Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1.S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[NH2:2][C:3]1[CH:8]([C:9]([O:11][CH3:16])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: NC1=NCCCC1C(=O)O
Agent: Cl
Product: COC(=O)C1CCCN=C1N
Temperature: 25 °C
Yield: 46 %

Procedure:
2-Amino-3,4,5,6-tetrahydropyridine-3-carboxylic acid HCl (1.2 g, 6.6 mmol) was suspended in anhydrous methanol (100 ml), and thionyl chloride (0.5 ml, 7 mmol) was added dropwise with stirring at room temperature. The resulting solution was refluxed overnight and then evaporated to dryness in vacuo. The resulting crude white solid was recrystallized from methanol/ether to give white crystals 613 mg (46%) mp 138°-139° C., identified as product by 300MHz nmr and ir 1737 cm-1. Calculated: C 43.64, H 6.8, N 14.55; found: C 43.75, H 6.87, N 14.57.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:23]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[CH:26]=[CH:25][C:24]=1[CH3:32])[CH2:9][C:10]([N:12]([N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CO[C:36](OC)([N:38](C)C)[CH3:37]>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([CH2:9][C:10]([N:12]([N:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22]1)[CH3:13])=[O:11])[C:23]1[CH:28]=[C:27]([C:29]2[O:30][N:38]=[C:36]([CH3:37])[N:31]=2)[CH:26]=[CH:25][C:24]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C)(OC)N(C)C
Reactant: Cc1ccc(C(N)=O)cc1N(CC(=O)OC(C)(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Product: Cc1noc(-c2ccc(C)c(N(CC(=O)OC(C)(C)C)CC(=O)N(C)N3Cc4ccccc4C3)c2)n1
Yield: 75 %

Procedure:
Using the compound (500 mg, 1.11 mmol) of Example 81, step B, and N,N-dimethylacetamide dimethylacetal (2.5 ml), and according to the method of Example 83, step A, the title compound (406 mg, yield 75%) was obtained as a pale-bistered amorphous solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH2:18][CH3:19])([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:18]([NH:17][C:11]1([C:14]([NH2:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:19]
Reactant: CCNC1(C(N)=O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCNC1(C(N)=O)CCNCC1

Procedure:
To a solution of 1-benzyl-4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1f; 7.39 g, 28.3 mmol) in methanol (100 ml) was added 20% Pd(OH)2 on carbon (50% water; 1.48 g). The mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature overnight. The mixture was filtered through a pad of Celite®, and then concentrated to give a colorless solid I-1A-1g (4.84 g, quantitative): +APcI MS (M+1) 172.2; 1H NMR (400 MHz, CD2Cl2) δ 2.89 (ddd, J=12.9, 8.7, 3.3 Hz, 2H), 2.75 (ddd, J=12.9, 6.6, 3.7 Hz, 2H), 2.45 (q, J=7.2 Hz, 2H), 1.95 (ddd, J=13.7, 8.3, 3.7 Hz, 2H), 1.55 (ddd, J=13.7, 6.6, 3.3 Hz, 2h), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[C:33]([F:34])([F:36])[F:35])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1cc(CCl)ccc1OCc1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(C(F)(F)F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (50 mL) at room temperature. The mixture was stirred for 1 h at this temperature and 1-benzyloxy-4-chloromethyl-2-trifluoromethyl-benzene (CAB03050, 1.50 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) and water (30 mL) were added. The mixture was transferred into a separation funnel and washed with water (2×30 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (40 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.87 g (83%). 1H-NMR (400 MHz, d6-DMSO) δ=5.05 (s, 2H), 5.23 (s, 2H), 6.78 (d, J=9.0 Hz, 2H), 7.26 (d, J=8.6 Hz, 1H), 7.30-7.44 (m, 5H), 7.51 (dd, J=8.6, 2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 8.79 (s, 2H). LRMS (FAB+): 450.2 (100, [M+H]+). HRMS (FAB+): 450.15404 C24H19N5OF3 requires 450.154170
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[I-].CS[C:16]1[S:17][CH2:18][C@@H:19]2[CH2:27][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]=12>>[CH3:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:16]1[N:20]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:27][C@H:19]3[CH2:18][S:17]1)[CH:11]=[CH:10][CH:9]=2
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: CSC1=[N+]2c3ccccc3C[C@H]2CS1
Agent: [I-]
Product: Cc1cc2c(N=C3SC[C@@H]4Cc5ccccc5N34)cccc2cn1
Yield: 72.9 %

Procedure:
Following the procedure of Example 1 but starting with 5-amino-3-methylisoquinoline (6.0 g) and (S)-3-methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (12.0 g), (S)-3-[(3-methylisoquinol-5-yl)imino]-9,9a-dihydrothiazolo[3,4-a]indole (8.3 g) is obtained, after recrystallisation from ethanol, in the form of white crystals melting at 182° C. [α]D20 =-92.5±1.5° (c=1, chloroform)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[BrH:11].CS(C)=O>C(O)(=O)C.O>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)c1ccccc1O
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1cc(Br)ccc1O
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-isopropylphenol (2.0 g) in acetic acid (20 mL) was added hydrobromic acid (48%, 10 mL) followed by dropwise addition of DMSO (10 mL). The mixture was stirred another 20 min and diluted with water, extracted with diethyl ether. The combined extract was washed with saturated NaHCO3, water, brine, dried and concentrated to give the product 4-bromo-2-isopropylphenol (2.2 g, HPLC purity 95%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[O:10]1CCOCC1.[F:16][CH2:17][F:18]>[OH-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:10][CH:17]([F:18])[F:16])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: FCF
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(Cl)cc(OC(F)F)n1
Reaction time: 1 h

Procedure:
A suspension of 16.4 g of 2-amino-4,6-dichloropyrimidine in 100 ml of 40% sodium hydroxide solution is stirred for 1 hour at a temperature of 95° to 100° C. After the addition of 200 ml of dioxane, there are added at a temperature of 70° to 75° C., within 1 hour, 20 g of gaseous difluoromethane. The organic phase is separated, and concentrated to about 1/5 of its volume; it is then poured into water and the solid precipitate is removed. The yield is 6 g of 2-amino-4-chloro-6-difluoromethoxy-pyrimidine, m.p. 118° to 119° C. (compound No. 1.7).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([OH:19])=[S:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)O[CH2:29][CH:30]([CH3:32])[CH3:31].Cl.CNO>ClCCl>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][C:17]([O:19][CH2:29][CH:30]([CH3:32])[CH3:31])=[S:18])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=1[OH:11])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(CC(O)=S)cc(C(C)(C)C)c1O
Reactant: CC(C)COC(=O)Cl
Agent: CNO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=S)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 53 %

Procedure:
To 20 ml of a solution of 1.48 g (5 mmol) of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)thioacetic acid (II1) in dichloromethane was added 555 mg (5.5 mmol) of triethylamine and 5 ml of a solution of 750 mg (5.5 mmol) of isobutyl chlorocarbonate in dichloromethane was added dropwise to the resulting mixture over an about 5 minutes period under cooling at -45° C.±5° C. and stirring. The mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 450 mg (5.5 mmol) of N-methyl hydroxylamine hydrochloride and then added dropwise 5 ml of a solution of 1.21 g (12 mmol) of triethylamine in dichloromethane. The mixture was stirred at the same temperature for 30 minutes and then additional 2 hours after removal of the cooling bath. The reaction mixture was poured into 50 ml of a cold 5% aqueous solution of hydrochloric acid and extracted with 50 ml of dichloromethane. The extract was washed twice with 50 ml of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel. The fractions eluted with a mixture of ethyl acetate-n-hexane (2:1) were collected. From the first fraction, 892 mg of isobutyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)thioacetate was obtained as colorless oil in 55% yield and the aimed compound (I1) obtained from the second fraction was recrystallized from a mixture of ether-n-hexane (1:1) to give 350 mg of colorless prismatic crystals in 21.5% yield. Mp. 84°-85° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].ClC([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.C(OCC)(=O)C.[CH3:23][CH2:24][CH2:25][CH2:26]CC.C[N:30](C=O)C>>[NH2:30][C:26]1[CH:25]=[CH:24][CH:23]=[C:14]2[C:15]=1[CH2:16][C@H:11]([OH:10])[CH2:12][CH2:13]2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)C=O
Reactant: CCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Nc1cccc2c1C[C@H](O)CC2
Temperature: 0 °C
Reaction time: 0.29 h
Yield: 53 %

Procedure:
To a stirred solution of stage-c product (5 g, 0.026 mol) in DMF (25 ml, 5 times), potassium carbonate (12.64 g, 0.09 mol, 3.5 eq) was added. Cooled the contents to 0° C., phenyl chloroformate (4.5 g (3.63 ml), 0.023 mol) was added drop wise and stirred the contents for 15-20 min. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.5). On completion of the reaction, filtered the contents and washed with ethyl acetate (100 ml). Filtrate was taken in cold water (150 ml), organic layer was separated and dried over sodium sulfate. The solvent removed under reduced pressure and the crude obtained was purified by column chromatography (silica gel, 20% ethyl acetate/hexane) to yield the titled product as a pale yellow colored solid (4.3 g, 53% yield, mp 142-144° C.).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:48][CH:49]([CH3:70])[C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:48][CH:49]([CH3:70])[C:50](=[O:51])[N:52]2[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:65]([F:66])([F:68])[F:67])[CH2:56][CH2:57]2)=[O:24])=[CH:25][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(N)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 48.2 %

Procedure:
DIPEA (131 mg, 0.17 mL, 0.76 mmol) was added to a stirred solution of 4-Benzyloxy-benzoic acid (58 mg, 0.25 mmol) in DMF (2 mL). HOBT (41 mg, 0.3 mmol) and EDCI (58 mg, 0.3 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propan-1-one (85 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using 60-120 silica gel and 10% MeOH in CHCl3 as eluent) to afford 65 mg (47% yield) of 4-benzyloxy-N-{1-methyl-2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 95%. 1H NMR (CDCl3): δ 7.76 (m, 3H), 7.6 (m, 2H), 7.4-7.3 (m, 5H), 7.1 (d, 1H), 7.0 (d, 2H), 5.22 (s, 2H), 4.2 (d, 1H), 3.82 (m, 2H), 3.7-3.4.(m, 6H), 2.0 (m, 1H), 1.4 (dd, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[O:12]1[CH:13]=[N:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-c2ncon2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2ncon2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of 4-nitrobenzonitrile (1 g, 0.0068 mol) in ethanol (20 mL) and water (8 mL) was added hydroxylamine hydrochloride (1.9 g, 0.0272 mol) followed by sodium carbonate (2.2 g, 0.0204 mol). The resulting mixture was heated to reflux at 85° C. under an atmosphere of nitrogen for 2 hours The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The volatiles were evaporated and the residue was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to get afford 1.2 g (98%) of N-hydroxy-4-nitro-benzamidine. 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 8.24 (d, 2H), 7.97 (d, 2H), 6.03 (s, 2H). To a stirred solution of N-hydroxy-4-nitro-benzamidine (1.2 g, 0.0066 mol) in THF (15 mL) was added triethyl orthoformate (2.93 g, 0.0198 mol). The resulting mixture was cooled to between 0 and 5° C. Boron trifluoride dimethyl ether (0.9 g, 0.0079 mol) was then added dropwise and the resulting mixture was stirred at ambient temperature for 3 hours. Volatiles were evaporated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.65 g (55%) of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole. To a stirred solution of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole (0.2 g, 0.001 mol) in THF (15 mL) was added ammonium chloride (0.214 g, 0.004 mol) in water (5 mL) followed by zinc powder (0.262 g, 0.004 mol) portionwise. The resulting mixture was stirred at ambient temperature for 1 hr and then heated to 65° C. for 5 hours. The mixture was then filtered through celite and the organic layers were concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layers were washed with brine solution, dried over Na2SO4 and evaporated under reduced pressure to afford 0.155 g (92%) of 4-[1, 2, 4]oxadiazol-3-yl-phenylamine. 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 7.7 (d, 2H), 6.7 (d, 2H), 5.8 (s, 2H).
Reaction SMILES: [CH3:1][N+:2]([CH3:4])=[CH2:3].[I-].[CH3:6][C:7]1([CH3:23])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[O:8]1>CC#N.CC(O)=O>[CH3:3][N:2]([CH3:4])[CH2:1][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([B:9]3[O:10][C:11]([CH3:13])([CH3:12])[C:7]([CH3:23])([CH3:6])[O:8]3)[CH:15]=2)[NH:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a suspension of Eschenmoser's salt (0.91 g, 4.9 mmol) in CH3CN (3 mL) and HOAc (1.5 mL) at rt was added a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (1.0 g, 4.1 mmol) in CH3CN (3 mL) dropwise over about 10 min. After about 2 hours, the reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to give crude N,N-Dimethyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]methanamine (0.60 g, 50%); RP-HPLC (Table 1, Method g) Rt 1.39 min; 1H NMR (d6-DMSO, 400 MHz) δ11.26 (br s, 1H), 8.07 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.37 (m, 2H), 3.92 (s, 2H), 2.40 (s, 6H), 1.31 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.C(O)(=O)C.[CH3:23][NH2:24].[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:24][CH3:23])=[CH:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.0 g) and molecular sieves in methanol (20 mL) at room temperature was added acetic acid (0.1 mL) and a solution of methylamine (219 mg) in methanol (1 ml). The reaction mixture was stirred at room temperature for 24 h. Then sodium borohydride (542 mg) was added portionwise and the reaction stirred at room temperature for a further 30 min. The reaction was then quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted into dichloromethane (2×10 mL). The combined organics were washed with brine (20 mL), dried (MgSO4) and reduced in vacuo to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine as a white solid (0.95 g).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13]C1C=C(C=CC=1)C(OO)=O.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.ClCCCl>[Cl:13][CH2:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cccnc1CCl
Reaction time: 72 h
Yield: 11 %

Procedure:
A solution of 9 g of ethyl 2-methylnicotinate in 250 mL methylene chloride is stirred at room temperature and 32 g of 80% metachloroperoxybenzoic acid is added in one portion. The resulting solution is stirred for three days. The precipitated solid is filtered off, and the filtrate is washed with cold, dilute aqueous sodium hydroxide, dried, and concentrated in vacuo to afford the crude N-oxide. This material is digested in 75 mL of 1,2-dichloroethane; 15 mL of phosphorous oxychloride is added, and the solution is heated at reflux overnight. The solution is concentrated in vacuo, and the residue is taken up in methylene chloride and neutralized with aqueous sodium acetate. The organic phase is dried, concentrated in vacuo, and the residue is chromatographed on silica gel using hexane-ethyl acetate mixtures to afford 1.2 g of the title product as an oil having
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([F:11])=[C:9]([F:12])[C:6]([CH2:7][OH:8])=[C:5]([F:13])[C:4]=1[F:14].[C:15]([C:17]([CH3:27])=[CH:18][C@@H:19]1[C@@H:21]([C:22](O)=[O:23])[C:20]1([CH3:26])[CH3:25])#[N:16]>CN(C)C1C=CN=CC=1.ClCCl>[C:15]([C:17]([CH3:27])=[CH:18][C@@H:19]1[C@@H:21]([C:22]([O:8][CH2:7][C:6]2[C:5]([F:13])=[C:4]([F:14])[C:3]([O:2][CH3:1])=[C:10]([F:11])[C:9]=2[F:12])=[O:23])[C:20]1([CH3:26])[CH3:25])#[N:16]
Reactant: COc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=C(C)C#N)C2(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Under a nitrogen atmosphere, 0.49 g of N,N-dicyclohexylcarbodiimide was added to a mixture of 0.50 g of 4-methoxy-2,3,5,6-tetrafluorobenzyl alcohol, 0.43 g of (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid, 0.087 g of 4-dimethylaminopyridine and 7 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.62 g of 4-methoxy-2,3,5,6-tetrafluorobenzyl(1R)trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate represented by the following formula:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:24].[NH4+]>S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)([C:14]([NH2:15])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#CC1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 71 %

Procedure:
To 1-Benzyl-4-(4-chloro-phenylamino)-piperidine-4-carbonitrile (1.97 g, 6.05 mmol) was added concentrated sulfuric acid (50 ml). The reaction stirred at room temperature as an orange homogeneous solution. After 24 hours the reaction was cooled to 0° C. and very slowly poured into concentrated ammonium hydroxide in ice. The precipitate was filtered and washed with water to give a white solid (202 mg, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromobenzene-1-sulfonyl chloride (2.56 g, 10.0 mmol) and triethylamine (1.82 mL, 13 mmol) in DCM (50 mL) was added morpholine (960 mg, 11.0 mmol) dropwise and the mixture was stirred for 30 minutes at room temperature. Then the mixture was concentrated and extracted with EA, washed with 0.1M HCl water solution (2×100 mL), NaHCO3 solution (2×100 mL) and brine, dried and concentrated to give product as a white solid.