Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:7]2[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd].O>[N:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CC(N2CCCCC2)CN1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1

Procedure:
A solution of 10.0 g of [4S]-1-[phenylmethoxy)carbonyl]-4-(1-piperidinyl)-L-proline, methyl ester in 100 ml of methanol is treated with a suspension of 2 g of 5% palladium on charcoal in 10 ml of water and placed under 3 atmospheres of hydrogen. After an equivalent quantity of hydrogen is consumed, the suspension is filtered and the solvent evaporated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH2:13])([O-:3])=[O:2].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:14]([NH:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2[nH]nc(NCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 32.9 %

Procedure:
To a suspension of 5-nitro-1H-indazol-3-ylamine (0.025 g, 0.140 mmol) and benzaldehyde (0.067 g, 0.60 mmol) in CH2Cl2 (3.0 mL) was added acetic acid (0.024 mL, 0.42 mmol) followed by sodium triacetoxyborohydride (0.059 g, 0.28 mmol). The resulting solution was allowed to stir at room temperature for about 19 hours. The reaction solution was diluted with CH2Cl2 (5 mL) and treated with an aqueous solution of NaOH (1N, 5 mL). The two phases were separated and the organic solvent was removed under reduced pressure. The residue was further purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8 Hypersil® HS C18 column; 5% acetonitrile/0.1 M aqueous ammonium acetate-100% acetonitrile over 20 min, 100% acetonitrile hold 5 minutes, 21 mL/min) to give benzyl-(5-nitro-1H-indazol-3-yl)-amine (0.012 g, 0.046 mmol) as an orange solid. RP-HPLC (Table 1, Method e) Rt 2.15 min.; m/z: (M+H)+ 269.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][NH:28][CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C)C=O.CCN(C(C)C)C(C)C>[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][N:28]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(S(C)(=O)=O)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To the stirred solution of 373 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate hydrochloride in 8 mL of N,N-dimethylformamide and 0.5 mL of Hunig's base was slowly added 104 mg of methanesulfonyl chloride. The solution was stirred at room temperature overnight. After removal of the N,N-dimethylformamide in vacuo, the residue was dissolved in 80 mL of ethyl acetate. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane to provide 233 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-(methylsulfonyl)pyrrolidine-3-carboxylate in 58% yield. MS: 576.1 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25]>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (4.8 mL, 45.42 mmol), potassium carbonate (13.8 g, 0.1 mol) and 2,4-dichloro-phenol (8.16 g, 50.06 mmol) in dry dimethylformamide (70 mL) was stirred at 100° C. for 2 h. Solids were filtered off, and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether and 1N sodium hydroxide, the organic layer was washed with 1N sodium hydroxide, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 11.69 g (91%) of the title compound as a yellowish oil, which solidifies on standing. Mp: 58-59° C. MS (EI) 285.2 (MH+). Lit. [Chem. Heterocycl. Compd. (Engl. Transl.) 11 (1975) 1356-1358] Mp: 57-58° C.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:25][CH:24]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: O=Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: Fc1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was refluxed in 400 ml of toluene that contained 3.5 g of morpholine and 3.10 g of 4-fluorobenzaldehyde that had been freshly washed in K2CO3. The reaction mixture was refluxed over two (2) nights and then concentrated, purified by flash chromatography (20% EtOAc/CH2Cl2) and recrystallized from dichloromethane/pentane to give 2.20 g of analytically pure product, m.p. 161°-163° C.
Reaction SMILES: OS([O-])=O.[Na+].[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O.[C:18]1([NH2:25])[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(O)C>[NH:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:25]=[C:6]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1
Reactant: Nc1ccccc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4141.5 %

Procedure:
An aqueous solution of NaHSO3 (20.0 mL, 40% in water) was treated with a solution of methyl 4-formylbenzoate (2.20 g, 13.4 mmol) in ethanol (15.0 mL) and stirred at ambient temperature for 1 h. 1,2-benzenediamine (1.45 g, 13.4 mmol) was added and the solution was heated to reflux overnight. Upon cooling, the solution was poured into ice water and the resultant precipitate was collected by filtration, washed with water, and dried in vacuo to provide the title compound as a grey solid (140 g; 100%). NMR (400 MHz, CHLOROFORM-d) ppm 8.19 (d, J=7.8 Hz, 2H) 8.15 (d, J=7.8 Hz, 2H) 7.70 (s, 2H) 7.34 (dd, J=6.1, 3.3 Hz, 2H) 3.98 (s, 3H). MS (ES+) m/e 253 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:6](=[O:40])[NH:7][C:8](=[O:39])/[C:9]/1=[CH:10]/[C:11]1[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].I[CH2:48][CH2:49][CH2:50][CH3:51]>CN(C=O)C.CCOCC>[CH2:1]([N:5]1[C:6](=[O:40])[N:7]([CH2:48][CH2:49][CH2:50][CH3:51])[C:8](=[O:39])/[C:9]/1=[CH:10]/[C:11]1[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(/C=C2/C(=O)NC(=O)N2CCCC)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1nc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of Z-1-butyl-5-[[2-butyl-3-(triphenylmethyl)-3H-imidazol-5-yl]methylene]-2,4 imidazolidinedione (1.20 g, 2.26 mmol) in DMF (5 mL) was added K2CO3 (1.56 g, 11.3 retool) and then 1-iodobutane (0.344 mL, 3.02 mmol). The mixture was stirred for 16 hours and then diluted with ether and washed with water and brine. After drying over MgSO4 the product was isolated by chromatography on silica eluting with 80 % petroleum ether 20 % ethyl acetate. MS (CI) 588
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)(C)C>[CH2:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)=[N:3][CH:4]=1)[CH3:9]
Reactant: OC1CCNCC1
Reactant: CCc1cnc(Br)cn1
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(O)CC2)cn1
Temperature: 150 °C

Procedure:
A mixture of 2-bromo-5-ethyl-pyrazine (1.66 g) and 4-hydroxy-piperidine (2.24 g) in isopropanol (15 mL) is heated to 150° C. overnight in an autoclave. After cooling to room temperature the solvent is evaporated in vacuo and water and dichloromethane are added. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound. LC (method 1): tR=0.66 min; Mass spectrum (ESI+): m/z=208 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]([NH2:35])=[NH:34].CO[Na]>CN(C=O)C.CC(=O)OCC>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][N:32]=[C:33]([NH2:35])[N:34]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Reactant: N=C(N)N
Agent: CO[Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(N)ncc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of compound 1 (3 g, 7.2 mmol) and guanidine (2 g, 35 mmol) in DMF (15 mL) was added MeONa (1.8 g, 35 mmol) and the mixture was heated to 100° C. and stirred for 4 h. The solution was cooled to r.t. and diluted with 80 mL of EA. The organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 2.1 g of 5-1 as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:19][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN1CCOCC1
Temperature: 0 °C
Yield: 17.2 %

Procedure:
A solution of Compound 107 (1 g, 2.64 mmol), 4-(2-chloro ethyl) morpholine (2.45 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0–10% methanol in ethylacetate gradient to yield 223 mg (17%) of white solids. M.P. 207° C. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 3.54 (m, 4H), 3.63 (m, 4H), 3.92 (m, 4H), 4.35 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.61 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 492 (M+1). Anal. (C26H29N5O3S) C, H, N.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1.CCOCC>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CCCCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 5-hexynyl alcohol (102 mmoles) in pyridine (150 ml), under argon, was cooled to 0° C. and p-toluenesulfonyl chloride (204 mmoles) was added. The reaction mixture was kept at about 4° C. for 18 hours, poured into ice-water and then taken up in ether. The ether extract was washed with cold 10% hydrochloric acid, water and brine. The organic layer was dried and concentrated in vacuo to give 5-hexynyl p-toluenesulfonate. A solution of phenylacetylene (97 mmoles) in tetrahydrofuran (200 ml) containing a trace of triphenylmethane was cooled to 0° C. and then n-butyl lithium (37.3 ml of 2.6 moles in hexane) was added dropwise. The resulting solution was stirred at 0° C. for 10 minutes and hexamethylphosphoramide (21 ml) was added dropwise. After stirring for 10 minutes a solution of 5-hexynyl p-toluenesulfonate (97.1 mmoles) in tetrahydrofuran (200 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, diluted with ether and the organic layer was washed with water and brine. The dried organic solution was concentrated and the product was purified by flash chromatography to give 1-phenylocta-1,7-diyne. A mixture of this compound (43 mmoles), 2-bromobenzaldehyde (35.8 mmoles), cuprous iodide (0.5 mmoles) and bis(triphenylphosphine) palladium (II) chloride (0.7 mmoles) in triethylamine (100 ml) was heated in an oil bath (95° C.) for one hour. The reaction mixture was cooled to 0° C., filtered and the filtrate was concentrated. The residue was dissolved in ether, washed with 10% hydrochloric acid, water and brine. The organic layer was dried and concentrated to give a product which was purified by flash chromatography to yield 2-(8-phenyl-1,7-octadiynyl)benzaldehyde. A solution of this compound (24.1 mmoles) in ethyl acetate (100 ml) and 10% palladium on charcoal (1 g) was hydrogenated (40 psi of hydrogen) at room temperature for 15 minutes. The catalyst was filtered off and the filtrate concentrated to give the 2-(8-phenyloctyl)benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[OH:13][C:14]1[CH:19]=[C:18]([CH3:20])[O:17][C:16](=O)[CH:15]=1>>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[N:1]1[C:18]([CH3:20])=[CH:19][C:14]([OH:13])=[CH:15][C:16]1=[O:17]
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: Cc1cc(O)cc(=O)o1
Product: COC(=O)c1ccc(Cl)c(-n2c(C)cc(O)cc2=O)c1

Procedure:
A condensation reaction with methyl 3-amino-4-chlorobenzoate (14.5 g, 78.2 mmol) and 4-hydroxy-6-methyl pyranone under reaction condition similar to the one described in Example 465-step 3 gave 12.32 (53.8%) of desired product.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:10].[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:11]=[O:12]
Reactant: COC(Cl)Cl
Reactant: COc1cccc(F)c1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c(F)c1Br
Temperature: 25 °C
Yield: 73.5 %

Procedure:
In a 3-necked 250 mL round-bottomed flask equipped with nitrogen lines and a stir bar was placed 2-bromo-1-fluoro-3-methoxy-benzene (I-29, 2.0 g, 9.75 mmol) and dichloromethane (48 mL). The solution was cooled in an ice water bath for 15 minutes and then titanium tetrachloride (5.02 mL, 45.8 mmol) and dichloromethyl methyl ether (1.32 mL, 14.6 mmol) were added and the reaction mixture was allowed to warm to room temperature and react for 2 hours. The reaction mixture was slowly added to ice water (250 mL) and extracted with dichloromethane (2×100 mL). The organic portions were combined, washed with a saturated sodium bicarbonate solution (75 mL), water (75 mL) and brine (75 mL), dried (MgSO4) and concentrated. The crude material was triturated with hexanes (15 mL) to produce 1.67 g of 3-bromo-2-fluoro-4-methoxy-benzaldehyde (I-30) as an off-white solid in 74% yield. MS (ESI+): 233.2 (M+)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[C:17](=[O:29])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=2)[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>CN1CCCC1.C(OCC)(=O)C>[CH2:32]([N:34]([CH2:35][CH3:36])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[C:17](=[O:29])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=2)[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1)[CH3:33]
Reactant: CCNCC
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(OCCBr)cc3ccoc23)C1=O
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1cc(C2=C(c3cn(C)c4ccccc34)C(=O)N(C)C2=O)c2occc2c1
Reaction time: 8 h

Procedure:
Add to a solution of 3-[5-(2-bromoethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (600 mg, 1.25 mmol) in 1-methylpyrrolidine (8 ml), diethylamine (0.65 ml, 6.28 mmol). Stir overnight under nitrogen atmosphere. Heat the reaction to 60° C. for 4 hours. Dilute with ethyl acetate, wash with water, brine, dry over magnesium sulfate, filter and concentrate to red oil. Flash chromatography through SCX column affords the title compound as a red oil. MS(ES+): 472.1; HRMS: calculated 472.2236 found 472.2235.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:24][N:25]([CH2:27][C:28](Cl)=[O:29])[CH3:26].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:22][C:21]1[C:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][N:25]([CH3:26])[CH3:24])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a suspension of 4-amino-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (2 g; 4.5 mmol; 1 eq) in DCM (100 mL) is added dimethylaminoacetyl chloride hydrochloride (710 mg; 4.5 mmol; 1 eq) and N-ethyldiisopropylamine (2.3 mL; 13.5 mmol; 3 eq) and the reaction mixture is stirred at room temperature overnight. To complete the reaction, dimethylaminoacetyl chloride hydrochloride (1.06 g; 6.74 mmol; 1.5 eq) is added and the reaction mixture is allowed to stir another 2 days. The precipitate formed is filtered off and the filtrate is treated with a solution of citric acid. The precipitate in the organic phase is filtered and the aqueous phase is basified with Na2CO3. The product is extracted with DCM and the organic phase is concentrated to near dryness to afford 1.5 g (80%) of the title compound as a yellow powder. HPLC (max plot) 85%; Rt 2.37 min. UPLC/MS (ES+) 420.2, (ES−) 418.3.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)=O)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[CH:29]([NH:32][C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:21][CH:20]([CH3:25])[CH3:9])[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:7][CH:6]([CH3:10])[CH3:5])[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)([CH3:31])[CH3:30]
Reactant: CS(=O)c1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(S(C)=O)n2)n1
Reactant: CC(C)N
Product: CC(C)Nc1nccc(-c2nn3c(NC(C)C)cccc3c2-c2ccnc(NC(C)C)n2)n1

Procedure:
N-Isopropyl-2,3-bis[2-(isopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine was prepared by treating 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine with isopropylamine as described in Example 7. 1H NMR, (CDCl3): δ 8.39 (d, 1H), 8.14 (d, 1H), 7.52 (m, 1H), 7.36 (d, 1H), 6.96 (m, 1H), 6.60 (d, 1H), 6.06 (d, 1H), 5.99 (d, 1H), 5.08 (m, 1H), 4.99 (m, 1H), 4.05–4.25 (m, 2H), 3.80–3.99 (m, 1H), 1.42 (d, 6H), 1.30 (d, 6H), 1.24 (m, 6H); MS m/z 446 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)cn1
Reactant: NN
Solvent: O
Product: NNc1ccc(Br)cn1
Temperature: 70 °C
Yield: 83 %

Procedure:
2-Chloro-5-bromopyridine (64 g, 333 mmol) was suspended in hydrazine monohydrate (250 mL) and the mixture was heated at 70° C. for 72 hours. The reaction mixture was then diluted with water (750 mL) and the resulting precipitate was filtered off and azeotroped, firstly with toluene (×2) then dichloromethane (×2), to afford the title compound as a pale brown solid in 83% yield, 52 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([CH2:12][C:13](O)=[O:14])=[C:4]2[N:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>O1CCCC1>[CH3:22][N:24]([CH3:25])[C:13](=[O:14])[CH2:12][C:11]1[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:9][N:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[N:3][C:4]=12
Reactant: Cc1cc(C)n2nc(-c3ccccc3)c(CC(=O)O)c2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(-c3ccccc3)c(CC(=O)N(C)C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A suspension of 3.0 g (0.011 mole) of 5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 1.73 g (0.011 mole) of 1,1'-carbonyldiimidazole in 120 ml of anhydrous tetrahydrofuran was stirred for 4 hours at room temperature while a stream of nitrogen was bubbled through the mixture. The solution was treated with a solution of dimethylamine in tetrahydrofuran (11.2 ml; 0.033 mole; 2.95M) and the mixture was stirred at room temperature for 17 hours under nitrogen. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane, extracted with aqueous 7% sodium bicarbonate, and with water, dried over magnesium sulfate and evaporated under reduced pressure (4.5 g). The residue was recrystallized from isopropanol to give 2.1 g (62%) of product, mp 171°-172° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([NH:13][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](=[O:17])[CH3:16])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH3:16][C:15]1[O:17][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13][C:14]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCC(=O)NC(C(C)=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCc1nc(-c2ccccc2)c(C)o1
Reaction time: 0.67 h

Procedure:
Phosphorous oxychloride (5.58 ml) was added to a solution of 1-hexanoylamino-1-phenyl-2-propanone (4.94 g) in toluene (50 ml) and the solution was refluxed with stirring for 40 minutes. The solvent was distilled off and water was added to the residue. The mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel chromatography [silice gel: 80 g; eluent: hexane-ethyl ether (4:1)] to give an oil of 5-methyl-2-pentyl-4-phenyloxazole, yield 4.25 g (92.8%).