Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][O:3][C:4](=[O:25])[CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>C(Cl)Cl.O>[C:13]1([P:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][C:4]([O:3][CH3:2])=[O:25])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 93.2 %

Procedure:
A mixture of (2-methoxy-2-oxoethyl)triphenylphosphonium bromide (10.0 g, 24.08 mmol) in 100 mL DCM, 50 mL water and NaOH (10 N) (4.82 ml, 48.2 mmol) was vigorously shaken in a separatory funnel. The organic layer was separated and the aqueous phase was extracted with DCM. The combined organic layers were dried (MgSO4) and concentrated to give methyl 2-(triphenylphosphoranylidene)acetate (7.5 g, 93% yield) as a white solid. A solution of 3-chloro-2-methylbenzaldehyde (0.7 g, 4.53 mmol) and 2-(triphenylphosphoranylidene)acetate (1.817 g, 5.43 mmol) in MeOH (22.6 ml) was stirred at room temperature for 2 h. The mixture was concentrated and purified by flash chromatography (0-30% ethyl acetate:hexanes) to afford the title compound (0.23 g, 24% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=15.9 Hz, 1H), 7.47-7.40 (m, 2H), 7.17-7.15 (m, 1H), 6.33 (d, J=15.9 Hz, 1H), 3.83 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13]C)=[O:11].C([O-])([O-])=O.[K+].[K+].CCOCC>CO.O>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)c1cc2ncccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc2ncccc2[nH]1
Temperature: 55 °C
Yield: 90 %

Procedure:
Add to ethyl 4-azaindole-2-carboxylate 4a (42.3 mmol) in MeOH (50 mL), K2CO3 (1.20 equiv, 50.7 mmol) and stir the suspension with heating to 55° C. for 1 h. Monitor the reaction by tlc (Et2O/hept). When complete, concentrate the reaction in vacuo, dilute with H2O and stir for 15 min. Collect the solid by filtration and dry in a vacuum oven at 65° C. for 3 h to afford about 90% to about 100% of the desired methyl 4-azaindole-2-carboxylate 5a.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([O:8]/[N:9]=[C:10](\[NH2:26])/[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=O)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]2[O:8][N:9]=[C:10]([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]4)[N:26]=2)=[CH:4][CH:3]=1
Reactant: N/C(CCCOc1ccc2c(c1)CCC(=O)N2)=N\OC(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCCCc3noc(-c4ccc(Cl)cc4)n3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a stirred solution of (Z)—N′-((4-chlorobenzoyl)oxy)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)butanimidamide (0.030 g, 0.074 mmol) in dry DMF/THF (4 mL, 1:1) at 0° C., TBAF (1 M in THF; 0.02 mL, 0.02 mmol) was added and allowed to stir at room temperature overnight. Solvent was removed under vacuum. Ice cold water (2 mL) was added to the residue. The solid which formed was filtered and dried to yield 6-(3-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.020 g, 71%) as an off-white solid. 1H NMR: 400 MHZ, DMSO-d6: δ 2.16 (t, J=6.80 Hz, 2H), 2.39 (t, J=7.20 Hz, 2H), 2.82 (t, J=8.00 Hz, 2H), 2.95 (t, J=7.60 Hz, 2H), 4.02 (t, J=6.00 Hz, 2H), 6.71-6.78 (m, 3H), 7.72 (d, J=8.40 Hz, 2H), 8.11 (d, J=8.80 Hz, 2H), 9.89 (s, 1H). LCMS: RT 2.06 min. LCMS (ES-API), m/z 384.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7]O.BrC(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:33]=[C:34]1[NH:39][C:38]2[CH:40]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:42][C:37]=2[C:36](=[O:49])[N:35]1[CH:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][N:39]1[C:38]2[CH:40]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:42][C:37]=2[C:36](=[O:49])[N:35]([CH:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:57])[CH2:52][CH2:51]2)[C:34]1=[O:33]
Reactant: Cc1ncoc1CO
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ncoc1Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2sc(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-methyl-1,3-oxazol-5-yl)methanol (489 mg, compound D26) in dry DCM (0.6 ml) are added tetrabromomethane (1.87 g) and triphenylphosphane (1.48 g) and the mixture is stirred for 1 h at RT. Subsequently the reaction mixture is transferred to a microwave vial and tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.00 g, compound B50), dry DMF (150 ml) and potassium carbonate (1.23 g) are added. The mixture is stirred for 4 h at 50° C. and subsequently poured into ice-cold water. After stirring for 5 min the resulting precipitate is filtered off, taken up in EtOAc and dried in vacuo at −78° C. The residue is taken up in EtOAc and dried in vacuo three more times to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][OH:10])[C:5]([F:13])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([F:13])=[CH:4][N:3]=1
Reactant: CC(O)(CO)c1cc(Br)ncc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(COS(C)(=O)=O)c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(2-bromo-5-fluoro-pyridin-4-yl)-propane-1,2-diol (17.45 g, 69.8 mmol) and triethylamine (19.45 ml, 14.12 g, 140 mmol) in DCM (350 ml) at 0° C. was added dropwise methanesulfonyl chloride (5.71 ml, 8.39 g, 73.3 mmol) over a period of 10 min. The reaction mixture was stirred at 0° C. for 30 min, then quenched with 1M aq. NaHCO3 soln. The phases were separated, the aq. phase was twice reextracted with DCM and the combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (gradient heptane: EtOAc 0-5 min 88:12, 5-37.5 min 24:76) yielded the title compound as a clear oil. HPLC RtH4=0.76 min; ESIMS: 328, 330 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, 1H), 7.82 (d, 1H), 4.58-4.47 (m, 2H), 3.04 (s, 3H), 3.00 (s, 1H), 1.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:18]([F:20])[F:19])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:21]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:18]([F:20])[F:19])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH2:21])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(OC(F)F)cc2C1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: NC1CCc2ccc(OC(F)F)cc2C1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl [1-(4-chlorobenzyl)-7-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (30 mg, 0.069 mmol) was dissolved in dichloromethane (2 mL). 5N isopropanolic hydrochloric acid (0.3 mL) were added and the reaction mixture was stirred at room temperature for 3 h. The solvents were evaporated in vacuo. Yield: 26 mg (0.069 mmol, 100%, colorless solid).
Reaction SMILES: [ClH:1].Cl.S1C2C=CC(C[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C@H:21]4[N:31]5[C:32]6[N:23]([C:24](=[O:34])[CH:25]=[CH:26][C:27]=6[CH:28]=[CH:29][C:30]5=[O:33])[CH2:22]4)[CH2:16][CH2:15]3)=CC=2N=N1.C(N(CC)CC)C.[F:42][C:43]1[C:48]2[O:49][CH2:50][CH2:51][O:52][C:47]=2[CH:46]=[C:45]([CH:53]=O)[CH:44]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[F:42][C:43]1[C:48]2[O:49][CH2:50][CH2:51][O:52][C:47]=2[CH:46]=[C:45]([CH2:53][NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][C@H:21]3[N:31]4[C:32]5[N:23]([C:24](=[O:34])[CH:25]=[CH:26][C:27]=5[CH:28]=[CH:29][C:30]4=[O:33])[CH2:22]3)[CH2:18][CH2:19]2)[CH:44]=1
Reactant: O=Cc1cc(F)c2c(c1)OCCO2
Reactant: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3snnc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc(F)c3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.6 %

Procedure:
A suspension of (1R)-1-({4-[(1,2,3-benzothiadiazol-5-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (50 mg, 0.134 mmol) in chloroform (2 ml) and methanol (0.100 ml) at rt under argon was treated with triethylamine (0.056 ml, 0.402 mmol) and stirred at rt for 15 min. The solution was then treated with 8-fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (for a synthesis see WO2007122258, Example 8(b)) (21.96 mg, 0.121 mmol) and stirred for a further 30 min. The solution was treated with sodium triacetoxyborohydride (85 mg, 0.402 mmol) and stirred at rt for 30 min, LCMS after 30 min showed there was still starting material and the imine of the product. So more sodium triacetoxyborohydride (40 mg) was added, the reaction was stirred for a further 30 min. LCMS after this time showed that the reaction was complete. The reaction was then treated with saturated aqueous NaHCO3 (10 ml) and extracted with 20% methanol/DCM (3×25 ml). The combined organic fractions were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound (6 mg, 9.6%) as a pale yellow solid and some crude product (15 mg, 24%) as an impure pale yellow solid which was purified using an SCX column to give more identical title compound, free base.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([C:30](=[O:37])[C@H:31]([O:33]C(=O)C)[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CO.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([C:30](=[O:37])[C@H:31]([OH:33])[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(=O)O[C@H](C)C(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A solution of 2.77 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(2(R)-acetoxypropionyl)-2′-isobutyl-4-methylvalerohydrazide in a mixture of 20 ml of methanol and 10 ml of water was treated with 1.35 g of potassium carbonate. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over anhydrous magnesium sulphate and evaporated to give a foam. Trituration of this foam with diethyl ether gave 2.12 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(2(R)-hydroxypropionyl)-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@H:12]([O:13]C(=O)C2C=CC=CC=2)[C:11](=[CH2:22])[O:10][C@H:7]([O:8][CH3:9])[CH2:6]1)(=[O:3])[CH3:2].C[O-].[Na+].C1C=CC=CC=1.CC(C)=O>CO>[C:1]([NH:4][C@@H:5]1[C@H:12]([OH:13])[C:11](=[CH2:22])[O:10][C@H:7]([O:8][CH3:9])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=C1O[C@H](OC)C[C@H](NC(C)=O)[C@@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: c1ccccc1
Product: C=C1O[C@H](OC)C[C@H](NC(C)=O)[C@@H]1O
Reaction time: 12 h

Procedure:
To a solution of Compound VII (5 g, 16.4 mmoles) in absolute methanol (30 ml) was added M sodium methoxide (0.5 ml), and the mixture was kept for 12 hours at 25° C, at which point, t.l.c. (2:3 benzene-acetone) indicated that saponification was complete. The solution was passed through a small bed (250 × 20 mm) of silica gel in a column, and the effluent was evaporated in vacuo to give Compound VIII as a syrup, yield 3.2 g (97%); this was subjected, without delay, to the hydrogenation step of Example 8.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23].O=C1C2C(=CC=CC=2)C2C(CC(N)=O)=CC=CC=2N1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[O:20]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=2[NH:16]1
Reactant: CCCNCCC
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: NC(=O)Cc1cccc2[nH]c(=O)c3ccccc3c12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and dipropylamine. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl-acetamide (45 mg) in N,N-dimethylformamide (10 mL) was added potassium phosphate (68 mg) and dipropylamine (0.027 mL). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered (25 mg). 1H-NMR (300 MHz, DMSO-d6), 11.70 (br s, 1H), 9.72 (br s, 1H), 8.33 (d, J=8.0 Hz, 2H), 7.89 (m, 1), 7.66 (m, 2H), 7.33 (m, 1H), 3.21 (s, 2H), 1.50 (m, 6H), 0.89 (m, 8H).
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[C:15]([OH:19])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][CH2:17][CH2:16][C:15]([OH:19])=[O:18])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C=CC(=O)O
Reactant: COc1cc(N)c2ncccc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NCCC(=O)O)c2ncccc2c1
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 5.0 g (19.56 mmol) of 6-methoxy-8-aminoquinoline hydrobromide, 1.48 ml (21.51 mmol) of acrylic acid and 5.45 ml (39.12 mmol) of triethylamine is dissolved in 25 ml of toluene and brought to 110° C. for 16 h, with magnetic stirring. 10 ml of a 10% (w/v) aqueous sodium hydroxide solution are then added and the reaction medium is kept at 100° C. for 20 min, with stirring. After returning to ambient temperature, the phase containing the toluene is eliminated and the aqueous phase is extracted with 100 ml of chloroform. The aqueous phase is then acidified by adding acetic acid until a pH of 5-6 is obtained. The precipitate obtained is filtered off and then washed with water. After drying under vacuum, the compound 26 is obtained in the form of a green powder: 1.77 g (yield=37%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:36][CH:37]=3)[C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(O)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of 4-tert-butyl-N-{6-[2-(4-hydroxyphenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (200 mg) in dimethylformamide (2 ml) is added sodium hydride (60% dispersion-type, 32 mg), and the mixture is stirred at room temperature for 30 minutes. To the mixture is added a solution of tert-butyl bromoacetate (77 mg) in dimethylformamide (2 ml) under ice-cooling, and the mixture is stirred at the same temperature for one hour. The reaction solution is poured into ice-water, and treated with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate=3:1), and crystallized from ethyl acetate/diisopropyl ether to give tert-butyl 4-{2-(6-(4-tert-butybenzenesulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy)ethoxy}phenoxyacetate (225 mg ).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[NH:11]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:1][N:11]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]2)=[CH:4][CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(CN2CC(C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 4-formylbenzonitrile (2.88 g, 22.0 mmol), azetidine-3-carboxylic acid (2.02 g, 20 mmol), and acetic acid (1.15 mL, 20.0 mmol) in dichloromethane (20 mL) and methanol (80 mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (6.78 g, 32.0 mmol) was added and stirring was continued at room temperature for 18 hr. The volatiles were removed under reduced pressure, and the residue was partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous layer was collected, washed with diethyl ether (50 mL), and concentrated. The residue was dissolved in water (20 mL) and loaded onto a 2.5×20 cm HP-20 column [Preparation of HP-20 Gel: ˜400 ml of dry, unused MCI CHP-20 Gel (75-150 micron) was swelled in methanol for 24 hrs. The gel was filtered and rinsed with 1 liter of methanol. It was then transferred to a bottle for storage under methanol. Immediately before use, the desired amount of gel was rinsed thoroughly with 20 volumes of water]. The column was eluted with 240 mL of water and 400 mL of methanol. The product containing fractions were concentrated and co-evaporated from ethanol and ethyl acetate/heptane to afford 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol, 75% yield) as a white solid. MS: (M+H)=217.18. 1H NMR (400 MHz, MeOD) δ ppm 3.39 (m, 1H), 4.08 (m, 4H), 4.32 (s, 2H), 7.63 (d, J=8.3 Hz, 2H), and 7.82 (d, J=8.3 Hz, 2H).
Reaction SMILES: CC1[N:3]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]2[N:14]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:15](=[O:27])[C:16]3[C:22]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:20]=[CH:19][C:17]=3[N:18]=2)C(C)=CC=1.Cl.NO>C(O)C>[NH2:3][C:8]1[S:12][CH:11]=[N:10][C:9]=1[C:13]1[N:14]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15](=[O:27])[C:16]2[C:22]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: Cc1ccc(C)n1-c1scnc1-c1nc2ccnc(C(F)(F)F)c2c(=O)n1CCc1ccccc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Nc1scnc1-c1nc2ccnc(C(F)(F)F)c2c(=O)n1CCc1ccccc1
Temperature: 80 °C
Yield: 25.7 %

Procedure:
To a solution of 2-(5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazol-4-yl)-3-phenethyl-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (7 mg, 0.014 mmol) in ethanol was added hydroxylamine hydrochloride (9.82 mg, 0.14 mmol) and the mixture was heated up to 80° C. for 60 hours. The reaction was then concentrated and purified with flash chromatography providing an off-white solid (1.5 mg). 1H NMR (400 MHz, CDCl3) δ 8.72 (d, 1H), 8.02 (s, 1H), 7.52 (d, 1H), 7.30 (m, 5H), 6.93 (s, br, 2H), 4.89 (t, 2H), 3.17 (t, 2H). MS m/z 418.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.N1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](=[O:29])(=[O:30])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
250 ml of dichloromethane is combined with 9.38 g (52.37 mmol) of 4-fluoro-2-trifluoromethylaniline and 6 ml (14.3 mmol) of pyridine. The mixture is cooled with ice water and under agitation and exclusion of moisture, 13.52 g (57.62 mmol) of 2-chlorosulfonylbenzoic acid methyl ester is added in small increments. The mixture is agitated overnight, washed with 2N hydrochloric acid and water, the dichloromethane solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ethyl acetate/hexane. The title compound melts at 143°-145° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[N:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][NH2:59])[CH:53]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([NH:59][CH2:58][C:54]3[CH:53]=[N:52][CH:57]=[CH:56][CH:55]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a solution of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid (0.20 g, 0.67 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (0.23 g, 1.73 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.17 g, 0.87 mmol), N,N-diisopropylethylamine (0.15 mL, 0.87 mmol) and pyridin-3-ylmethanamine (0.081 mL, 0.80 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained solid was washed with 5% ethyl acetate in hexanes and dried in air to afford the title compound as a white solid (0.16 g, 60%): mp 212-213° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.53 (br s, 1H), 7.98-7.95 (m, 1H), 7.73-7.66 (m, 1H), 7.43-7.22 (m, 6H), 6.28 (t, J=5.6 Hz, 1H), 5.55 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 2.67 (s, 3H); MS (ES+) m/z 391.3 (M+1).