Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH2:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)[CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:29]3[CH:30]=[CH:31][C:26]([CH2:25][O:24][CH2:22][CH3:23])=[CH:27][CH:28]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: CCOCc1ccc(I)cc1
Product: CCOCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-ethoxymethyl-4-iodo-benzene (for synthesis: M. Schamchal et al; J. Gen. Chem. USSR (Engl. Transl.); 34; 1964; 1830). White solid. MS (ESI): 463.2 MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]2[C:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][C:13]=2[N:14]\1[CH2:15][CH:16]([CH3:18])[CH3:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7](=[S:37])/[N:9]=[C:10]1\[S:11][C:12]2[C:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][C:13]=2[N:14]\1[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C(=S)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of Example 89G (0.25 g, 0.61 mmol) in toluene (10 mL) was added Lawesson's Reagent (0.25 g, 0.61 mmol, Aldrich) and stirred at 80° C. for 2 hr. The reaction mixture was then cooled and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in hexanes) to afford 0.18 g (70%) of the title compound. MS (ESI+) m/z 425 (M+H)+
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[N:6][CH2:7][CH:8]=[CH2:9])[CH:2]=[CH2:3].[N:10]#[C:11][NH2:12]>ClCCCl>[CH2:1]([NH:4][C:5]([NH:6][CH2:7][CH:8]=[CH2:9])=[N:12][C:11]#[N:10])[CH:2]=[CH2:3]
Reactant: N#CN
Reactant: C=CCN=C=NCC=C
Solvent: ClCCCl
Product: C=CCNC(=NC#N)NCC=C

Procedure:
A solution of 0.7 g N,N'-bis(allyl)carbodiimide in 10 ml of 1,2-dichloroethane is reacted with 0.27 g of cyanamide and the reaction mixture is worked up as described in Example 4. Recrystallisation from diethyl ether yields a crystalline product which melts at 66.5°-67.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:17]1([C:20]([NH2:28])([C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH3:21])[CH2:19][CH2:18]1>>[CH:17]1([C:20]([NH:28][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])([C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH3:21])[CH2:19][CH2:18]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(Cl)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (27.7 mg, 35%) as colorless oil; MS (ESI, m/z): 405.0 (M+H+).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH3:13][C:14]1[N:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][CH:15]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Cc1cccc(C=O)n1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: Cc1cccc(C=NNC(=S)NC2CC3C=CC2C3)n1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.545 mmol) and 6-methyl-2-pyridine carboxaldehyde (66 mg, 0.545 mmol) similar to Example 3 and isolated as a pale white solid (83 mg, 53%). 1H NMR (CDCl3): 10.46 (s, 1H), 8.00 (s, 1H), 7.68-7.61 (m, 3H), 7.15 (dd, J=2.1, 6.3 Hz, 1H), 6.22-6.13 (m, 2H), 4.28 (s, 1H), 3.07 (s, 1H), 2.94 (s, 1H), 1.91-1.83 (m, 1H), 2.57 (s, 3H), 1.64 (d, J=9.0 Hz, 1H), 1.53 (d, J=8.7 Hz, 1H), 1.49-1.43 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27]>>[OH:28][C:26]([CH3:29])([CH3:27])[CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(O)CN
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(C)(C)O)cn1
Yield: 49 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of 2-aminoethyl isopropylether, to the title compound (215 mg, 49%) which was obtained as a white solid. MS: m/e=380.0 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[CH3:17][C:16]1([CH3:18])[C:19]([CH3:21])([CH3:20])[O:12][B:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:13])[F:14])[CH:5]=2)[O:11]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(C)(O)C(C)(C)O
Product: CC1(C)OB(c2cccc(OC(F)(F)F)c2)OC1(C)C
Yield: 25 %

Procedure:
The title compound (25%, oil) was prepared from 3-trifluoromethoxyphenylboronic acid and pinacol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[Br:11][CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:14][CH2:13][CH2:12][Br:11])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: BrCCCBr
Reactant: c1ccc2c(c1)NCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCN1CCOc2ccccc21
Temperature: 70 °C

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (3.0 g, 1 eq, 22.2 mmol), 1,3-dibromopropane (22.5 ml, 10 eq, 222 mmol) and anhydrous sodium carbonate (7.05 g, 3 eq, 66.6 mmol) in dry DMF (200 ml) was heated at 70° C. for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to yield the title compounds as liquid mass (2.6 g, 47%).
Reaction SMILES: N1C=CC=CC=1.[N:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[NH2:13][C:12]1[N:7]=[C:8]([NH:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccc(N)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(N)n1
Temperature: 0 °C
Yield: 50 %

Procedure:
Pyridine (0.130 mL, 1.60 mmol) was added to pyridine-2,6-diamine (350 mg, 3.21 mmol) in DCM (6.4 mL). The reaction mixture was cooled to 0° C., and then methanesulfonyl chloride (0.124 mL, 1.60 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-100% acetone/hexanes, linear gradient) to afford N-(6-aminopyridin-2-yl)methanesulfonamide (˜50% purity) that was used without further purification. MS ESI calc'd. for C6H10N3O2S [M+H]+ 188. found 188.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22][CH:21]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:23]4[C:24]5[C:29](=[N:28][CH:27]=[CH:26][CH:25]=5)[N:20]=[CH:21][CH:22]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Reactant: O=Cc1ccnc2ncccc12
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4ccnc5ncccc45)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 1,8-naphthyridine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 9.15 (dd, J=4.1, 1.7 Hz, 1H), 9.07 (d, J=4.6 Hz, 1H), 8.69 (dd, J=8.3, 1.66 Hz, 1H), 7.99 (s, 1H), 7.69-7.65 (m, 1H), 7.46 (d, J=4.6 Hz, 1H), 5.00-4.93 (m, 1H), 4.14 (s, 3H), 3.26 (t, J=8.3 Hz, 1H), 3.03 (d, J=9.5 Hz, 1H), 2.92-2.90 (m, 1H), 2.80-2.76 (m, 1H), 2.52-2.43 (m, 1H), 1.50-1.46 (m, 6H), 1.20 (d, J=6.6 Hz, 3H). MS: (M+H m/z=404.1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=2)[O:21][N:20]=1)(=[O:12])=[O:11].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C.ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]=[O:33])=[CH:30][CH:31]=2)[O:21][N:20]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(c1nc2ccccc2[nH]1)N1CCCCC1c1noc(COc2ccc(CO)cc2)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1ccc(OCc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Tetrapropylammonium perruthenate (14.4 mg) was added to a stirred suspension of 4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)phenylmethanol (384 mg) [see Preparation 21], N-methylmorpholine oxide (166 mg) and 4 Å molecular sieves in 10% v/v acetonitrile/dichloromethane (4 ml). The reaction mixture was stirred for 1 hour after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate to afford 4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzaldehyde (342 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]O)=[CH:4][N:3]=1.[Br:14]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.[OH-].[Na+]>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][Br:14])=[CH:4][N:3]=1
Reactant: Nc1ncc2ncn(CCO)c2n1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Nc1ncc2ncn(CCBr)c2n1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
17.92 g (0.1 mole) of 2-amino-9-(2-hydroxyethyl)purine was completely dissolved in 400 ml of acetonitrile, to which 84.42 g (0.20 mole) of dibromotriphenylphosphine was then added. The mixture was stirred for 5 hours at a temperature of 30-40° C. After completion of the reaction, 300 ml of water was added to the reaction product. The resulting solution was neutralized with aqueous sodium hydroxide solution and extracted four times with 500 ml portions of a mixed solution of chloroform and methanol (4:1). The organic layer was collected, and dried with anhydrous magnesium sulfate, followed by filtration and washing. The resulting filtrate was concentrated under reduced pressure, and crystallized from chloroform, 22.03 g (91%) of white 2-amino-9-(2-bromoethyl)purine.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[S:10](=[O:12])(=[O:11])[C:4]=2[CH:3]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.[Li]CCCC.Cl>C1COCC1>[C:16]([O:15][C:13]([N:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:20]=[CH:21][C:2]([B:22]([OH:27])[OH:23])=[CH:3][C:4]=2[S:10]1(=[O:12])=[O:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2S1(=O)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2S1(=O)=O
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a solution of the product obtained in Step F above (21.6 g, 57.3 mmol) and 40 ml of triisopropyl borate in 210 ml of THF, cooled to −65° C. and under N2, there are added dropwise 90 ml (143 mmol) of 1.6M nBuLi solution. The reaction mixture is stirred for 1 hour at −65° C. and allowed to return to ambient temperature. After stirring for 1 hour, the solution is cooled in an ice bath and hydrolysed by adding 320 ml of 0.5M HCl solution. After extracting 3 times with CH2Cl2, the organic phase is washed with brine, dried over MgSO4 and evaporated. The residue is taken up in heptane and, after evaporation, is triturated in heptane and filtered to yield the title product.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)=[NH:4].[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])N>>[Br:18][C:19]1[CH:20]=[C:21]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: CS(=O)(=O)NCCNc1nonc1C(=N)NO
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-bromo-4-fluoroaniline [Oakwood Products, Inc., product #013091] as the starting materials. LCMS for C12H15BrFN6O4S (M+H)+: m/z=437.0, 439.0. 1H NMR (400 MHz, DMSO-d6): δ 11.49 (s, 1H), 8.90 (s, 1H), 7.17 (m, 2H), 7.09 (dd, J=6.3, 2.5 Hz, 1H), 6.26 (t, J=6.1 Hz, 1H), 3.33 (m, 2H), 3.13 (q, J=6.0 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH:26](OC)OC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CN(C=O)C>C1C=CC=CC=1>[C:1]([N:9]1[C@@H:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:17][CH:24]1[O:25][CH3:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1OC(OC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 103 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
[R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (1.16 mmol) was suspended in benzene (10 ml), and trimethoxymethane (3.44 mmol) and PPTS (72 mg) were added. Heating to reflux (103° C.) did not dissolve the starting compound. 2 ml of DMF were then added so that most of the starting compound dissolved, although the solution remained somewhat turbid. The flask was equipped with a Soxhlet extractor. The thimble of the extractor was filled with 4 Å mol. sieves. After 1 hour, and approximately 3 to 4 cycles in the Soxhlet extractor, TLC showed consumption of the starting material, and a new major spot of the title product. It was diluted with EtOAc, washed with NaHCO3 and H2O, dried and the solvent removed. NMR showed the presence of the title product and a small impurity. The product was purified on HPLC (hexane:ethyl acetate, 3:1) to give 358 mg (87%) of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH2:24])=[S:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][CH:26]=[C:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:24]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: COc1ccc(N2CCN(c3ccc(NC(N)=S)cc3)CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N2CCN(c3ccc(Nc4nc(-c5ccccc5)cs4)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
A mixture of 5 parts of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea, 3 parts of 2-chloro-1-phenylethanone, 1.7 parts of sodium acetate and 100 parts of acetic acid was stirred for 4 hours at 80° C. After cooling, the reaction mixture was evaporated and the residue was stirred in 130 parts of dichloromethane. The whole was neutralised with a sodium hydrogen carbonate solution. The precipitated product was filtered off, washed with water and dichloromethane and crystallized from 1,4-dioxane. The product was filtered off and dried, yielding 4.5 parts (69.6%) of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4-phenyl-2-thiazolamine; mp. 269.7° C. (int. 2).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:3]1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1)([O-:14])=[O:13]>C(Cl)(Cl)Cl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:22](=[O:21])[C:17]3=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:25][CH:24]=[C:18]3[C:19]2=[O:20])[CH2:3][CH2:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCCCN1CCC(N)CC1
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)CC1

Procedure:
4.69 Grams of 4-amino-1-n-butylpiperidine in 100 milliliters of chloroform were added to a suspension of 5.79 grams of 4-nitrophthalic anhydride in 75 milliliters of chloroform and the solution was evaporated to dryness. 40 Milliliters of acetic anhydride were added and the mixture was then heated on a steam bath for half an hour. The excess acetic anhydride was evaporated off and the residue dissolved in 40 milliliters of methanol and ethereal hydrogen chloride was added to give a solid which was collected giving 2.50 grams of the title compound as the monohydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@@H]2CNCCO2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
(R)-2-(6-Methoxy-pyridin-3-ylmethyl)-morpholine-4-carboxylic acid tert-butyl ester (194 mg, 0.63 mmol) was dissolved in dichloromethane (2 mL), cooled to 0° C. and treated with TFA (1 mL). The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was taken up in dichloromethane and extracted with 1M NaOH. The mixture was extracted 3 times with dichloromethane. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to afford (R)-2-(6-methoxy-pyridin-3-ylmethyl)-morpholine (130 mg, 99%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.52-2.63 (m, 2H) 2.65-2.75 (m, 1H) 2.75-2.81 (m, 1H) 2.81-2.91 (m, 2H) 3.49-3.63 (m, 2H) 3.85 (ddd, J=11.28, 3.22, 1.34 Hz, 1H) 3.91 (s, 3H) 6.68 (d, J=8.33 Hz, 1H) 7.44 (dd, J=8.60, 2.42 Hz, 1H) 7.99 (d, J=2.15 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([Cl:10])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([Cl:10])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc(CO)c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1c(Br)cnc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
To a solution of (5-bromo-3-chloro-4-methylpyridin-2-yl)methanol (255.6 mg; 1.081 mmol) in methylene chloride (8 mL; 124.8 mmol) was added Dess-Martin periodinane (0.5655 g; 1.293 mmol). The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with additional dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-80% ethyl acetate in dichloromethane) to yield 226.5 mg (89%) of the title compound. LCMS (ESI): M+H=234.2; 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 8.75 (s, 1H), 2.63 (s, 3H).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C:7]1[CH:57]=[CH:56][C:10]([O:11][CH2:12][C@@H:13]([OH:55])[CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:54]=[CH:53][C:21]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[CH:36][C:35]=4[O:51][CH3:52])=[O:30])[CH2:25][CH2:24]3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:52][O:51][C:35]1[CH:36]=[C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:38]=[CH:39][C:34]=1[CH2:33][CH2:32][NH:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][NH:15][CH2:14][C@H:13]([OH:55])[CH2:12][O:11][C:10]3[CH:56]=[CH:57][C:7]([OH:6])=[CH:8][CH:9]=3)=[CH:54][CH:53]=2)[CH2:24][CH2:25]1)=[O:30]
Reactant: COc1cc(OCCCOc2ccccc2)ccc1CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(OCCCOc2ccccc2)ccc1CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 59.2 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl (diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]-amino}ethyl)anilino]-N-[2-methoxy-4-(3-phenoxypropoxy)phenethyl]-1-piperidinecarboxamide (0.25 g, 0.26 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol) to give the title compound (0.11 g, 0.154 mmol).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH2:20][CH2:21][C:22]([NH:24][NH2:25])=[O:23])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:19][C:16]([C:13]1[CH:12]=[C:11]([CH2:20][CH2:21][C:22]2[O:23][C:1](=[S:2])[NH:25][N:24]=2)[CH:10]=[C:9]([C:6]([CH3:5])([CH3:7])[CH3:8])[C:14]=1[OH:15])([CH3:17])[CH3:18]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 15.8 %

Procedure:
Thiophosgene (0.55 mL, 6.80 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (2.0 g, 6.8 mmol) in tetrahydrofuran (200 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a heavy oil which is crystallized from ethyl acetate/hexane. The product is chromatographed on a column of silica with ethyl acetate/dichloromethane (5/95) and recrystallized from dichloromethane/hexane to afford 0.36 g (16%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]-1,3,4-oxadiazole-2(3H)-thione, mp 164.5°-165.5° C.