Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[C:10]2/[C:11](=O)[CH2:12][CH2:13][C:14]3[C:19]/2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30].O>C(O)C.C1(C)C=CC=CC=1.ClCCl>[CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([C:9]2[O:30][N:29]=[C:11]3[CH2:12][CH2:13][C:14]4[C:19]([C:10]=23)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(/C=C2/C(=O)CCc3ccccc32)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2onc3c2-c2ccccc2CC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one (50 mg, 0.16 mmol) were dissolved in ethanol (2.0 ml) and then anhydrous sodium acetate solution (14.5 mg, 0.18 mmol, saturated with hot acetic acid) and hydroxylamine hydrochloride salt solution (12.2 mg, 0.18 mmole, ethanol 2.0 ml) were added respectively. Then, the solution was heated and refluxed for about 5 hours and cooled to room temperature. Afterward, water and dichloromethane were added, separated to layers, washed with the saturated brine and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure so as to obtain a solid. Again, toluene (5 ml) was poured, refluxed, stirred for 24 hours and cooled to room temperature. After condensing with reduced pressure, the resulting remnant was purified through silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1, v/v). As a result, 35 mg of the present compound (productive yield 71%) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[F:34]>>[F:34][C:25]1[CH:24]=[CH:29][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:27][C:26]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cc(C(F)(F)F)ccc1F)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromo-1-fluoro-4-trifluoromethyl-benzene. Light yellow solid. MS (ESI): 477.1 (MH+)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1>C(O)C.[Pd]>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: OCC#Cc1cccc(CO)c1
Agent: [Pd]
Solvent: CCO
Product: OCCCc1cccc(CO)c1

Procedure:
A solution of 3-(3-(hydroxymethyl)phenyl)prop-2-yn-1-ol [Aromatic Intermediate 18, step a] (0.44 g) in ethanol (20 mL) was hydrogenated using an H-Cube™ Hydrogenation Reactor (ThalesNano Nanotechnology Inc) with 10% Pd/C catalyst at 50° C. and 40 bar. The solution was passed through the H-cube three times, and concentrated in vacuo to afford the subtitled compound as a pale yellow oil. Yield (0.40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH:12]([CH2:16][CH2:17]O)[CH2:13][CH2:14]O>>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]2[O:10][CH2:17][CH2:16][NH:12][CH2:13][CH2:14][O:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: OCCNCCO
Product: Fc1ccc(B2OCCNCCO2)cc1Cl
Yield: 87 %

Procedure:
The title compound (87%, oil) was prepared from 3-chloro-4-fluorophenylboronic acid and diethanolamin.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](O)[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[CH:18]=2)=[CH:5][CH:4]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:20])[CH3:1])=[CH:4][CH:5]=2)[CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(O)n2)cc1
Solvent: CCN(CC)c1ccccc1
Product: CN(C)c1ccc(-c2cc3ncccc3c(Cl)n2)cc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(4-dimethylaminophenyl)-[1,6]naphthyridin-5-ol (Example 1) (1.2 g, 5 mmol), POCl3 (10 mL) and N,N-diethylaniline (0.15 g, 1.0 mmol) were stirred at 110° C. for 16 hours. The contents were cooled to room temperature and excess POCl3 was removed in vacuo. The residue was quenched with water and neutralized with aqueous sodium carbonate. The aqueous solution was then extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a tan oil. Purification by flash chromatography eluting with hexanes/EtOAc (1:1) afforded the title compound as a yellowish solid (1.1 g). 1H NMR (CDCl3, 400 MHz) δ 9.03 (dd, 1H), 8.54 (d, 1H), 8.13 (s, 1H), 8.08 (d, 2H), 7.46 (dd, 1H), 6.81 (d, 2H), 3.05 (s, 6H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CO.[Zn]>[C:1]([NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)Nc1ncccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the N-tert-butyl-3-nitropyridin-2-amine in MeOH (200 mL), was added solid NH4Cl (16.4 g, 306.54 mmol) and zinc dust (10.0 g, 153 mmol). The suspension was heated under reflux for 3 hours and then cooled to RT. After filtration through Celite™, the solvent was removed by vacuum evaporation. The resulting black residue was taken up to EtOAc (300 mL) and filtered through Celite™ again to remove the remaining NH4Cl. The solvent was again evaporated and the residue was dried on the high vacuum oil pump overnight to yield N2-tert-butylpyridine-2,3-diamine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[S:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=2)=[CH:16]1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.CCN(CC)CC>[S:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27](=[O:29])[O:28][CH2:2][C:3]=3[C:5]3[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=3)=[CH:24][CH:25]=2)=[CH:16]1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=C(O)Cc1ccc(-c2ccsc2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(-c4ccsc4)cc3)C(=O)OC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a suspension of 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (0.27 g, 1 mmol) and 4-(3-thienyl)phenylacetic acid (0.19 g, 0.9 mmol) in acetonitrile (5 mL) was added Et3N (0.33 mL) at 0° C. under nitrogen. After stirring for 20 minutes at room temperature, the mixture was chilled in ice bath. DBU (0.29 mL) was added to the mixture, and stirred for 20 minutes at 0° C. To the mixture was added 1N HCl solution (8 mL) and ice-water (10 mL), and the mixture was stirred for 2 minutes. The whole was extracted with CH2Cl2 (50 mL×3), the combined organic layer washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1/1) followed by recrystallization from ethyl acetate/hexane to provide the title compound (0.15 g, 39% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:30]C(=O)OC(C)(C)C)[C:9](=[O:29])[NH:10][C@@H:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[O:13][C@@H:12]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:30][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][C@@H:12]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Yield: 98.7 %

Procedure:
tert-Butyl ((1S)-1-(4-fluorophenyl)-2-oxo-2-{[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]amino}ethyl)carbamate (65a) (202 mg, 0.400 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (4 mL) and kept at ambient temperature for 1 h. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford the title compound (160 mg, 99%) as a yellow oil. MS APCI, m/z=406 (M+1). LC/MS: 1.60 min.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>ClCCl.CCOCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:15]
Reactant: OC1CCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 887.3 %

Procedure:
To a solution of cyclohexanol (1.0 g, 0.95 mmol) in dichloromethane (30 mL) is added rhodium (II) acetate dimer (44 mg) followed by ethyl diazoacetate (1.14 g, 10.0 mmol). The reaction mixture is stirred at RT for 20 min. The reaction mixture is diluted with Et2O, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.57 g of the product 407. 1H NMR (CDCl3) δ 4.23 (q, 2H), 4.10 (s, 2H), 3.33 (m, 1H), 1.93 (m, 2H), 1.74 (m, 2H), 1.54 (m, 1H), 1.4-1.1 (m, 8H)
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[C:22](Cl)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>CN(C=O)C>[Cl:15][C:16]1[C:22]([N:5]2[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]2)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(N2CCC(F)(F)C2)c(Cl)cc1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
3,3-Difluoropyrrolidine hydrochloride (3.12 g, 21.7 mmol) followed by potassium carbonate (4.00 g, 29.0 mmol) were added to 4,5-dichloro-2-nitroaniline (3.00 g, 14.5 mmol) in DMF (60 mL). The reaction mixture was stirred at 130° C. over the weekend. After cooling the reaction mixture was poured into ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried, concentrated and the crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:36]3[CH2:37][CH2:38][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])=[CH:18]1
Reactant: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Product: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-3-(1H-Indol-3-yl)-propionic acid was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=103-107° C.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][NH:29][CH3:30])[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:29]([CH3:30])[C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=2)[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: Cc1nccc(Cl)n1
Reactant: CNC/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccc(N(C)C/C=C/COC[C@H]2CC[C@H](CN(C)S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)n1
Temperature: 25 °C

Procedure:
A solution of 77 mg (0.17 mmol) trans-N-methyl-N-[4-(4-methylamino-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide (example 20.6), 0.044 g (0.34 mmol) of 4-chloro-2-methyl-pyrimidine [Ger. Offen. (1990), DE3905364 A1] and 0.06 ml (0.34 mmol) N-ethyl-diisopropylamine in 1 ml of N,N-dimethylformamide was stirred for 2 hours at 80° C. The reaction mixture was then cooled to room temperature, poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 95:5:1 v/v/v mixture of dichloromethane, methanol and saturated aqueous ammonia as the eluent giving 55 mg (59%) trans-N-methyl-N-(4-{4-[methyl-(2-methyl-pyrimidin-4-yl)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-4-trifluoromethyl-benzenesulfonamide as yellowish viscous oil, MS: 541 (MH+).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][C@H:2]1[C@H:7]([O:8][C:9]2[N:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: C[C@H]1[C@H](Oc2ncc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1NCCC[C@H]1Oc1ncc(C(F)(F)F)cn1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To the title compound of step A (813 mg) in DCM (6 mL) was added TFA (2 mL). After 1 h, the reaction was diluted with saturated Na2CO3 (aq) and extracted with DCM. The organic layers were dried (MgSO4) and concentrated to give the title compound (452 mg) that was used without further purification.
Reaction SMILES: [Br:1]Br.[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([Br:1])=[CH:9][N:8]=1
Reactant: N[C@H](CNc1cc(-c2ccncc2)ccn1)Cc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: N[C@H](CNc1cc(-c2ccncc2)c(Br)cn1)Cc1ccccc1
Reaction time: 1 h

Procedure:
Bromine (757 mg, 4.7 mmole) in CHCl3 (10 mL) was added in one portion to a stirring solution of 2-((S)-2-amino-3-phenylpropylamino)-4-(4-pyridyl)pyridine (1.44 g, 4.7 mmole) in CHCl3 (30 mL) at room temperature. After 1 hr, the mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic solvent was washed with brine, dried and evaporated. The residue was purified on a column of silica gel (CH2Cl2-MeOH-Conc. NH4OH=1000:110:8). MS (m/z): Calcd. C19H19N4Br (M+): 383, found: 383, 385.1. 1H-NMR (CDCl3, 400 MHz) δ: 8.62(d, 2H), 8.20(s, 1H), 7.30-7.10(m, 7H), 6.32(s, 1H), 5.78(bs, 1H), 3.70-3.30(m, 3H), 2.97(dd, 1H), 2.92(dd, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45]>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:45][CH2:44][CH:40]2[CH2:41][CH2:42][CH2:43][O:39]2)=[O:34])[C:15]1=[O:38]
Reactant: NCC1CCCO1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Solvent: CCO
Product: O=C(NCC1CCCO1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (2.5 mL) under nitrogen was treated with 1-(tetrahydro-2-furanyl)methanamine (0.025 mL, 0.24 mmol) for 40 min. (130° C. in a microwave vessel. The reaction was then cooled to ambient temperature and the resulting suspension was filtered, washed with EtOH and Et2O then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.7 (m, 4 H), 3.2 (m, 2 H), 3.6 (m, 2 H), 3.8 (m, 1 H), 3.9 (t, J=5.7 Hz, 2 H), 4.1 (s, 2 H), 4.6 (m, 1 H), 7.1 (m, 2 H), 7.3 (m, 2 H), 7.8 (s, 4 H), 8.2 (s, 1 H), 8.5 (d, J=1.4 Hz, 1 H), 10.0 (t, J=5.8 Hz, 1 H); ES+ MS: 571 (M+H+).
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([CH3:18])=[N+:6]([O-:17])[C:7]([CH3:16])=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1)#[N:3].[OH-:19].[Na+]>>[CH3:18][C:5]1[C:4]([C:2]([NH2:3])=[O:19])=[C:9]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH:8]=[C:7]([CH3:16])[N+:6]=1[O-:17]
Reactant: Cc1cc(N2CCSCC2)c(C#N)c(C)[n+]1[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(N2CCSCC2)c(C(N)=O)c(C)[n+]1[O-]

Procedure:
3 g (0.012 mol) of 3-cyano-2,6-dimethyl-4-(4-thiomorpholinyl)pyridine 1-oxide hydrochloride (from Example 1) were dissolved in 10 ml of 10 N sodium hydroxide solution, and the solution was heated under reflux for 6 hours. It was then evaporated until a precipitate formed, the mixture was cooled, and the solid was filtered off and recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.N[C@@H:32](CCN1CC(OC2C=CC(Cl)=C(C)C=2)C1)CO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:29][C:30]=1[CH3:32]
Reactant: Cc1cc(OC2CN(CC[C@H](N)CO)C2)ccc1Cl
Reactant: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Product: Cc1cc(OC2CN(CC[C@@H](CO)NC(=O)Nc3cc(C4CC4)nn3C)C2)ccc1Cl

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 83 except using (S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-ol in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][C:7]=2[CH:16]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:29])C.Cl>O>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][C:7]3[CH:16]=[C:3]([CH:2]=[O:29])[CH:4]=[CH:5][C:6]=3[O:15][C:10]=12
Reactant: CC(=O)O
Reactant: ClCc1ccc2c(c1)Cc1cccnc1O2
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1ccc2c(c1)Cc1cccnc1O2

Procedure:
A mixture of 52 g of 7-chloromethyl-5H-[1]benzopyrano[2,3-b]pyridine, 63 g of hexamethylenetetramine, 160 ml of water and 160 ml of acetic acid is stirred under reflux for 3 hours. To the reaction mixture is added 80 ml of concentrated hydrochloric acid, and the whole mixture is refluxed for 20 minutes, then diluted with 200 ml of water, and cooled. The crystalline precipitate is filtered off, washed with water, dried, and then recrystallized from dioxane to give 5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde melting at 171°-173°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[N:13]1[S:14][N:15]=[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=12.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:22][C:20]1[CH:19]=[CH:18][C:17]2=[N:13][S:14][N:15]=[C:16]2[CH:21]=1)[CH3:2]
Reactant: Oc1ccc2nsnc2c1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1ccc2nsnc2c1
Yield: 81.9 %

Procedure:
A mixture of 2-chloro-nicotinic acid ethyl ester (0.516 g, 3 mmol), benzo-[2,1,3]-thiadiazol-5-ol (0.46 g, 3 mmol), and cesium carbonate (2.07 g, 6.3 mmol) was stirred in 40 ml N,N-dimethylformamide at 80° C. for 48 h. The dark orange mixture was cooled and poured into water (600 ml) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, and dried over (Na2SO4). The mixture was concentrated in vacuo to give 0.74 g of a yellow solid (82% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14](O)[CH2:15]C=C)=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.CSC.[CH3:31][OH:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][CH:31]=[O:32])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=CCC(O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Solvent: CSC
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=CC=O
Reaction time: 2 h

Procedure:
N-[4-(4-fluorophenyl)-5-(1-hydroxybut-3-enyl)-6-isopropyl-pyrimidin-2-yl]-N-methylmethanesulfonamide (4 g, 10.2 mmol) is diluted in 102 mL methanol. O3 gas is bubbled through the solution at −15° C. to −10° C. for 60 min. Reaction solution is bubbled with Argon for 2 min to remove the excess of O3. Dimethylsulfide (1.5 ml, 20.3 mmol) is added to the solution, maintaining stirring for 2 hours. Upon completion of the reaction, the solution is distilled under reduced pressure to remove the excess of dimethylsulfide and solvent. The residue is diluted in 200 mL dichloromethane, washed with DM water (50 mL), brine (50 mL) and dried over magnesium sulfate (1 g). The solvent is removed by distillation under reduced pressure to afford 4.1 g of N-[4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl]-N-methylmethanesulfonamide.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: OB(O)c1ccncc1
Product: Nc1nc2c(-c3ccncc3)cccn2n1

Procedure:
8-Pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 4-pyridylboronic acid (0.81 g, 6.6 mmol) in a manner analogous to Step 2c. The product of the reaction was isolated as a pale yellow solid (0.54 g, 54%). MP=209-215° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.69 (dd, J=4.8, 1.4 Hz, 2H), 8.65 (dd, J=6.5, 0.8 Hz, 1H), 8.18 (dd, J=4.7, 1.6 Hz, 2H), 7.94 (dd, J=7.5, 0.9 Hz, 1H), 7.03 (t, J=6.8 Hz, 1H), 6.24 (s, 2H). MS=212 (MH)+.