Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Br[C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[N:21][CH:22]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([CH:18]=2)[CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cncc(-c2ccc(F)cc2)c1
Reaction time: 2 h

Procedure:
13.2 g of 4-fluorobenzeneboronic acid and 10.8 g of sodium hydrogen-carbonate are initially introduced, and a mixture of 16.1 g of 5-bromo-3-hydroxymethylpyridine, 30 ml of water and 60 ml of toluene is added with stirring and under a protective gas. A further 14 ml of water, 28 ml of toluene and 0.5 g of tetrakis(triphenylphosphine)palladium (0) are subsequently added. The reaction mixture is heated to reflux and held at this temperature for 2 hours. After cooling, the mixture is subjected to conventional work-up, giving 5-(4-fluorophenyl)nicotinyl alcohol. The alcohol is subsequently oxidized by conventional methods to give 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=2)[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:39][C:40]1[C:45]([Cl:46])=[CH:44][C:43]([Cl:47])=[CH:42][C:41]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[Cl:46][C:45]1[C:40]([OH:39])=[C:41]([S:48]([N:11]([CH2:10][C:9]2[CH:27]=[CH:28][CH:29]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=3)[CH:8]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)(=[O:50])=[O:49])[CH:42]=[C:43]([Cl:47])[CH:44]=1
Reactant: CCCCCCCCc1ccc(CNCc2cccc(Oc3ccc(F)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(CN(Cc2cccc(Oc3ccc(F)cc3)c2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a mixture of N-(3-(4-fluorophenoxy)benzyl)-1-(4-octylphenyl)methanamine (100 mg, 0.238 mmol, 1.0 eq) in DCM (10 mL) was added triethylamine (72 mg, 0.72 mmol, 3.0 eq) followed by 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (62 mg, 0.238 mmol, 1.0 eq). After stirring at ambient temperature for 4 h, the reaction mixture was diluted with 100 mL DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified by preparative HPLC to afford the title compound (25 mg, 16%). 1H NMR (400 MHz, CD3OD) δ 7.64-7.63 (d, 1H), 7.55-7.54 (d, 1H), 7.21 (m, 1H), 7.19-7.11 (m, 2H), 7.09-7.02 (m, 4H), 6.95-6.91 (m, 2H), 6.88-6.86 (d, 1H), 6.80-6.78 (d, 1H), 6.68 (s, 1H), 4.43-4.40 (d, 4H), 3.35-3.30 (m, 6H), 2.55-2.51 (t, 2H), 1.57-1.56 (t, 3H), 1.3 (s, 10H), 0.87-0.91 (t, 3H). MS (ESI): 644.0 (M−H)−.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]([S:16][Na])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)(=O)C>[CH:13]([S:16][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: CC(C)S[Na]
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SC(C)C)cc1
Temperature: 80 °C
Yield: 67.3 %

Procedure:
A mixture of ethyl 4-fluorobenzoate (390 mg, 2.32 mmol) and isopropylsulfanylsodium (273 mg, 2.78 mmol) in DMF (2.5 mL) was heated at 80° C. for 36 h. The reaction mixture was diluted with ethyl acetate before being washed with 1N NaOH and then brine. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting with 50-100% ethyl acetate in hexanes to give ethyl 4-isopropylsulfanylbenzoate (350 mg).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].ClCC(OC(=O)CCl)=O.[CH3:15][C:16]1[O:17]C=[CH:19][CH:20]=1>C1(C)C=CC=CC=1>[C:16]([C:15]1[O:5][CH:1]=[CH:2][CH:3]=1)(=[O:17])[CH2:20][CH3:19]
Reactant: CCC(=O)O
Reactant: Cc1ccco1
Agent: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 7 h
Yield: 47.7 %

Procedure:
In 50 ml of toluene were dissolved 3.7 g (0.05 mole) of propionic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 5.36 g (0.065 mole) of 2-methylfuran and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 7 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 2.96 g of 2-propionylfuran.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10].[Li+].[OH-]>C1COCC1.O>[CH3:16][O:15][CH2:14][CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6]/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10]
Reactant: COCCN(C/C=C/C(=O)OC)CCOC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCN(C/C=C/C(=O)O)CCOC

Procedure:
(E)-Methyl 4-(bis(2-methoxyethyl)amino)but-2-enoate (77) (10.0 g, 43 mmol) was hydrolyzed with LiOH (5.4 g, 130 mmol) in THF (100 mL) and H2O (50 mL) to give (E)-4-(bis(2-methoxyethyl)amino)but-2-enoic acid (78) (quantative yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 218.1.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:35])[CH2:32][O:33][CH3:34]>>[CH3:34][O:33][CH2:32][C:31]1[N:35]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COCC(N)=NO
Product: COCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (0.25 mmol) of the compound from Example 44A and 31 mg (0.30 mmol) of N′-hydroxy-2-methoxyethanimidamide (J. Med. Chem., 1997, 40, 8, 1230-1246) were reacted according to the General Method 1. Yield: 19 mg (16% of theory).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[N+]([O-])=O)[C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl-].[Na+]>CN1CCN(C)C1=O.O>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[S:2][CH3:1])[C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Sodium thiomethoxide (8.05 g, 0.115 mol) is added portionwise to a stirred solution of methyl 3-cyclopentyloxy-4-nitrobenzoate (26.5 g, 0.1 mol) in N,N'-dimethylimidazolidinone (200 mL) at ambient temperature under an atmosphere of nitrogen and stirring continued for 4 hours. The mixture is then diluted with water (1200 mL) containing sodium chloride (200 g) and extracted with ethyl acetate (2×300 mL). The combined extract is washed with saturated brine (2×300 mL) and then evaporated under reduced pressure to give methyl 3-cyclopentyloxy-4-(methylthio)benzoate (24.4g, 91.7%) as an orange brown solid which is used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(O)c1C
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (1.00 g, 6.57 mmol) in ethanol (10 mL) was added sulfuric acid (0.16 g, 1.64 mmol), and the mixture was heated under reflux for 12 hours. The reaction solution was cooled to room temperature, and one half of the solvent was concentrated under reduced pressure. Then, water (30 mL) was added thereto, and the mixture was neutralized with sodium carbonate. The mixture was extracted with diethyl ether, and the organic layer was washed with water, and then concentrated under reduced pressure. To the resulting residue was added hexane and crystallized to give the title compound (1.12 g, yield 95%).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][C:17]=2[O:21][CH3:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(OC)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(OC)c1
Temperature: 25 °C

Procedure:
18.7 g of 1acetylisonipecotoyl chloride, Example 1(b) are added slowly to a stirred mixture of 40.0 g of m-dimethoxybenzene and 19.2 g of aluminum chloride in 75 ml of carbon disulfide. The reaction mixture is stirred at ambient temperature for an hour, poured into ice-water and extracted with chloroform, the combined extracts are dried and the chloroform is removed, leaving a yellow oil. The oil is triturated with ether to give a white solid, which is recrystallized twice from ethyl acetate to give the pure solid, mp 132°-134° C., 1-acetyl-4-(2,4-dimethoxybenzoyl)piperidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].Cl.N1C=CC=CC=1>CC(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 74.9 %

Procedure:
A stirred mixture of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile (10.7 g, 40 mmol), 3-chloro-4-fluoroaniline (7.0 g, 48 mmol), pyridine hydrochloride (4.6 g, 40 mmol), and 200 ml of 2-propanol was heated to reflux temperature and maintained for 1 h. The 2-propanol was evaporated off, and the residue was stirred in water with potassium bicarbonate (pH˜8). The resulting solid was filtered, washed with water and 5:1 hexane-DCM, and dried. Recrystallization from EtOH gave 11.3 g of yellow solid, mp 259-263°; ms 377.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1Cl)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1Cl)CCCC3
Yield: 73.1 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.300 g; 0.78 mmol), LHMDS 1N in THF (0.86 mL; 0.86 mmol), 1-iodopropane (0.114 mL; 1.17 mmol) in DMF (3.1 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.244 g (74%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.S([O-])(O[O-])(=O)=[O:19].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:19])=[O:15])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C#Cc2ccc(F)cc2)cc1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 4-[(4-fluorophenyl)ethynyl]benzaldehyde (10.39 g; 46.37 mmol, intermediate which may be obtained according to methods disclosed in EP03 103780.7) in DMF (400 mL) was added potassium peroxomonosulfate (28.5 g, 46.4 mmol) in one portion at rt. The reaction mixture was stirred at rt overnight. The reaction mixture was poured in water (2 L) and the resulting precipitate was filtered off, washed with water and dried under reduced pressure to give 10.45 g (94%) of the title compound as a white powder. HPLC, Rt: 3.98 min (purity: 98.6%). 1H NMR (DMSO-d6) δ: 13.15 (brs, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.64 (m, 4H), 7.29 (t, J=8.9 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N+:39]([O-:41])=[O:40])=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([N+:39]([O-:41])=[O:40])=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1)=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Ethoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH2:21][C:22]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]>CN(C=O)C.C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:22]([NH:21][C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[O:12])=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A slurry of 1-isopropylpiperidine-4-carboxylic acid (501.0 mg, 2.92 mmol) and 50% DMF/THF (6.3 mL) was cooled in an ice bath, and a solution of iso-butyl chloroformate (0.34 mL, 2.63 mmol) and 50% DMF/THF (0.7 mL) was added over 10 min via syringe. The ice bath was removed at addition's end, and the mixture was allowed to warm to ambient temperature. After 1 h, 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (414.8 mg, 1.47 mmol) was added in one portion, and the slurry was heated to 70° C. in an oil bath. Analysis by HPLC after 17 h showed only 2.5% of unacylated amine remained, so the volatiles were removed under reduced pressure, and EtOAc (25 mL) and water (20 mL) were added. The organic layer was extracted with saturated NaHCO3 (2×20 mL), and the combined aqueous layers were back-extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to 0.97 g of yellow solid which was found to be contaminated with 45 wt % DMF. Corrected yield was 0.53 g (83% yield), and no further purification was performed:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.C([C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])=O>O1CCCC1>[OH:3][N:2]=[C:12]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:14]([CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13]1
Reactant: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1=CC=C(CN2C(=O)c3ccccc3C2=O)CC1=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
5.2 g of hydroxylamine hydrochloride, 12.2 g of sodium acetate, and 50 ml water were added to a mixture of 20 g N-(3-formyl-4-methoxybenzyl)phthalimide and 200 ml tetrahydrofuran, and stirred at room temperature for 1 hr. It was stirred at 60° C. for 1 hr, and then evaporated. Water was added to the resulting residue, and the insoluble matters were collected by filtration. These were washed with diethyl ether to give 20 g of N-(3-hydroxyimino-4-methoxybenzyl)phthalimide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11].[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].C(N(CC)CC)C>C(O)C>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=2[O-:11])[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Br)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cc([N+](=O)[O-])cc[n+]2[O-])CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 111.2 %

Procedure:
To a solution of 2-bromo-4-nitropyridine N-oxide (12 g), which is prepared according to the method disclosed in J. Org. Chem., 21, 1077 (1956), in ethanol (300 ml) are added 4-piperidinecarboxylic acid ethyl ester (22 g) and triethylamine (11.6 ml), and the mixture is stirred at 80° C. for 5 hours. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate, washed with water, and the solvent is evaporated under reduced pressure to give the title compound (18 g).
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:15][N:14]([C:16]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([NH2:25])=[C:18]([CH3:26])[CH:17]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[Cl:34][C:35]1[C:40]([CH:41]=O)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1>CO.[Pd]>[Cl:34][C:35]1[C:40]([C:41]2[NH:22][C:20]3[CH:21]=[C:16]([N:14]4[CH2:13][CH2:12][CH2:11][C:10]5([CH2:27][CH2:28][CH2:29][NH:8][CH2:9]5)[CH2:15]4)[CH:17]=[C:18]([CH3:26])[C:19]=3[N:25]=2)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1
Reactant: O=Cc1c(I)ccnc1Cl
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of 4-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-2-methyl-6-nitro-phenylamine (394 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (100:9:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (288 mg, 55%). 1H NMR (CDCl3) δ 1.28-1.72 (8H), 2.57 (s, 3H), 2.57-3.12 (8H), 6.82 (s, 1H), 6.92 (s, 1H), 6.73 (d, J=6 Hz, 1H), 7.98 (d, J=6 Hz, 1H). ESI-MS m/z 522 (MH+).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[O:10][C:9]([C:19]2[N:24]=[CH:23][N:22]3[CH:25]=[CH:26][CH:27]=[C:21]3[CH:20]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[CH:15]=2)[O:10][C:9]([C:19]2[N:24]=[CH:23][N:22]3[CH:25]=[CH:26][CH:27]=[C:21]3[CH:20]=2)=[CH:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(C=O)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(CNCc3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of 4-tert-Butoxyimino-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carbaldehyde (example 144B) (50 mg; 0.14 mmol) in dichloromethane (5 ml), was added molecular sieves and 4-Fluoro-benzylamine (19 mg; 0.15 mmol). After 2 hours at room temperature, sodium triacetoxyborohydride (29 mg, 0.14 mmol) and acetique acid (2 ml), were added. After stirring at room temperature for 18 hours, the reaction mixture was quenched with a saturated solution of sodium hydrogenocarbonate and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-100%) to afford the title compound (20 mg, 30%) as a green solid.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][C:5]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.O.C(O)([C:20](F)([F:22])[F:21])=O.C(OO)(C)(C)C>FC(C1C=CC=CC=1)(F)F>[F:21][CH:20]([F:22])[C:13]1[N:12]=[CH:11][C:10]([C:5]2([C:8]#[N:9])[CH2:4][CH2:3][C:2]([F:1])([F:16])[CH2:7][CH2:6]2)=[CH:15][N:14]=1
Reactant: N#CC1(c2cncnc2)CCC(F)(F)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OO
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: N#CC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of compound 4,4-difluoro-1-(pyrimidin-5-yl)-cyclohexanecarbonitrile (1.5 g, 6.72 mmol) and DFMS (6.0 g, 0.02 mol) in trifluoromethylbenzene (53 mL) and H2O (21 mL) at room temperature was added TFA (766 mg, 6.72 mmol) followed by slow addition of t-BuOOH (5.2 g, 70% solution in H2O) with vigorous stirring. The reaction mixture was stirred at room temperature overnight. TLC indicates about 50% starting material remained, a second addition of DFMS (6.0 g, 0.02 mol) and t-BuOOH(5.2 g, 70% solution in H2O) were added to the reaction mixture. Upon consumption of starting material, the reaction mixture was portioned between DCM (20 mL) and saturated NaHCO3 solution (20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (3×20 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (Petroleum ether:EtOAc=3:1) to give 1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexanecarbonitrile (800 mg, Yield: 44.4%). 1H NMR (CDCl3 400 MHz): δ9.03 (s, 2H), 6.71 (t, J=54.4 Hz, 1H), 2.40-2.27 (m, 6H).