Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:28])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24]C(=O)C)[CH2:6]1)(=O)C.[O-]S([O-])(=O)=O.[Mg+2].C1C(I)=C(I)C(C(O)=O)=CC=1I>CCCCC>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C@H:9]([OH:28])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:24])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C(O)c1cc(I)cc(I)c1I
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCC
Product: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 3β,17β diacetoxyandrost-5-en-7-one (0.9581 g, 2.466 mmol) and pentane (30 mL), dried over MgSO4) were mixed under a nitrogen atmosphere. TIBA (9.5 mL, 9.5 mmol, 1M in toluene) was then added dropwise by syringe. The solution was stirred at room temperature for about 1 hour. The reaction was terminated by the addition of diluted hydrochloric acid (approximately 5 mL). This solution was added to water (100 mL) and extracted with ethyl acetate (3 times with 50 mL). The organic layers were combined and then washed several times with saturated sodium bicarbonate solution (50 ml), saturated sodium chloride solution (two times with 50 mL,) and water (50 mL). The organic layer was dried over magnesium sulfate and the solvent removed by rotary evaporation to yield 86% crude product. 1H NMR indicated that the crude product contained 3β,17β,-diacetoxy-7-β-hydroxyandrost-5-en-7-one (86%) and 3β,17β -diacetoxy-7-α-hydroxyandrost-5-ene.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCOCC1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)C1CCOCC1
Yield: 99.3 %

Procedure:
Tetrahydro-2H-pyran-4-carboxylic acid (1.00 g, 7.68 mmol) was slowly added to a stirred suspension of anhydrous potassium carbonate (1.17 g, 8.45 mmol) in acetone (40 mL), followed by dimethyl sulfate (0.8 mL, 8.45 mmol). The mixture was stirred and heated for 3 h. The inorganic salts were then removed by filtration and washed with acetone, and the filtrate was dried and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (1.1 g, 99%), which was used in the next step without further purification. GC-MS m/z 145 (MH+); 1H NMR (300 MHz, CDCl3) δ 11.70-1.80 (m, 4H), 2.47-2.52 (m, 1H), 3.34-3.43 (m, 2H), 3.65 (s, 3H), 3.88-3.95 (m, 2H).
Reaction SMILES: C(OC(=O)[N:10]([CH2:20][C@H:21]([NH:27][C:28](=[O:44])[CH2:29][C:30](=[O:43])[NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([NH2:42])[CH:33]=1)[C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])C1C=CC=CC=1.[CH:46](=O)[CH2:47][CH3:48].C([BH3-])#N.[Na+]>CO>[CH3:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][CH2:20][C@H:21]([NH:27][C:28](=[O:44])[CH2:29][C:30]([NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[C:34]([NH:42][CH2:46][CH2:47][CH3:48])[CH:33]=1)=[O:43])[C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCC=O
Reactant: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1cc(N)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNc1cc(NC(=O)CC(=O)N[C@@H](CNCc2ccc(C)cc2C)[C@@H](O)CCC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of {(2S,3S)-2-[2-(3-amino-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxyhexyl}-(2,4-dimethyl-benzyl)-carbamic acid benzyl ester (97 mg, 0.15 mmol) in MeOH (3 mL) was charged with propionaldehyde (0.01 mL, 0.15 mmol), stirred for 15 min at RT, and then charged with sodium cyanoborohydride (12 mg, 0.19 mmol). The reaction was stirred at RT for 12 h, concentrated in vacuo, and dissolved in EtOAc. The resultant solution was washed successively with water, sat. NaHCO3, water, and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL). This solution was charged with 5% Pd/C, Degussa style (11 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=537.4.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:15]#[CH:16]>C(NCC)C.[Cu]I>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[C:15][CH2:14][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C#CCOCCCCCCO
Reactant: Ic1ccc(N2CCCCC2)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCCCCCCOCC#Cc1ccc(N2CCCCC2)cc1
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 1-(4-iodophenyl)piperidine (1.5 g), 6-[(2-propynyl)oxy]-1-hexanol (820 mg), BTPC (35 mg) and copper (I) iodide (20 mg) in diethylamine (30 ml) under nitrogen, was stired at room temperature overnight. The solvent was evaporated and the residue was partitioned between EA (50 ml) and 8% aqueous sodium bicarbonate (50 ml). The organic layer was washed with water and brine, dried and concentrated to a dark oil which was purified by FCC eluting with ER to give the title compound as an orange oil (1.2 g), t.l.c. (ER) Rf 0.70.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[F:24])=O)=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[F:24])=[N:31]/[OH:32])=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)c1cc(OC)c(Cl)cc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1/C(=N/O)c1cc(OC)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of the product from Step 3 (1.4 g, 3.2 mmol), hydroxylamine hydrochloride (2.2 g, 32 mmol) and sodium acetate (2.6 g, 32 mmol) in ethanol (30 mL) was stirred in a sealed tube at 60° C. for 72 h. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the oxime product.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[N:4][C:5]2[CH:6]=[CH:7][C:8]3[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([OH:20])=[N:4][C:5]2[CH:6]=[C:7]([N+:21]([O-:23])=[O:22])[C:8]3[C:15]([S:16](=[O:18])(=[O:19])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1
Reactant: NS(=O)(=O)c1cccc2c1ccc1nc(O)c(O)nc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: NS(=O)(=O)c1cccc2c1c([N+](=O)[O-])cc1nc(O)c(O)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 1,0 g (3,4 mmol) 2,3-dihydroxy-7-sulphamoylbenzo[f]quinoxaline in 25 ml concentrated sulfuric acid was added at 0° C. 0,15 ml 100% nitric acid. Stirring was continued at 0° C. for 30 min, and then the mixture was poured into 100 ml ice-water to give a precipitate. The crude product was recrystallized (dimethylformamide-water) to give 0,7 g (61%) 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline, m.p. 360° C. NMR (DMSO-d6): 12,4 (1H, broad s), 12,3 (1H, broad s), 8.7 (1H, d), 8.5 (1H,d), 8.17 (1H,s), 7.9 (1H,t), 7.4 (2H, broad s).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].O=[C:12]([CH3:16])[C:13](O)=[O:14]>CO>[CH2:1]([N:3]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:12]([CH3:16])[C:13]1=[O:14])[CH3:2]
Reactant: CC(=O)C(=O)O
Reactant: CCNc1ccccc1N
Solvent: CO
Product: CCn1c(=O)c(C)nc2ccccc21
Yield: 56.7 %

Procedure:
5.4 g (39.6 mM) of N-ethylbenzene-1,2-diamine and 2.76 ml (39.6 mM) of 2-oxopropanoic acid in 200 ml of methanol were refluxed for 8 h. The solvent was removed under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane, followed by dichloromethane/dimethylketone (95/5) as eluant to give 4.2 g of 1-ethyl-3-methyl-quinoxalin-2(1H)-one as a yellow solid. Yield: 56.7%.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([NH2:13])=[CH:11][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
Chloroacetyl chloride (0.68 mL, 8.58 mmol) was added dropwise to a stirred solution of 4-fluoro-N2-phenylbenzene-1,2-diamine (1.24 g, 6.13 mmol) and pyridine (2.0 mL, 24.5 mmol) in DCM (8 mL) at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 20 min, the mixture was slowly warmed to RT and stirring at RT was continued for 2 h. The mixture was partitioned between DCM and aqueous HCl (1M, 50 mL) cooled at 0° C. and the aqueous phase was further extracted with DCM (×3). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in cyclohexane) to afford the title compound as a white crystalline solid (750 mg, 44%). LCMS (Method C): RT 3.42 min [M+H]+ 279.2.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[NH2:22][C@H:23]1[CH2:27][C:26](=[O:28])[N:25]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:37].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:30]([O:29][N:25]1[C:26](=[O:28])[CH2:27][C@H:23]([NH:22][S:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)(=[O:17])=[O:16])[C:24]1=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N[C@H]1CC(=O)N(OCc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C[C@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Temperature: 25 °C
Yield: 35 %

Procedure:
4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl chloride (256 mg; 0.78 mmol), (3S)-3-Amino-1-benzyloxy-pyrrolidine-2,5-dione hydrochloric acid (112 mg; 0.44 mmol), Et3N (230 ul; 1.65 mmol) and DMAP (43 mg; 0.35 mmol) was dissolved in DMF (2 ml). The mixture was heated in a microwave oven at 200 W for 2×10 seconds, allowed to cool to room temperature and then heated for another 10 seconds at 200 W. Evaporation of solvent and the residue was partitioned between EtOAc and 5% KHSO4, separation. Organic phase were washed with H2O and brine, the combined waterphases was extracted twice with warm DCM. Organic phases were combined and evaporated directly onto Si-60 gel. Purified by flash chromatography on 20 g of Si-60 gel using a gradient solvent system of 100% iso-Hexane to 100% EtOAc. Fractions containing the product was evaporated to give the title compound as a slightly yellow solid. Obtained 78 mg (35% yield). Purity by H-nmr was 90%, considered pure enough to use in next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29](C(OC(C)(C)C)=O)[N:28]=[CH:27]4)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]([O:2][CH3:1])=[O:40])[CH:12]=[CH:11][CH:10]=4)[N:22]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: COC(=O)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (18 mg, 0.033 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ethyl ether to get a yellow solid to afford methyl 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenylamino)-2-oxoacetate. (15 mg, 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:45])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([N:42]([CH3:44])[CH3:43])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:44][N:42]([CH3:43])[C:40]1[N:39]=[CH:38][N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:45])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=1
Reactant: CN(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(N(C)C)ncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[3-(6-dimethylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K55) (150 mg, 0.44 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (143 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7].OCCN1C[CH2:38][O:37][CH2:36]C1>>[N:2]1([CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH2:30][CH2:38][O:37][CH2:36][CH2:1]1
Reactant: OCCN1CCOCC1
Reactant: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc(NCCN(CCN2CCOCC2)S(=O)(=O)c2ccccc2[N+](=O)[O-])nc1

Procedure:
Made using the same procedure as for polymer-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine except that 4-(2-hydroxyethyl)morpholine (5.1 mL, 42 mmol) was used.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][C:27]3([F:33])[F:32])=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:41](=[O:43])[CH3:42])[CH2:28][C:27]3([F:32])[F:33])=[CH:24][CH:25]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(C3CCNCC3(F)F)cc1)nn2-c1c(F)cccc1F
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nccc2c1c(-c1ccc(C3CCN(C(C)=O)CC3(F)F)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a mixture of 1-(2,6-difluorophenyl)-3-(4-(3,3-difluoropiperidin-4-yl)phenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridine (186 mg) and triethylamine (91.0 mg) in dichloromethane (4 mL) was added acetic anhydride (67.0 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and diluted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (200 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC(C)(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 3,3-dimethylbutylamine (0.272 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting t-rough a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.421 g, 45.9%): TOF MS ES+ 359.2 (M+H)+, HRMS calcd for C19H27N4O3 359.2083 (M+H)+, found 359.2093, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.0 min, 98.0% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(S(Cl)(=O)=O)CCCC.N1C[CH2:43][S:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([N:19]2[CH2:40][CH2:41][S:42][CH2:43][CH2:20]2)(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCCS(=O)(=O)Cl
Product: C[C@H](CCCS(=O)(=O)N1CCSCC1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 64 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4[(4-thiomorpholinyl)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with thiomorpholine. Yield=64%; MS (ESI+), 571 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[NH2:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([CH3:15])[C:10]([Br:16])=[C:9]([F:17])[CH:8]=1>S(=O)(=O)(O)O>[NH2:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[C:9]([F:17])[C:10]([Br:16])=[C:11]([CH3:15])[C:12]=1[C:13]#[N:14]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(Br)c(F)cc(N)c1C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(Br)c(F)c([N+](=O)[O-])c(N)c1C#N
Reaction time: 0.17 h

Procedure:
With cooling with ice, potassium nitrate (2.43 g, 21.8 mmol) was gradually added to a concentrated sulfuric acid (20 ml) solution of 6-amino-3-bromo-4-fluoro-2-methylbenzonitrile (I-265) (5.00 g, 21.8 mmol). After stirring for 10 minutes, the reaction liquid was poured into ice and stirred.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([O:17][CH2:18][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][OH:21])[C:13]=2[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:35]=[C:36]=[O:37])(=O)=O.O>C(Cl)Cl>[C:36]([O:21][CH2:20][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][O:17][C:14]1[C:13]2[CH:30]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:10]=[CH:11][C:12]=2[O:16][N:15]=1)(=[O:37])[NH2:35]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.47 g of 5-tert-butoxycarbonylamino-3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 10 ml of methylene chloride is added 0.21 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. Subsequently, 10 ml of water is added, and they are subjected to reaction at 20°-25° C. for one hour. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the crystals obtained are collected by filtration, to obtain 0.47 g of colorless, crystalline 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-tert-butoxycarbonylamino-1,2-benzoisoxazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[CH3:23])[O:9][CH2:8][CH2:7][CH:6]2[C:24]([O:26][CH3:27])=[O:25])#[N:2].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][CH2:69][NH2:70])=[CH:64][CH:63]=1.Cl>CN(C=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][CH2:69][NH:70][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:24]([O:26][CH3:27])=[O:25])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[C:15]([CH3:23])[CH:16]=2)=[O:20])=[CH:64][CH:63]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3C)c(C#N)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3C)c(C#N)cc21
Reaction time: 48 h
Yield: 33.6 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)-3-methylbenzoic acid (0.013 g, 0.03539 mmol) in 1 ml dry DMF was treated with N-ethyl-N-isopropylpropan-2-amine (0.01233 ml, 0.07078 mmol), HBTU (0.01610 g, 0.04247 mmol) and 2-(4-chlorophenyl)ethanamine (0.009843 ml, 0.07078 mmol) at ambient temperature. After 48 h, the reaction was poured into 10% aqueous HCl, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated to provide the crude material as a yellow film. Purification of the crude material on silica gel, eluting with 1% MeOH/DCM, provided the title compound (6 mg, 34%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:16])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:16])([C:13]([N:19]2[CH2:20][CH2:22][CH2:25][CH2:23]2)=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of 3-methylpyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (348 mg, 1.52 mmol) in DMF (10 mL) were added DIPEA (0.53 mL, 3.04 mmol), pyrrolidine (0.25 mL, 3.04 mmol) and HATU (693 mg, 1.82 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc. The organic layer was separated and washed with a 0.1N aqueous HCl solution and brine, dried over Na2SO4, filtered and concentrated to give the desired product as a white solid (334 mg, 78%). 1H NMR (400 MHz, CHCl3-d): δ 3.61-3.38 (m, 8 H); 2.00-1.79 (m, 6 H); 1.47-1.44 (m, 9 H); 1.33 (s, 3 H).