Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[CH3:7][C:8]([CH3:19])([C:13](=O)[C:14]([O:16][CH3:17])=[O:15])[C:9]([O:11][CH3:12])=[O:10].C([O-])(=O)C.[Na+]>O>[C:4]([NH:3][N:2]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:8]([CH3:19])([CH3:7])[C:9]([O:11][CH3:12])=[O:10])(=[O:5])[NH2:6]
Reactant: NNC(N)=O
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)C(=NNC(N)=O)C(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
10 g (90 mmol) of semicarbazide hydrochloride, 15.5 g (82 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate and 8.1 g (82 mmol) of sodium acetate were stirred in 135 ml of water at RT overnight and left to stand for two days. The mixture was cooled with ice-water, and the colourless precipitate was filtered off, washed with a little water and dried.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[O:13][CH:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]1)[C:15]#[CH:16].[F-].[K+].O.Cl>C(N(CC)C1C=CC=CC=1)C>[F:12][C:11]1[C:2]([F:1])=[C:3]2[C:4]([CH:16]=[CH:15][CH:14]([CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]3)[O:13]2)=[C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:10]=12
Reactant: C#CC(Oc1cc2c(c(F)c1F)OCCC2)C1CCC(CCC)CC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)c1ccccc1
Product: CCCC1CCC(C2C=Cc3c4c(c(F)c(F)c3O2)OCCC4)CC1

Procedure:
6.0 g (17.2 mmol) of 7,8-difluoro-6-[1-(4-propylcyclohexyl)prop-2-ynyloxy]-chroman are heated at 200° C. for 6 h together with 2.0 g (34.4 mmol) of potassium fluoride in 55 ml of N,N-diethylaniline. After cooling, water is added, and the mixture is acidified using 25% hydrochloric acid. The batch is extracted with MTBE, and the organic phase is washed with saturated sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, 1-chlorobutane), giving 5,6-difluoro-8-(4-propylcyclohexyl)-1,2,3,8-tetrahydropyrano[3,2-f]chromene as a pale-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[C:23]([F:22])([F:32])[F:33])=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Product: O[C@H](CNCc1ccccc1C(F)(F)F)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 2-(trifluoromethyl)benzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=96%, [M+H]+=461.
Reaction SMILES: [BrH:1].Br.[NH2:3][C:4]1[C:9](Cl)=[C:8]([NH2:11])[C:7](Cl)=[C:6](Cl)[N:5]=1.[H][H]>C(O)C.[Pt]=O>[BrH:1].[BrH:1].[NH2:11][CH:8]1[CH2:7][CH2:6][NH:5][C:4](=[NH:3])[CH2:9]1
Reactant: Nc1nc(Cl)c(Cl)c(N)c1Cl
Reactant: [H][H]
Agent: O=[Pt]
Agent: Br
Solvent: CCO
Product: N=C1CC(N)CCN1

Procedure:
2,4-Diamino-3,5,6-trichloropyridine dihydrobromide (1.1 g) and platinum oxide (520 mg) in ethanol (50 mL) were shaken on a Parr hydrogenation apparatus at 55 psi of hydrogen for 48 hours. The contents were filtered and the filtrate was concentrated in vacuo leaving a waxy solid. The solid was triturated with ether/EtOH to give 4-amino-2-iminopiperidine dihydrobromide as a white solid. The analysis of the product was found to be consistent with the proposed structure. MH+=114; 1H NMR (D2O): δ3.80-3.60 (m, 1H); 3.55-3.25 (m, 1H); 3.08-2.95 (m, 1H); 2.76-2.62 (m, 1H); 2.25-2.13 (m, 1H); 1.95-1.80 (m, 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:37]#[N:38])[C:22]3[C:27]([C:28]=2[OH:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=3)=[O:18])[CH2:13][CH2:12][S:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:37]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:28]([OH:29])=[C:19]([C:17]([NH:16][CH2:15][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][S:11](=[O:14])[CH2:12][CH2:13]2)=[O:18])[N:20]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCS(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCS(=O)CC2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of 4-{[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-1-oxo-hexahydro-1λ4-thiopyran-4-carboxylic acid tert-butyl ester (23 mg), TFA (5 mL) and DCM (5 mL) was stirred at rt overnight; then concentrated, the residue was treated with water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (20 mg). LC MS ESI+: 480 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:18][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: COc1ccc(N2CCC(CO)CC2)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(N2CCC(CBr)CC2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanol (300 mg, 1.35 mmol) is dissolved in methylene chloride (10 mL). carbon tetrabromide (561 mg, 1.69 mmol) is added and dissolved. The solution is cooled to 0° C. and triphenylphoshine (529 mg, 2.02 mmol) is added portionwise. The reaction is allowed to come to r.t. and is stirred for 30 min. The volume is then reduced under vacuum to ˜2 ml and purified by flash chromatography on silica gel using 2% methanol/methylene chloride as the eluent to provide 4-bromomethyl-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl. 1H NMR (300 MHz, CD3OD) δ 7.74 (d, 1H), 7.43 (dd, 1H), 6.72 (d, 1H), 3.83 (s, 3H), 3.54 (m, 2H), 3.38 (d, 2H), 2.65 (dt, 2H), 1.94 (m, 2H), 1.75 (m, 1H), 1.44 (m, 2H); MS (EI) 284 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccncc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and pyridine-4-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.50 min; Mass spectrum (ESI+): m/z=382 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]2.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc2cc(CBr)ccc21
Yield: 59.8 %

Procedure:
A solution of tert-butyl 5-methylindole-1-carboxylate (2.07 g, 9.0 mmol) in CCl4 (50 mL) was treated with N-bromosuccinimide (1.60 g, 9.0 mmol) and benzoyl peroxide (75% in H2O, 276 mg, 9.0 mmol), refluxed for 3 h, concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (20:1)] to give the title compound (1.67 g, 60%) as an orange oil: NMR δH (400 MHz, CDCl3) 8.11 (1H, br d, J 8.5 Hz), 6.72 (1H, d, J 3.5 Hz), 7.59 (1H, d, J 1.5 Hz), 7.35 (1H, dd, J 8.5, 1.5 Hz), 6.54 (1H, d, J 4.0 Hz), 4.64 (2H, s) and 1.67 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13]1([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:14]=1.C(=O)([O-])O.[Na+].Cl>CO.C(#N)C>[Cl:22][S:19]([C:15]1[CH:14]=[C:13]([S:23]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[C:7]3[OH:12])(=[O:25])=[O:24])[CH:18]=[CH:17][CH:16]=1)(=[O:20])=[O:21]
Reactant: Nc1cccc2c(O)cccc12
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=S(=O)(Cl)c1cccc(S(=O)(=O)Nc2cccc3c(O)cccc23)c1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a stirred mixture of 2.1 g of 5-amino-1-naphthol (1/2 H2SO4 salt), 4.2 g of benzene-1,3-disulfonyl chloride, 10 ml of acetonitrile and 30 ml of methanol was added portionwise 3.4 g of sodium hydrogen carbonate at a temperature of 0° to 5° C. The mixture was stirred for 1 hour at 0° to 5° C. and poured into 300 ml of a 3% hydrochloric acid aqueous solution. The precipitated crude product was collected by filtration and recrystallized from benzene-ethyl acetate (1:1 by volume) to produce 2.9 g of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>C1COCC1>[C:1]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([B:23]([OH:28])[OH:24])=[CH:14][C:13]=3[CH:17]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(c1ccccc1)c1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1ccccc1)c1ccc2oc(B(O)O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(1-phenylethyl)benzofuran (0.713 g, 3.21 mmol) in 32 mL THF at −78° C. was added 1-butyllithium (1.54 mL, 3.85 mmol) slowly dropwise. The reaction was allowed to stir for 25 min, at which point triisopropyl borate (1.08 mL, 4.72 mmol) was added slowly dropwise. After 0.5 h, the bath was removed and the reaction was allowed to warm to ambient temperature. After 0.5 h, 50 mL 2N HCl was added. The mixture was extracted 2×MTBE, and the combined organics were washed with brine, dried over anhyd. sodium sulfate, filtered, and concentrated in vacuo to give an oil. Treatment with 30 mL hexanes and sonication for 5 min resulted in a white solid which was collected by filtration and dried in vacuo to give 5-(1-phenylethyl)benzofuran-2-ylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49-8.57 (m, 2H), 7.58 (s, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.40 (s, 1H), 7.12-7.32 (m, 6H), 4.26 (q, J=7.5 Hz, 1H), 1.62 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][C:15]2=3)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:35]>CCOC(C)=O.O1CCOCC1>[ClH:35].[C:1]1([O:11][CH2:12][CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:15]2=3)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3cccc4c3CCCC4)c3ccccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1cc2c(c(OCCn3c4c(c5ccccc53)CCNCC4)c1)CCCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.302 mmol) was dissolved in THF (6 mL). 5,6,7,8-Tetrahydronaphthalen-1-ol (0.067 g, 0.454 mmol) was added, and after 25 min di-tert-butyl azodicarboxylate (0.105 g, 0.454 mmol) was added. The reaction mixture was stirred at 40° C. for 5 h. The solvent was removed in vacuo. The crude product was flash chromatographed (9:1 hexane:EtOAt) and tert-butyl 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate was obtained in 22% yield. tert-Butyl 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.028 g, 0.061 mmol) was dissolved in EtOAc (5 mL). 4N HCl in dioxane (2 mL) was added. The reaction mixture was stirred at rt under N2 for 20 h. The solvent was removed in vacuo. The crude product was dissolved in EtOAc (2 mL) and Et2O (3 mL) was added dropwise. The precipitate was collected by filtration, wash with Et2O and dried in vacuo at reduced pressure to yield 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride in 73% yield. 1H NMR (400 MHz, CD3OD) δ 1.66-1.72, 2.35-2.39, 2.65-2.72, 3.20-3.23, 3.36-3.50, 4.23-4.28, 4.61-4.64, 6.51, 6.63, 6.93, 7.10, 7.18, 7.44, 7.50; MS (ESI+) for C24H28N2O m/z 361.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH3:11].[Br:12]NC(=O)CCC(N)=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][Br:12]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COc1cc(C)c(Br)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)c(Br)c(CBr)c1
Temperature: 75 °C
Yield: 92 %

Procedure:
A solution of 2-bromo-5-methoxy-1,3-dimethyl-benzene ((Example 192: step a) 1.01 g, 4.70 mmol) in CCl4 (50 mL) was treated with N-bromosuccinamide and AIBN (catalytic amount) and heated to 75° C. 3.5 h. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product 2-bromo-1-bromomethyl-5-methoxy-3-methyl-benzene (1.27 g, 92%) as a pale orange solid. 1H NMR (CDCl3): δ 6.641 (s, 2H), 4.601 (s, 2H), 3.760 (s, 3H), 2.380 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13]C(=O)C2C=CC=CC=2)[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1c(C)cc(OC(=O)c2ccccc2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCOc1c(C)cc(O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
Then, 26 g of 3-chloro-4-methoxymethoxy-5-methyl-1-benzoyloxybenzene was dissolved in 200 ml of methanol, and the solution was stirred at room temperature for 1 hour, while adding dropwise 60 ml of 10% aqueous potassium hydroxide solution. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was added to 150 ml of water, neutralized with 10% aqueous hydrochloric acid solution, and extracted with 200 ml of diethyl ether. The solvent was removed by distillation under reduced pressure, and the residue was subjected to silica gel chromatography, which afforded 17.4 g of 3-chloro-4-methoxymethoxy-5-methylphenol (96% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=O)=[CH:4][CH:3]=1.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=CCc1ccc(F)cc1
Reactant: CON
Agent: Cl
Product: CON=CCc1ccc(F)cc1
Yield: 43 %

Procedure:
Reaction of 4-fluorophenylacetaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (43% yield). 1HNMR indicated a 1:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.51 (2H, d, J=6.7 Hz, CH2), 3.66 (2H, d, J=5.5 Hz, CH2), 3.88 (3H, s, OCH3), 3.96 (3H, s, OCH3), 6.79 (1H, t, J=5.5 Hz, CH), 7.03 (2H, m, aromatics), 7.19 (2H, m, aromatics), 7.45 (1H, t, J=6.7 Hz, CH).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][NH2:14])=[O:12])=[CH:9][CH:8]=1.[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1>[F:1][C:2]([F:17])([F:18])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]2[O:12][C:19](=[O:20])[NH:14][N:13]=2)=[CH:9][CH:8]=1
Reactant: NNC(=O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]nc(-c2ccc(OCCCC(F)(F)F)cc2)o1

Procedure:
4.09 g of 4-(4,4,4-trifluorobutoxy)benzoic acid hydrazide, dissolved in 56 ml of hot toluene, are introduced into a 100 ml three-necked flask under nitrogen at room temperature. 12.1 ml of phosgene dissolved in toluene (1.93M) are then added dropwise. The mixture is heated to 100°-110° C. for 1 h 30 min and the excess phosgene is then stripped off using a stream of nitrogen. The reaction medium is cooled and the precipitate formed is filtered off and dried under vacuum. 4.4 g of product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[CH2:11])[CH2:9][OH:10])[CH:5]=[N:6][CH:7]=1.[OH-:12].[Na+].OO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: C=C(CO)c1cncc(Br)c1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC(CO)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.7 %

Procedure:
To a stirred solution of 2-(5-bromopyridin-3-yl)prop-2-en-1-ol (0.600 g, 2.79 mmol) in tetrahydrofuran (5 mL) at 0° C. under nitrogen was added borane-methyl sulfide complex (0.85 g, 11 mmol). The reaction mixture was heated to 25° C. and stirred for 5 h. The reaction mixture was cooled to 0° C. and 1.0 N sodium hydroxide (0.8 mL) was added drop wise followed by the addition of hydrogen peroxide (1.0 mL, 35 wt % solution in water). The reaction mixture was stirred at 0° C. for 2 h then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic portions were combined, washed with water, aqueous sodium sulfite and brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. 2-(5-Bromopyridin-3-yl)propane-1,3-diol (0.29 g, 44.7%) was isolated by silica gel column chromatography using 50% EtOAc in hexanes as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.53 (d, 1H, J=2 Hz), 8.43 (d, 1H, J=4.8 Hz), 4.92 (s, 1H), 4.69 (t, 1H, J=4.4 Hz), 3.71-3.64 (m, 2H), 3.62-3.58 (m, 2H), 2.87 (t, J=6.4 Hz). LCMS Method W: retention time 0.80 min; [M+1]=232.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([C:17]#[N:18])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>C(OCC)C.C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:17](=[NH:18])[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[CH:15]=[CH:16][C:7]([NH:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=2[O:2][CH3:1])=[N:8]3)=[CH:26][CH:25]=1
Reactant: COc1ccccc1CNc1ccc2c(C#N)cccc2n1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2c(C(=N)c3ccc(F)cc3)cccc2n1
Temperature: 0 °C
Yield: 41.3 %

Procedure:
To a cooled (ice bath) and stirred suspension of 2-(2-methoxy-benzylamino)-quinoline-5-carbonitrile (289 mg, 1.0 mmol) in diethylether (3 ml) and THF (1 ml) was added drop wise a 1M solution of 4-fluorophenyl-magnesium bromide (4 ml, 4.0 mmol), the reaction mixture was heated under reflux conditions for 24 h and poured into ice-water (15 ml). 2N HCl (5 ml) was added, the mixture was stirred at room temperature for 10 min, 3 N NaOH (5 ml) was added and the mixture was extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (2×20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white solid (159 mg, 41%).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][O: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][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH2:1]([O:8][CH:9]([CH2:12][O: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][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:10][O:11][S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COS(=O)(=O)c1ccc(C)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
In 5 ml of pyridine were dissolved 1 g (2.3 mmole) of 2-O-benzyl-3-O-octadecylglycerol and 1.144 g (6.0 mmole) of tosyl chloride, and the solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and 20 ml of 10% aqueous hydrogencarbonate solution and 20 ml of ether were added to the residue, followed by shaking thoroughly. The ether layer was separated, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by 15 g of silica gel, with n-hexane-ethyl acetate (9:1) used as an eluent, to give 1.2 g (yield of 88.6%) of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH2:13][CH3:14]>>[CH2:12]([NH:15][C:16]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCN=C=O
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Product: CCCNC(=O)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6u (96% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and n-propyl isocyanate as a white solid. IR(KBr) 3294, 1709, 1635, 1520 cm−1; 1H-NMR (CDCl3) δ1.00 (t, J=7.3 Hz, 3H), 1.61-1.71 (m, 2H), 3.38-3.44 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.79 (br s, 1H); ESIMS m/e 271 and 273 (M++1, 35Cl and 37Cl).
Reaction SMILES: C(O[C:4]([S-:6])=[S:5])C.[Na+].Cl[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>CN(C)C=O>[SH:6][C:4]1[S:5][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Sc1nc2ccccc2s1
Temperature: 80 °C
Yield: 94.4 %

Procedure:
A solution of 216.2 g of sodium ethylxanthate in 250 ml of dimethylformamide is added dropwise to a solution, heated to 140°-150° C., of 63.8 g of 2-chloroaniline in 150 ml of dimethylformamide in the course of one hour, under a nitrogen atmosphere. During this addition, the internal temperature is kept at 150° C. by removing some of the distillate. The reaction mixture is then subsequently stirred under reflux for about 12 hours, cooled to about 80° C. and stirred into 1.2 l of ice-water. The resulting cloudy solution is acidified and the 2-mercaptobenzothiazole which has precipitated is filtered off. After washing and drying, 79 g (94.6% of theory) of 2-mercaptobenzothiazole of melting point 179°-180° C. are obtained.