Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[ClH:19].OC(C1C=CN=CC=1)(C)CC1C=CC=CC=1.Cl>[Pd].O.C(O)(=O)C>[ClH:19].[OH:1][C:2]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(O)(Cc1ccccc1)c1ccncc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(O)(Cc1ccccc1)C1CCNCC1

Procedure:
The mixture of 4.0 g of 4-(α-hydroxy-α-methylphenethyl)-pyridine, 100 ml of glacial acetic acid, 20 ml of water and 2.0 g of 10% palladium on charcoal is treated with hydrogen at 4.1 atm and room temperature. Following the theoretical uptake of hydrogen the reaction mixture is filtered to remove the catalyst. The filtrate is evaporated to dryness under reduced pressureand the residue treated with 50% aqueous sodium hydroxide. The resulting mixture is extracted with methylene chloride; the extract is dried and evaporated under reduced pressure to give an oil which is converted into the hydrochloride with ethanolic hydrogen chloride to give 4-(α-hydroxy-α-methylphenethyl)-piperidine hydrochloride of melting point 162°-164°.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)([CH3:5])[CH3:4].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Cl)[CH:17]=1>CN(C=O)C>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:3]([CH3:5])[CH3:4])[CH:17]=1
Reactant: CC(C)c1ncc[nH]1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nccn1Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.073 g, 1.82 mmol) in DMF (3 mL) was added 2-isopropyl-1H-imidazole (0.173 g, 1.57 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 3-bromo-5-chloromethyl-pyridine (0.25 g, 1.21 mmol) was added and the resulting suspension was heated at 60° C. overnight. The mixture was quenched with water (2 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.275 g, 81%) as a light yellow oil. MS: 280.0, 282.0 (M+H+).
Reaction SMILES: C=CC[C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([OH:17])=[C:15]([OH:18])[CH:14]=[C:13]([CH2:19][CH:20]=[CH2:21])[CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28]I.[CH3:30][C:31]([CH3:33])=O>C(OC(=O)C)C.CCCCCC>[CH2:30]([C:5]1[CH:4]=[CH:9][C:8]([O:10][C:11]2[C:16]([O:17][CH3:28])=[C:15]([OH:18])[CH:14]=[C:13]([CH2:19][CH:20]=[CH2:21])[CH:12]=2)=[CH:7][CH:6]=1)[CH:31]=[CH2:33]
Reactant: C=CCc1cccc(Oc2cc(CC=C)cc(O)c2O)c1
Reactant: CC(C)=O
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCc1ccc(Oc2cc(CC=C)cc(O)c2OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of obovatol (1 g) in acetone (200 ml) were added potassium carbonate (K2CO3) (1.1 g) and methyl iodide (0.3 g), followed by stirring the solution at room temperature for 5 hours. After completion of the reaction, the organic layer containing the active material was collected and concentrated in a vacuum. The concentrate (1.2 g) was dissolved in methylene chloride (30 ml) and loaded onto a silica gel (Merck, Art No. 9385) so as to adsorb the active material thereonto. Silica gel column chromatography eluting with a gradient of a mixture of ethylacetate and hexane from 10:90 to 20:80 afforded colorless 3-(4-allylphenoxy)-5-allyl-2-methoxyphenol (0.91 g, yield 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17](OC2C=CC([N+]([O-])=O)=CC=2)=[O:18])[CH2:13][N:12]1[C:29](=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:18])[CH2:13][N:12]1[C:29](=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-(4-nitro-phenoxycarbonyloxy)-pyrazolidine-1-carboxylic acid benzyl ester, 39, (462 mg, 0.882 mmol) is dissolved in dichloromethane (9 mL). Morpholine (770 μL, 8.82 mmol) is added and the reaction immediately develops a light yellow color. After stirring about 1.5 hours at room temperature, the reaction is diluted with dichloromethane (20 mL) and washed with a 5% solution of Na2CO3 (2×20 mL). The combined aqueous layers are extracted with dichloromethane (20 mL), the organic layers combined, washed with water, brine, and dried. The solvent is removed in vacuo to afford 414 mg of the desired product as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Product: O=[N+]([O-])c1c(-c2ccc(C(F)(F)F)cc2Cl)ccnc1OCc1ccccc1
Yield: 79 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference in its entirety) (2.0 g, 7.56 mmol) and 2-chloro-4-trifluoromethylphenylboronic acid (2.31 g, 11.3 mmol) were treated substantially as described in Part A of Example 19a to give 2.44 g (79%) of 2-benzyloxy-4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridine: MS (AP) m/z 408.8 [(M+H)+, 72].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[CH:36][N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:38].CCOC(C)=O>CO.C(Cl)Cl>[ClH:38].[C:28]1([C:27]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)=[N:19][C:20]3[CH:21]=[CH:22][N:23]4[CH:36]=[N:35][N:34]=[C:24]4[C:25]=3[CH:26]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5cnnc5c4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccn5cnnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl{1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6b) (1.07 g, 2.177 mmol) in MeOH (5 mL) and DCM (15 mL) was added a 4N solution of HCl in EtOAc (5.44 mL, 21.77 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 4 hours the reaction mixture was filtered to give 1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine hydrochloride (1-15) as a tan solid. HRMS (M+H)+: observed=392.1872, calculated=392.1870.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][I:19]>C(#N)C>[I-:19].[CH3:18][N+:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][N:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[N:9]=1
Reactant: CI
Reactant: c1ccc(-c2cn(-c3ccncc3)nn2)cc1
Solvent: CC#N
Product: C[n+]1nn(-c2ccncc2)cc1-c1ccccc1
Product: [I-]

Procedure:
4-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine, excess methyl iodide, and acetonitrile were added to a 100 mL round-bottom flask and refluxed for about 19 hours. The reaction was concentrated and the resulting solid was recrystallized from ethyl acetate and methanol. The precipitate was filtered and dried in vacuo at 60° C. The following 3-methyl-4-phenyl-1-(pyridin-4-yl)-1H-1,2,3-triazol-3-ium iodide structure was confirmed:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[F:28][C:29]1[CH:30]=[C:31]([SH:37])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[F:28][C:29]1[CH:30]=[C:31]([S:37][C:2]2[CH:3]=[CH:4][N:5]3[C:10]=2[C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]3)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(S)cc1F
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Sc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)cc1F
Yield: 71 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (286 mg, 0.60 mmol) was treated with 3-fluoro-4-methoxybenzenethiol (141 mg, 0.89 mmol), potassium carbonate (123 mg, 0.89 mmol) and copper(I) iodide (170 mg, 0.89 mmol) according to the method described in Preparation 44. The crude was purified using SP1® Purification System (0%-25%, hexane-ethyl acetate) to give 226 mg (71% yield) to the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:12]#N)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:14].[K+].C(O)C[OH:18]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:12]([OH:18])=[O:14])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: N#CC1(c2cccc(F)c2)CCC1
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)C1(c2cccc(F)c2)CCC1
Temperature: 150 °C

Procedure:
A mixture of 1-(3-fluorophenyl)cyclobutanecarbonitrile (7.41 g, 42.3 mmol) and powdered potassium hydroxide (7.0 g, 125 mmol) in ethylene glycol (100 mL) is heated at 150° C. for 7 hours. The cooled reaction mixture is diluted with ice water (140 mL) and extracted with ether (3×100 mL). The combined organics are washed with water (2×35 mL). The combined aqueous washings are cooled to 0° C. and brought to pH 3 with 6 N aqueous hydrochloric acid (30 mL). Nitrogen is bubbled through the solution to give a solid precipitate. The solid is isolated by filtration, washed with water and dried in a vacuum oven at 60° C. for 48 hours to afford 7.04 g of 1-(3-fluorophenyl)cylobutanecarboxylic acid. 1H NMR (CDCl3) δ7.27 (m, 2 H), 7.00 (m, 4 H), 2.84 (m, 2 H), 2.48 (m, 2 H), 2.10 (m, 1 H), 1.93 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Br)c(OCc3ccccc3)ccc2c1
Reactant: Oc1ccc(OCCN2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OCc3ccccc3)ccc2c1
Temperature: 174 °C
Yield: 29.3 %

Procedure:
Combine toluene (200 mL), 2-benzyloxy-1-bromo-6-methoxy-naphthalene (30 g, 87.4 mmol), 4-(2-piperidin-1-yl-ethoxy)phenol (23.2 g, 105 mmol) and cesium carbonate (34.4 g, 105 mmol), and heat the mixture to reflux. Remove a portion of the toluene (100 mL). Add ethyl acetate (390 mg, 437 mmol) and copper triflate benzene complex (2.20 g, 4.37 mmol) to the reaction mixture and stir for 5 minutes. Remove the solvent by distillation and heat the resulting residue to 174° C. for 1.5 hours. Dissolve the residue in a mixture of ethyl acetate (200 mL) and aqueous HO (1 N, 90 mL). Separate and concentrate the organics to a residue. Column chromatograph the residue to give 12.4 g of 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-piperidine (30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=[N:23]C2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-].CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]#[CH:18])[C:13]([NH2:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: On1nnc2cccnc21
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(4-methylphenyl sulfonamido)pent-4-ynoic acid (1.0 g, 3.7 mmol), HOAt (0.76 g, 5.6 mmol), iPr2NEt (2.17 g, 16.9 mmol), NH4Cl (0.6 g, 11 mmol), and EDCI (1.07 g, 5.61 mmol) in 20 mL DMF was stirred for 18 h at RT. Water was added, which caused a precipitate to form. The white solid was filtered and air dried to afford the title compound. MS (m/z, m+1): 267.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[C:29]([O:28][C:26]([CH:25]=[N:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Product: CC(C)(C)OC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(N=CC(=O)OC(C)(C)C)c3)n2)c1

Procedure:
N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 29.34 min.; purity: 97.2%; MS (m/e): 427.07 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][CH3:28].[Cl-].[NH4+].[O:37]1CCCC1>CCCCCC.C(OCC)C>[CH2:1]([N:8]([C@@H:24]([CH2:25][CH2:26][CH2:27][CH3:28])[C@H:23]([OH:37])[C:22]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CCCC/C=C/C(=O)OC(C)(C)C
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[C@@H]([C@H](O)C(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 0.66 ml of (S)-(−)-N-benzyl-α-methylbenzylamine in 10 ml of tetrahydrofuran was cooled to 0° C. and 1.88 ml of a 1.6M solution of n-butyllithium in hexane were added dropwise via a syringe. The resulting dark pink solution was stirred at 0° C. for 45 minutes and then cooled to −78° C. A solution of 0.184 g of tert-butyl (E)-2-heptenoate in 2 ml of anhydrous diethyl ether was added and the mixture was stirred for 2 hours at −78° C. 0.37 g of solid (1S)-(+)-(10-camphorsulphonyl)oxaziridine was added and the mixture was stirred at −78° C. for 1 hour. The mixture was warmed to 0° C. and a saturated ammonium chloride solution was added. The tetrahydrofuran was evaporated and the aqueous phase was diluted with water and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, evaporated and purified by chromatography on silica gel using a 10% solution of diethyl ether in hexane for the elution to give 0.35 g of tert-butyl 3(S)-[N-benzyl-N-(α(S)-methylbenzyl)amino]-2(S)-hydroxyheptanoate as a colorless oil, MS: m/e 412.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14].C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:33])[CH:25]=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C#N)ccc2OCC3)c(Cl)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C(N)=O)ccc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2-chloro-4-(methylcarbamoyl)phenyl)-9-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 298 (100 mg) and potassium carbonate (37 mg) in DMSO (3 mL) at 0° C. was added hydrogen peroxide (30 μL of a 33% solution in water). The reaction was stirred at room temperature for 16 h. Water was then added and the resulting solid collected by filtration and air-dried to give 306. NMR: (DMSO): 2.81 (3 H, d, J 4.5, Me), 2.91-2.93 (2 H, m), 3.68 (3 H, s, Me), 4.19-4.22 (2 H, m), 6.41 (1 H, s, NH), 7.03 (1 H, d, J 8.4, Ar), 7.35 (1 H, s), 7.71-7.77 (2 H, m, Ar), 7.92 (1 H, dd, J 8.3 and 2.0, Ar), 8.03-8.05 (3 H, m) and 8.65-8.67 (1 H, m). MS: (ESI+) MH+ 469.35
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH3:9])[CH:6]=1.CC(C)=[O:13].C[N+]1([O-])CCOCC1.[OH2:23]>O=[Os](=O)(=O)=O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:13])([CH:8]([OH:23])[CH3:9])[CH3:10])[CH:6]=1
Reactant: CC(C)=O
Reactant: CC=C(C)c1csc(Br)c1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Product: CC(O)C(C)(O)c1csc(Br)c1
Reaction time: 24 h
Yield: 90 %

Procedure:
To a solution of 2-bromo-4-(1-methyl-propenyl)-thiophene (19.1 mmol, 4.15 g) in a cosolvent of acetone and water (15 mL/30 mL) was added at room temperature N-methyl morpholine oxide (NMO) (21.0 mmol, 4.92 g, 50% in H2O) and OsO4 (0.2 mmol, 1.27 g, 4% in H2O). The reaction mixture was stirred for 24 h at the temperature. After evaporation of acetone in vacuo, it was extracted with EtOAc (70 mL×4). The combined solution was washed with brine (70 mL), dried (MgSO4) and concentrated in vacuo. Chromatography on SiO2 (EtOAc/Hexanes, 2/3) gave 4.3 g (90%) of 2-(5-bromo-thiophen-3-yl)-butane-2,3-diol as an oil of isomeric mixture (major/minor, 8/1). Major isomer; 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J=1.7 Hz, 1H), 7.02 (d, J=1.7 Hz, 1H), 3.81 (m, 1H), 2.54 (s, 1OH), 1.99 (d, J=5.7 Hz, 1OH), 1.53 (s, 3H), 1.04 (d, J=6.4 Hz, 3H). Minor isomer; 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J=1.7 Hz, 1H), 7.04 (d, J=1.7 Hz, 1H), 3.90 (m, 1H), 2.58 (s, 1OH), 2.07 (d, J=4.0 Hz, 1OH), 1.46 (s, 3H), 1.13 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(C(C)C)CC)(C)C.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24][NH:25][CH2:26][CH2:27][CH3:28])[CH:17]=[CH:16]1>C(Cl)Cl>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24][N:25]([CH2:26][CH2:27][CH3:28])[C:3](=[O:4])[CH2:2][Cl:1])[CH:17]=[CH:16]1
Reactant: CCCNCc1cccc2cc[nH]c12
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(Cc1cccc2cc[nH]c12)C(=O)CCl
Reaction time: 2 h
Yield: 100 %

Procedure:
Add chloroacetyl chloride (1.7 ml, 21.71 mmol) and diisopropylethylamine (10.38 ml, 62.04 mmol) to a solution of (1H-Indol-7-ylmethyl)propylamine (3.89 g, 20.68 mmol) in methylene chloride. Stir for 2 hours, quench with saturated aqueous ammonium chloride and extract into ethyl acetate. Wash the organic layers with saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure to yield N-(1H-indol-7-yl)methyl N-propyl 2-chloroacetamide (5.47 gm, 20.68 mMol).
Reaction SMILES: [C:1]([NH:3][C:4](=[O:25])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[CH3:6])#[N:2].[C:26](=O)([O-])[O-].[K+].[K+].CI>CC(CC)=O>[C:1]([N:3]([CH3:26])[C:4](=[O:25])[CH:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[CH3:6])#[N:2]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)NC#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)N(C)C#N
Reaction time: 2 h
Yield: 59.8 %

Procedure:
17.5 g (0.05 mole) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid N-cyanamide are dissolved in 60 ml of methylethyl ketone and with 7.6 g (0.055 mole) of potassium carbonate heated for 30 minutes to reflux. Then 3.6 ml (0.057 mole) of methyl iodide are added at 30° C. to the colourless suspension and the mixture is stirred for two hours at the same temperature. The reaction mixture is then filtered and the filtrate is concentrated by evaporation. The oily residue is chromatographed through silica gel eluted with petroleum ether/ethyl acetate (3:1) and the main fraction is concentrated by evaporation, affording 10.9 g (59.9% of theory) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid N-cyano-N-methylamide as a clear, colourless oil with a refractive index of nD23 =1.5228.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[F:16][C:17]1([C@H:20]([NH2:22])[CH3:21])[CH2:19][CH2:18]1.FC1([C@H](NC2C3N(C=CC=3)N=CC=2C(N)=O)C)CC1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:22][C@@H:20]([C:17]3([F:16])[CH2:19][CH2:18]3)[CH3:21])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@@H](N)C1(F)CC1
Agent: C[C@@H](Nc1c(C(N)=O)cnn2cccc12)C1(F)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1(F)CC1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 200 mg, 0.73 mmol), (R)-1-(1-fluorocyclopropyl)ethanamine hydrochloride (153 mg, 1.1 mmol, from step 4 of Intermediate 5), and diisopropylethylamine (0.38 mL, 2.2 mmol) in NMP (0.7 mL) was heated to 150° C. for 1 hour in the CEM microwave. The mixture was cooled to rt, diluted with MeOH and purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aqueous sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded 40 mg (16%) of a pale yellow solid as the title compound. HPLC (condition B): retention time=3.75 min. LCMS (condition B): MH+ m/z 342.7.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:17]([CH2:14][CH2:15][CH3:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC(CCl)OCc1ccccc1
Reactant: CCCN
Solvent: O
Product: CCCN1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 67 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloropropane, 59.1 parts of n-propylamine and 59.1 parts of water were added to an autoclave, and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result 13.7 parts of 3-benzyloxy-1-(n-propyl)azetidine boiling at 101° - 103° C. under 2 mm Hg were obtained. The yield was 67%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows: