Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[CH3:40][O:39][C:37](=[O:38])[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:23](=[O:25])[CH3:24])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:34][CH:35]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)NCCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
(2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (150 mg, 0.30 mmol) was dissolved in DCM (1 mL). To this solution was added TEA (36.4 mg, 0.36 mmol) followed by methyl chloroformate (34 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in DCM (15 mL). The reaction mixture was washed with sat. aq. NaHCO3 (15 mL), water (15 mL) and brine (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5/95 ethyl acetate/hexane-50/50 ethyl acetate/hexane gradient) to afford white solid product (71 mg, 52%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3B3OC(C)(C)C(C)(C)O3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C.I[C:44]1[CH:45]=[C:46]([C:52]2[CH:53]=[CH:54][C:55]([C:59]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[O:60])=[N:56][C:57]=2[CH3:58])[CH:47]=[CH:48][C:49]=1[O:50][CH3:51].[OH-].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:21]=3[C:48]3[C:49]([O:50][CH3:51])=[CH:44][CH:45]=[C:46]([C:52]4[CH:53]=[CH:54][C:55]([C:59]([O:61][CH2:62][C:63]5[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=5)=[O:60])=[N:56][C:57]=4[CH3:58])[CH:47]=3)[C@H:14]2[CH3:39])[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2ccc(C(=O)OCc3ccccc3)nc2C)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)OCc3ccccc3)nc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.5 h

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one-methane (385 mg, 0.644 mmol) (INTERMEDIATE 9), benzyl 5-(3-iodo-4-methoxyphenyl)-6-methylpyridine-2-carboxylate (148 mg, 0.322 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (71 mg, 0.097 mmol), aqueous potassium hydroxide (215 μL, 3M, 0.645 mmol) and 1,4-dioxane (2 mL) were charged into a tube. The vessel was purged with nitrogen and then sealed. The reaction mixture was irradiated by microwave at 120° C. for 20 minutes then at 140° C. for 30 minutes. The reaction mixture was treated with water followed by extraction with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil. This oil was purified by preparative TLC on SiO2 (eluted with 45% ethyl acetate in hexanes) to afford a dark oil. The resulting oil was further purified by reverse-phase preparative-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. The appropriate fractions were pooled and evaporated into a dark oil. This oil treated with sodium bicarbonate aqueous solution (sat.) followed by ethyl acetate extractions. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford a dark oil. The oil still contained some baseline impurities. The resulting oil was again purified by preparative TLC on SiO2 (eluted with 50% ethyl acetate in hexanes) to afford benzyl 5-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridine-2-carboxylate. LCMS calc.=802.21; found=803.21 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:14])[CH:3]=1.[CH3:37][O:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][C:41]=1[N+:50]([O-:52])=[O:51].N1C=CC=CC=1.C(O)(=O)C>C(Cl)Cl>[C:32]([C:22]1[CH:23]=[C:24]([C:27]([CH2:30][CH3:31])([CH3:28])[CH3:29])[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13]([C:4]1[CH:3]=[C:2]([NH:1][S:46]([C:43]2[CH:44]=[CH:45][C:40]([C:39]([O:38][CH3:37])=[O:53])=[C:41]([N+:50]([O-:52])=[O:51])[CH:42]=2)(=[O:47])=[O:48])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12])=[O:14])([CH2:35][CH3:36])([CH3:34])[CH3:33]
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(NS(=O)(=O)c3ccc(C(=O)OC)c([N+](=O)[O-])c3)c3ccccc3c2O)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Amino-N-[4-(2,4-di-t-pentylphenoxy)butyl]-1-hydroxy-2-naphthamide (11.7 g, 23.8 mmoles) was dissolved in methylene chloride (300 ml) under nitrogen and reacted with intermediate (B) (6.7 g, 25.2 mmoles) in the presence of pyridine (2.0 g). After 5 hours of stirring at room temperature, acetic acid (2 ml) was added and the mixture was evaporated to dryness. Trituration of the residue gave a solid which was collected by filtration and recrystallized from ethanol; yield, 8.0 g (46.8 percent).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].[BH4-].[Na+].C(N(CC)CC)C>O1CCOCC1>[OH:3][CH2:2][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cc(CO)cc([N+](=O)[O-])c1

Procedure:
A stirred solution of the product from step (i) (46.54 g) and sodium borohydride (13.01 g) in 1,4-dioxane (200 ml) was heated at reflux for 17 hours. The mixture was cooled and treated with triethylamine (27.9 ml), poured onto ice-water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. The product was recrystallised from isohexane. Yield 19.38 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH2:15].C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: C=Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 2,4-dinitrofluorobenzene (6.38 g, 34 mmol), 4-vinylphenol (4.32 g, 36 mmol), 4.97 g K2CO3 and 2-3 crystals of BHT inhibitor was dissolved in 75 ml NMP and stirred at 40° C. under nitrogen for 4 hr. The reaction mixture was poured into a separatory funnel containing 150 ml water and extracted 3×100 mls with ethyl acetate. The combined organics were washed with 100 ml 10% KOH, and brine, dried with anhydrous MgSO4 and concentrated. The residue was recrystallized from 70% ethyl acetate in hexane yielding 9.5 g product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.C(NC(C)C)(C)C.Cl.Cl.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[CH2:23][NH:24][NH2:25].O>C(O)CCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]([CH:9]=1)=[N:25][N:24]([CH2:23][C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[F:20])[C:6]=2[NH2:7]
Reactant: NNCc1ccccc1F
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCO
Product: Nc1c2ccc(Br)cc2nn1Cc1ccccc1F
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a solution of 4-bromo-2-fluorobenzonitrile (3.19 g, 15.64 mmol) and diisopropylamine (13.16 mL, 93.86 mmol) in n-butanol (70 mL) was added (2-fluorobenzyl)hydrazine dihydrochloride (10 g, 46.93 mmol) and the very thick slurry was heated to 125° C. (the mixture became a cloudy solution at 90° C.) for 18 h. The reaction mixture was poured into water and ethyl acetate. The organic layer was isolated and washed with brine, dried over Na2SO4 and concentrated. The resulting light brown solid was taken up in DCM (60 mL) and the suspension stirred for 15 min and filtered. The filter cake was washed with very little DCM and hexanes and dried on a high vacuum pump to give the product as a light brown solid (1.55 g, 31%). LC-MS [M+H]+=320.3, 322.3, RT=2.33 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=O.[CH3:30][NH2:31]>CCO>[CH3:30][NH:31][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:2]
Reactant: CN
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: CCO
Product: CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 80 °C

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (15 mg, 0.039 mmol) and methylamine (1 mL, 2 M in THF) in EtOH (2 mL) was heated in a sealed tube at 80° C. for 16 h. Solvent was evaporated in vacuo, and the residue was chromatographed (0-5% MeOH/CH2Cl2) to give 4.9 mg of the title compound as a pale yellow solid. MS: (+) m/z 386.21 (M+1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][C:10]([CH3:12])=[CH:9][CH2:8][N:7]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])C.[ClH:20]>>[ClH:20].[CH2:13]([N:7]1[CH2:8][CH:9]=[C:10]([CH3:12])[CH2:11][CH:6]1[C:4]([OH:5])=[O:3])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CC(C)=CCN1Cc1ccccc1
Agent: Cl
Product: CC1=CCN(Cc2ccccc2)C(C(=O)O)C1

Procedure:
A stirred solution of 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine-2(R,S)-carboxylic acid ethyl ester (Preparation17(a); 20.1 g, 77.5 mmol) in 5M hydrochloric acid (200 ml) was heated at 100° C. for 4.5 hours and then evaporated to dryness under reduced pressure. Residual water was removed azeotropically using dichloromethane followed by toluene to give the required product (24.0 g) as a white foam, Rf 0.40 (SS 13), which was used without further purification in the next step.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1.O>CN(C=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([N:3]2[CH2:8][CH2:7][CH:6]([NH:9][C:10]3[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=3)[CH2:5][CH2:4]2)=[O:39])=[CH:33][CH:32]=1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCNCC2)nc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)nc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To an ice-cooled solution of ethyl (2E)-3-[6-(4-piperidylamino)-3-pyridyl]acrylate dihydrochloride (309 mg) and Et3N (0.448 ml) In DMF (3 ml) was added 1-chloro-4-isocyanatobenzene (136 mg), the mixture was stirred at 23° C. for 1 hour. The mixed solution was poured into water (20 ml). The precipitate was collected, washed with hexane and water, dried under reduced pressure to give ethyl (2E)-3-{6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate (341 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][CH2:13]O)([O-:3])=[O:2].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:13][CH2:12][CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1NCCCO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1NCCCCl
Reaction time: 6 h
Yield: 100 %

Procedure:
To a stirred mixture of 39:2 parts of 3-(2-nitrophenyl)amino-1-propanol and 225 parts of trichloromethane are added dropwise 35.7 parts of sulfinyl chloride (exothermic reaction: the temperature rises to 45° C.). Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated, yielding 43 parts (100%) of N-(3-chloropropyl)-2-nitrobenzenamine as a residue.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]Cl)[CH2:10][CH2:9]1)=[O:7].[I-].[Na+].[CH3:19][NH2:20]>CO>[CH3:19][NH:20][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:9][CH2:10]1
Reactant: CN
Reactant: O=C(c1ccco1)N1CCN(CCCl)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CNCCN1CCN(C(=O)c2ccco2)CC1
Yield: 82 %

Procedure:
A solution of 1.0 g of 1-(2-furanylcarbonyl)-4-(2-chloroethyl)piperazine and 200 mg of sodium iodide in 40 ml of methanol which contained 25% of methylamine was reacted at 70° C. in a sealed tube for 24 hours. After allowing the reaction mixture to cool down, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: a 20:1:0.1 mixture of chloroform, methanol, and methanol containing 40% methylamine) to give 800 mg of crystals (yield: 82%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Li+].[OH-].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>O>[CH3:18][O:17][C:15]([NH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:16]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a solution of (R)-2-amino-2-phenylacetic acid (14 g, 92.6 mmol) in water (250 mL) was added LiOH (14.8 g, 618.7 mmol) at 0° C. and the mixture was stirred for 15 minutes. To this solution, methyl chloroformate (17.9 mL, 231.5 mmol) was added drop wise and the mixture was stirred for 2 hours at 0° C. The mixture was then acidified until pH 1 with concentrated HCl. The mixture was extracted with EtOAc and the organic phase was concentrated in vacuum. The residue was dried overnight in vacuum, resulting in (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (11.8 g; 60.9 mmol).
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(Nc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(Nc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 15, the desired compound was prepared from 8.5 g of ethyl 2-anilinothiazol-4-carboxylate, 2 g of lithium aluminum hydride and 150 ml of tetrahydrofuran, as colorless flakes having the following physical properties.
Reaction SMILES: Br[C:2]1C2C(=C([C@H](OCC3(C4C=CC(F)=CC=4)CCN(C)CC3)C)C=C(Br)C=2)NN=1.[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C@H:40]([O:42][CH2:43][C:44]3([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=4)[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH3:41])[CH:39]=1)[NH:36][N:35]=[C:34]2[CH3:57]>>[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([C@H:40]([O:42][CH2:43][C:44]3([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=4)[CH2:49][CH2:48][N:47]([CH3:2])[CH2:46][CH2:45]3)[CH3:41])[CH:39]=1)[NH:36][N:35]=[C:34]2[CH3:57]
Reactant: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Br)cc2c(Br)n[nH]c12
Reactant: Cc1n[nH]c2c([C@@H](C)OCC3(c4ccc(F)cc4)CCNCC3)cc(Cl)cc12
Product: Cc1n[nH]c2c([C@@H](C)OCC3(c4ccc(F)cc4)CCN(C)CC3)cc(Cl)cc12

Procedure:
Prepared according to the procedure used to prepare (R)-3,5-dibromo-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indazole using (R)-5-chloro-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-3-methyl-1H-indazole as starting material. 1H-NMR (CDCl3, 500 MHz) δ 9.82 (bs, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.23 (dd, J=8.9, 5.5 Hz, 2H), 7.00 (dd, J=8.9, 8.5 Hz, 2H), 6.92 (d, J=1.8 Hz, 1H), 4.43 (q, J=6.4 Hz, 1H), 3.33 (d, J=8.9, 8.5 Hz, 2H), 6.92 (d, J=1.8 Hz, 1H), 4.43 (q, J=6.4 Hz, 1H), 3.33 (d, J=8.9 Hz, 1H), 3.24 (d, J =9.2 Hz, 1H), 2.40-2.65 (m, 5H), 1.85-2.30 (m, 9H), 1.38 (d, J=6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 142.3, 136.7, 128.7 (d, J=7.7 Hz), 127.6, 125.3, 124.4, 124.0, 118.5, 115.3 (d, J=21 Hz), 78.7 (br), 78.1, 51.9, 51.8, 46.2, 40.4, 32.6, 32.4, 22.0, 11.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:14])([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.O.C(Cl)Cl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][Br:16])=[CH:11][CH:12]=1)([CH3:14])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(C)c1ccc(CBr)cc1
Yield: 97.7 %

Procedure:
To a solution of 2-methyl-2-p-tolyl-propionic acid ethyl ester (263 mg, 1.27 mmol) and N-bromosuccinimide (272 mg, 1.53 mmol) in CCl4 (15 mL) was added 1,1′-azobis(cyclohexanecarbonitrile) (15.5 mg, 0.06 mmol). The reaction was heated at reflux for 1 h and was diluted with water and CH2Cl2. The layers were separated and the aqueous layer was washed with CH2Cl2 (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (95:5 hexanes:EtOAc) provided 2-(4-bromomethyl-phenyl)-2-methyl-propionic acid ethyl ester (354 mg). 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 4H), 4.47 (s, 2H), 4.10 (q, 2H), 1.54 (s, 6H), 1.17 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[NH:14][C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33][CH:34]([CH3:37])[CH2:35]I>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]([CH2:33][CH:34]([CH3:37])[CH3:35])[C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1N=C(C2CCCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCCC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cycloheptyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (1.26 g) at 0° C., under an atmosphere of nitrogen, was added sodium hydride (125 mg of a 50% dispersion in mineral oil). After stirring for 1 h at 0° C. 2-methylpropyl iodide (399 μl) was added and the mixture allowed to warm to ambient temperature over 3 h. More sodium hydride (16 mg of a 50% dispersion in mineral oil) followed by 2-methylpropyl iodide (40 μl) was added and the solution stirred at room temperature for 18 h. More sodium hydride (103 mg of a 50% dispersion in mineral oil) followed by 2-methylpropyl iodide (210 μl) was added and the solution stirred for 4 h at room temperature. The solvent was then evaporated in vacuo and the residue partitioned between dichloromethane (30 ml) and water (30 ml). The organic phase was separated and the aqueous layer washed further with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was azeotroped with toluene (2×20 ml), then chromatographed on silica gel using 4:1 petrol:ethyl acetate as the eluant. The product was isolated as a viscous oil which solidified on addition of petrol:ethyl acetate (4:1) (20 ml). After evaporation of the solvent the resultant solid was triturated with petrol (60/80) and the title compound (830 mg) isolated as a white solid. 1H NMR (360 MHz, CDCl3) δ 0.73 (3H, d, J=6.6 Hz), 0.79 (3H, d, J=6.6 Hz), 1.43-1.83 (12H, m), 2.06-2.20 (1H, m), 2.94-3.06 (1H, m), 3.43 (1H, dd, J=13.8 and 5 Hz), 4.27 (1H, dd, J=13.8 and 9.3 Hz), 5.10 (3H, m), 6.56 (1H, d, J=8.2 Hz), 7.24=7.35 (7H, m), 7.49 (1H, dd, J=8.4 and 8.4 Hz), 7.58 (1H, d, J=7.9 Hz). MS (CI, NH3) 462 (M+).
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:21][N:22]([CH3:29])[CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26]>O>[CH:17]1([C:3]2[C:2]([NH:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][N:22]([CH3:29])[CH3:21])=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CN(C)CC(C)(C)CN
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Solvent: O
Product: CN(C)CC(C)(C)CNc1nn2c(-c3ccccc3)nnc2cc1C1CCC1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine (100 mg) and N,N,2,2-tetramethyl-1,3-propanediamine (2 ml) were heated together in a sealed tube at 70° C. for 16 hours. Cooled and water (5 ml) added. Precipitate filtered, washed (water, ether) and dried. 1H NMR (250 MHz, DMSO) δ 1.20 (6H, s), 2.10 (1H, m), 2.24–2.65 (14H, m), 3.53–3.70 (2H, m), 7.69–7.82 (4H, m), 8.03 (1H,s), 8.70 (2H, m). MS (ES+) MH+=379
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:15])=[N:4][CH:5]=[C:6]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O[CH:38](OCC)[CH2:39][NH2:40])C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:15])=[N:4][CH:5]=[C:6]([N:8]2[CH:38]=[CH:39][N:40]=[C:9]2[C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: O=C(Nc1cnc(Cl)c(Br)c1)C(F)(F)F
Reactant: CCOC(CN)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1nccn1-c1cnc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
3-Bromo-2-chloro-5-trifluoroacetamidopyridine (0.53 g, 1.75 mmol) and triphenylphosphine (550 mg, 2.10 mmol) in carbon tetrachloride (50 ml) was refluxed for 16 hrs and then cooled to 0° C. Aminoacetaldehyde diethyl acetal (0.25 ml, 1.72 mmol) was added and the mixture stirred at 0° C. for 1 hr, then at 22° C. for 2 hrs. After concentration in vacuo, acetic acid (4 ml) was added and the mixture refluxed for 7 hrs, then cooled. Ethyl acetate (20 ml) was added and the resulting solution was washed with sodium hydroxide solution (50 ml, 2M) and brine (50 ml) before being dried (MgSO4) and concentrated. The residue was purified by silica chromatography to give the product as yellow solid (104 mg).