Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[S:15])[NH2:14])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].N1C=CC=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[S:15][CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]=3)[CH:10]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc(Cn2cc(C(N)=S)cn2)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(-c2cnn(Cc3ccc(OC)cc3)c2)n1
Yield: 57.7 %

Procedure:
According to Scheme 1 Step 5: A solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide (26.7 mmol, 6.60 g), ethyl 3-bromo-2-oxopropanoate (29.4 mmol, 4.62 mL) and pyridine (29.4 mmol, 2.37 mL) in acetone (53 mL) was stirred at room temperature for 2 hours and at 45° C. for 52 hours. After evaporation, the crude residue was partitioned between EtOAc and a saturated solution of Na2CO3. The aqueous phase was extracted with EtOAc and then with DCM. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel using DCM/EtOAc (100:0 to 70:30) to yield ethyl 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (15.4 mmol, 5.28 g, 58%) as a dark oil.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: OB(O)c1ccc(O)cc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(O)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-hydroxybenzene-boronic acid gives “A72”; method 1: HPLC/MS: 1.07 min, [M+H]=307;
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]([C:17]1[NH:21][N:20]=[C:19]([NH:22][C:23]2[C:24]3[CH2:40][CH2:39][CH2:38][C:25]=3[N:26]=[C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[C:34](OC)=[O:35])[N:28]=2)[CH:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:34]([C@@H:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:27]2[N:28]=[C:23]([NH:22][C:19]3[CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[NH:21][N:20]=3)[C:24]3[CH2:40][CH2:39][CH2:38][C:25]=3[N:26]=2)=[O:35])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (6.05 g, 13 mmol) in dry THF (100 mL) was added 2M solution of isopropylmagnesium chloride in THF (27 mL, 54 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (5 g, 13 mmol) in THF (20 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL). The product was extracted with EtOAc (2×40 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave solid residue which was purified by column chromatography on silica gel using 1-2% MeOH-DCM system as eluent followed by chiral purification to afford (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (2.2 g). 1H NMR (CDCl3, freebase) δ (ppm): 1.22 (d, 6H), 1.90-2.21 (m, 6H), 2.60-2.70 (m, 1H), 2.72 (t, 2H), 2.88 (t, 2H), 2.81-2.96 (m, 1H), 3.60-3.80 (m, 2H), 4.77 (d, 2H), 6.40 (s, 1H), 6.74 (s, 1H), 6.82 (d, 1H), 7.90 (s, 1H), 8.13 (s, 1H). The other enantiomer was prepared using the (R) chiral starting material.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][CH:11]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:12]([OH:27])[C:13]([N:15]1[CH2:26][CH2:25][CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:2][C@H:3]([C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:12]([OH:27])[C:13]([N:15]1[CH2:26][CH2:25][CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=Cc1ccccc1
Agent: Cl
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NCc1ccccc1
Yield: 91.5 %

Procedure:
Following a procedure similar to that described in Example 67, but using 500 mg (1.01 mmol) of 1-[3-(L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride and 123 μl (1.21 mmol) of benzaldehyde, 510 mg of the title compound were obtained as a colorless powder, melting at 96°-99° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:17]2[C:18]([Cl:25])=[C:19]([Cl:24])[C:20]([OH:23])=[C:21]([Cl:22])[C:16]=2[O:15][N:14]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:23][C:20]1[C:19]([Cl:24])=[C:18]([Cl:25])[C:17]2[C:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[F:6])=[N:14][O:15][C:16]=2[C:21]=1[Cl:22])[CH3:32]
Reactant: Oc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(Cl)c(Cl)c2c(-c3ccccc3F)noc2c1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 12.5 g of 3-(2-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole is added 80.0 g of pyridine hydrochloride. The mixture is immersed in an oil bath at 200° C. for thirty minutes with stirring. The melt is poured into one liter of iced-hydrochloric acid solution, stirred for thirty minutes, and the resultant precipitate collected and dried to yield 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, mp 110° C. (dec). To 50 ml of dry dimethylformamide is added 12 g of 3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, 4.4 ml of ethyl bromoacetate and 20 g of potassium carbonate. The reaction is stirred at 70° C. for 2 hrs, filtered and solvent evaporated to afford an oil, which is stirred with 500 ml water for ten minutes and then extracted with ether/ethyl acetate. The organic extract is washed with water (2X), saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate followed by recrystallization from 95% ethanol yields ethyl{[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}acetate, mp 140°-3° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>CCO.[Pd]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([CH:15]=[CH:14][CH:13]=2)[NH2:1])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(CN2CCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CN2CCCC2)c1
Yield: 70 %

Procedure:
1-(Bromomethyl)-3-nitrobenzene (51; 5 g, 23.1 mmol) was taken up in 100 mL of anhydrous THF along with pyrrolidine (2.3 mL, 27.72 mmol) and K2CO3 (4.8 g, 34.6 mmol). The reaction mixture was stirred at room temperature for 18 h and then filtered. The filtrate was concentrated under reduced pressure to afford 1-(3-nitrobenzyl)pyrrolidine 52. This material 52 was taken up in 100 mL of absolute EtOH and 10% Pd on C (300 mg) was added. The resulting reaction mixture was stirred at room temperature under 1 atm of hydrogen for 18 h. The mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 2.81 g of 3-(pyrrolidin-1-ylmethyl)aniline 53 (70%).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19].CC(O)C>CCCCCC>[CH:18]([C@@H:17]([C@H:5]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH:16]=[O:21])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])/C=C/c1cccc2ccccc12
Reactant: CC(C)CC=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC(C)[C@H](C=O)[C@@H](C[N+](=O)[O-])c1cccc2ccccc12

Procedure:
The title compound was prepared from (E)-1-(2-nitrovinyl)naphthalene and isovaleraldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 254 nm (2-propanol:hexane=10:90), 1 mL/min, tmajor=13.7 min, tminor 16.8 min, the diastereomeric ratio was determined by
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1cc(C(=O)NCCCN2CCCC2)[nH]c1C=O
Product: Cc1cc(C(=O)NCCCN2CCCC2)[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Yield: 17.3 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.16 g, 0.76 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (0.2 g, prepared by method C) to give 60 mg (17%) of the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:13][C:12]2([Cl:15])[Cl:14])=[CH:7][C:5]([NH2:6])=[C:4]([F:16])[CH:3]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>C(O)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:13][C:12]2([Cl:14])[Cl:15])=[CH:7][C:5]([N:6]2[C:20](=[O:21])[C:19]3[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=3[C:17]2=[O:22])=[C:4]([F:16])[CH:3]=1
Reactant: Nc1cc(OCC2CC2(Cl)Cl)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OCC2CC2(Cl)Cl)c(Cl)cc1F
Temperature: 0 °C

Procedure:
8.9 g (0.031 mol) 4-Chloro-2-fluoro-5-(2,2-dichlorocyclopropylmethoxy) aniline was dissolved in 12.5 ml acetic acid and 3.85 g 3,4,5,6-tetrahydrophthalic anhydride added. The mixture was heated under reflux for 3 hours, then poured into ice-water and extracted with ether. The ether phase was neutralised with aqueous sodium hydrogen carbonate, washed with saturated brine, dried over magnesium sulphate and the solvent removed. The residue was chromatographed on silica gel using a mixture of 9 parts hexane and 1 part ethyl acetate as eluent.
Reaction SMILES: C1(C)C=CC(S(OC[CH:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3C=[CH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)(=O)=O)=CC=1.[C:28]([O-:31])(=O)[CH3:29].[Na+]>C(O)(=O)C>[OH:31][C:28]1[C:29]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:18]=[CH:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2c3ccccc3C=Cc3ccccc32)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OC1=Cc2ccccc2C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 5-p-toluenesulphonyloxymethyldibenzo[a,d]cycloheptene (17 g) in glacial acetic acid (150 ml) was added anhydrous sodium acetate (8.2 g) and the solution refluxed with stirring for 4 h. The solvents were removed in vacuo, the residue dissolved in methanol (100 ml), cooled to 0° C. and enough solid potassium hydroxide added to give pH 14. The suspension was stirred at room temperature for 2 h. then the methanol was removed in vacuo and the residue Partitioned between ether (200 ml) and water (50 ml). The organic layer was washed three times with water (50 ml), then dried and evaporated to qive the crude alcohol which was crystallised from n-hexane/5% ethyl acetate (10.2 g), mp 120°-1° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C1CNCCN1
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCN4CCNCC4)c23)ccc1OCc1ccccn1
Yield: 42 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and piperazine to give the title compound in 42% yield; NMR Spectrum: 2.40 (br s, 4H), 2.64-2.65 (m, 4H), 2.75 (t, 2H), 4.41 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.55-7.58 (m, 2H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.51 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 481 (MH+).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C([Li:24])CCC.CCCCCC>CCOCC>[C:3]1([Li:24])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:2]=1
Reactant: [Li]CCCC
Reactant: Brc1ccc2c3ccccc3c3ccccc3c2c1
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1cccc2c3ccccc3c3ccccc3c12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a suspension of 2-bromotriphenylene (7.28 g, 23.70 mmol) in ether (50 mL) was added n-butyllithium solution in hexane (14.81 mL, 23.70 mmol) dropwise at −78° C. The suspension was gradually warmed to 0° C. and stirred for 3 hours to yield a solution of triphenylenyllithium. In a separate flask a solution of 3-bromophenyllithium was prepared by dropwise addition of n-butyllithium solution in hexane (14.81 mL, 23.70 mmol) into a solution of 1,3-dibromobenzene (2.87 mL, 23.70 mmol) in ether (50 mL). The solution was stirred at this temperature for 2.5 hours before being transferred into a solution of dichlorodiphenylsilane (4.88 mL, 23.70 mmol) in ether (30 mL) at −78° C. After stirring for another 2 h, the triphenylenyllithium solution prepared above was introduced dropwise into the flask containing the dichlorophenylsilane. The reaction mixture was allowed to gradually warm to room temperature and was stirred overnight. The mixture was quenched with water and the organic phase was isolated. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (85/15, v/v) as eluent to yield (3-bromophenyl)diphenyl(triphenylen-2-yl)silane (8.5 g, 75%) as a white powder.
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]([CH3:9])([CH3:8])[C:5]#[C:6][Cl:7].[C:10]1([O-:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CN(C)C=O>[Cl:7][CH:6]=[C:5]([O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([CH3:9])([CH3:8])[C:3]#[CH:2]
Reactant: [O-]c1ccccc1
Reactant: CC(C)(C#CCl)C=CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)C(=CCl)Oc1ccccc1
Reaction time: 4 h
Yield: 63.9 %

Procedure:
163 g (1 mole) of 1,5-dichloro-3,3-dimethyl-pent-1-en-4-ine and 232 g (2 moles) of sodium phenolate in 1 liter of absolute N,N-dimethylformamide are heated to 140° C. in the course of 3 hours and stirring is then continued for 4 hours. The mixture is worked up as described for method A, giving 204 g of crude product, which after distillation (boiling point 0.15/87°-94° C.) gives 141 g (that is to say 64% of theory) of 1-chloro-3,3-dimethyl-2-phenoxy-pent-1-en-4-ine.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:22])(C)(C)C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:22])[NH:13]2
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Reactant: CC(C)(C)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Yield: 97 %

Procedure:
4-(2,3-difluoro-phenyl)-1H-indole 6c (744 mg, 3.25 mmol) was dissolved in 12 ml of ethanol under stirring, and added successively with tert-butanol (21 ml), glacial acetic acid (6.4 ml) and pyridinium tribromide (3.12 g, 9.7 mmol) at room temperature. Upon completion of the addition, the reaction mixture was stirred for 3 hours, added with glacial acetic acid (16 ml) and zinc dust (1.1 g, 16.25 mmol), and stirred for another 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was added with ethyl acetate (30 ml), washed successively with water (10 ml), saturated sodium bicarbonate solution (10 ml) and saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d (780 mg, yield 97%) as a white solid.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:13][C:14]([F:19])([F:18])[C:15](Cl)=[O:16].C(N(CC)CC)C>C(OCC)C>[C:1]12([CH2:11][O:12][C:15](=[O:16])[C:14]([Br:13])([F:19])[F:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(Cl)C(F)(F)Br
Reactant: OCC12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)Br
Temperature: 0 °C
Yield: 95 %

Procedure:
Into a 50-L reaction vessel, 476 g (3.18 mol, 1.11 eq) of 1-adamantanemethanol and 5.5 kg of diethyl ether were added. The resulting solution was suspended by stirring, followed by adding thereto 615 g (2.86 mol, 1.0 eq) of bromodifluoroacetyl chloride. The suspended solution was cooled down to 0° C. Then, 578 g (5.72 mol, 2.0 eq) of triethylamine was slowly dropped to the cooled suspended solution. This reaction solution was left, while stirring, until it reached room temperature. The reaction solution was further stirred for 1 hour at room temperature. Subsequently, the reaction solution was washed with 5 kg of water. The thus-obtained organic layer was washed with 5 kg of saturated sodium hydrogencarbonate solution, with 5 kg of saturated sodium chloride solution, and then, with 5 kg of water. The washed organic layer was dried with magnesium sulfate and subjected to solvent distillation. With this, 878 g of target bromodifluoroacetic acid adamantane-1-ylmethyl ester was obtained (yield: 95%, purity: 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15](=O)OC(C)(C)C)=[N:7][CH:8]=1)#[N:2].ClC[C:24](Cl)=[O:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:25]=[C:24]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[CH2:10][CH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccc(C#N)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCNCC2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TEA (1 eq) was added dropwise to a solution of tert-Butyl (2-{[2-(5-cyanopyridin-2-yl)ethyl]amino}ethyl)carbamate (1 eq) and chloroacetyl chloride (1 eq) in 200 mL of DCM at 0° C. The mixture was stirred at room temperature for 30 minutes and washed with water and brine, dried over anhydrous Na2SO4 and condensed under vacuum. The resulting solid (1.0 g, 2.7 mmol) was added to the mixture of 10 mL TFA and 10 mL of DCM and stirred at RT for 1 hour then concentrated by vacuum. The residue was re-dissolved in CH3CN, K2CO3 was added and the mixture was stirred at RT for 2 hours. The mixture was poured into water and extracted with EtOAc twice. The combined organic layers were concentrated and the residue was purified by flash chromatography (DCM:MeOH=10:1) to afford the title compound 1H-NMR (400 MHz, CDCl3) δ ppm 8.74 (d, J=1.6 Hz, 1H), 7.81-7.83 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.71 (t, J=7.2 Hz, 2H), 3.42 (d, J=7.2 Hz, 2H), 3.24 (t, J=5.6 Hz, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.98 (t, J=5.6 Hz, 2H).
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]2[N:18]=[C:17]([C:19]([O:21]C)=O)[C:16]([O:23]CC3C=CC(OC)=CC=3)=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:7][CH2:6][N:5]1[CH3:33])(=[O:3])[CH3:2].O.[C:35](O)([C:37]([F:40])(F)F)=O>C(#N)C>[C:1]([N:4]1[CH:8]([C:9]2[N:18]=[C:17]([C:19]([NH:14][CH2:15][C:10]3[CH:11]=[CH:35][C:37]([F:40])=[CH:8][CH:9]=3)=[O:21])[C:16]([OH:23])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:7][CH2:6][N:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1nc(C2CCN(C)N2C(C)=O)c2cccnc2c1OCc1ccc(OC)cc1
Solvent: CC#N
Solvent: O
Product: CC(=O)N1C(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)CCN1C
Temperature: 120 °C

Procedure:
A solution of the above acetylpyrazolidine (50 mg, Step 1), water (0.25 mL), and TFA (0.15 mL) in acetonitrile (5 mL) was stirred at room temperature for 6 hours. The resultant mixture was concentrated under vacuum. Residual water and TFA was removed by co-evaporation with additional acetonitrile (3×5 mL). Without further purification, the residual oil was treated with 4-fluorobenzylamine (0.2 mL) in a mixture of methanol (1 mL) and toluene (8 mL) in a sealed tube was heated in an oil bath at 120° C. for 2 hours. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO, and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].Cl.[O:27]1[CH2:32][CH2:31][CH:30]([NH:33][NH2:34])[CH2:29][CH2:28]1>>[CH3:25][O:24][C:22]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:15][N:14]1[C:16]1[N:33]([CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[N:34]=[C:18]([CH3:19])[CH:17]=1)=[O:23]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNC1CCOCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCOCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with (tetrahydropyran-4-yl)hydrazine hydrochloride (CAS Reg. No. 194543-22-1) to give the title compound as orange oil. MS (ESI): m/z=468.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.O>[Br:16][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][N:11]2[CH2:13][CH2:14][CH2:15][C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2cc3n(n2)CCC3)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1ccc(-c2nn3c(c2Br)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (44.5 g, 0.22 mol) in 600 mL chloroform is added at 0° C. N-bromosuccinimide (117 g, 0.66 mol). The mixture is stirred 17 h at RT. Thereafter, the mixture is diluted with water and extracted with dichloromethane. The combined organic phases are dried and evaporated. The obtained crude material is purified by column chromatography on silica (6 cm×40 cm, eluent dichloromethane). The obtained product is further purified by trituration with a MTBE-hexane mixture and 38.2 g (61%) of the product are obtained as solid.