1]([C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][C@H:5]1[OH:15])=[N+:2]=[N-:3].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:15][C@H:5]2[CH2:6][C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[C@H:4]2[N:1]=[N+:2]=[N-:3])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: COc1ccc2c(c1)[C@@H](N=[N+]=[N-])[C@H](O)C2
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)[C@@H](N=[N+]=[N-])[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
Step AC (3): To a solution of (1R,2R)-1-azido-6-methoxy-2,3-dihydro-1H-inden-2-ol (400 mg) from Step AC (2), 4-nitrobenzoic acid (813 mg), triphenyl phosphine (1.28 g) in benzene (10 mL) at rt was added DEAD dropwise (0.77 mL), and the reaction mixture was stirred at rt for 12 h. Saturated sodium bicarbonate was added, the aqueous layer was separated, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by preparative TLC eluting with 30% EtOAc/70% hexanes to give (1R,2S)-1-azido-6-methoxy-2,3-dihydro-1H-inden-2-yl 4-nitrobenzoate compound as a colorless oil (284 mg). NMR (400 MHz, CDCl3) δ 8.28 (2H, dd), 8.22 (2H, dd), 7.20 (1H, d), 6.93 (2H, m), 7.79 (1H, q), 4.94 (1H, d), 3.83 (3H, s), 3.29 (1H, dd), 3.22 (1H, dd).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:24]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2)[CH3:23])[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCN2
Yield: 98.6 %

Procedure:
To 7.3 g (20.2) 5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 15 ml CH2Cl2, 10 ml trifluoro acetic acid were added at 0° C. The mixture was stirred at reflux for 3 h and was concentrated in vacuo. Water and 2M NaOH were added and the inorganic phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Evaporation yielded 5.2 g (98%) Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine as orange oil, MS: 261 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:12][O:11][C:9](=[O:10])[C:8]([C:4]1[CH:3]=[C:2]([B:15]([OH:19])[OH:16])[CH:7]=[N:6][CH:5]=1)([CH3:14])[CH3:13]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COC(=O)C(C)(C)c1cncc(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)c1cncc(B(O)O)c1
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 53 Step H (0.10 g, 0.39 mmol), bis(pinacolato)diboron (0.12 g, 0.47 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.035 g, 0.039 mmol), tricyclohexylphosphine (0.022 g, 0.077 mmol) and potassium acetate (0.114 g, 1.16 mmol) was added 1,4-dioxane (3.9 mL). The reaction was heated to 80° C. for 16 hours. It was then cooled to room temperature, passed through a syringe filter, and concentrated under reduced pressure to afford the title compound: LCMS m/z 224.19 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][OH:11].C1C=CC=CC=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]3[C:46]4[C:41](=[CH:42][C:43]([O:47][CH3:48])=[CH:44][N:45]=4)[N:40]=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[N:21][N:20]=1>>[CH3:48][O:47][C:43]1[CH:42]=[C:41]2[C:46]([C:37]([S:36][C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:22]4[C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:19]([O:11][CH2:10][CH2:9][CH:4]5[CH2:5][CH2:6][CH2:7][CH2:8][NH:3]5)=[N:20][N:21]=4)=[CH:31][CH:32]=3)=[CH:38][CH:39]=[N:40]2)=[N:45][CH:44]=1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: OCCC1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1cnc2c(Sc3ccc(Nc4nnc(OCCC5CCCCN5)c5ccccc45)cc3)ccnc2c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Sodium Hydride (11 mg, 449 μmol), 2-(piperidin-2-yl)ethanol (58 mg, 449 μmol), and benzene (2243 μl, 449 μmol) were combined in a resealable tube capped with a septum and heated to 40° C. for 30 minutes. 4-Chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (200 mg, 449 μmol) was added, and the reaction mixture was allowed to stir at 80° C. for 18 hours. The mixture was concentrated in vacuo and the crude material was partitioned between methylene chloride and water. The organic layers were combined and over Na2SO4 and concentrated. The crude material was purified via ISCO, 12 g RediSep column eluting with a 20-100% gradient of 90:10:1 (DCM:MeOH:NH4OH) in DCM. The product fractions were combined and concentrated in vacuo to afford N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(2-(piperidin-2-yl)ethoxy)phthalazin-1-amine. MS: [M+H]=539.
Reaction SMILES: [NH2:1][C:2](=[O:38])[CH:3]([OH:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:35]=[C:23]2[CH2:24][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27][C:22]2=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)CCl.ClC(Cl)C(O)=O.C([O-])(O)=O.[Na+]>CS(C)=O.[Cl-].[Na+].O>[NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:35]=[C:23]2[CH2:24][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][CH2:27][C:22]2=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCN(Cc1ccccc1)C2
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.3 %

Procedure:
To a solution of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(5-benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)nicotinamide (45 mg, 0.088 mmol) in DMSO (1200 μL) at room temperature, EDC (160 mg, 0.835 mmol) was added, and after 5 min of stirring 2,2-dichloroacetic acid (40 μL, 0.487 mmol). The mixture was stirred for 45 min at room temperature, and then 10 mL of brine and 10 mL of saturated aqueous NaHCO3-solution were added, the precipitate formed filtered off and dried in vacuo. The yellow solid obtained was crystallized from 2-propanol, the resulting precipitate washed and treated with MTB and n-pentane to afford 27 mg of an off-white amorphous solid; ESI-MS [M+H]+: 509.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.86 (m, 1H), 8.47 (m, 1H), 8.07 (m, 1H), 7.98 (m, 1H), 7.76 (m, 1H), 7.65 (m, 1H), 7.35-7.18 (m, 11H), 5.33 (m, 1H), 4.05 (m, 1H), 3.68 (s, 2H), 3.45-3.16 (m, overlapping with water), 2.91 (dd, 1H), 2.72 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCCCCCC>CC#N>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:16]2[N+:17]([O-:19])=[O:18])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CBr
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CC#N
Solvent: ClCCl
Product: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.6 %

Procedure:
To a solution of N-benzylmaleimide (5.0 g, 26.7 mmol) in MeCN (334 ml) was added bromonitromethane (1.87 ml, 26.7 mmol). K2CO3 (3.69 g, 26.7 mmol) was added and the reaction mixture vigorously stirred at r.t. After 4 h an additional portion of bromonitromethane (0.2 ml) was added. Further addition of bromonitromethane (0.2 ml) was added at further 4 h intervals (×4). After 48 h, TLC (50% DCM/heptane) indicated reaction completion. The reaction mixture was evaporated to dryness. The brown residue was purified by column chromatography (100% DCM), giving the title compound as a white solid (3.0 g, 42%). 1H NMR (300 MHz, CDCl3) δ: 3.35 (2H, s), 4.50 (1H, s), 4.55 (2H, s), 7.2-7.4 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:31][C:26]5([CH3:25])[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CCCC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCCC4)c3n2)c2ccc(F)cc21
Reaction time: 0.15 h
Yield: 22.9 %

Procedure:
A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (62 mg, 0.20 mmol), 1-methylcyclopentanamine hydrochloride (35 mg, 0.26 mmol), HATU (98 mmol, 0.26 mmol) and DIEA (42 mg, 0.33 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure to give a crude product, which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopentyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 22.9%) as an off-white solid. MS: (M+H)+=393; 1H NMR (300 MHz, DMSO): δ 12.84 (s, 1H), 9.09 (s, 1H), 8.49-8.44 (m, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 7.72 (d, 1H, J=7.8 Hz), 7.17 (t, 1H, J=8.1 Hz), 4.17 (s, 3H), 2.19 (brs, 2H), 1.79-1.76 (m, 6H), 1.57 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:49][C:44]1[CH:43]=[C:42]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[CH2:21]2)[CH:47]=[CH:46][C:45]=1[Cl:48]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: CS(=O)(=O)OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[[3,5-bis(trifluoromethyl)phenyl]acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C([O:14][C:15](=O)[CH2:16][C:17]([CH3:19])=O)C>>[CH3:19][C:17]1[CH2:16][C:15](=[O:14])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1

Procedure:
From the reaction of p-hydrazinobenzoic acid and ethylacetoacetate, 4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-propoxyaniline yields 4-(4,5-dihydro-3-methyl-5-oxo-4-(2-propoxyanilinomethylene)-1H-pyrazol-1-yl)-benzoic acid, Mp 259.6° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([S:13]([NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[NH2:19])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([S:13]([NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[NH:19][C:34]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Br:26])=[O:35])(=[O:14])=[O:15])[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:8]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccccc1Br)Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from [2-(3,5-bistrifluoromethylphenyl) sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanate (305 mg, 1.5 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (10 mg, 1%). EI-MS m/z 580 (M−H)−.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[C:5]=1[C:6]([OH:8])=O.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([N:36]2[CH2:43][CH:42]3[CH:38]([CH2:39][NH:40][CH2:41]3)[CH2:37]2)[N:30]=1>CC(O)=O.C1(C)C=CC=CC=1>[CH3:35][C:33]1[CH:34]=[C:29]([CH3:28])[N:30]=[C:31]([N:36]2[CH2:43][CH:42]3[CH2:41][N:40]([C:6]([C:5]4[C:9]([N:13]5[N:17]=[CH:16][CH:15]=[N:14]5)=[CH:10][CH:11]=[CH:12][C:4]=4[F:3])=[O:8])[CH2:39][CH:38]3[CH2:37]2)[N:32]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a 3-necked, 3 L, round-bottomed flask equipped with a nitrogen line, temperature probe, heating mantle, reflux condenser, mechanical stirrer, and 1 N aq. NaOH scrubber were added 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 12, 120.98 g, 75 wt %, 90.74 g actual, 438 mmol) and toluene (1 L). The mixture was warmed to 50° C. for 1 h with stirring. The mixture was then cooled to 25° C. and thionyl chloride (47.9 mL, 657 mmol) was added. The mixture was warmed back to 50° C. and held for 1 h. During this time, in a separate 5 L jacketed reactor equipped with a mechanical stirrer and temperature probe were added toluene (600 mL), aqueous sodium carbonate (185.7 g, 1.75 mol in 1.6 L water), and 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.HOAc (Intermediate 23, 122 g, 438 mmol). This biphasic mixture was cooled to 0° C. After cooling to 0° C., the original slurry was poured through a filter and over the stirring biphasic mixture of amine and aqueous sodium carbonate. The mixture was allowed to warm to room temperature. After 2 h, additional 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.HOAc (4 g, 14 mmol) was added and the mixture was stirred for 30 additional minutes. At the end of this period, the layers were separated and 100 mL of methanol were added to the organic layer. The organic layer was dried over MgSO4, filtered, and concentrated to a white solid. This solid was taken up in ethanol (1.4 L) and warmed to 77° C. The mixture was then cooled to 55° C. and seeded with previously crystallized material. (Note: The seeds were generated from slurrying the initial product in 2-propanol at room temperature [100 mg/mL]). The mixture was cooled to room temperature at a rate of 5° C. per hour. After stirring at room temperature for 14 h, the mixture was filtered and dried to provide the final product as a white crystalline solid (136.84 g, 74%). 1H NMR (400 MHz, CDCl3): 7.88-7.78 (m, 1.78H), 7.75-7.69 (s, 1.22H), 7.51-7.43 (m, 1H), 7.17-7.11 (m, 1H), 6.30-6.28 (m, 1H), 4.03-3.48 (m, 7H), 3.29-3.21 (m, 1H), 3.15-2.92 (m, 2H), 2.30 (s, 6H). MS (ESI) mass calcd for C21H22FN7O, 407.19; m/z found, 408 [M+H]+. Anal. calcd. for C21H22FN7O C, 61.90; H, 5.44; N, 24.06. found C, 61.83; H, 5.42; N, 24.08.