Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:14]([F:17])([F:16])[F:15])=[N:5][N:6](C)[C:7]=1[O:8][CH:9]1[CH2:12][O:11][CH2:10]1.NC(N)=S.[CH3:22][S:23]([C:26]1[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][N:27]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:31][C:29]1([CH3:32])[O:28][N:27]=[C:26]([SH:23]([CH2:2][C:3]2[C:4]([C:14]([F:17])([F:16])[F:15])=[N:5][NH:6][C:7]=2[O:8][CH:9]2[CH2:12][O:11][CH2:10]2)[CH3:22])[CH2:30]1
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1OC1COC1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[SH](Cc1c(C(F)(F)F)n[nH]c1OC1COC1)C1=NOC(C)(C)C1
Yield: 33.8 %

Procedure:
4-Bromomethyl-1-methyl-5-(oxetan-3-yloxy)-3-trifluoromethyl-1H-pyrazole (10.1 g, 32.2 mmol) and thiourea (2.7 g, 35.5 mmol) were stirred in ethanol (100 ml) at room temperature until the solids were dissolved. 3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (6.28 g, 35.5 mmol) and potassium carbonate (4.91 g, 35.5 mmol) were added and the mixture was heated under reflux for 2 hours. The mixture was concentrated and purified by chromatography (eluent: ethyl acetate/hexane) to give the product as a white solid (4 g, 34% yield over two steps).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:18][C:19]1([CH3:45])[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[C:21](=[CH:22][C:23]([O:41][CH2:42][CH2:43][CH3:44])=[C:24](/[C:35](/[CH3:40])=[C:36](/[F:39])\[CH:37]=O)[CH:25]=2)[O:20]1>>[CH3:18][C:19]1([CH3:45])[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[C:21](=[CH:22][C:23]([O:41][CH2:42][CH2:43][CH3:44])=[C:24](/[C:35](/[CH3:40])=[C:36](/[F:39])\[CH:37]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=2)[O:20]1
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(c1ccccc1)=CC(C)(C)O2
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure O, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (237 mg, 0.83 mmol) and (2E)-3-(2,2-dimethyl-4-phenyl-7-propoxy-2H-chromen-6-yl)-2-fluoro-but-2-enal (Compound 102, 107 mg, 0.29 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:10]2[C:9]([S:21][CH3:22])=[N:8][N:7]3[C:2]([NH2:24])=[CH:3][C:4]([CH3:23])=[N:5][C:6]=23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(F)cc1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-3-(4-fluoro-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-fluoro-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([S:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[NH2:12][C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8][CH2:9][CH2:10][OH:11]
Reactant: Nc1cccc(SCCO)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(SCCO)c1N
Yield: 86.2 %

Procedure:
2-(3-Amino-2-nitro-phenylsulfanyl)-ethanol (1.02 g, 4.8 mmol) was reduced by hydrogenation using 45 psi of H2 with 10% Pd—C (180 mg) in EtOAc (25 mL) for 6 h. After filtering through Celite, solvent was removed in vacuo. Purification by silica gel chromatography (EtOAc) gave 762 mg (87%) of 2-(2,3-diamino-phenylsulfanyl)-ethanol as a faintly yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.98 (dd, 1H, J=7.5, 1.5 Hz), 6.60–6.72 (m, 2H), 3.65 (t, 2H, J=5.7 Hz), 3.55 (br s, 5H), 2.91 (t, 2H, J=5.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[O:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][N:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[C:15](=[N:16][N:17]([CH2:28][C:29]4[O:30][C:31]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[N:32][N:33]=4)[N:18]=3)[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: ClCc1nnc(-c2ccccc2)o1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3nn(Cc4nnc(-c5ccccc5)o4)nc23)c1
Reaction time: 16 h

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (100 mg, 0.328 mmol), cesium carbonate (107 mg, 0.328 mmol) and 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole (64 mg, 0.328 mmol) were combined and suspended in DMF (2 mL). After 16 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (1 mL) and extracted with EtOAc (2×25 mL). The combined organic fractions were evaporated under reduced pressure. The resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. The product fractions were concentrated to yield the title compound. 1H NMR (DMSO-d6) δ 8.01 (d, J=9.1 Hz, 1H) 7.92 (d, J=8.6 Hz, 2H), 7.72 (m, 1H), 7.68 (m, 1H), 7.60 (m, 5H), 6.50 (s, 1H). HRMS (M+1)=463.0464.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32]>CO.O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)O
Reaction time: 0.08 h

Procedure:
5 g of sunitinib base were suspended in 100 ml of methanol. 1.684 g of Malic acid dissolved in 15 ml of water was added at RT. A partial dissolution of the mixture was observed and after 5 minutes there was the formation of a precipitate. The suspension was filtered and washed with 50 ml methanol. Dried at 50° C. under vacuum for 16 h.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)#[N:2].CS(C)=[O:20].[OH-].[Na+].OO>C(O)C.O>[NH2:2][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)=[O:20]
Reactant: COC(=O)c1ccc(C#N)c(OC2CCC2)c1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(C(=O)O)cc1OC1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of methyl 4-cyano-3-(cyclobutyloxy)benzoate (0.051 g, 0.23 mmol) in 2 ml of ethanol was added 0.5 ml of DMSO, 1 ml of 1N aqueous sodium hydroxide, 1 ml of 30% aqueous hydrogen peroxide, and the reaction mixture was stirred at RT for 18 hrs. The reaction mixture was diluted with 10 ml of water and the aqueous solution extracted three times with ethyl acetate (20 ml). The aqueous layer was acidified to pH 3-4 by portion-wise addition of aqueous hydrochloric acid, then extracted with ethyl acetate (3×20 mL). The organic solution was rotary evaporated to dryness and dried in vacuo to provide 4-(aminocarbonyl)-3-(cyclobutyloxy)benzoic acid (0.026 g, 50%). 1H NMR (400 MHz, DMSO-d6): 13.25 (s, 1H), 7.80 (d, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.55 (d, 1H), 7.41 (s, 1H), 4.88-4.85 (m, 1H), 2.44-2.43 (m, 2H), 2.18-2.14 (m, 2H), 1.99-1.73 (m, 2H). MS (EI) for C12H13NO4: 236 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Cl:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([C:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)=[O:7])[CH2:26][CH2:25]1
Reactant: Cc1cccc(N2CCNCC2)c1Cl
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(c3cccc(C)c3Cl)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
3,4,5-Trimethoxybenzoyl chloride (2.03 g, 8.8 mmol) in dichloromethane (10 mL) is added dropwise to a solution of 2-chloro-3-methylphenyl piperazine (1.98 g, 8.0 mmol) and triethylamine (4.5 mL, 32.0 mmol) in dichloromethane (90 mL) and stirred for 2 hours at room temperature. The reaction mixture is washed with water, dried (magnesium sulfate), and concentrated in vacuo. The resulting solid is purified by medium pressure liquid chromatography (MPLC) on silica gel eluting with 40% ethyl acetate/hexane to give 2.52 g of the title compound as a white solid; mp 156-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:18]([O:21][CH2:22][CH3:23])([CH3:20])[CH3:19])[C:13]([O:15]CC)=[O:14])[N:4]=1.[OH-].[Na+]>C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:18]([O:21][CH2:22][CH3:23])([CH3:19])[CH3:20])[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: CCOC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(C)(C)C(Oc1nc(OC)cc(OC)n1)C(=O)O
Reaction time: 1 h
Yield: 84.9 %

Procedure:
That is, to Compound 50 (32.8 g, 0.1 mol) prepared in the above (1) dissolved in ethanol (100 ml) was added 5N sodium hydroxide (40 ml), and the mixture was stirred for one hour. Subsequently, ethanol was removed under reduced pressure, 5N hydrochloric acid (50 ml) was added to the residue obtained, and the residue was extracted with chloroform. The chloroform layer was washed with water and dried, and then chloroform was removed under reduced pressure to obtain 25.5 g (yield: 85.0%) of the title compound as white crystals.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:53][CH:54]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C.C(OCC)C>[CH:54]([NH:53][C:12]([C@@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.51 g, 2.0 mmol, Example 1, Step B) was dissolved in dry DMF (6 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.74 g, 2.0 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; aminodiphenylmethane hydrochloride (0.43 g, 2.0 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc-hexanes afforded 0.67 g (82%) of the pure titled compound as a white solid: mp 180-181° C. APCI-MS m/z 422.3 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Br:23][C:24]1[C:29](F)=[CH:28][C:27]([NH2:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1>O>[Br:23][C:24]1[C:29]([O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:28][C:27]([NH2:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(N)c([N+](=O)[O-])cc2Br)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
5.2 g of 4-methanesulfonyl-phenol and 5.7 g of potassium carbonate were added in order to an N,N-dimethylformamide (50 ml) solution of 6.4 g of 4-bromo-5-fluoro-2-nitrophenylamine, and the reaction liquid was stirred at 120° C. for 3 hours. 200 ml of water was added to the reaction liquid, and the precipitated solid was taken out through filtration and dried to obtain the entitled compound as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:32]([C:27]3[C:28]4[C:23](=[C:22]([N:21]([CH3:36])[CH3:20])[CH:31]=[CH:30][CH:29]=4)[CH:24]=[CH:25][CH:26]=3)(=[O:34])=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCCn3cnc4c(N)nc5ccccc5c43)cccc12
Temperature: 60 °C

Procedure:
A suspension of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 2.0 mmol) in pyridine (250 mL) was warmed to 60° C. to dissolve the amine. The solution was allowed to cool to about 30° C. and then 5-dimethylamino-1-naphthalenesulfonyl chloride (0.5 g, 1.8 mmol) was slowly added. After 1 hour 0.3 g of 5-dimethylamino-1-naphthalenesulfonyl chloride was added. The reaction mixture was warmed to 60° C. and maintained at that temperature overnight. The reaction mixture was concentrated under vacuum. The residue was recrystallized from propyl acetate to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonamide as a solid, m.p. 200–201° C.
Reaction SMILES: [Cl-].[NH4+].CO.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-])=O>O.C1COCC1.[Zn]>[N:14]1([C:11]2[CH:10]=[CH:9][C:8]([NH2:5])=[CH:13][CH:12]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
Ammonium chloride (1.2 g, 23.0 mmol) in water (4.5 mL) then MeOH (9 mL) were added to a stirred solution of 4-(4-nitro-phenyl)-morpholine (480 mg, 2.3 mmol) in THF (9 mL). Zinc powder (1.2 g, 18.4 mmol) was then added portion wise and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered over celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 316 mg (77%) of 4-morpholin-4-yl-phenylamine. 1H NMR: (DMSO-d6): δ 6.7 (m, 2H), 6.5 (m, 2H), 4.6 (s, 2H), 3.7 (t, 4H), 2.8 (t, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[I:11]I.S([O-])([O-])=O.[Na+].[Na+]>CO.O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[C:3]=1[I:11]
Reactant: Oc1ccc2ncsc2c1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc2ncsc2c1I
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
6-Hydroxy-benzothiazole (0.39 g) and iodine (1.32 g) were dissolved in methanol/water (15 ml/5 ml) to prepare a solution which was then stirred at room temperature for 2 days. An aqueous sodium sulfite solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6-hydroxy-7-iodo-benzothiazole (211 mg, yield 29%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10]C)=[O:8].[OH-].[Na+].C(Cl)(Cl)=[O:16].C1(C)C=CC=CC=1>CO>[CH3:12][C:5]1[C:6]2[C:7](=[O:8])[O:9][C:10](=[O:16])[NH:1][C:2]=2[S:3][CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1c(C)csc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1csc2[nH]c(=O)oc(=O)c12
Yield: 59 %

Procedure:
A mixture of ethyl 2-amino-4-methylthiophene-3-carboxylate (5 g, 0.03 mol) in methanol (25 ml) and aq. 2M sodium hydroxide (20.24 ml, 0.04 mol) was heated under reflux for 4 h. After cooling the solvents were evaporated, the residue dissolved in water (30 ml) and a 20% solution of phosgene in toluene (24 ml, 0.05 mol) added dropwise with ice cooling. After a further 30 min the solid which had precipitated was filtered, washed with water then ether, and dried to give the title compound 2.93 g (59%). 1H NMR (d6-DMSO) δ 2.31 (3H, s), 6.78 (1H, s), 12.50 (1H, br. s).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=2[F:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=2[F:20])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2cc(F)c(C(=O)O)cc2F)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)N1CCC(c2cc(F)c(C(=O)O)cc2F)CC1

Procedure:
A solution of 0.84 g (3 mmol) of 1-acetyl-4-(4-carboxy-2,5-difluorophenyl)-1,2,3,6-tetrahydropyridine in 250 ml of acetic acid with 0.5 g of 10% Pd/c catalyst was hydrogenated at 50 psi. The title compound was isolated after filtration of the catalyst, evaporation and crystallization from acetic acid-water, mp 206°-207° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:18](O)(C)C>C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:10]=1)=[O:5])([CH3:18])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(Cl)c2)cn1
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)OC(=O)c1cn(-c2cccc(Cl)c2)cn1
Yield: 63 %

Procedure:
A solution of 0.4 g of 1-(3-chlorophenyl)-imidazole-4-carboxylic acid ethyl ester in 40 ml of i-propanol is mixed with 0.5 ml of titanium tetraisopropanolate and refluxed for 8 hours. After concentration of the solution, it is filtered over silica gel and recrystallized from diisopropyl ether. 267 mg (63%) of the title compound with a melting point of 109° C. is obtained from diisopropyl ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:18]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[CH2:20][N:19]1[CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:24]=[CH:25][CH:26]=2>>[CH2:18]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[CH2:20][N:19]1[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:24]=[CH:25][CH:26]=2
Reactant: NCCCCN1Cc2cccc3cccc(c23)C1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1Cc2cccc3cccc(c23)C1

Procedure:
Batch size: 1.8 g (12.1 mmol) 3-(3-pyridyl)-acrylic acid, 4.0 g (31.5 mmol) oxalyl chloride and 2.6 g (10.8 mmol) 4-(1H,3H-benzo[de]isoquinolin-2-yl)-butylamine.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15]>C1COCC1>[C:13]([O:4][CH2:3][CH2:2][CH2:1][OH:5])(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)Cl
Reactant: OCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCO
Yield: 50 %

Procedure:
1,3-Propanediol (by Tokyo Kasei) and triethylamine were dissolved in THF, and in an ice-water bath, acryloyl chloride was added thereto. After the reaction, the reaction liquid was washed with aqueous saturated sodium hydrogencarbonate solution added thereto, and then the organic layer was washed with 1 N hydrochloric acid and saturated saline water. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography to obtain 32 g of 3-hydroxypropyl acrylate (yield: 50%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]=1[O:1][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])#[N:5]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a stirred mixture of 2-hydroxy-4-nitrobenzonitrile (2 g, 12.19 mmol), cesium carbonate (6 g, 18.29 mmol) and DMF (20 mL) was added tert-butyl 4-bromobutylcarbamate (4.59 g, 18.29 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL), and washed with brine (2×50 mL). The organic layer was dried with anhydrous sodium sulphate and concentrated in vacuo to give tert-butyl 4-(2-cyano-5-nitrophenoxy)butylcarbamate (2.1 g, 52%) as a light yellow solid. LC-MS (M+H)+=335.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (1H, d, J=8.4 Hz), 7.96 (1H, s), 7.90 (2H, d, J=8.8 Hz), 6.84 (1H, br s), 4.30 (2H, t, J=6.4 Hz), 3.53 (2H, t, J=6.4 Hz), 2.98-2.89 (2H, m), 1.81-1.76 (2H, m), 1.48 (9H, s).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]Br>C(OCC)C>[Br:9][CH2:2][C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccco1
Solvent: CCOCC
Product: O=C(CBr)c1ccco1
Reaction time: 2 h

Procedure:
To a 5 liter round bottomed flask is added 2-acetylfuran (440 grams, 4 moles) and 2.4 liters of ethyl ether at 5 C in an ice bath. To this solution is added, dropwise over a period of two hours, with vigorous stirring, 230 mL bromine (713 grams, 4.46 moles). After the bromine addition is complete, the reaction mixture is stirred for an additional two hours, and then quenched with the addition of 300 mL of water. The mixture is then allowed to separate overnight, and the ether layer is washed with water (3×300 mL), dried over magnesium sulfate, and filtered. Removal of the solvent affords the title product having 1H-NMR (CDCl3) delta 7.53 (t, 1J, J=0.72 Hz), 7.21 (d, 1H, J=3.68 Hz), 6.46 (dd, 1H, J=3.66 Hz and 1.48 Hz), 4.20 (s, 2H). 13C (CDCl3 189.22, 150.12, 147.61, 119.42, 112.93, 30.46 ppm.