Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]1[C:10]([N+]([O-])=O)=[CH:9][N:8]=[C:7]([C:14]2[CH:15]=[CH:16][C:17]([F:38])=[C:18]([CH:37]=2)[CH2:19][N:20]([CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:6]=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([N:20]([CH2:19][C:18]2[CH:37]=[C:14]([C:7]3[CH:6]=[C:5]4[CH:4]=[CH:3][NH:2][C:10]4=[CH:9][N:8]=3)[CH:15]=[CH:16][C:17]=2[F:38])[CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:29])=[CH:23][CH:24]=1
Reactant: CN(C)/C=C/c1cc(-c2ccc(F)c(CN(CCN3CCCC3)C(=O)c3ccc(F)cc3)c2)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)N(CCN1CCCC1)Cc1cc(-c2cc3cc[nH]c3cn2)ccc1F
Yield: 55.5 %

Procedure:
N-{5-[4-((E)-2-Dimethylamino-vinyl)-5-nitro-pyridin-2-yl]-2-fluoro-benzyl}-4-fluoro-N-(2-pyrrolidin-1-yl-ethyl)-benzamide (485 mg, 0.9 mmol) in 30 mL of ethyl acetate was treated with 100 mg of 10% Pd/C under 3 bar of hydrogen for 18 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was chromatographed (alumina, elution with 2% methanol/dichloromethane) to afford 230 mg of product. LC/MS: Retention time, 1.79 min; (M+H)=461. 1H NMR (400 MHz, DMSO-D6) δ ppm: 1.61 (br s, 4H) 2.37 (br ss, 2H) 2.56-2.71 (br s, 2H) 3.45 (t, J=6.26 Hz, 2H) 4.75 (s, 2H) 6.55 (s, 1H) 7.17-7.28 (m, 3H) 7.45-7.52 (m, 2H) 7.56 (t, J=2.64 Hz, 1H) 8.00 (ddd, J=8.30, 5.44, 2.31 Hz, 2H) 8.07 (d, J=7.47 Hz, 1H) 8.82 (s, 1H) 11.40 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:10]1[CH:15]=[C:14]([CH2:16][C@H:17]2[C@@H:21]([CH2:22][OH:23])[O:20][C:19]([CH3:25])([CH3:24])[N:18]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:13]=[CH:12][N:11]=1>CN1C(=O)CCC1.CCOC(C)=O>[OH:23][CH2:22][C@H:21]1[O:20][C:19]([CH3:24])([CH3:25])[N:18]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[C@H:17]1[CH2:16][C:14]1[CH:15]=[CH:10][N:11]=[C:12]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO)OC1(C)C
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(OCC(F)(F)F)c2)[C@@H](CO)OC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (60% by weight in mineral oil) (0.672 g, 16.8 mmol) was added carefully to trifluoroethanol (20.0 ml, 276 mmol) cooled at 0° C. and then stirred at RT for 30 minutes. The resulting solution is added to (4S,5S)-tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (0.400 g, 1.12 mmol) dissolved in 10 mL of NMP and the resulting solution was microwaved for 30 minutes fixed at 180° C. The reaction was diluted with EtOAc and washed repeatedly with water. The combined aqueous layers were back extracted with EtOAc and the combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The product was purified by silica gel chromatography (2:1 to 1:1 Hexanes/EtOAc) to afford the title compound. MS m/z: 421.3 (100%, M+1).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12]>CC(O)(C)C>[CH3:14][O:13][C:11]([CH:10]([C:9]([O:16][CH3:17])=[O:15])[C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:1](=[O:8])[CH2:2]1)=[O:12]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C1C=CCCCC1
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)[C@@H]1CCCCC(=O)C1
Temperature: 30 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=100) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 111 μL (1.0 mmol) of 2-cycloheptenone, 114 μL (1.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 72 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 181 mg (75% yield) of the title compound. The optical rotation [α]D27 was +45.2 (c 1.76, CHCl3). This was reacted with (2R,3R)-butanediol in the presence of a catalytic amount of p-toluenesulfonic acid so as to be converted into a ketal derivative. The 13C NMR spectrum of this derivative was measured, and the optical purity was determined from the ratio of the integrals of the peaks of two diastereomers, with the result that it was >99% ee.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH:3]1[CH2:7][N:6]2[C:8](=[O:28])[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[N:5]2[CH2:4]1.[CH3:30][C@H:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:29])[CH:3]1[CH2:7][N:6]2[C:8](=[O:28])[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:38][C@H:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:30])[N:12]=3)[N:5]2[CH2:4]1
Reactant: CN(C)C1Cn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Reactant: C[C@H](N)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC(N(C)C)C3)n1)c1ccccc1
Temperature: 140 °C

Procedure:
A solution of the crude 6-dimethylamino-2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 25, prepared as described herein above (4.2 g, 10 mmol) and (S)-(−)-α-methyl-benzyl amine (45.2 mL, 351 mmol) are dissolved in toluene (100 mL). The resulting mixture is heated to 140° C. for 12 hours, cooled to room temperature and the solvent removed in vacuo. The resulting residue is purified over silica (1:1 EtOAc/hexanes) to afford the desired product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[C:15]1([CH2:21][CH2:22][NH:23][C:24]([NH2:26])=[S:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C)C=O>O>[C:15]1([CH2:21][CH2:22][NH:23][C:24]2[S:25][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=3)[N:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: NC(=S)NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2csc(NCCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 2-bromo-1-[4-(trifluoromethyl)phenyl]-ethanone (5.34 g), N-(2-phenylethyl)thiourea (3.60 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (5.20 g, yield 74%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:33])[C:27]=3[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1>>[F:33][C:32]1[C:27]2[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=[C:24]([C:22]([C:18]3[CH:17]=[C:16]([NH:15][C:10](=[O:12])[CH2:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=4)[CH:21]=[N:20][CH:19]=3)=[O:23])[C:28]=2[CH:29]=[N:30][CH:31]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using 3-trifluoromethylphenylacetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26). The residue was purified using preparative TLC eluting with 5% MeOH in EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:5][CH:4]=1.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:28][C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Product: COc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(4-Methoxyphenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[O:5])[CH2:3][CH2:2]1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.[OH-].[K+]>CC(C)=O>[CH:1]1([C:4]([NH:6][C:7]2[CH:15]=[CH:14][C:13]([O:16][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[C:18]([F:17])([F:27])[F:28])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[O:5])[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C(O)c1cc(O)ccc1NC(=O)C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(OCc2ccccc2C(F)(F)F)ccc1NC(=O)C1CC1
Reaction time: 4 h
Yield: 49.4 %

Procedure:
A mixture of 2-(cyclopropanecarbonyl-amino)-5-hydroxy-benzoic acid (7.0 g, 32 mmol) and 2-(trifluoromethyl)-benzyl bromide (9.09 g, 38 mmol) in 0.5 M KOH (158 mL, 79 mmol) and acetone (200 mL) was heated to reflux. After 4 hours, acetone was evaporated and the resulting mixture was diluted with more water and washed with CH2Cl2. The water phase was acidified with 1 M HCl and the resulting solid was collected by filtration. Recrystallisation in methanol gave the product as an off-white powder (6.0 g, yield 50%).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3>C(O)(=O)C>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[C@@H:20]3[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=4)[C@@H:7]1[CH2:8][CH2:9][C:10]2=[O:11]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 19-nortestosterone 52 (26.85 g, 97.85 mmol) in acetic acid (200 mL) was added a CrO3 (7.4 g, 74 mmol) in acetic acid (150 mL) and stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to half of its initial volume, poured into 1 M hydrochloric acid (500 mL) and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous MgSO4, filtered, and then concentrated to afford dione 53 as a white solid (25.3 g, 95%): 1H NMR (300 MHz, CDCl3) δ0.94 (s, 3, CH3), 5.85 (s, 1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1>C1COCC1>[OH:2][CH:1]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[CH:24]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: COc1cccc([Mg]Br)c1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cnccc2-c2cccc(C#N)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 1.0 M 3-methoxyphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(3-methoxy-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH:12]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH:12]([C:21](=[O:25])[N:22]([CH3:23])[CH3:24])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N(C)C)Oc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)C1Cn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (100 mg, 0.22 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 18 hr. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform:methanol=30:1-20:1) to give 12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (9 mg, yield 9.4%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O.CCOCC>[Si:12]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 33.93 g of ethyl glycolate, 62.7 g of t-butyldimethylchlorosilane and 58.5 g of imidazole in 150 ml of dimethylformamide is stirred at room temperature for 15 h. The mixture is diluted with ether and washed with water (2×100 ml), brine, dried (MgSO4) and evaporated. The residue is distilled to give ethyl t-butyldimethylsilyloxyacetate, b.p. 100°-105° C. (14 mm/Hg).
Reaction SMILES: N[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].C(I)[I:25].N(OCCC(C)C)=O>>[F:19][C:18]([F:21])([F:20])[C:10]1[CH:9]=[C:8]([CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=1)[CH2:7][N:6]1[C:2]([I:25])=[C:3]([C:22]#[N:23])[N:4]=[CH:5]1
Reactant: ICI
Reactant: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N
Agent: CC(C)CCON=O
Product: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1I
Reaction time: 0.5 h

Procedure:
Combine 5-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-imidazole-4-carbonitrile (0.066 g, 0.20 mmol), CH2I2 (3 mL), and isoamyl nitrite (250 μL, 2 mmol) in a round bottom flask and stir the mixture at 100° C. After 30 min., remove from heat and concentrate. Purify by flash chromatography on silica gel to give the title compound. MS (ES) 443.9 (M−1); 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.78 (s, 1H), 7.58 (s, 2H), 5.31 (s, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][CH:4]=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18](Cl)=[O:19]>O>[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18](=[O:19])[NH:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][CH:4]=[CH:3]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N[C@@H]1C=CC[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H]1C=CC[C@H]1O)OCC(Cl)(Cl)Cl

Procedure:
A 10.18 (103 mM) quantity of crude (3R, 4R)-3-amino-4-hydroxycyclopentene (prepared as in Preparation 19, step 4) is dissolved in 75 ml of water and the mixture treated with 10.6 g (100 mM) of sodium carbonate. The mixture is then cooled in an ice bath to <10° and treated dropwise while stirring vigorously, with 24 g (100 mM) of trichloroethylchloroformate over 30 minutes. After 3 hours the reaction is filtered and the collected solid product washed throughly with water. On drying there is obtained 22.43 g of (1R, 5R)-2,2,2-trichloroethyl-5-hydroxy-2-cyclopentene-1-carbamate as crystalline solid, m.p. 82°-84°. Recrystallization of a small sample from isopropylether-Skellysolve B gives material with a m.p. 87°-87.5° [α]-92° (C=0.14, MeOH).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]=[C:9]([Cl:12])[O:10][CH:11]=1)(=O)=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[I-].[Na+].Cl>C(#N)C>[Cl:12][C:9]1[O:10][CH:11]=[C:7]([CH2:6][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: CS(=O)(=O)OCc1coc(Cl)n1
Reactant: C1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc(CN2CCCCC2)co1
Yield: 40 %

Procedure:
A solution of (2-chloro-1,3-oxazol-4-yl)methyl methanesulfonate i59 (7.9 g, 37.44 mmol, 1 eq), piperidine (7.41 ml, 74.89 mmol, 2 eq) and sodium iodide (0.56 g, 3.74 mmol, 0.1 eq) in acetonitrile (250 ml) is stirred at room temperature overnight. The mixture is then poured into a 0.1 N hydrochloric acid solution and extracted with diethyl ether. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 98:1.8:0.2) affords 3 g of 1-[(2-chloro-1,3-oxazol-4-yl)methyl]piperidine i60.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:33])[N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:48][C:49]1[CH2:53][O:52][C:51](=[O:54])[CH:50]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:33])[N:27]3[CH2:28][CH2:29][N:30]([CH2:48][C:49]4[CH2:53][O:52][C:51](=[O:54])[CH:50]=4)[CH2:31][CH2:32]3)[N:9]=2)[CH:7]=1
Reactant: O=C1C=C(CBr)CO1
Reactant: O=C(Nc1cn(CC(=O)N2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C=C(CN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.19 mmol) in DMF (3 mL) was added DIEA (48.8 mg, 0.38 mmol), 4-(bromomethyl)-2,5-dihydrofuran-2-one (66.4 mg, 0.38 mmol). The resulting solution was stirred at room temperature for 4 h and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (34.0% up to 39.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 34.0% in 2 min); Detector, UV 254/220 nm. This resulted in 53.4 mg (45%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxo-2,5-dihydrofuran-3-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 24) [M+H]+=627.1, RT=1.55 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (d, 1H, J=6.8 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.2, 7.0 Hz), 7.09 (t, 1H, J=73.2 Hz), 6.12 (s, 1H), 5.25 (s, 2H), 4.91 (s, 2H), 3.51 (t, 4H, J=5.4 Hz), 3.41 (s, 2H), 2.50-2.40 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[NH:14][CH3:15].[N:16]([O-])=[O:17].[Na+]>Cl.O>[Cl:1][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([N:16]=[O:17])[CH3:15]
Reactant: O=N[O-]
Reactant: CNC1=C(Cl)C(=O)c2c(cnn2C)C1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(N=O)C1=C(Cl)C(=O)c2c(cnn2C)C1=O

Procedure:
6-Chloro-5-methylamino-1-methylindazole-4,7-dione (4.5 grams) in 30 % hydrochloric acid (50 milliliters was stirred at 0° C and treated dropwise with a solution of sodium nitrite (3.0 grams) in water (20 milliliters). After 1 hour the orange solid which had separated out was collected, washed with water and dried over silica gel to yield the desired product having a melting point of 124°-125° C (with decomposition).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:8]([CH3:22])[CH2:7]1)(=O)=O.[CH3:30][N:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>CN(C)C=O>[CH3:30][N:31]1[CH2:35][C:34](=[O:36])[N:33]([CH2:5][C@@H:6]2[CH2:20][C@H:19]3[C@@H:9]([CH2:10][C:11]4[C:21]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]3=5)[NH:13][CH:12]=4)[N:8]([CH3:22])[CH2:7]2)[C:32]1=[O:37]
Reactant: CN1CC(=O)NC1=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CN1CC(=O)N(C[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)C1=O
Yield: 69.9 %

Procedure:
A mixture of 0.5 g of 6-methylergolin-8β-ylmethyl tosylate, 1.0 g of 1-methylimidazolidin-2,4-dione, 1.0 g of potassium carbonate, 10 ml of methyl ethyl ketone and 10 ml of dimethylformamide was refluxed for 4 hours with stirring, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue (which was dissolved in dichloromethane and adsorbed on silica gel) was purified by silica gel column chromatography (eluted with ethyl acetate and then with ethyl acetate:isopropyl alcohol=1:1 by volume). The product was recrystallized from dichloromethane-hexane to obtain 0.3 g of the titled product as colorless needles having a melting point higher than 210° (with decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][OH:34].O1CCCC1>O>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][O:34][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[CH:4][N:3]=1
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2ccccn2)cc1Cl
Reactant: OCc1ccccn1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(OCc3ccccn3)ncc2C(=O)c2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylcarbonyl)pyrimidine (prepared in Example 90-(3)) 110 mg, 2-pyridinemethanol 34 mg, 10% sodium hydride 12 mg and tetrahydrofuran 3 ml is stirred at room temperature for 5 minutes. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent: ethyl acetate) and triturated with ethyl ether to give 2-(2-pyridylmethoxy)-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylcarbonyl)pyrimidine, 104 mg. mp 81-84° C., MS(m/z): 462(M+H)+