Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10])#[N:2].[F:13][C:14]1([F:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[ClH:12].[F:13][C:14]1([F:20])[CH2:19][CH2:18][N:17]([S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][NH2:2])(=[O:11])=[O:10])[CH2:16][CH2:15]1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: FC1(F)CCNCC1
Product: Cl
Product: NCc1ccccc1S(=O)(=O)N1CCC(F)(F)CC1
Yield: 24.9 %

Procedure:
(2-(4,4-Difluoropiperidin-1-ylsulfonyl)phenyl)methanamine hydrochloride (81 mg) was prepared in two steps from commercially available 2-cyanobenzene-1-sulfonyl chloride (201 mg) and 4,4-difluoropiperidine (316 mg) in 25% overall yield following a procedure analogous to that used in the preparation 210A. LC-MS: 291.19 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4].[CH2:22](Br)[CH:23]=[CH2:24].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH2:24][CH:23]=[CH2:22])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)C(C)Cc2cc(O)c(Br)cc21
Reactant: C=CCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A solution N-trifluoroacetyl-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.030 g, 0.082 mmol) in dichloromethane (2 mL) was treated with allyl bromide (0.030 g, 0.246 mmol), DBU (0.037 g, 0.246 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (2 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.028 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.32 (s, 1 H), 6.62 (m, 1 H), 6.02 (m, 1 H), 5.45 (d, J=17 Hz, 1 H), 5.30 (d, J=11 Hz, 1 H), 4.58 (s, 2 H), 4.36 (m, 1 H), 3.62 (m, 1 H), 3.23 (m, 1 H), 3.11 (m, 1 H), 2.81 (d, J=10 Hz, 1 H), 2.70 (m, 1 H), 1.34 (m, 3 H), 1.21 (m, 3 H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(#N)C.CS(C)=O>[ClH:21].[F:20][C:2]([F:1])([F:19])[C@@H:3]([O:18][C:29](=[O:30])[NH:28][C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: O[C@@H](CN1CCOC(c2ccc(F)cc2)C1)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CS(C)=O
Product: Cl
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCOC(c2ccc(F)cc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.2 %

Procedure:
(2 S)-1,1,1-trifluoro-3-(2-(4-fluorophenyl)morpholino)propan-2-ol (39 mg, 133 μmol), TEA (92.7 μL, 665 μmol) and 1-chloro-4-isocyanatobenzene (20.4 mg, 133 μmol) were combined in 2 mL of acetonitrile and stirred at room temperature overnight. Several drops of DMSO were added to the mixture to make a clear solution. The solution was separated by reverse phase column chromatography (50-100% acetonitrile in water). The desired fractions were pooled, treated with 5 drops of conc. HCl and the solution lyophilized to afford the title compound (38 mg, 59%) as a white solid. (M+H)+=447 m/e.
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[CH2:5]=[C:6]1[C@H:12]([CH3:13])[O:11]C(O)[CH2:8][C@@H:7]1[NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:5]=[C:6]1[C@H:12]([CH3:13])[O:11][CH:1]([Cl:4])[CH2:8][C@@H:7]1[NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17]
Reactant: C=C1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Reactant: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=C1[C@@H](NC(=O)C(F)(F)F)CC(Cl)O[C@H]1C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of 0.51 g (2 mmol) of the intermediate VIII in 10 ml of acetic acid and 40 ml of water was heated at 100° C. for two hours, then evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranose (IX, 0.47 g, 99%) as a white solid: m.p. 168°-170° C., [α]D20° -160° (c=0.5, CHCl3). Treatment of IX (0.36 g, 1.5 mmol) in 25 ml of dry methylene dichloride with 4 ml of trifluoroacetic anhydride for 2 hours at 0° C. and 1 hour at 20° C. gave, after evaporation, the 1-0-trifluoroacetate (X), which was directly used for the preparation of the corresponding 1-chloro-derivative by treatment with dry hydrogen chloride in anhydrous diethyl ether at 0° C. After standing at 0° C. overnight, the reaction mixture was evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranosyl chloride (III-A, 0.35 g, 90%), suitable for the subsequent coupling reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1>CN(C=O)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C:34]2[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:33]=2[CH2:32][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:11]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[CH:46][CH:45]=1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3nc4cc(C#N)ccc4n3C3CCCCC3)cc2)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A suspension of compound 6 (0.330 g, 1.04 mmol) in DMF (2.4 mL) and cesium carbonate (339 mg, 1.04 mmol) was heated at 40° C. until almost clear. Compound 14 (356 mg, 1.14 mmol) was added in portions. The reaction mixture was stirred at rt for 18 h. The mixture was concentrated on a rotary evaporator. The residue was washed with water and collected by filtration. This material was purified by column chromatography (silica gel, 50% to 100% hexane/ethyl acetate (v/v) to give compound 15 (0.55 g, 100% yield). ESI-MS m/e 548 (M=1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[N:19]([CH2:20][C:21]([OH:23])=[O:22])[N:18]=[N:17][N:16]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:29](O)[CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][O:22][C:21](=[O:23])[CH2:20][N:19]1[C:15]([C:13]2[S:14][C:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)=[N:16][N:17]=[N:18]1
Reactant: O=C(O)Cn1nnnc1-c1ccc(CCCc2ccccc2)s1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccc(CCCc2ccccc2)s1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a solution of 300 mg (0.9 mM) of [5-[5-(3-phenylpropyl)-2-thienyl]tetrazol-1-yl] acetic acid in 2 ml of ethylene glycol was added 0.2 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=30/1) for separation and purification, to give 300 mg (yield 88.2%) of [5-[5-(3-phenylpropyl)2-thienyl]tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1>>[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(I)cc2)o1
Yield: 62 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (1.00 g, 4.60 mmol) was converted using 4-iodobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.21 g, 62%) which was obtained as a white solid. MS: m/e=430.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.[NH4+].[Cl-]>CCO.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[CH3:11]
Reactant: Cc1ncc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ncc(N)cc1Br
Temperature: 75 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 3-bromo-2-methyl-5-nitropyridine (2.3 g, 10.5 mmol) in EtOH (20 mL) was added water (40 mL), NH4Cl (2.25 g, 42 mmol) and iron powder (2.94 g, 52.5 mmol). The mixture was stirred at 75° C. for 2 hours. After the reaction mixture was cooled to room temperature, it was filtered through a celite pad. Organic solvent was removed under reduced pressure, and it was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4, and solvent was removed to give an off-white solid (1.52 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12](=O)[CH3:13])[CH:3]=1.Cl.[NH2:16][OH:17].CC([O-])=O.[Na+]>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12](=[N:16][OH:17])[CH3:13])[CH:3]=1
Reactant: CC(=O)c1cc(F)cc2c1cnn2C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1cc(F)cc2c1cnn2C
Temperature: 40 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To the solution of 1-(6-fluoro-1-methyl-1H-indazol-4-yl)ethanone (900 mg, 4.68 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (1.64 g, 23.4 mmol, 5.0 eq.) and NaOAc (3.84 g, 46.8 mmol, 10 eq.). The mixture was stirred at 40° C. overnight, and the solvent was concentrated in vacuo to afford 1-(6-fluoro-1-methyl-1H-indazol-4-yl)ethanone oxime as a white solid (848 mg, 87%). MS (ESI): m/z=208.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:33])([F:32])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]([F:33])([F:32])[F:19])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=463.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16].O1CC1>CCO>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reactant: CCNCC
Solvent: C1CO1
Solvent: CCO
Product: CCN(CC)CC(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of 2-(4-nitro-phenoxymethyl)-oxirane (9.75 g, 50 mmol) in absolute EtOH (100 mL) was heated at 70° C. until 2-(4-nitro-phenoxymethyl)-oxirane is dissolved then the solution was allowed to cool to room temperature. Subsequently the room temperature solution was treated with diethylamine (5.2 mL, 1.0 equiv.) in one portion. The reaction mixture is stirred at room temperature for 15 min during which time starting material (oxirane) began to precipitate out of solution. The reaction mixture was heated to 50° C. and an additional amount of diethylamine (2.6 mL) was added to achieve complete dissolution of starting oxirane. The reaction mixture was heated for an additional 5 h at 55° C. at which point thin layer chromatography (9:1, chloroform: methanol) indicated complete consumption of the starting oxirane. The reaction mixture was cooled to room temperature and concentrated in vacuo. The oily light brown residue obtained after evaporation, was purified by flash silica gel chromatography, (CHCl3 to 1:9, MeOH:CHCl3 gradient eluant) to give the 1-diethylamino-3-(4-nitro-phenoxy)-propan-2-ol as a yellow oil (11.9 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:57]1([CH3:66])[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][CH2:64][NH2:65]>CN(C=O)C>[C:57]1([CH3:66])[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][CH2:64][NH:65][C:18]([C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[O:10][C:11]=2[CH:17]=1)=[O:20]
Reactant: Cc1ccccc1CCN
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1CCNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-benzooxazole-6-carboxylic acid (8.9 mg) in anhydrous DMF (0.5 mL) was added BOP (17.4 mg), diisopropylethylamine (0.014 mL), and 2-o-tolyl-ethylamine (5.5 mg). The reaction mixture was stirred at 85° C. overnight, quenched with 1N NaOH aqueous solution at 0° C., extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica SPE eluting with EtOAc/Hexane to give 2-(2,6-dichlorophenyl)-benzooxazole-6-carboxylic acid (2-o-tolyl-ethyl)-amide: MS (m/z) 425.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[F:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: Cc1ccc(F)cc1-c1ccc2c(F)c(N)ncc2c1
Reaction time: 16 h
Yield: 49.1 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (203 mg, 806 μmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (313 mg, 883 μmol) were dissolved together in acetonitrile (2.0 mL) at ambient temperature and the mixture stirred for 16 h, at which time LCMS indicated approx 40% conversion. The mixture was diluted with water, extracted three times into dichloromethane and the combined organic phases washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0-6% methanol in dichloromethane) to yield the impure title compound as a pale solid (107 mg), used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH3:2].[CH3:15][N:16]=[C:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:15][NH:16][C:17](=[O:18])[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH:4]2[CH2:5][CH2:6][CH2:7][N:3]2[CH2:1][CH3:2])[CH:9]=1
Reactant: CN=C=O
Reactant: CCN1CCCC1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1CCCC1c1cccc(OC(=O)NC)c1
Yield: 96 %

Procedure:
To a solution of 3-[1-ethyl-2-pyrrolidinyl]phenol (0.8 g) in dry tetrahydrofuran (40 ml) was added methyl isocyanate (0.26 ml) at ambient temperature, under nitrogen, with stirring for ten mins. Milled potassium carbonate was added and the reaction mixture was stirred for 4 hrs, and filtered through a pad of celite. The solids were washed with ethyl acetate, and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane/0-30% methanol), and the eluant flushed through alumina (ethyl acetate) to give 1.0 g (96%) of product. Recrystallization from ether/petroleum ether gave the analytical sample, mp 67°-69° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:25]=[C:26]([C:30]3[N:31]=[C:32]4[CH2:37][CH2:36][CH2:35][CH2:34][N:33]4[CH:38]=3)[CH:27]=[C:28]([CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3].ClC[CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([O-:45])=[O:44].[CH3:48]N(C)C=O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24][CH2:48][O:45][C:43](=[O:44])[C:42]([CH3:47])([CH3:46])[CH3:41])=[O:23])=[CH:12][CH:11]=2)[C:7]2[CH:25]=[C:26]([C:30]3[N:31]=[C:32]4[CH2:37][CH2:36][CH2:35][CH2:34][N:33]4[CH:38]=3)[CH:27]=[C:28]([CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: CN(C)C=O
Reactant: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
Prepared analogously to Example 215 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and chloromethylpivalate in dimethylformamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1C1C2C(=CC(C=O)=CC=2)NN=1>>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:3]1[C:4]2[C:9](=[CH:8][C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2c(-c3cccs3)n[nH]c2c1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(-c3cccs3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one, except substituting 3-(thiophen-2-yl)-1H-indazole-6-carbaldehyde (29 m 0.13 mmol), the title compound was prepared as a yellow solid (19.7 mg, 45%). 1H NMR (400 MHz, d6-DMSO) δ 10.64 (br s, 1H), 8.22 (d, J=8.5 Hz, 1H), 7.92 (s, 1H), 7.79 (s, 2H), 7.61 (d, J=7.5 Hz, 1H), 7.59 (d, J=5.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.26-7.20 (m, 2H), 6.89 (d, J=7.5 Hz, 1H), 6.85 (t, J=7.5 Hz, 1H); MS ESI 344.1 [M+H]+, calcd for [C20H13N3OS+H]+ 344.08.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH:26](/B(O)O)=[CH:27]\[CH3:28].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:8]([C:7]1[C:2](/[CH:26]=[CH:27]/[CH3:28])=[N:3][C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:5][C:6]=1[CH3:19])=[O:9]
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: C/C=C/B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: C/C=C/c1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 110 °C
Yield: 72.7 %

Procedure:
To a solution of 400 mg (1.1 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide in toluene (15 ml) were added 140 mg (1.7 mmol) (E)-prop-1-enylboronic acid, 1.1 g (3.3 mmol) CsCO3 and EtOH (1.5 ml). After degassing with argon for 15 min 370 mg (0.32 mmol) Pd(PPh3)4 were added and the RM was heated to 110° C. for 5 h. Subsequently the RM was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 300 mg (0.8 mmol, 74%) (E)-N-(3-fluorobenzyl)-4-methyl-6-morpholino-2-(prop-1-enyl)-pyridine-3-carboxylic acid amide (example 9). [M+H]+ 370.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[CH:31]1[CH:36]=[CH:35][C:34]([C@H:37]([NH2:41])[C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:41][C@@H:37]([C:34]3[CH:33]=[CH:32][CH:31]=[CH:36][CH:35]=3)[C:38]([O:40][C:3]([CH3:22])([CH3:4])[CH3:2])=[O:39])=[CH:12][CH:13]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[O:30]
Reactant: N[C@H](C(=O)O)c1ccccc1
Reactant: CS(=O)(=O)OCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Product: CC(C)(C)OC(=O)[C@@H](NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)c1ccccc1

Procedure:
From Intermediate 4J and L-Phenylglycine tbutyl ester. LC/MS: m/z 542 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 10.30 (1H, br s), 7.51-7.45 (3H, m), 7.38 (2H, d, J=6.9 Hz), 7.27-7.04 (9H, m), 5.82 (1H, d, J=9.6 Hz), 4.20 (1H, s), 2.86-2.75 (4H, m), 2.04 (1H, br s), 1.31 (9H, s).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:7][C:8]=1[F:9].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[ClH:20].[F:19][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:21]2[CH:22]=[C:23]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[N:24]=[N:25][CH:26]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2ccc(F)c(C(F)F)c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2ccc(F)c(C(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=319.4 (M+H+), was prepared from 2-(3-difluoromethyl-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([CH2:10][C:11](Cl)=[O:12])([CH3:9])([CH3:8])[CH3:7]>ClCCl>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:11](=[O:12])[CH2:10][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: NCCCO
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)CC(=O)NCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
3-Amino-1-propanol (6.0 mL, 0.078 mol) was dissolved in dichloromethane (68 mL) then cooled at 0° C. A solution of tert-butylacetyl chloride (2.7 mL, 0.020 mol) in dichloromethane (25 mL) was added dropwise over 10 min. The reaction mixture was stirred for 1 h then concentrated to dryness. The residue was dissolved in EtOAC (100 mL) and washed with brine (3×). The organic extract was dried over Na2SO4, filtered, and concentrated to dryness to give the title compound as a clear oil (3.1 g, 91% yield). 1H NMR (DMSO, 400 mHz) δ (ppm): 7.64 (bs, 1H), 4.36 (t, J=5.3 Hz, 1H), 3.38-3.33 (m, 2H), 3.02 (q, J=6.8 Hz, 2H), 1.88 (s, 2H), 1.52-1.45 (m, 2H), 0.90 (s, 9H).