Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]2[N:10]=[C:11]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:8]2[N:7]=[C:6]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[N:5]=1.IC.[CH3:28]C(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C)C=O.O>[F:25][C:20]1[CH:19]=[C:18]([C:6]2[N:5]=[C:4]([NH:3][CH3:28])[N:9]3[N:10]=[C:11]([C:13]4[O:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:8]3[N:7]=2)[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Nc1nc(-c2cc(F)cc(F)c2)nc2nc(-c3ccco3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CNc1nc(-c2cc(F)cc(F)c2)nc2nc(-c3ccco3)nn12

Procedure:
Sodium hydride (86 mg of a 50% dispersion in oil) was added to a stirred solution of 7-amino-5-[3,5-difluorophenyl]-2-(2-furyl)-1,2,4-triazolo[1,5-a][1,3,5]triazine (0.421 g) in dimethylformamide (5 ml). The mixture was stirred until the effervesence had ceased and a clear solution was obtained. Iodomethane (0.256 g, 0.11 ml) was then added and the reaction mixture was stirred at ambient temperature for 2 hours. Water (25 ml) and glacial acetic (0.5 ml) were then added and the resulting aqueous suspension was extracted with ethyl acetate (3×50 ml). The organic extracts were combined and washed with water (2×25 ml) and brine (25 ml), dried (MgSO4) and evaporated to give a yellow solid. This was purified by chromatography on silica. Elution with toluene containing ethyl acetate (10% v/v) gave 5-[3,5-difluorophenyl]-2-(2-furyl)-7-methylamino-[1,2,4]triazolo[1,5-a][1,3,5]triazine as a white solid m.p. 231°-4° C. microanalysis, found: C, 55.0; H, 3.1; N, 25.5% C15H10F2N6O requires C15H10F2N6O C, 54.9; H, 3.1; N, 25.6%; NMR 3.16 (s, 3H, CH3N), 6.73 (d of d, 1H, furyl-4H), 7.21 (d of d, 1H, furyl-3H), 7.47 (t of t, 1H, phenyl-4H), 7.93 (d, 1H, furyl-5H), 7.97-8.05 (complex, 2H, phenyl-2H and phenyl-6H) and 9.31 (s, 1H, NH); m/e 329 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1Br)(=[O:3])[CH3:2].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:32]1[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1-c1ccc(C(F)(F)F)cc1

Procedure:
By following a procedure analogous to Example 27 starting from 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-(trifluoromethyl)-phenylboronic acid, 4-[4-(trifluoromethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=31%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11](F)[CH:12]=1)[C:8]#[N:9]>CO.CN(C)C=O.CCOCC>[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:2][CH3:1])[CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(F)cc(C#N)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium methoxide (1.50 ml of a 4.5M solution in methanol, 7.10 mmol) was added dropwise to a stirred solution of 3,5-difluorobenzonitrile (1.00 g, 7.10 mmol) in N,N-dimethylformamide (36 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and stirred for 14 hours. The reaction was diluted with ether (40 ml), washed with water (3×100 ml) and brine (100 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5, by volume) to provide the title compound (418 mg) as a yellow oil.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH:36]([O:39][C:40]([N:42]1[C:51]2[C:46](=[N:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=2)[C@H:45]([N:54]([CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:64]=[C:63]([C:71]([F:74])([F:73])[F:72])[CH:62]=2)[C:55]2[N:56]=[N:57][NH:58][N:59]=2)[CH2:44][C@@H:43]1[CH2:75][CH3:76])=[O:41])([CH3:38])[CH3:37]>ClCCl>[CH:36]([O:39][C:40]([N:42]1[C:51]2[C:46](=[N:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=2)[C@H:45]([N:54]([CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:68])([F:69])[F:70])[CH:64]=[C:63]([C:71]([F:72])([F:73])[F:74])[CH:62]=2)[C:55]2[N:56]=[N:57][N:58]([CH3:1])[N:59]=2)[CH2:44][C@@H:43]1[CH2:75][CH3:76])=[O:41])([CH3:38])[CH3:37]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2nc(OC)ccc2N1C(=O)OC(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
Add triphenylphosphine (27 mg, 0.104 mmol), methanol (17 mg, 0.52 mmol), and diisopropylazodicarboxylate (0.018 mL, 0.104 mmol) to a solution of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester in dry dichloromethane (1 mL) and stir the mixture for 15 h at room temperature. Remove the solvent in vacuo and purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford the title compound (41 mg, 66%). MS (ES+): 602 (M+H).
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(N(C)C)=O.O>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][C:5]2[C:6]([CH3:8])=[N:7][C:2]([I:1])=[CH:3][C:4]=2[CH3:10])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1cc(I)nc(C)c1O
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(I)nc(C)c1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 20 %

Procedure:
A solution of 6-iodo-2,4-dimethylpyridin-3-ol (5.10 g, 20.48 mmol) in DMA (60 mL) was sparged with Ar, treated with 2,4-dichloropyridine (3.94 g, 26.60 mmol) and K2CO3 (3.40 g, 24.57 mmol) and heated at 105° C. overnight. The mixture was cooled to RT, treated with EtOAc and water, filtered to remove solids, then treated with charcoal, warmed to reflux, cooled to RT and filtered through diatomaceous earth. The layers of the filtrate were separated, the aqueous layer extracted with additional EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2,4-dimethylpyridine (1.476 g, 20%). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=5.8 Hz, 1 H), 7.75 (s, 1 H), 7.05 (d, J=2.3 Hz, 1 H), 6.89 (dd, J=5.8, 2.3 Hz, 1 H), 2.20 (s, 3 H), 2.02 (s, 3 H); MS (ESI) m/z: 361.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:25][C:26](=[O:28])[CH3:27])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH2:25][C:26]([CH3:27])=[O:28])[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: CC(=O)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)COc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (5 g, 28 mmol) in DMF (50 ml), potassium carbonate (7.7 g, 56 mmol) was added and the mixture was stirred for 30 min at 30° C. Thereafter, 2-oxopropyl methanesulfonate (4.7 g 30 mmol) was added drop wise and the reaction mixture was heated at 60° C. for 16 h. After completion, the crude was diluted with ethyl acetate (200 ml) and washed with water (3×500 ml). The organic layer was washed with brine, dried over sodium sulphate and evaporated under reduced pressure to get the crude which was then purified by column chromatography with silica gel (100-200 mesh) eluted with 10-25% ethyl acetate in hexane as eluent to get compound 1-{[3-(4-fluorophenyl)-1H-pyrazol-5-yl]oxy}acetone (2.5 g, yield 38%). MS (ESI): 231.0 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=[O:36])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([OH:35])[CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[CH2:23][CH2:22]1)(C)(C)C.[O:37]=[C:38]1[NH:43][C:42]2[CH:44]=[C:45](C(O)=O)[CH:46]=[CH:47][C:41]=2[S:40][CH2:39]1>>[CH3:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH:28]([O:35][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1)[CH2:27][N:24]1[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:45]2[CH:46]=[CH:47][C:41]3[S:40][CH2:39][C:38](=[O:37])[NH:43][C:42]=3[CH:44]=2)=[O:36])[CH2:26][CH2:25]1
Reactant: COc1ccc2ncc(Cl)nc2c1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COCCOCC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Product: COCCOCC(CN1CCC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1)Oc1cnc2ccc(OC)cc2n1

Procedure:
The title compound is prepared as a white lyophilizated powder following Scheme 1 and in analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline, {1-[2-hydroxy-3-(2-methoxy-ethoxy)-propyl]-piperidin-4-yl}-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:22].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([OH:7])[C@@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9]2)=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)c2ccc(Cl)c(F)c2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(O)c2ccc(Cl)c(F)c2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
(R)-tert-Butyl 3-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (920 mg, 2.806 mmol) was dissolved in THF (14.0 mL, 0.2M), degassed with N2, and cooled to −78° C. Lithium tri-sec-butylborohydride (1M in THF; 4210 μL, 4.210 mmol) was added slowly drop wise by syringe. The reaction was then stirred at −78° C. for 30 minutes. Water (5 mL) was then added to quench the reaction. The mixture was concentrated by rotovap to remove the bulk of the THF. The remaining mixture was diluted to 50 mL with water and extracted with 4/1 dichloromethane/isopropyl alcohol (2×50 mL). The combined organics were washed with water (100 mL), were isolated, dried over sodium sulfate, filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a gradient from 1% to 55% ethyl acetate in hexanes. Product containing fractions were pooled and concentrated to afford (3R)-tert-butyl 3-((4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate as an oil and as a 1:1 mixture of diastereomers (640 mg, 69% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[O:8][CH2:9][C:4]=2[C:3]=1[CH3:13].[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:12]=[C:11]([N+:14]([O-:16])=[O:15])[C:5]2[NH:6][C:7](=[O:10])[O:8][CH2:9][C:4]=2[C:3]=1[CH3:13]
Reactant: Cc1c(Br)ccc2c1COC(=O)N2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(Br)cc([N+](=O)[O-])c2c1COC(=O)N2
Reaction time: 14 h

Procedure:
To a solution of 6-bromo-5-methyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one (0.726 g, 3 mmol) in concentrate H2SO4 (4 mL), KNO3 (0.303 g, 3 mmol) was added at 0° C. Reaction mixture stirred 14 hours and poured over crushed ice. Yellow precipitate was obtained, which was filtered and dried.
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=[O:9].Cl>CO.CS(C)=O>[CH3:1][O:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=[O:9]
Reactant: C[O-]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(C(=O)O)ccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
28% Sodium methoxide in methanol (50 ml) was added to a solution of 3-fluoro-4-(trifluoromethyl)benzoic acid (20.8 g) in dimethylsulfoxide (200 ml). The mixture was stirred at 90° C. for 3.5 hours. After cooling at room temperature, the resulting mixture was poured into ice-water (1.5 l) and made acidic with diluted hydrochloric acid. After being stirred for 30 minutes, the resulting precipitates were collected by filtration and air-dried to give a colorless powder of 3-methoxy-4-(trifluoromethyl)benzoic acid (22.95 g).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:45])=[CH:40][C:39]=1[N+:58]([O-])=O>>[NH2:58][C:39]1[CH:40]=[C:41]([S:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:45])[CH:42]=[CH:43][C:38]=1[NH2:37]
Reactant: Nc1ccc(S(=O)c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(S(=O)c2ccc(-c3ccccc3)cc2)cc1N
Yield: 95 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 4-(4-amino-3-nitrophenylsulfinyl)-biphenyl, the title compound is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:22]([O:26][C:27](=[O:37])[C@H:28]([C:30]([S:33][C:34](=[O:36])[CH3:35])([CH3:32])[CH3:31])[NH2:29])([CH3:25])([CH3:24])[CH3:23].C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[C:22]([O:26][C:27](=[O:37])[C@H:28]([C:30]([S:33][C:34](=[O:36])[CH3:35])([CH3:31])[CH3:32])[NH:29][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(=O)SC(C)(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)SC(C)(C)[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)OC(C)(C)C

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles S-acetyl-penicillamine t-butyl ester toluene sulfonic acid, neutrallized with N-ethyl morpholine, in dichloromethane: DMF (4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to the above reaction mixture. The reaction mixture is stirred in an ice water bath for 1 hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether, yielding the named product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][CH2:29][CH2:30][Cl:31].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:31][CH2:30][CH2:29][CH2:28][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: ClCCCBr
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCCl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (278 mg, 0.783 mmol) in DMSO (4.0 mL) was added 3-bromo-1-chloropropane (1.23 g, 7.83 mmol) and Cs2CO3 (765 mg, 2.35 mmol), and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (silica gel, CH2Cl2/MeOH, 100:1) yielded 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one. To a solution of 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (84 mg, 0.19 mmol) in DMF (1.0 mL) was added K2CO3 (0.13 g, 0.97 mmol), dimethylamine (1.94 mL, 3.88 mmol, 2.0 M in THF) and KI (32 mg, 0.19 mmol), and the reaction was heated to 45° C. for 18 h. The reaction mixture was cooled, diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. Flash chromatography (Biotage 25+M column, CH2Cl2/MeOH/NH4OH, 50:1:0 to 20:1:0.1) provided the title compound (54 mg, 63%): 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H), 7.75-7.70 (m, 5H), 7.60-7.43 (m, 3H), 6.92-6.91 (m, 1H), 6.53-6.51 (m, 1H), 4.49 (t, J=6.8 Hz, 2H), 2.29 (t, J=6.8 Hz, 2H), 2.23 (s, 6H), 2.13-2.08 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH3:35][C:36]([OH:53])([CH3:52])[CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>O.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>[CH3:35][C:36]([OH:53])([CH3:52])[CH2:37][N:38]1[CH:42]=[C:41]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:21])[F:22])[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:40]=[N:39]1
Reactant: FC(F)(F)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4CC(F)(F)F)nc2-3)cn1
Temperature: 25 °C

Procedure:
8-Bromo-2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (110.0 mg, 0.2557 mmol) dissolved in Acetonitrile (0.534 mL, 10.2 mmol) and with dissolved 2.00 M of Potassium carbonate in Water (0.256 mL). Degas by bubbling nitrogen for 5 min. The reaction was charged with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (102 mg, 0.384 mmol) then Tetrakis(triphenylphosphine)palladium(0) (41.36 mg, 0.03579 mmol). The reaction was heated in microwave at 140 C for 10 min. The reaction was cooled to r.t. then extracted with ethyl acetate. Combined organics concentrated and purified by reverse phase HPLC to give 355. MS: (ESI+)=490.1. 1H NMR (400 MHz, DMSO) δ 8.24 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.41 (dd, J=8.3, 1.8 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 5.74 (q, J=8.9 Hz, 2H), 4.71 (s, 1H), 4.37 (t, J=5.0 Hz, 2H), 4.03 (s, 2H), 3.40 (t, J=5.0 Hz, 2H), 1.09 (s, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][C:13]([NH:15][C@H:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.Cl[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]Cl.CCO.O.[NH4+].[OH-].[CH2:36](O)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([O:19][C:18](=[O:20])[CH2:17][C@@H:16]([CH3:21])[NH:15][C:13](=[O:14])[CH2:12][N:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([N:1]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH2:37][CH2:38][CH3:39]
Reactant: C[C@H](CC(=O)O)NC(=O)CN1Cc2ccc(N)cc2C1=O
Reactant: ClCCNCCCl
Reactant: CCCCO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOC(=O)C[C@@H](C)NC(=O)CN1Cc2ccc(N3CCNCC3)cc2C1=O

Procedure:
N-{[6-Amino-2,3-dihydro-1(1H)-isoindolone-2-yl]acetyl}-(R)-methyl-β-alanine (2-7) (203 mg, 0.7 mmol) and bis(2-chloroethyl) amine hydrochloride (137 mg, 0.77 mmol) in n-butanol (10 mL) were heated at 110° C. for 3 days. The solvent was removed and the residue chromatographed OEtOH/H2O/NH4OH 10:0.5:0.5) to give 2-8. Rf (silica; EtOH/H2O/NH4OH 10:0.5:0.5)=0.61. ##STR62##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22][CH2:21][CH2:20][C:19]([C:23](O)=[O:24])=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:49][N:50]([CH2:57][C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1)[CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>CN(C=O)C.C(N(CC)CC)C>[CH3:49][N:50]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([NH:62][C:23]([C:19]2[CH2:20][CH2:21][S:22][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[CH:26][C:17]=3[CH:18]=2)=[O:24])=[CH:63][CH:64]=1)[CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3SCC2)cc1)C1CCOCC1
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 7- (4-morpholinophenyl) -2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (0.11 g) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g), and the mixture was stirred for 1 hour. To the mixture was added a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (135 mg) and triethylamine (0.11 ml) in DMF (5 ml), and the mixture was stirred for 18 hours. Under reduced pressure, the mixture was concentrated, and to the mixture was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:2) to give yellow crystals of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 285) (113.9 mg).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][NH2:6].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10]N=1.O1CCOC[CH2:15]1>O.C(Cl)Cl>[O:3]([CH2:4][CH2:5][NH2:6])[C:10]1[CH:15]=[CH:8][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: Clc1ccccn1
Reactant: C1COCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NCCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Add sodium hydride (60% in mineral oil, 6.63 g, 166 mmol) to a solution of 2-hydroxyethylamine (10.0 mL, 166 mmol) in dioxane (150 mL) at room temperature under nitrogen. After stirring for 10 minutes at room temperature, add 2-chloropyridine (15.6 mL, 166 mmol) and heat the reaction mixture to reflux. After stirring at reflux for 14 hours, cool the reaction mixture to room temperature and dilute with water (100 mL) and methylene chloride (200 mL). Extract the aqueous layer with methylene chloride (2×100 mL). Wash the combined organic phase with brine (200 mL), dry over magnesium sulfate, filter, and concentrate to an orange oil. Flash chromatography on silica gel eluting with 50% of a (80:18:2 CHCl3/MeOH/concentrated NH4OH) solution in methylene chloride affords 2-phenoxy-ethylamine as a yellow oil (17.9 g, 78%). 1H NMR (CDCl3) δ 8.09-8.15 (m, 1H), 7.53-7.56 (m, 1H), 6.80-6.85 (m, 1H), 6.70-6.75 (m, 1H), 4.27-4.31 (m, 2H), 3.06-3.10 (m, 2H); MS (ES): m/z 139 (M+H).