Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[OH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.[OH-].[Na+].Cl>C(O)CC>[OH:7][CH2:8][CH2:9][N:10]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:12][OH:13]
Reactant: OCCNCCO
Reactant: COC(=O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: O=C(O)CN(CCO)CCO

Procedure:
Methyl bromoacetate (152.98 grams, 1 mole) is dissolved in 1-propanol (500 ml.) and bis-(2-hydroxyethyl)amine (105.14 grams, 2 moles) and triethylamine (111.1 grams, 1.1 moles) are added and the mixture is stirred and heated at reflux for 3 hours. The mixture is treated with 10 normal sodium hydroxide (110 ml., 1.1 moles) and the solvents are removed by distillation in vacuo. The residue is filtered and the solid is washed with 1-propanol. The combined filtrates are dissolved in ethanol (400 ml) and 10 normal sodium hydroxide (130 ml, 1.3 moles) is added. The mixture is stirred and heated at reflux for 3 hours. The mixture is acidified with 12 normal hydrochloric acid (108 ml, 1.3 moles). Upon cooling, N,N-bis-(2-hydroxyethyl)aminoacetic acid separates and is collected by filtration, and is washed with a 50% aqueous ethanol and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25](O)=[O:26])=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:26])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COCCN
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: CN(C)C=O
Product: COCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Yield: 82.1 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3.5 g) in anhydrous dimethylformamide (80 cc), N,N'-carbonyldiimidazole (1.6 g) and 2-methoxyethylamine (0.65 g). After recrystallization in ethanol, [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1isoindolinyloxy]-N-(2-methoxyethyl)acetamide (3 g), m.p. 172° C., is obtained.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.C(N(CC)CC)C.C(O)C=[C:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:5]([O:4][CH2:2][CH:1]=[C:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)(=[O:6])[CH3:7]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=CCO)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC=C1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
0.24 ml of acetanhydride, 0.36 ml of triethylamine and 50 mg of 4-dimethylaminopyridine are added to 400 mg of the pregna-1,4,17(20)-triene-21-ol-3-one produced in accordance with Example 1 in 10 ml of absolute methylene chloride, followed by stirring for 30 minutes at 0° C. A thin-layer chromatogram shows that the reaction is quantitative after this period. The reaction solution is successively washed with ice-cold dilute HCl, NaHCO3 solution and finally with water. The CH2Cl2 phase is dried over Na2SO4, the drying agent is filtered off and the residue is concentrated to dryness. The residue is substantially pure product in a yield of more than 90%. 1H-NMR (80 MHz, COCl3 ; δ-value):
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=S)[NH:22][CH2:23][CH3:24])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(O)(=[O:30])C>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]([NH:22][CH2:23][CH3:24])=[O:30])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2]
Reactant: CCNC(=S)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of mercuric acetate (0.70 g) in acetic acid (11 cc) is added dropwise during a period of 10 minutes to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-N-ethyl-2-phenothiazinecarbothioamide (0.87 g) in glacial acetic acid (11 cc). The reaction mixture is stirred for 90 minutes at 25° C. and then filtered on sintered glass covered with supercel. The celite is washed with acetic acid (2×2 cc) and the combined filtrates are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a residue which is diluted in ethyl acetate (50 cc). The organic phase is washed with 1 N sodium hydroxide (20 cc) and distilled water (3×20 cc) and then with brine (1×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a residue which is purified by chromatography on a column (height: 15.5 cm; diameter: 1.6 cm) of alumina (0.05-0.16 mm), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (375 cc) and 75:25 (3 liters), collecting 25-cc fractions. The first three liters are discarded and fractions 3 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-ethyl-2-phenothiazinecarboxamide (0.54 g).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:9]([CH2:11]C(OC(C)(C)C)=O)#[N:10].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]2[CH:11]=[C:9]([NH2:10])[N:1]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NNc1ccccn1
Product: COc1ccc(-c2cc(N)n(-c3ccccn3)n2)cc1
Yield: 95 %

Procedure:
Following the procedure described in Reference Example 2-4, the title compound was prepared from 2-hydrazinopyridine and 3-(4-methoxyphenyl)-3-oxypropanenitrile prepared from tert-butyl cyanoacetate and 4-methoxybenzoyl chloride according to the method described in Synthesis, p. 337 (1997) (3.48 g, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[OH-].[K+]>C(O)(=O)C.C(O)C.O.[Fe]>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: [Fe]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (0.95 g, 4.23 mmol) in acetic acid (8.46 mL), ethanol (8.46 mL) and water (4.23 mL) was added iron powder (1.18 g, 21.15 mmol) and the reaction was stirred at room temperature for 30 minutes. To this was added carefully 2 M KOH and extracted with ethyl acetate. The ethyl acetate layers were combined, dried (MgSO4), filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (0-10% methanol/dichloromethane) to give the desired product as a white solid (0.66 g, 80%): 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=2.6 Hz, 1H), 8.49 (dd, J=4.7, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.53 (s, 1H), 7.37 (ddd, J=8.4, 4.7, 0.6 Hz, 1H), 3.17 (bs, 2H).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH2:17][CH2:16]1>CO>[ClH:1].[ClH:1].[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(N3CCOCC3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1coc(N2CCOCC2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 85 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-morpholinooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (165 mg, 0.277 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure to give 105.5 mg (85%) of the title compound as a white solid. LC-MS: RT=2.70 min, [M+H]+=374.0.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:18]=[N:19][C:20]([CH:21]=[O:22])=[C:4]2[CH2:3]1.[B].[SH:24][CH2:25][CH2:26]O>ClCCl>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([C:14]([F:15])([F:17])[F:16])=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:18]=[N:19][C:20]([CH:21]3[S:24][CH2:25][CH2:26][O:22]3)=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(C(F)(F)F)c2C1=O
Reactant: OCCS
Agent: [B]
Solvent: ClCCl
Product: CN1Cc2c(C3OCCS3)ncn2-c2cccc(C(F)(F)F)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of 400 mg (1.29 mmol) of 5,6-dihydro-5-methyl-6-oxo-7-trifluoromethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde in 12 ml of dichloromethane with 0.04 ml of boron trifluoroethate, there was added a solution of 0.18 ml (1.29 mmole) of 2-mercaptoethanol in 40 ml of dichloromethane dropwise over 5 hours. After 18 hours further 0.02 ml of boron trifluoroetherate was added and the reaction mixture was stirred for 24 hours at ambient temperature. The reaction mixture was extracted with aqueous sodium bicarbonate, water, dried over MgSO4 and concentrated in vacuo to obtain a 47% yield of 5,6-dihydro-5-methyl-3-(1,3-oxathiolan-2-yl)-7-trifluoromethyl-imidazo[1,5-a][1,4]benzodiazepine-6(4H)-one after chromatography over silica gel.
Reaction SMILES: [Mg].Br[CH:3]1[CH2:6][CH2:5][CH2:4]1.BrCCBr.Br[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:13]=1>C1COCC1.CCOCC>[CH:3]1([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH:13]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: BrC1CCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Agent: [Mg]
Solvent: CCOCC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2CCC2)c2cccnc21
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A round bottom flask under a nitrogen atmosphere was charged with magnesium turnings (155 mg, 6.38 mmol) and dry ether (5 mL). Bromocyclobutane (340 mg, 2.52 mmol) was added, followed by 1,2-dibromoethane (50 μL) and refluxing was observed after a few minutes of stirring. This mixture was then warmed back to reflux for 5 hours and then allowed to cool to room temperature. The Grignard reagent was then added to a THF solution (5 mL) of 3-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.74 mmol) and NiCl2(dppf) (10 mg, 0.015 mmol). The mixture was heated at reflux for 16 hours and then allowed to cool to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (2×). The extracts were dried over sodium sulfate and concentrated. Flash 40 Biotage (40M cartridge, 3:1 hexane:EtOAc) afforded 3-cyclobutyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (45 mg, 19%). m/z (APCI-pos) M+1=313.1.
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[Cl:22][C:23]([F:25])=[CH2:24].[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-]>C1CCCCC1>[Cl:22][C:23]1([F:25])[CH2:24][CH:28]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(F)Cl
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Solvent: C1CCCCC1
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Cyclohexane (76.6 g), 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (75.8 mg, 0.26 mmol), and copper (I) trifluoromethanesulfonate benzene complex (58.3 mg, 0.23 mmol) were added in an autoclave, and then 1-chloro-1-fluoroethylene (78.9 g, 0.98 mol) was charged under elevated pressure. After the mixed solution was cooled to 10° C., the a mixed solution containing 95% of ethyl diazoacetate (12.0 g, 100 mmol) and cyclohexane (50 g) was charged into the autoclave under elevated pressure over five hours. Cyclohexane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to give a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (170.0 g). The content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 6.45% (yield based on ethyl diazoacetate: 65.6%), and the ratio of cis-isomer/trans-isomer was 64.6/35.4. The optical purity of the cis-isomer was 99% e.e. (1S,2R), and the optical purity of the trans-isomer was 92% e.e. (1S,2S).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10]Br>CC(O)=O>[Br:10][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: BrBr
Reactant: Nc1cccc(F)c1F
Solvent: CC(=O)O
Product: Nc1ccc(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,3-difluoroaniline (20 g, 154.9 mmol) in HOAc (230 mL) was added over 1 hour a solution of bromine (24.75 g, 7.978 mL, 154.9 mmol) in HOAc (70 mL) at RT. The reaction mixture was stirred at RT for another 1 hour and a white precipitate appeared. The solvent was removed under reduced pressure, the residue was made basic with 6M NaOH at 0° C., and the basic solution was extracted with DCM. After drying the organics over MgSO4, the volatiles were removed in vacuo to provide 4-bromo-2,3-difluoroaniline (Compound 1079); LC/MS (M+H)=207.96. This compound was reacted with the acyl chloride of 2-fluoronicotinic acid and carried through the sequence of reactions as described in Example 19 to produce N-tert-butyl-3-(1-(4-bromo-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1080); 1H NMR (300 MHz, DMSO-d6): δ 8.21 (dd, J=1.9, 4.8 Hz, 1H), 7.90-7.84 (m, 1H), 7.54-7.48 (m, 1H), 7.44 (dd, J=1.9, 7.7 Hz, 1H), 6.71 (s, 1H), 6.58 (dd, J=4.8, 7.7 Hz, 1H) and 1.31 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:26][C:27](=[O:30])[CH:28]=[CH2:29]>CCO.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[C:13]([C:11]1[CH:10]=[C:7]([C:8](=[O:9])[CH2:29][CH2:28][C:27](=[O:30])[CH3:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(C)=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=O)CCC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 77.5 °C
Yield: 44.4 %

Procedure:
To a solution of 3,5-di-tert-butylbenzaldehyde (10.9 g, 50 mmol) in EtOH (200 mL) was added DIPEA (12.9 g, 100 mmol), but-3-en-2-one (3.5 g, 50 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (2.5 g, 10 mmol). This mixture was heated to 75-80° C. overnight, evaporated, diluted with water (50 mL) and extracted with EA. The organic layer was washed with brine, dried, concentrated and purified by CC (EA/PE=1/100) to afford compound 5a (6.4 g, 44%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[Cl:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccc(Cl)cc1Cl
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(Cl)cc2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33.1 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (0.690 g, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.1 g, 0.016 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (1.20 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (410 mg, 27%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][N:5]=1.[CH3:12]I.O>CN(C=O)C>[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][N:5]=1
Reactant: Cc1cc(O)cnc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(Cl)c(C)c1
Yield: 101.5 %

Procedure:
Into a flame dried flask under N2 was placed DMF (150 mL), NaH (50% oil dispersion, 4.0 g, 0.08 mol) and 2-chloro-5-hydroxy-3-methylpyridine (11.7 g, 0.08 mol). The solution was stirred at 0°-5° C. until the evolution of H2 ceased and then a solution of CH3I (5.6 mL, 0.09 mol) in DMF (50 mL) was added dropwise. After the addition, the solution was allowed to stir at room temperature overnight. The resulting slurry was added to H2O and extracted with Et2 0 (3×). The organic layer was concentrated and the residue distilled at 85° C. (0.6 mm) to yield 12.8 g of 2-chloro-5-methoxy-3-methylpyridine (95%) as an oil; 1H NMR (CDCl3) δ2.35 (3H, s), 3.8 (3H, s), 7.1 (1H, d, J=3) and 7.9 (1H, d, J=3); MS m/e (M+) 157.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:34]=[CH:33][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc4ccccc4c3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (150 mg, 0.35 mmol, see step (b) Example 1) and 2-naphthyl-boronic acid (91 mg, 0.53 mmol). Yield 66 mg, (34%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:23][CH2:22]1.S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:35][C:30]2[CH:29]=[C:28]([CH2:27][N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)[CH:33]=[CH:32][C:31]=2[N:34]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (85 mg, 0.309 mmol) and 4-(morpholinomethyl)benzene-1,2-diamine (64 mg, 0.309 mmol) were dissolved in dry THF (8 mL) and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR: (400 MHz, CD3OD): δ 9.42 (d, 1H, J=2.0 Hz), 8.32 (dd, 1H, J=2.0 and 8.8 Hz), 7.92-7.87 (m, 1H), 7.67 (m, 2H), 7.32 (d, 1H, J=8.4 Hz), 5.97 (dd, 1H, J=2.8 and 8.8 Hz), 3.99 (m, 1H), 3.88-3.82 (m, 1H), 3.72 (m, 6H), 2.57 (m, 5H), 2.19 (m, 2H), 1.88 (m, 1H), 1.73 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[C-]#N.[Na+].[C-]#N.C[C:18]#[N:19]>CS(C)=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([CH2:2][C:18]#[N:19])[CH:8]=[C:7]([CH3:9])[CH:6]=1
Reactant: CC#N
Reactant: COc1cc(C)cc(CBr)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C)cc(CC#N)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 3-bromomethyl-5-methylanisole (17 g; 0.008 mol; from step (i) above) in DMSO (25 mL) was added NaCN (8.2 g; 0.16 mol). The mixture, which became very warm upon the addition of the cyanide, was left to cool to room temperature over 1 hour. CH3CN (25 mL) was then added, and the mixture refluxed for 1 hour. The reaction mixture was concentrated, water (200 mL) was added, and the resultant solution was extracted 3 times with ether. The combined organic phase was washed with water, dried (Na2SO4), and concentrated to give 9 g (70%) of the sub-title product as a yellow oil, which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1csc(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1csc(-c2ccc(F)cc2)n1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a stirred solution of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate (4.56 g, 15.5 mmol) in 1:1:1 THF/ethanol/water (45 mL) was added lithium hydroxide monohydrate (2.93 g, 69.8 mmol). The reaction was stirred overnight, concentrated and redissolved in water (175 mL). The solution was washed with ether (1×100 mL), acidified by the addition of 1.0 N HCl (80 mL) and extracted with ethyl acetate (2×70 mL). The combined extracts were dried (Na2SO4) and concentrated to afford 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (4.04 g, 98%). This material was used in the next step without purification.