Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH+:7]=1.[C:16](=[C:19]1[C:23](=O)[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[S:20]1(=[O:30])=[O:29])([CH3:18])[CH3:17]>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][C:16]1[C:19]2[S:20](=[O:30])(=[O:29])[C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]=2[N+:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[CH:17]=1
Reactant: CC(C)=C1C(=O)c2ccccc2S1(=O)=O
Reactant: C1=[NH+]CCc2ccccc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Cc1cc2[n+](c3c1S(=O)(=O)c1ccccc1-3)CCc1ccccc1-2

Procedure:
3,4-Dihydroisoquinolinium perchlorate (1.2 g) and 2-isopropylidenebenzothien-3-one-1,1-dioxide (2 g) were heated together at 150° for 16 hours. The reaction mixture was triturated with hot methanol and filtered. The product was purified by recrystallization from acetonitrile. Yield 0.6 g, m.p. > 330°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9](=[O:22])[CH2:8][CH2:7]2)([O-])=O.N>CO.[Ni].CO.C(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:9](=[O:22])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCCCC1
Agent: [Ni]
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2c(c1)CCC(=O)N2CCN1CCCCC1
Yield: 77.6 %

Procedure:
A solution of 6-nitro-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.65 mmol) in 10 mL methanol was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad was washed with 10 mL methanol. The filtrate was concentrated to give a dark brown residue was subjected to flash silica gel chromatography using 5% 2M NH3 in MeOH/CH2Cl2 to give an off-white solid (350 mg, 77.7%). 1H-NMR (DMSO-d6) δ: 6.81 (d, J=8.2 Hz, 1H), 6.46-6.41 (m, 2H), 4.84 (br s, 2H), 3.87 (t, J=7.1 Hz, 2H), 2.66 (t, J=6.5 Hz, 2H), 2.40-2.32 (m, 8H), 1.46-1.35 (m, 6H); MS (ESI): 274.2 (M+1, 100%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.C([N:23](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:15])[NH:16][NH2:23])=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncncc12
Reactant: CCN(CC)CC
Agent: NN
Solvent: CCO
Solvent: O
Product: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
610 mg (approx. 1.92 mmol, purity 86%) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were initially charged in 10 ml of ethanol and cooled to 0° C. 777 mg (7.68 mmol) of triethylamine and 120 mg (1.920 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 590 mg (purity 89%, 95% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:22])=[O:21]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
3.7 g (25 mmole) p-cyanophenethylalcohol was dissolved in 15 ml dichloromethane, 5.2 ml (87.5 mmole) triethylamine was added and the mixture was cooled on an ice bath. 2.52 ml (32.5 mmole) methanesulfonyl chloride in 5 ml dichloromethane was slowly added at 0-7° C. The reaction was allowed to reach room temperature and then stirred at room temperature. The reaction mixture was washed with cooled 2 N hydrochloric acid, water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 5.3 g (yield 95%) of 4-cyanophenethyl methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:13])[CH:8]=2)[N:3]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([CH3:22])[N:16]=1.Cl>C(O)CO.O>[Cl:14][C:15]1[N:20]=[C:19]([NH:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[NH2:12])[CH:18]=[C:17]([CH3:22])[N:16]=1
Reactant: Cc1cc(N)c2cc(N)ccc2n1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: OCCO
Solvent: O
Product: Cc1cc(Nc2ccc3nc(C)cc(N)c3c2)nc(Cl)n1
Reaction time: 4.5 h
Yield: 27 %

Procedure:
Diaminoquinoline 7 (72.0 g, 0.416 mol) and 2,4-dichloro-6-methylpyrimidine (8) (67.8 g, 0.416 mol) were suspended in ethylene glycol (1 L). Addition of 37% HCl (35 mL, 0.43 mol) resulted in a yellow solution which was heated to and held at 50° C. for 4.5 h. The mixture was diluted with chilled water (1 L) which resulted in a thick white paste-like precipitate and the mixture was filtered through Celite. The Celite and solid containing the product and bis-substituted by-product was slurried in water (4 L) and the Celite and insoluble by-product were removed by filtration. The filtrate pH was adjusted to 14 using 1N aqueous NaOH (1 L) resulting in precipitation of product which was removed by filtration. The damp product was transferred to a rotovap flask and dried in vacuo by azeotropic water removal with toluene (3×1.5 L). Product 9 was obtained as an off-white solid (33.4 g, 27% yield; Notebook reference A134-137). Another batch of 9 (7.4 g, 17% yield; Notebook reference A 134-134) was similarly obtained by reaction of 7 (25.0 g, 0.144 mol) and recovery as above; MS [M+1]=300, 302; 13C NMR (DMSO) δ 167.51, 162.58, 159.22, 157.61, 151.05, 145.99, 133.17, 128.96, 125.39, 117.38, 114.23, 102.45, 102.26, 24.68, 23.19.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].Br[CH2:15][CH2:16][O:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:15][CH2:16][O:17][CH3:18])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(C#N)cc1C(=O)OC
Temperature: 60 °C

Procedure:
Methyl 5-cyano-2-hydroxybenzoate (Astatech, 3.0 g, 16.9 mmol), 1-bromo-2-methoxyethane (2.6 g, 18.6 mmol), and K2CO3 (2.3 g, 16.9 mmol) were mixed in 25 mL of DMF and heated at 60° C. for 48 hours. The reaction was diluted with 100 mL of EtOAc washed with water, brine, dried with MgSO4 and the solvent removed to provide the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 3.46 (s, 3H) 3.79-3.84 (m, 2H) 3.90 (s, 3H) 4.23-4.28 (m, 2H) 7.07 (d, J=8.82 Hz, 1H) 7.72 (dd, J=8.65, 2.20 Hz, 1H) 8.11 (d, J=2.37 Hz, 1H). MS (DCI/NH3) m/z 236.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[O:6][C:7]=1[CH3:8].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:21]([C:22]1[CH:30]=[CH:29][C:27]([O:28][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=3)[C:14]([O:16][CH3:17])=[O:15])[O:6][C:7]=2[CH3:8])=[C:24]([O:25][CH3:26])[CH:23]=1)=[O:20]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)c1cc(-c2nc(CCl)c(C)o2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)ccc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of methyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)-2-methylbenzoate (1.21 g), vanillin (0.65 g), anhydrous potassium carbonate (0.59 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate as colorless crystals (1.45 g, yield 85%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:26][C:27](=[O:29])[CH3:28])=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[O:22][C:23](=[O:25])[CH3:24])[CH3:2].C(O)(=[O:32])C>[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:3][C:4]1[C:5]([O:26][C:27](=[O:29])[CH3:28])=[CH:6][C:7]2[C:8](=[O:32])[CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[O:22][C:23](=[O:25])[CH3:24])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOc1cc2c(cc1OC(C)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: [Cr+6]
Agent: [O-2]
Product: CCOc1cc2c(cc1OC(C)=O)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Temperature: 15 °C
Reaction time: 0.58 h
Yield: 55 %

Procedure:
A solution of chromium trioxide (1.6 g, 16 mmol) in 90% glacial acetic acid (7.5 mL) was added dropwise at 15° C. to a solution of 2-ethoxy-3,17β-diacetyl derivative (5), (1.5 g, 3.7 mmol) in glacial acetic acid (12 mL). The resulting mixture was stirred at 15° C. for 35 min. The mixiure was poured onto ice-water mixture (150 mL) and compound was extracted into ethyl acetate (3×180 mL). The combined organic layer was washed with water (100 mL), NaHCO3 solution (100 mL), water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The organic layer, upon evaporation under reduced pressure, provided a crude compound, which on purification on a silica gel column using hexane: ethyl acetate mixture aas eluant gave 1.20 g (55%) of estradiol (7): mp 195° C.; IR (KBr) 2980-2810, 1765, 1730, 1715, 1665, 1600, 1500, 918, 880 cm-1 ; 1H NMR (CDCl3) δ 0.89 (s, 3 H), 1.30-1.85 (m, 9 H), 1.90-2.45 (m, 11 H), 2.47-2.85 (m, 2 H), 4.15 (q, J=6.4 Hz, 2 H), 4.78 (t, J=8.5 Hz, 1 H), 6.95 (s, 1 H), 7.77 (s, 1 H). Anal. (C24H30O6) C, H.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:11]=[C:10]([Br:12])[S:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[N+:18]([O-])([OH:20])=[O:19]>>[Br:6][C:7]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]([Br:12])[S:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1sc(Br)cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1sc(Br)c([N+](=O)[O-])c1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.54 %

Procedure:
Sulfuric acid (27.6 g, 15.0 ml, 281.0 mmol) was added in a dropwise manner to ethyl 3,5-dibromothiophene-2-carboxylate (Prepared according to procedure reported in JCS Perkin Trans-1:Organic and Bioorganic Chemistry (1972-1999), 1973, p 1766-1770), 5.0 g (15.92 mmol), at room temperature (about 25° C.). The reaction mixture was then cooled to −5° C. and to the cooled mixture was added nitric acid (2.0 g, 2.04 ml, 31.84 mmol) slowly. The reaction mixture was then stirred at 0° C. for 1 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then poured onto ice-water (150 ml). The mixture so obtained was extracted with ethyl acetate (2×100 ml). The combined organic layer was dried over sodium sulphate and was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in hexanes as an eluent to obtain the title compound (3.40 g, 59.54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 2-amino-5-bromopyridine (43 mg, 0.25 mmol) according to general procedure II. Obtained as an orange solid (14 mg, 15%). MS (ISP) 386.3 [(M+H)+]; mp 233-235° C.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:13][CH2:12][C:5]2([NH:9]C(=O)N[C:6]2=[O:11])[CH2:4][CH2:3]1.[OH-:15].[K+]>>[NH2:9][C:5]1([C:6]([OH:15])=[O:11])[CH2:12][CH2:13][C:2]([F:14])([F:1])[CH2:3][CH2:4]1
Reactant: O=C1NC(=O)C2(CCC(F)(F)CC2)N1
Reactant: [OH-]
Agent: [K+]
Product: NC1(C(=O)O)CCC(F)(F)CC1

Procedure:
Under nitrogen gas, 4.10 g of the compound of Example 2A were suspended in 100 ml of 30% strength aqueous potassium hydroxide solution, and the mixture was stirred at reflux overnight. The mixture was concentrated to about 25% of the volume and, at 0-10° C., adjusted to pH 5.5 using concentrated aqueous hydrogen chloride solution. The solution was concentrated and dried. The residue (4.30 g) was used directly for the esterification.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[NH:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH:26]([CH3:28])[CH3:27])[C:19](Cl)=O.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH:7]=[CH:8][N:9]=[CH:10]4)[N:4]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Reactant: N=C(NO)c1cccc2cnccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1Cl
Temperature: 25 °C
Yield: 87.2 %

Procedure:
N-hydroxy-5-isoquinolinecarboximidamide (D1; 1.18 g, 6.30 mmol) was added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (D4; 1.54 g, 6.62 mmol), triethylamine (0.966 ml, 6.93 mmol) and N,N-dimethylformamide (DMF) (10 ml) at 0° C. under a blanket of nitrogen. The mixture was allowed to warm to room temperature over 1 h and then heated at 120° C. under nitrogen overnight. The mixture was allowed to cool and then filtered. An off-white solid was collected and washed with acetonitrile to give the title compound (2.01 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[N:33]1[C:40]2[N:36]([N:37]=[C:38]([C:41]3[S:45][CH:44]=[N:43][CH:42]=3)[CH:39]=2)[CH:35]=[CH:34]1.[F:46][S:47]([F:60])([F:59])([F:58])([F:57])[C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51](O)=[O:52]>CN(C=O)C>[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][CH:56]=[C:48]([S:47]([F:60])([F:46])([F:57])([F:58])[F:59])[CH:49]=2)=[CH:28][C:27]=1[N:33]1[C:40]2[N:36]([N:37]=[C:38]([C:41]3[S:45][CH:44]=[N:43][CH:42]=3)[CH:39]=2)[CH:35]=[CH:34]1
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cncs3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cncs3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
193 mg (0.51 mmol) of HATU and 62 mg (0.51 mmol) of 4-N,N-dimethylaminopyridine (DMAP) were added to a solution of 100 mg (0.34 mmol) of the compound of Example 89A and 92 mg (0.37 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid in 2 ml of DMF. The reaction was stirred at RT for 20 h. The reaction mixture was then purified directly by preparative HPLC (Method 16). This gave 50.2 mg (27% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]2[CH2:19][NH:20][C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[N:27][N:28]3C(OC)=O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[NH:28]1[C:29]2[C:25](=[C:24]([NH:23][C:21]([NH:20][CH2:19][CH:10]3[CH2:11][CH2:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]3[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3CCc3ccccc3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCC1CCc2ccccc2N1CCc1ccccc1)Nc1cccc2[nH]ncc12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
The product from Example 53A (0.1913 g, 0.40 mmol) was dissolved in methanol (5 mL). A NaOH solution (1.0 mL, 5 M in methanol) was added and stirred for 30 minutes. The reaction mixture was then diluted with water until a precipitate formed. The solid was collected by filtration, washed with water and dried under vacuum to afford the title compound (0.1294 g, 76%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.98 (s, 1H) 8.69 (s, 1H) 8.07 (s, 1H) 7.60 (d, J=7.46 Hz, 1H) 7.24 (m, 6H), 7.04 (m, 2H) 6.94 (d, J=6.44 Hz, 1H) 6.71 (d, J=8.14 Hz, 1H) 6.51 (t, J=6.95 Hz, 2H), 3.71 (m, 1H) 3.37 (m, 3H) 3.11 (m, 1H) 2.83 (m, 3H) 2.62 (m, 1H) 1.87 (m, 1H), 1.54 (m, 1 H). MS (ESI) m/z 426 (M+H)+, 424 (M−H)−. Calcd For C26H27N5O: C 73.39; H 6.40, N 16.46. Found C 73.22; H, 6.36; N, 16.30.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]#[C:9][CH2:8][CH2:7][CH2:6][N:19]=[N+:20]=[N-:21])=[CH:12][CH:13]=1)#[N:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C#CCCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of the product of step B (13.40 g, 50.9 mmol) in dimethylformamide (35 mL) was added NaN3 (16.5 g, 255 mmol). The reaction was stirred at room temperature for 18 hours then at 60° C. for 2 hours, cooled to room temperature, diluted with water (400 mL) and extracted with ethyl acetate. The organic layer was washed with water (2×) then with brine and dried (Na2SO4). Evaporation under reduced pressure afforded 10.70 g (100%) of product as a tan oil.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:8]([F:18])[CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].CN(C)C=O>O>[C:20]1(=[O:30])[N:24]([CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:8]([F:18])[CH:7]=2)[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O[C@@H](CCl)CNc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C

Procedure:
The mixture of (N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline obtained in example 1, potassium phthalimide (40 gm) and Dimethyl formamide (400 ml) is heated for 5 hours at reflux temperature. The reaction mixture is cooled to ambient temperature, poured in to water (2 L) and filtered the solid obtained, and recrystallized from isopropyl alcohol to give 50 gm N-[3-pthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl)aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]#[N:14])[NH:6][C:5]2=[O:15].[Cl:16][C:17]1[C:18]([CH3:27])=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[Cl:16][C:17]1[C:18]([CH3:27])=[C:19]([S:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][CH2:12][C:13]#[N:14])[NH:6][C:5]3=[O:15])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: N#CCCn1[nH]c(=O)c2cc(N)ccc21
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2c(c1)c(=O)[nH]n2CCC#N
Temperature: 60 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
To a solution of 3-(5-amino-3-oxo-2,3-dihydro-indazol-1-yl)-propionitrile (0.08 g) in pyridine (1 mL) was added 3-chloro-2-methylbenzenesulfonylchoride (0.089 g) in one go. The solution was stirred at 60° C. for 24 hours. The pyridine was then removed in vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous phase was extracted a further two times with EtOAc and the combined organic phases were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the volatiles were removed in vacuo to afford a crude residue. The crude material was purified via flash column chromatography eluting with EtOAc/nHeptane/1% AcOH) to afford the desired 3-Chloro-N-[1-(2-cyano-ethyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl]-2-methyl-benzenesulfonamide (0.087 g) as a light brown solid. MS (ESI+): 391.0 [M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]([C:12]([O:14]C(OCC)C)=[O:13])[OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CS(Cl)(=O)=O.[CH2:37]1[CH2:41][O:40][CH2:39][CH2:38]1>CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]1[O:14][C:12](=[O:13])[CH:10]([O:11][CH:39]([O:40][CH2:41][CH3:37])[CH3:38])[CH:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)OC(=O)C(O)C(NC(=O)OC(C)(C)C)c1ccccc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 409 mg (1.16 mmol) of N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3-phenylisoserine (3) in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture was stirred at 25° C. for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added and the mixture was stirred at 25° C. for 1.5 h. The mixture was diluted with 80 mL of hexane and ethyl acetate and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase was dried over sodium sulfate and concentrated to give 235 mg (70%) of 2-tertbutoxy-4-phenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.