Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1>C1COCC1.O=O>[Br:5][CH2:2][CH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:30][CH:29]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)c1ccc(CCO)cc1
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
7.16 g (21.59 mmol) of tetrabromomethane and 5.66 g (21.59 mmol) of triphenylphosphine are dissolved in 70 ml of THF with exclusion of oxygen and stirred at room temperature for 30 minutes. Then 3.2 g (14.4 mmol) of tert-butyl 4-(2-hydroxyethyl)benzoate, dissolved in 30 ml of THF, are added dropwise, and the reaction mixture is stirred at room temperature for 12 hours. After conversion is complete, the mixture is evaporated to dryness and the resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 3.9 g (13.7 mmol, 87% yield) of the title compound are obtained as a colourless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:9][CH3:13])=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4,5-Difluoro-2-nitrophenol (INTERMEDIATE 51) (2.02 g, 11.54 mmol) and potassium carbonate (2.39 g, 17.3 mmol) were added into a 50 mL round-bottomed flask. DMF (10 mL) was added. Iodomethane (1.08 mL, 17.3 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was poured into water (60 mL) and stirred for 10 min. Filtration afforded the title product as a precipitate (1.9 g, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Br)=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][C:16]#[N:17]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][N:13]([CH3:12])[CH2:14][CH2:15][C:16]#[N:17])=[CH:4][CH:3]=1
Reactant: CNCCC#N
Reactant: Clc1ccc(C=CCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(CC=Cc1ccc(Cl)cc1)CCC#N
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A solution of 116 g of p-chlorocinnamyl bromide in 500 ml of methylene chloride is added dropwise with stirring to a mixture of 42 g of 3-methylamino-propionitrile and 8.9 g of benzyl-tri-(n-butyl)ammonium bromide in 1 liter of methylene chloride and 500 ml of 2 N sodium hydroxide solution at room temperature and under a nitrogen atmosphere, and the emulsion stirred for 65 hours at room temperature. The organic phase is separated, washed with water, dried over sodium sulphate and evaporated to yield 3-[N-(p-chlorocinnamyl)-methylamino]-propionitrile. M.P. 143° [hydrogen oxalate form]
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:12]([C:2]1[O:1][C:10]2[C:5]([C:4](=[O:11])[CH:3]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1cc(=O)c2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1cc(=O)c2ccccc2o1
Temperature: 0 °C

Procedure:
Combine chromone-2-carboxylic acid chloride (2.0 g, 9.6 mmol) and aluminum chloride (3.84 g, 28.7 mmol) in benzene (70 mL). Heat at reflux for 4 hours. Pour the reaction mixture into ice-water (150 mL). Extract with dichloromethane twice. Dry the separated organic layers over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 15% ethyl acetate/hexane. Evaporate the product containing fractions to give the title compound as a solid.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([NH2:6])=[O:5])[CH2:2]1.CCN(CC)CC.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>CC#N.C(O)C.O>[C:4]([CH:3]1[CH2:7][CH2:8][CH2:9][N:1]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:2]1)(=[O:5])[NH2:6]
Reactant: ClCc1ccc(Cl)cc1
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: NC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 50 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A solution of nipecotamide (6.40 g, 50 mmol) in CH3CN (150 mL) and ethanol (20 mL) was treated with Et3N (7.0 mL, 50 mmol) and 4-chlorobenzyl chloride (8.05 g, 50 mmol). The reaction mixture was stirred at 50° C. for 16 h. After cooling to room temperature, saturated aqueous NaHCO3 (50 mL) and water (150 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (150 mL×3) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give a pale red solid. The crude solid was washed with ether (100 mL) to afford 3-carbamoyl-1-(4-chlorobenzyl)piperidine (6.98 g, 54%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCC=CCCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: OCCCCCCCCCCCc1ccccc1

Procedure:
A solution of 11-phenyl-8-undecenol (Example 29(c), 2.9 g) in ethanol (300 ml) was hydrogenated at 60 p.s.i. over 10% palladium on charcoal (0.6 g) for 1 hour. The catalyst was filtered off and the filtrate was evaporated to give the title compound as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[NH2:25][C:23]([C:22]1[CH:21]=[C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])[S:19][C:18]=1[NH:17][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[N:10]=2)[N:7]=1)=[O:24]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)NC(=O)c1cn2nc(Cl)ccc2n1
Product: CC(C)NC(=O)c1cn2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2n1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 6-chloro-N-isopropylimidazo[1,2-b]pyridazine-2-carboxamide (149 mg, 0.62 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (177 mg, 0.57 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([CH3:22])[N:16]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.C(O)C.O>[F:21][C:20]1[C:15]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][C:17]([CH3:22])=[CH:18][CH:19]=1
Reactant: Cc1ccc(F)c(Br)n1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(F)c(-c2ccc(C(F)(F)F)nc2)n1
Temperature: 120 °C
Yield: 284 %

Procedure:
A 20 mL microwave vial was charged with 6-(trifluoromethyl)pyridin-3-ylboronic acid (553 mg, 2.89 mmol), 2-bromo-3-fluoro-6-methylpyridine (500 mg, 2.63 mmol), bis(triphenylphosphine)palladium(II) chloride (92 mg, 0.132 mmol), and K2CO3 (727 mg, 5.26 mmol), followed by the addition of DME (9.0 mL), water (3.86 mL) and ethanol (2.57 mL). The reaction mixture was heated in the microwave at 120° C. for 10 minutes. To the reaction mixture was added 200 mL EtOAc, and washed with 200 mL water and 200 mL brine. The organic phase was separated, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 40 g column, eluted with 0-40% EtOAc in Hexanes (25 mL/min) to provide the title compound (7.47 mmol, 95% yield) as a white solid. MS (ESI+) m/z 257.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.59-8.52 (m, 1H), 8.07 (d, J=8.2, 1H), 7.84 (dd, J=11.1, 8.5, 1H), 7.46 (dd, J=8.5, 3.5, 1H), 2.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:21])[CH2:9][O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(OCC)(=O)C>CN(C)C=O>[C:30]([Si:27]([CH3:29])([CH3:28])[O:21][C@H:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][O:10][S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(Cl)nc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
To a cooled (50° C.), stirred solution of (R)-toluene-4-sulfonic acid 2-(6-chloro-pyridin-3-yl)-2-hydroxy-ethyl ester (4.9 g) and imidazole (2.0 g) in anhydrous dimethyformamide (14 mL) was added t-butyldimethylsilyl chloride (2.8 g). The reaction mixture was allowed to warm to room temperature and stirring was continued for 18 h. Ethyl acetate was added, followed by washing with water (2×), drying over sodium sulfate and concentration in vacuo to afford an oil. Chromatography (Flash 40M®) utilizing 10% ethyl acetate/hexanes afforded 5.6 g of the title compound (I-2e) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.COC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1[CH:2]=[CH:7][CH:6]=[C:5]2[C:37]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:3]=[N:4]2
Reactant: O=Cc1ccccc1B(O)O
Reactant: Nc1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC
Product: c1ccc2c(c1)cnc1cccnc12
Yield: 50.5 %

Procedure:
2.3 g 3-amino-2-chloropyridine (20 mmol) was dissolved by 45 mL dimethyl ether (DME) in a round-bottomed flask. 0.24 g palladium acetate (Pd(OAc)2), 0.567 g triphenylphosphine (PPh3), and 27 mL sodium carbonate (Na2CO3) solution were mixed in another flask. After the two flasks were mixed and stirred until a white solid was precipitated, 3.5 g 2-formyl phenyl boronic acid (23.3 mmol) was added and stirred for 24 hr under nitrogen. After extraction by ethyl acetate, drying, concentration, and purification by silicon-gel column, 1.82 g yellow solid was obtained, with a yield of 51%.
Reaction SMILES: N1C=CC=CC=1.Cl.Cl.[N:9]1([CH2:15][CH2:16][NH:17][N:18]=[CH:19][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[C:31]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40]([CH2:44][C:45](=[O:47])[NH2:46])=[C:39](O)[CH:38]=[CH:37]2)(=[NH:33])[NH2:32].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)=O>[N:9]1([CH2:15][CH2:16][NH:17][N:18]=[CH:19][NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][C:39]3[CH:38]=[CH:37][C:36]4[C:41](=[CH:42][CH:43]=[C:34]([C:31](=[NH:32])[NH2:33])[CH:35]=4)[C:40]=3[CH2:44][C:45](=[O:47])[NH2:46])=[O:26])=[CH:28][CH:29]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(NC=NNCCN2CCCCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=CO
Solvent: c1ccncc1
Solvent: CCC(C)=O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC=NNCCN4CCCCC4)cc3)ccc2c1
Reaction time: 2 h
Yield: 48.8 %

Procedure:
30 Milliliters of 20% hydrous pyridine was added to 1.71 g of 4-[(2-piperidinoethyl)aminoiminomethylamino]benzoic acid.dihydrochloride, 1.2 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.06 g of DCC and 52.4 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 4 days at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of DMF, and the solution was added dropwise to a mixed liquid of 300 ml of acetone and 100 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-formic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 20 ml of methanol and 2.1 ml of concentrated hydrochloric acid, and the solution was added dropwise to 450 ml of acetone, followed by stirring for 30 minutes under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.08 g of the desired product.
Reaction SMILES: C([C:3]1[C:4](Cl)=[N:5][C:6]([Cl:9])=[N:7][CH:8]=1)C.[CH3:11][S-:12].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[C:4]([S:12][CH3:11])[CH:3]=[CH:8][N:7]=1
Reactant: C[S-]
Reactant: CCc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine (20.0 g, 0.13 mol) in 150 mL of anhydrous tetrahydrofurane was added sodium thiomethoxide (49.30 mL, 0.15 mol) at −10° C. The reaction mixture was allowed to warm up to room temperature and then stirred for 5 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (×2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was slurrified with diethyl ether and then collected by filtration to afford the desired intermediate 10 as a white solid (11.2 g, 52%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=1[CH3:21])[O:8][CH:7]([C:22]([F:25])([F:24])[F:23])[C:6]([C:26]([O:28]CC)=[O:27])=[CH:5]2.[OH-].[Li+].C(O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=1[CH3:21])[O:8][CH:7]([C:22]([F:25])([F:23])[F:24])[C:6]([C:26]([OH:28])=[O:27])=[CH:5]2
Reactant: C#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)OCC)C(C(F)(F)F)O3)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)c(C)c1
Temperature: 80 °C
Yield: 32.3 %

Procedure:
The product of step 1 (230 mg, 0.53 mmol) was dissolved in 3 ml of tetrahydrofuran. To the resulting solution was added a solution of lithium hydroxide (111 mg, 2.6 mmol) in 3 mL of water, followed by addition of 3 mL of ethanol. The resulting solution was heated to 80° C. for one hr, LC-MS indicated that the reaction was complete. The volatiles were removed. The residue was diluted with water, and acidified at 0° C. with dilute hydrochloric acid to pH=1.0. The product was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After removing the volatiles, the crude product was purified by reverse phase HPLC. The product was obtained 70 mg (28.8%) of a light yellow solid: 1H NMR (CDCl3/300 MHz) 7.82 (s, 1H), 7.48(s, 1H), 7.42-7.40(m, 2H), 6.93(d, J=8.1 Hz, 1H), 6.36(s, 1H), 5.66(q, J=6.9 Hz, 1H), 3.11(s, 1H), 2.23(s, 3H). MS (ESI+) 409.0(M+1, 100). MS(ES−) 407.0(M−H, 100). HRMS (ES−) m/z calcd for (M−H; C20H11ClF3O4): 407.0292, found: 407.0317
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(CC)C(C)C)(C)C.[OH:30][C:31]1([CH3:35])[CH2:34][NH:33][CH2:32]1>C(Cl)(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:33]1[CH2:34][C:31]([OH:30])([CH3:35])[CH2:32]1)=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CC1(O)CNC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(C)(O)C3)nc2c1C#N
Temperature: 100 °C
Yield: 92.1 %

Procedure:
Under nitrogen atmosphere, 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (216 mg, 0.753 mmol) was dissolved in N,N-dimethylsulfoamide (10 ml), then N,N-diisopropylethylamine (584 μl, 3.35 mmol) and 3-hydroxy-3-methylazetidine (132 mg, 1.51 mmol) dissolved in N,N-dimethylsulfoamide (5 ml) were added, followed by stirring under heat at 100° C. for 20 hours. After cooling, diluting with chloroform and washing with water, the organic layer was dried over anhydrous magnesium, sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (234 mg, 92%) as a white solid.
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Al].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>CN(C)C=O>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 254 mg (9.42 mmol) of aluminum (foil) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at 100° C. for 30 min. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 sulfuric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 737 mg (3.96 mmol) of diphenylphosphine in 84% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[O:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ncco3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1coc(-c2ccc(N3CCNCC3)cc2)n1

Procedure:
Prepared in analogy to example 4.4(b) from 4-(4-Oxazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 230.1 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][NH:9][C:10](=[O:13])[CH2:11][Cl:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:12][CH2:11][C:10]1[O:13][C:6]([C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1
Reactant: O=C(CCl)NNC(=O)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: ClCc1nnc(-c2ccc(Cl)cc2)o1
Yield: 80.8 %

Procedure:
To a mixture of 4-chlorobenzohydrazide 5 (1 g, 5.86 mmol) and K2CO3 (0.97 g, 7.03 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.68 g, 6.08 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford 4-chloro-N′-(2-chloroacetyl)benzohydrazide 6 (1.2 g, 82%) which was used for the next step without further purification. A mixture of 4-chloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.6 g, 2.43 mmol) and phosphorous oxychloride (0.37 g, 2.43 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 7 (0.45 g). Yield: 82%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:19]([O-])=O)[C:8]([O:17][CH3:18])=[C:9]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:19][C:7]1[C:8]([O:17][CH3:18])=[C:9]([CH:11]([OH:16])[C:12]([F:14])([F:15])[F:13])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: COc1c(C(O)C(F)(F)F)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1c(N)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Yield: 100.1 %

Procedure:
To a solution of 1-(5-tert-butyl-2-methoxy-3-nitrophenyl)-2,2,2-trifluoroethanol (0.440 g, 1.43 mmol) in ethanol (4.7 mL) and water (2.3 mL), ammonium chloride (0.230 g, 4.30 mmol) and iron powder (0.240 g, 4.30 mmol) were added, and the resulting mixture was heated to reflux for 15 hours. The temperature of the reaction solution was returned to room temperature, the insoluble materials were filtered through a Celite pad. After evaporating the organic solvent under reduced pressure, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to obtain 0.397 g of the crude product containing the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].Cl[CH2:12][CH:13]=O>O>[CH3:10][C:6]1[CH:7]=[CH:8][N:9]2[CH:12]=[CH:13][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: O=CCCl
Reactant: Cc1ccnc(N)c1C#N
Solvent: O
Product: Cc1ccn2ccnc2c1C#N
Temperature: 80 °C
Yield: 75 %

Procedure:
To a stirred solution of compound 2-amino-4-methylnicotinonitrile (1 equiv.) in water was added chloroacetaldehyde (55% aq. solution) (1.2 equiv.) and the reaction was heated at 80° C. for 16 h. On completion, it was quenched by 1N NaOH till pH 8. Solid precipitated was filtered and vacuum dried to afford the title compound (75% yield).
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][C:12]=2[C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1.O.C(OCC)(=O)C>[C:3]1([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:23][C:12]=2[C:13]([OH:15])=[O:14])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCCCC2)ccc1OCc1ccccc1

Procedure:
LiOH (1.25 mL, 3.74 mmol) was added to a stirred solution of phenylmethyl 2-[(phenylmethyl)oxy]-5-(1-piperidinyl)benzoate (may be prepared as described in Description 41; 150 mg, 0.37 mmol) in a mixture of THF:water (3:1, 10 ml). The mixture was heated to reflux for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over magnesium sulphate, and concentrated to give a yellow oil. The crude product was purified using Comflash to yield the title compound. 80 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27])[N:22]=1.C(OC(N[C@@H](CC(C)C)C(O)=O)=O)(C)(C)C>>[CH3:30][CH:29]([CH3:31])[CH2:28][C@H:26]([NH:27][C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:18])[N:14]=1)=[O:17])[C:23]1[N:22]=[C:21]([CH3:20])[O:25][N:24]=1
Reactant: O=C(O)c1cccc(C(O)c2ccc(F)cc2)n1
Reactant: Cc1nc([C@@H](N)CC(C)C)no1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: Cc1nc([C@H](CC(C)C)NC(=O)c2cccc(C(O)c3ccc(F)cc3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((4-fluorophenyl)(hydroxy)methyl)picolinic acid and (S)-5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine hydrochloride (which was prepared from (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid (CAN 13139-15-6) in analogy to the procedures described in Example 38 a to e) as starting materials. MS (EI): m/e=399.2 [M+H]+.