Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]1[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=1>>[CH3:27][C:28]1[S:29][C:30]([C:34]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:35])=[C:31]([CH3:33])[N:32]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5sc(C)nc5C)c4)CC3)cccc2n1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]([CH3:64])=[C:50]([NH:52][C:53]([C:55]2[S:63][C:58]3=[N:59][CH:60]=[CH:61][N:62]=[C:57]3[CH:56]=2)=[O:54])[CH:51]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:45][C:46]1[CH:47]=[CH:48][C:49]([CH3:64])=[C:50]([NH:52][C:53]([C:55]2[S:63][C:58]3=[N:59][CH:60]=[CH:61][N:62]=[C:57]3[CH:56]=2)=[O:54])[CH:51]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: Cc1ccc(N)cc1NC(=O)c1cc2nccnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(Br)c2)cc1NC(=O)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
A solution of 2-bromoisonicotinic acid (160 mg, 0.792 mmol), HATU (331 mg, 0.871 mmol) and DIPEA (0.655 mL, 3.96 mmol) in DMF (8 mL) was stirred at rt for 10 min. N-(5-amino-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide hydrochloride 29 (248 mg, 0.871 mmol) was added and stirred at rt for 3 h. Quenched in 3% citric acid solution and the resulting precipitate was collected. Triturating with acetonitrile gave N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide (30) (163 mg, 44%). (m/z)=468 and 470 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(OCC)C>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C1Cc2ccccc2N1C1CCNCC1
Yield: 150.4 %

Procedure:
4-(2-Oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 12.3 mmol) was set stirring in 30 mL of 1:1 TFA/CH2Cl2. After 45 min the solvent was evaporated under reduced pressure to give a clear purple oil. The oil was brought up in diethyl ether and cooled on ice to give a precipitate. The solid was filtered, washed with ether and air dried to give 4.0 g (100%) of the title compound as a TFA salt. 1H NMR (400 MHz, DMSO-d6): 8.6 (br s, 1H), 7.27 (m, 3H), 7.03 (m, 1H), 4.45 (m, 1H), 3.56 (s, 2H), 3.42 (m, 2H), 3.09 (m, 2H), 2.53 (m, 2H), 1.78 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.CCN(CC)CC.Cl.Cl[CH2:22][CH2:23][N:24]([CH2:32][CH2:33]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCO>[CH2:25]([N:24]1[CH2:32][CH2:33][N:12]([C:10]2[CH:11]=[C:2]([Br:1])[CH:3]=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)[CH2:22][CH2:23]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: Nc1cc(Br)cc2cccnc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Brc1cc(N2CCN(Cc3ccccc3)CC2)c2ncccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
The free base of bis(2-chloroethyl)-benzlyamine (5.12 g, 19.3 mmol) was prepared by washing the HCl salt with 1 M NaOH (200 mL) and extracting into EtOAc. The resulting organic phases were dried over Na2SO4 and concentrated. To this flask was added 6-bromo-8-amino-quinoline (2.15 g, 9.6 mmol), n-BuOH (100 mL), and Et3N (4 mL, 28.9 mmol). The resulting reaction mixture was stirred at 100° C. overnight. TLC analysis showed starting amine was still present, therefore an additional portion of bis(2-chloroethyl)-benzylamine hydrochloride (5 g) was added. The reaction was heated an additional 72 hours. The cooled reaction mixture was quenched with 1 M NaOH (200 mL) and extracted into EtOAc (3×200 mL). The organic fractions were combined, dried over Na2SO4, and concentrated. The resulting gold oil was purified three times by column chromatography (40% EtOAc/hexanes) affording 1.2 g (33%) of a viscous orange oil which solidified upon standing: mp 65-68° C., MS (+) APCI m/z 382 [M+H]+.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH2:11]([C:15]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:38][OH:39])[N:17]([CH:40](C)[CH3:41])[N:16]=1)[CH2:12][CH2:13][CH3:14].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[CH2:11]([C:15]1[C:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)=[C:18]([C:38]([OH:39])=[O:6])[N:17]([CH2:40][CH3:41])[N:16]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nn(C(C)C)c(CO)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCCCc1nn(CC)c(C(=O)O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A solution of sodium chlorite (80%;0.44 g) and sodium dihydrogen phosphate (0.44 g) in water (5 ml) was added to a mixture of the product of Example 27 (203 mg), 2-methyl-2-butene (2M,0.62 ml) and t-butanol (4 ml) in THF (10 ml) at room temperature. The mixture was stirred vigorously for 20 mins. The mixture was partitioned between ethyl acetate (3×15 ml) and water (15 ml). The combined organic extracts were dried. The solvent was evaporated to give a colourless foam (0.2 g) which was purified by column chromatography on silica gel eluting with System G (50:50:1) to give the title compound as a colourless solid (60 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(Br)c1
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A mixture of 3-bromotoluene (42.8 g, 0.25 mol), N-bromosuccinimide (48.9 g, 0.275 mol) and benzoyl peroxide (0.75 g) in tetrachloromethane (500 mL) was stirred and heated to reflux for 3 h. The mixture was left to stand overnight at laboratory temperature, the solid was filtered off, washed with tetrachloromethane and the filtrates were evaporated. The residue was distilled in vacuo to yield 52.7 g (62.5%) of 1-bromo-3-bromomethylbenzene, b.p. 135-140° C./1.6 kPa.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[OH:8])/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:13]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=1[Cl:11]
Reactant: COc1ccc(CS)c(Cl)c1
Reactant: C#Cc1ccc(O)c(O)c1
Agent: [Na]
Product: COc1ccc(C(/C=C\c2ccc(O)c(O)c2)SC(/C=C\c2ccc(O)c(O)c2)c2ccc(OC)cc2Cl)c(Cl)c1

Procedure:
A solution of 3,4-dihydroxyphenylacetylene (0.02 mol), 2-chloro-4-methoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3,4-dihydroxystyryl-2-chloro-4-methoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]1[C:17]2[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]1[C:17]2[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1occc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1occc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A mixture of tert-butyl 9-(2-methyl-3-furyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.911 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (3 ml) was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (230 mg, 95.0%) as a solid.
Reaction SMILES: C([NH:3][C:4]1[CH:5]=[C:6]([C:14]([NH2:16])=[O:15])[C:7]2[N:11]=[CH:10][NH:9][C:8]=2[C:12]=1[CH3:13])=O.Cl>CO>[NH2:3][C:4]1[CH:5]=[C:6]([C:14]([NH2:16])=[O:15])[C:7]2[N:11]=[CH:10][NH:9][C:8]=2[C:12]=1[CH3:13]
Reactant: Cc1c(NC=O)cc(C(N)=O)c2nc[nH]c12
Agent: Cl
Solvent: CO
Product: Cc1c(N)cc(C(N)=O)c2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 6-(Formylamino)-7-methyl-1H-benzimidazole-4-carboxamide (11) (0.35 g, 1.6 mmol), 1M aqueous HCl (10 mL) and methanol (3 mL) is heated to reflux for about 1 hour. The reaction mixture is allowed to cool to ambient temperature and is then concentrated in vacuo to a white solid. The white solid is recrystallized from ethanol/water (3/1 v/v) to provide 6-(Amino)-7-methyl-1H-benzimidazole-4-carboxamide; hydrochloric acid salt (12) as a white solid (0.164 g, 54% Yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH2:16][CH2:15][N:23]2[C:11](=[O:12])[C:6]3=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]3[C:8]2=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCc1ccccc1
Reaction time: 2.5 h
Yield: 88.6 %

Procedure:
A mixture of 4-nitrophthalic anhydride (18 g, 93.3 mmol) and phenethylamine (11.5 g, 95 mmol) in toluene (250 mL) was heated to reflux. After 2.5 h, the mixture was concentrated to solid residue, which was triturated and filtered to yield the title compound (24.5 g, 89%). Mp 142°-3° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36]1([CH2:39][N:40]2[CH:45]=[C:44]([OH:46])[C:43](=[O:47])[C:42]([C:48]3[N:52]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:51]=[CH:50][CH:49]=3)=[N:41]2)[CH2:38][CH2:37]1.[CH3:59][N:60]1[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=2[N:62]=[C:61]1[CH2:69][CH2:70][CH2:71]O>C1(C)C=CC=CC=1>[CH:36]1([CH2:39][N:40]2[CH:45]=[C:44]([O:46][CH2:71][CH2:70][CH2:69][C:61]3[N:60]([CH3:59])[C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=4[N:62]=3)[C:43](=[O:47])[C:42]([C:48]3[N:52]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:51]=[CH:50][CH:49]=3)=[N:41]2)[CH2:37][CH2:38]1
Reactant: O=c1c(O)cn(CC2CC2)nc1-c1ccnn1-c1ccccc1
Reactant: Cn1c(CCCO)nc2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1c(CCCOc2cn(CC3CC3)nc(-c3ccnn3-c3ccccc3)c2=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
Toluene (10 mL) was added to di-tert-butyl diazene-1,2-dicarboxylate (173 mg) and triphenylphosphine (229 mg) and the mixture was stirred at room temperature for 10 min. Then, 1-(cyclopropylmethyl)-5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (154 mg), and further, 3-(1-methyl-1H-benzimidazol-2-yl)propan-1-ol (143 mg) were added, and the mixture was stirred at room temperature for 22 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol). A fraction containing the title compound was again purified by NH silica gel column chromatography (hexane/ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (110 mg) as white prisms.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:41])[C@H:22]([NH:27][C:28](=[O:40])[C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:31])[CH3:30])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:7]2.[CH:42](=O)[CH3:43].C(#N)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:42]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:41])[C@H:22]([NH:27][C:28](=[O:40])[C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:30])[CH3:31])[CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:7]2)[CH3:43]
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2N(Cc2ccccn2)C1=O
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCNc1cccc2c1N(Cc1ccccn1)C(=O)C(NC(=O)[C@@H](CC(C)C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2
Reaction time: 0.08 h

Procedure:
tert-Butyl 1-((2R)-1-(8-amino-2-oxo-1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (59 mg) and acetaldehyde (29 μL) were sequentially added to acetonitrile (730 μL), and sodium cyanoborohydride (7 mg) and acetic acid (18 μL) were added to the mixture under cooling on ice, followed by stirring for 5 minutes. The resultant mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, and the combined organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1), whereby the title compound (58 mg) was yielded.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:9][C:10]1[C:16](F)=[CH:15][C:13]([NH2:14])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.O>O1CCCC1>[F:9][C:10]1[C:16]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][C:13]([NH2:14])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1
Reactant: COCCCO
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cc(N)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
In a 250 ml three-necked flask under an argon atmosphere, 1 g of 3-methoxy-1-propanol in 20 ml of tetrahydrofuran are cooled to 0° C. using an ice bath and then 450 mg of sodium hydride at 50% in liquid petroleum jelly are introduced in fractions. After stirring for 15 minutes at 0° C., add, over 5 minutes, a solution of 1.5 g of 4,5-difluoro-2-nitroaniline in 20 ml of tetrahydrofuran and then heat in the region of 70° C. for 1 hour 30 minutes. The reaction mixture is poured into 200 ml of water, and extracted with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and brought to dryness under reduced pressure. After purification by flash chromatography on silica gel (15-20 μm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), in this way we obtain 1 g of 4-fluoro-5-(3-methoxypropoxy)-2-nitrophenylamine, in the form of a red solid, which is used as it is in the following stage, with the following characteristic:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:24]([Si:21]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])([CH3:23])[CH3:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc(F)c(F)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a solution of 4,5-difluoro-2-methoxy-phenol (3.75 g, 23.42 mmol, Example 264) in methylene chloride (60 mL) cooled to 0° C. were added N,N-diisopropylethylamine (4.895 mL, 28.10 mmol), tert-butyldimethylsilyl chloride (4.367 g, 28.10 mmol, Aldrich), and dimethylaminopyridine (286 mg, 2.342 mmol, Aldrich). At the end of addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. Water (30 mL) was added and the layers were separated. The aqueous layer was extracted with methylene chloride (20 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 3% ethyl acetate in hexanes) yielded tert-butyl-(4,5-difluoro-2-methoxy-phenoxy)-dimethyl-silane as a clear oil (5.22 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]2[O:9][CH:8]([CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12](Cl)=[O:13])[CH2:7][C:6]=2[CH:19]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]2[O:9][CH:8]([CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[O:13])[CH2:7][C:6]=2[CH:19]=1
Reactant: CCCCN(CC1Cc2cc(Cl)cc(Cl)c2O1)C(=O)Cl
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCCCN(CC1Cc2cc(Cl)cc(Cl)c2O1)C(=O)n1ccnc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
13.5 g (0.04 mole) of N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylcarbamyl chloride were added dropwise to a solution of 6.8 g (0.1 mole) of imidazole in 150 ml of dry tetrahydrofuran at 20° C. The mixture was stirred for 6 hours at 70° C., after which it was cooled to 20° C., and the resulting precipitate was filtered off under suction. The filtrate was evaporated down under reduced pressure, the residue was dissolved in 200 ml of methylene chloride, the solution was washed with three times 80 ml of water, dried and evaporated down, the resin which remained was left to stand for 3 hours at 0° C. with 30 ml of diethyl ether, and the crystals formed were filtered off under suction. 12.8 g of 1-(N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylcarbamyl)imidazole of melting point 98°-100° C. were obtained (compound No. 1).
Reaction SMILES: [CH:1]1([CH3:20])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([O:12][CH:13]2[CH2:17][O:16]C(C)(C)O2)=[O:11])[CH2:2]1.[C:21](O)(C(F)(F)F)=[O:22]>>[CH:1]1([CH3:20])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([C:10]([O:12][CH2:13][CH:17]([CH2:21][OH:22])[OH:16])=[O:11])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(C(=O)OC2COC(C)(C)O2)C1
Reactant: O=C(O)C(F)(F)F
Product: CC1CCC(C(C)C)C(C(=O)OCC(O)CO)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(p-Menth-3-oyloxy)-2,2-dimethyl-1,3-dioxolan (3 g.) was stirred for 5 minutes at room temperature with 90% CF3COOH (15 ml.), and the CF3COOH removed in vacuo. The residual oil was stirred for 4 hours at room temperature with a solution of K2CO3 (7%) in water:methanol (2:5) (50 ml.). The methanol was removed on a rotary evaporator, water (30 ml.) added and the mixture extracted four times with ether. The combined extracts were dried (MgSO4). Removal of the ether left an oil which was distilled to yield 1-(p-menth-3-oyl)glycerol as a colourless liquid b.p. 135° /0.1 mm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](C)([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[CH3:15]C(C1C=CC=C(O)C=1)=O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: CCCCC(C)(O)c1cccc(O)c1
Product: CCCCCC(O)c1cccc(O)c1

Procedure:
1-(3-hydroxyphenyl)-1-methyl-1-pentanol (using 3-hydroxyphenyl methyl ketone in lieu of the aldehyde); and
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28](=S)=[S:29]>C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]=[C:28]=[S:29])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C=S
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CN=C=S)cc1
Reaction time: 12 h

Procedure:
8.16 g of 4-t-butylbenzylamine was added dropwise at -10° C. with stirring to a mixture of 10.32 g of dicyclohexylcarbodiimide (DCC), 20 ml of carbon disulfide and 100 ml of diethyl ether. The temperature of the mixture was returned to room temperature, and it was left to stand for 12 hours. The reaction solution was filtered, and the residue was washed with diethyl ether. The filtrate was combined with the washing, and the solvent was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (19:1) to give 8.41 g of the desired 4-t-butylbenzyl isothiocyanate.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+].C(O)CCCCC>>[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCO
Product: NC1CCCCNC1=O
Temperature: 150 °C

Procedure:
300 mmols of L-lysine hydrochloride 1 is neutralized with 300 mmols of NaOH and then 1.2 L of 1-hexanol is added. This mixture is heated to 150° C. and is refluxed for 8 hours. The yield of α-amino-ε-caprolactam 2 produced by this reaction is about 91%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[OH-].[Na+].[F:7][C:8]1[CH:9]=[C:10]([C:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH2:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1>C(O)C>[F:7][C:8]1[CH:9]=[C:10]([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]3[NH:1][CH2:2][CH2:3][S:4]3)[CH2:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1ccccc1OCCN1CC=C(c2cccc(F)c2)CC1
Reactant: NCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1cccc(C2=CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
8.09 g of cysteamine hydrochlorideare dissolved in 450 ml of ethanol, and 2.93 g of sodium hydroxide are added thereto. The mixture is stirred at room temperature for 10 minutes. A solution of 21.05 g of 2-{2-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethyloxy}benzaldehyde in 50 ml of ethanol is added to the mixture, and the mixture is further stirred at room temperature for 14 hours. The mixture is concentrated and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then evaporated to remove the solvent. The residue is recrystallized from n-hexane. 21.62 g of 2-{2-[2-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)ethyloxy]phenyl}thiazolidine are obtained. Yield: 69%.
Reaction SMILES: O.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH:11](=O)[CH:12]([CH3:14])[CH3:13].N1CCCCC1>C1C=CC=CC=1.C(O)(=O)C>[CH3:11][CH:12]([CH3:14])[CH:13]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[C:9]#[N:10]
Reactant: CC(C)C=O
Reactant: N#CCc1ccccn1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(C)C=C(C#N)c1ccccn1

Procedure:
In a flask equipped with a water separator are placed 7 g of 2-pyridyl acetonitrile, 12.8 g of isobutyraldehyde, 0.9 ml of acetic acid, 0.18 ml of piperidine and 250 ml of dry benzene. The mixture is heated under reflux for 3 hours. After cooling, the reaction mixture is washed with water, the organic phase is dried over sodium sulfate then the solvent is evaporated to dryness.