Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([C:7]([O:9][CH3:10])=[O:8])[C@@H:5]([CH3:11])[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:31]=1[CH:32]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:15]([O:14][C:12]([N:4]1[C@H:5]([CH3:11])[C@H:6]([C:7]([O:9][CH3:10])=[O:8])[C@H:2]([NH:1][CH2:32][C:31]2[CH:34]=[C:35]([O:38][C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: COC(=O)[C@H]1[C@H](N)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a stirred solution of (2S*,3S*,4S*,5R*)-3-amino-1-benzyloxycarbonyl-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine (793 mg, 2.15 mmol) and 2-methoxy-5-trifluoromethoxybenzaldehyde (569 mg, 2.58 mmol) in dry CH2Cl2 (10 ml) was added NaBH(OAc)3 (639 mg, 3.01 mmol) portionwise at room temperature. After stirring for 2 h at room temperature, the reaction mixture was basified to pH 10-11 by adding 10% NaOH aq. solution with ice-cooling. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (60 ml×4). The combined CH2Cl2 solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give crude title compound (1.32 g) as a yellow viscous oil. This was purified by column chromatography on silica gel (65 g) with hexane-ethyl acetate (3:1-2:1) to give the pure title compound (1.08 g, 88%) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:4]=1.[C:20](#[N:22])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:8][N:7]1[C:3]([CH2:2][C:20]#[N:22])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[N:6]1
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CC#N

Procedure:
In analogy to the procedure described for example 9 b], 5-chloromethyl-1-methyl-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole was reacted with tetrabutylammonium cyanide in acetonitrile to give [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetonitrile as yellow solid.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br)([F:12])[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([F:5])[F:4].[C-:21]#[N:22].[K+].CC(C)=O>O>[F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][C:21]#[N:22])([F:12])[C:3]([F:5])([F:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: FC(F)(c1ccccc1)C(F)(F)c1ccccc1CBr
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCc1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
2-(α,α,β,β-Tetrafluorophenylethyl)benzyl bromide, 3.5 g. (0.01 mole), and 2.0 g. (0.0308 mole) of potassium cyanide are dissolved in 35 ml. of acetone - 5 ml. of water and the solution is heated to refluxing for about 18 hours. The organic phase is separated, acetone is distilled under reduced pressure, and the residual oil is dissolved in benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the residual brown oil.
Reaction SMILES: C(O[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C@@H:15](C)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.CS([O-])(=O)=O>>[CH2:13]([NH:14][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[CH:22][CH:23]=1)[C:12]1[CH:22]=[CH:23][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@H](NCc1ccc(OCc2ccccc2)cc1)C(=O)N(C)C
Agent: CS(=O)(=O)[O-]
Product: CN(C)C(=O)CNCc1ccc(NCc2ccccc2)cc1

Procedure:
(S)-2-(4-Benzyloxybenzyl)amino-N,N-dimethylpropionamide, methanesulfonate.
Reaction SMILES: Cl.Cl.NC1CCN(C2CCCCC2(CCC2C=C(C3C=CC([Cl:31])=C(Cl)C=3)C=CC=2)O)CC1.[Cl:33][C:34]1[CH:35]=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]([C:63]3([OH:69])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]3)[CH2:48][N:49]3[CH2:54][CH2:53][CH:52]([NH:55]C(=O)OC(C)(C)C)[CH2:51][CH2:50]3)[CH:42]=2)[CH:37]=[CH:38][C:39]=1[Cl:40].Cl>>[ClH:31].[ClH:33].[NH2:55][CH:52]1[CH2:53][CH2:54][N:49]([CH2:48][CH:47]([C:63]2([OH:69])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]2)[C:43]2[CH:42]=[C:41]([C:36]3[CH:37]=[CH:38][C:39]([Cl:40])=[C:34]([Cl:33])[CH:35]=3)[CH:46]=[CH:45][CH:44]=2)[CH2:50][CH2:51]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1
Reactant: NC1CCN(C2CCCCC2(O)CCc2cccc(-c3ccc(Cl)c(Cl)c3)c2)CC1
Agent: Cl
Product: NC1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 135, step 3 1-[2-(4-aminopiperidin-1-yl)-1-(3′,4′-dichloro-1,1′-biphenyl-3-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {1-[2-(3′,4′-dichloro-1,1′-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-yl}carbamate. MS (ES) m/z 447.2 ([M+H]+); HRMS: calcd for C25H32Cl2N2O.2.00 HCl, 518.1425; found (ESI), 447.1962.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[OH:17].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[O:17][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N)cc1OCCN1CCCC1
Temperature: 25 °C
Yield: 87 %

Procedure:
A stirred DMF suspension (5 mL) of 2-methoxy-5-nitrophenol (0.5 g, 2.96 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.75 g (4.43 mmol) and K2CO3 (1.02 g, 7.4 mmol) was heated at 80° C. for 2 hr. After cooling to RT, the reaction was diluted with 20 mL of H2O and extracted with EtOAc (3×20 mL). The combined EtOAc layers were washed brine and dried over MgSO4. After concentration under vacuum, the resulting residue was chromatographed on silica gel. Gradient elution CH2Cl2 to 10% MeOH/CH2Cl2 eluted N-(2-(2-methoxy-5-nitrophenoxy)ethyl)pyrrolidine (507 mg) as a light orange solid. Subsequent conversion of the aryl nitro substituent to the title aryl amine was accomplished in 87% yield following the procedure described in step C of Example 6. MS (ESI) 237 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:14](Br)[CH2:15][CH:16]=[CH2:17].CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:17]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13])[CH2:16][CH:15]=[CH2:14]
Reactant: O=C1CCCCC1
Reactant: C=CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCCC1CCCCC1=O
Temperature: 0 °C

Procedure:
A suspension of potassium t-butoxide in toluene cooled to 0° C. in an ice bath under N2 is treated with cyclohexanone. To the reaction mixture is slowly added 3-butenyl bromide. The reaction is warmed to room temperature. The reaction is then poured into EtOAc and washed once with 10% potassium hydrogen sulfate. The organic solution is then washed with brine, dried over magnesium sulfate, and the solvent evaporated under reduced pressure to afford 2-(3-butenyl) cyclohexanone.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>C(O)C>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][C:12](=[N:23][OH:24])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC(COCc2ccccc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCCC(COCc2ccccc2)C1
Temperature: 0 °C
Yield: 74.5 %

Procedure:
To a solution of the compound (11) (1.0 g; 4.6 mmol). in ethanol (25 ml), sodium acetate (0.754 g; 9.2 mmol) and hydroxylamine hydrochloride (0.384 g; 5.5 mmol) are added, and the resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water, extracted with chloroform, washed with water and dried. After concentration under reduced pressure, the residue is chromatographed on a silica gel column to give 3-benzyloxymethylcyclohexanone oxime (12) (0.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[N+:14]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25])([O-:16])=[O:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:24]([C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N+:14]([O-:16])=[O:15])(=[O:25])=[O:26])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: COc1cc(N)c2ncccc2c1
Product: COc1cc(NS(=O)(=O)c2ccc(C)cc2[N+](=O)[O-])c2ncccc2c1
Yield: 58.2 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methoxyquinolin-8-amine (Intermediate 23) (120 mg, 0.69 mmol) and 4-methyl-2-nitrobenzenesulfonyl chloride (Intermediate 20) (186 mg, 1.03 mmol) gave the title compound (150 mg, 58%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18])=[CH:13][CH:12]=3)[CH2:6][C:5]=12.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=3)[CH2:6][C:5]=12
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CN2CCn3cnnc3C2)cc1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1ccc(CN2CCn3cnnc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 1-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)phenyl)ethylcarbamate (168 mg, 0.47 mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol) slowly at −78° C. The reaction was stirred at room temperature for 1 h then concentrated and diluted with DCM (10 mL). The solution was stirred with 3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 hour at room temperature. The resin was removed by filtration and washed (2×5 mL) with DCM. The filtrate was concentrated and the crude residue was used to next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][C:17]3[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])=[CH:19][CH:18]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.[O:38]1CCCC1>>[CH3:1][C:2]1([CH3:37])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][C:17]3[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]([NH2:30])=[O:38])=[CH:19][CH:18]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: C1CCOC1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(OCCOCc4cccc(C#N)c4)cc3)ccc2O1
Product: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(OCCOCc4cccc(C(N)=O)c4)cc3)ccc2O1
Temperature: 70 °C

Procedure:
A solution of 3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzonitrile (4.6 g) in tetrahydrofuran (70 ml) was treated with potassium trimethylsilanoate (9.32 g) and heated at 70° C. for 71 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phase washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, eluted with a gradient between dichloromethane and 10% methanol in dichloromethane) to give the title compound (1.01 g). LCMS RT=2.42 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:52]=[CH:51][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:53][CH3:54]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:52]=[CH:51][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:53][CH3:54])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Yield: 47.8 %

Procedure:
A mixture of 0.0628 g (0.19 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0542 g (0.285 mmole) of toluenesulfonic acid monohydrate, 0.0527 g (0.19 mmole) of 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 25 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (90:10:1) and then recrystallization from acetonitrile to give 0.0519 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide (I-255) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CN(C)C=O.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[S:1]1[C:5]2[C:6]([C:10]([Cl:20])=[O:12])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1cccc2nnsc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc2nnsc12

Procedure:
290 g of benzo-1,2,3-thiadiazole-7-carboxylic acid are suspended in 1.6 l of toluene, 3.5 ml of dimethylformamide and 129 ml of thionyl chloride are added and the mixture is stirred at 80°-90° C., the suspension turning into a solution as the release of gas progresses. When the reaction has ended, the solution is cooled and filtered over a little Hyflo, the residue is rinsed with toluene and the filtrate is evaporated. 297 g (93%) of crude acid chloride, which can be further reacted directly, result.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][CH2:2][CH2:3][C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)([OH:8])[CH2:5][CH:6]=[CH2:7])[CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccc(F)cc1
Yield: 38.6 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (760 mg, 3.3 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.0 g, 5 mmol), KI (1.1 g, 6.7 mmol) and K2CO3 (920 mg, 6.7 mmol) in acetonitrile (33 mL) was heated to reflux overnight. The reaction mixture was filtered. The filtrate was condensed to give the crude product, which was purified by preparative TLC to afford (3S)-tert-butyl-3-(3-(4-fluorophenyl) -3-hydroxyhex-5-enylamino)piperidine-1-carboxylate (500 mg, 38%). 1H NMR: (CDCl3): 1.23 (m, 1H), 1.38 (d, 9H), 1.57 (m, 1H), 1.75 (broad, 1H), 1.94 (m, 2H), 2.37 (m, 1H), 2.43 (m, 2H), 2.56 (m, 1H), 2.80 (broad, 3H), 3.49 (broad, 1H), 3.71 (broad, 3H), 4.95 (d, 2H), 5.56 (m, 1H), 6.95 (t, 2H), 7.32 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([CH2:23][CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=3[CH:13]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CC1=Cc2cc(OCCCc3ccccc3)ccc2OC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: A solution of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (5.0 g, 28.4 mmol) in 100 ml of DMF is treated with potassium carbonate (7.85 g, 56.8 mmol) and 1-bromo-3-phenylpropane (6.22 g, 31.2 mmol). The reaction mixture is stirred for 2 days at room temperature. This is partitioned between water and dichloromethane and the aqueous layer is extracted twice with dichloromethane. The combined organic layer is dried (MgSO4), and evaporated. The residue is chromatographed (silica gel, 20% ethyl acetate/hexane) to afford 6-(3-phenylpropyloxy)-2H-1-benzopyran-3-carboxaldehyde, m.p. 71°-73° C., as an oil which crystallizes on standing. The aldehyde is converted to 3-(N-hydroxyaminomethyl)-6-(3-phenylpropyloxy)-2H-1-benzopyran as described above.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2.CN(C)[CH:16]=[O:17].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:16][OH:17])[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2
Reactant: Cc1cn2c(n1)sc1ccccc12
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2sc3ccccc3n2c1CO
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In 100 ml of n-butanol were heated 30.0 g of 2-aminobenzothiazole and 25.0 g of propargyl bromide at 100° C. for 6 hours. After cooling, the precipitated crystals were taken out by filtration and recrystallized from water to give 40.0 g of the intermediate. Next, the intermediate was added to 250 ml of sodium ethoxideethanol solution (Na, 3.3 g). The mixture was heated under reflux for one hour. After completion of the reaction, the solvent was removed and water was added to the residue. The precipitated crystals were taken out by filtration to give 22.4 g of 2-methylimidazo[2,1-b]benzothiazole. The benzothiazole was added to a mixture of 300 ml of dry dimethylformamide and 30.0 ml of phosphorus oxychloride followed by heating at 60° C. for 6 hours. After completion of the reaction, the reaction mixture was poured onto 1 liter of chilled water and then was neutralized with ammonium hydroxide. Then, the precipitated crystals were taken out by filtration. The thus obtained formyl compound, 20.5 g, was suspended in 300 ml of methanol and 1.5 g of sodium borohydride was added to the suspension followed by stirring at room temperature for 2 hours. After methanol was removed, the residue was treated with 200 ml of water and filtered to give 20.0 g of the title compound.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[N:20]=[C:19]2[C@H:28]([NH2:30])[CH3:29])=[CH:14][CH:13]=1)[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH2:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[N:20]=[C:19]2[C@H:28]([NH:30][CH2:7][CH:4]2[CH2:3][CH2:2][S:1][CH2:6][CH2:5]2)[CH3:29])=[CH:16][CH:17]=1)[CH3:10]
Reactant: O=CC1CCSCC1
Reactant: CCOc1ccc(-n2c([C@@H](C)N)nc3cc(F)ccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)NCC3CCSCC3)nc3cc(F)ccc32)cc1
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Tetrahydro-thiopyran-4-carbaldehyde (35.80 g, 275.4 mmol) was added to a solution of compound A2 (80.73 g, 270 mmol) in dichloroethane (700 mL) at −20° C., followed by sodium triacetoxyborohydride (85.84 g, 405 mmol). The mixture was kept at that temperature for 4 h. The solution was diluted with dichloromethane, washed by saturated aqueous sodium bicarbonate, water, brine and dried over anhydrous sodium sulfate The solvent was evaporated and the residue was purified by flash column to yield A3 as a yellow solid (55 g). MS(ESI+) 414.1 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][N:10]=1)=O)C.[NH3:15]>>[C:11]([C:8]1[O:7][C:6]([C:4]([NH2:15])=[O:3])=[N:10][CH:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1ncc(C(C)(C)C)o1
Reactant: N
Product: CC(C)(C)c1cnc(C(N)=O)o1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The mixture of 5-tert-butyl-oxazole-2-carboxylic acid ethyl ester(0.52 g, 2.64 mmol) and NH3 (2.0M solution in MeOH, 6.6 mL, 13.2 mmol) was stirred at RT under N2 for 20 h. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc washed with brine, dried with Na2SO4 and filtered. Removal of the solvents afforded the title compound as a white solid. MS m/z: 169.2 (M+H). Calc'd for C8H12N2O2-168.19
Reaction SMILES: [K+].[C:2]1(=[O:18])[N:6]([CH2:7][CH2:8][S:9]([O-])(=[O:11])=[O:10])[C:5](=[O:13])[C:4]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:3]12.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[C:2]1(=[O:18])[N:6]([CH2:7][CH2:8][S:9]([Cl:20])(=[O:11])=[O:10])[C:5](=[O:13])[C:4]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:3]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Temperature: 0 °C
Yield: 79.3 %

Procedure:
60 g of the compound obtained in step A in 300 ml of toluene are heated to reflux for 1 hour in the presence of 30.7 g of phosphorus pentachloride. 30.7 g of phosphorus pentachloride are added again and refluxing is maintained for 90 minutes. 280 g of ice are added to the reaction medium, the mixture is stirred, and the insoluble matter is filtered off and then washed with ice-cold water. The residue is dried over P2O5 and then recrystallized in dichloroethane to obtain 32 g of the expected product, m.p.=160° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([NH:9][CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1ccc(Cl)nc1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(Cl)nc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (6-chloropyridin-3-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 60% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.82 (t, J=5.8 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.2, 2.5 Hz, 1H), 7.51-7.28 (m, 6H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.39 (d, J=5.8 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 467.0 (M+1).