Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:6][CH2:5]CC=[CH:2]1.[Br:18]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.Cl.[CH2:31]([OH:33])[CH3:32]>C1COCC1>[Br:18][CH:2]1[CH:31]([OH:33])[CH2:32][CH2:5][CH2:6][CH:1]1[N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1C1C=CCCC1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCCC(O)C1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Cyclohex-2-enyl-isoindole-1,3-dione (520 g, 2.30 mol) and N-bromosuccinimide (416 g, 2.35 mol) were mixed in a cosolvent of chloroform (3000 mL) and ethanol (120 mL) and stirred at room temperature for 16 h. When HPLC showed the starting material was consumed, the reaction mixture was concentrated to give the residue, which was diluted with hydrochloride solution (450 mL, 2.0 mol) and THF (2000 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product. The crude product was washed with ethanol (2 times) to give 2-(2-bromo-3-hydroxy-cyclohexyl)-isoindole-1,3-dione (400 g, 1.23 mol) as a white solid. 1H NMR (CD3OD, 400 MHz): δ ppm 7.87 (m, 4H), 4.70 (m, 1H), 4.33 (m, 1H), 3.70 (m, 1H), 2.15 (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH2:6][NH:5]1.[C:17](=[S:19])=[S:18].[CH2:20](N(CC)CC)C.CI>CO>[OH:1][CH2:2][CH2:3][C@H:4]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH2:6][N:5]1[C:17]([S:19][CH3:20])=[S:18]
Reactant: OCC[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: CCN(CC)CC
Reactant: S=C=S
Solvent: CI
Solvent: CO
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2C[C@@H]1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
(3R)-3-(2-Hydroxyethyl)-1,2,3,4-tetrahydro-β-carboline (94 mg) is dissolved in 80% methanol (2.4 ml), and thereto are added CS2 (0.026 ml) and triethylamine (0.061 ml). The mixture is stirred at room temperature for 30 minutes, and thereto is added dropwise methyl iodide (0.027 ml), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is distilled to remove the solvent. The residue is dissolved in ethyl acetate. The solution is washed with water, dried over sodium sulfate and then distilled to remove the solvent. The residue is purified by thin layer chromatography (solvent, ethyl acetate:n-hexane=2:3) to give the title compound (51 mg, 38.3%) as colorless needles, m.p. 166°-167° C., NMR (CDCl3, δ): 2.72 (s, 3H, CSSCH3); Mass m/e: 306 (M+), 258 (M+ --CH3SH); [α]D20 -178.0° (c=0.1, methanol).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17](/[CH:19]=[CH:20]/[Sn](CCCC)(CCCC)CCCC)=[CH:18][C:13]=2[O:12][CH2:11]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>CN(C=O)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:10]1[C:14]2[CH:15]=[CH:16][C:17](/[CH:19]=[CH:20]/[C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: CCCC[Sn](/C=C/c1ccc2c(c1)OCO2)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(Cl)cc1/C=C/c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 3-bromo-5-chloro-2-pyridinamine (318 mg, 1.5 mmol), [(E)-2-(1,3-benzodioxol-5-yl)ethenyl](tributyl)stannane (250 mg, 1.7 mmol) (A. J. Bridges, A. Lee, C. E. Schwatrz, M. J. Towle, B. A. Littlefield, Bioorg. Med. Chem., 1993, 1, 403), palladium acetate (19 mg, 0.08 mmol) and tri-o-tolylphosphine (50 mg, 0.16 mmol) in DMF (0.5 ml) and triethylamine (0.5 ml) in a teflon pressure vessel was heated in a microwave (full power) for 20 sec, allowed to cool to RT heated in a microwave for a further 20 sec and then 1 min 20 sec. After allowing to cool, the reaction mixture was poured into water (20 ml) and extracted with EtOAc (3×20 ml). The combined extracts were washed with water (2×20 ml), dried over MgSO4 and concentrated. Recrystallisation from EtOAc—hexane gave the title compound as a brown solid (170 mg, 0.6 mmol):
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(O[C:28]1(O[Si](C)(C)C)[CH2:30][CH2:29]1)C.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:28]1[CH2:30][CH2:29]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)C1CC1
Yield: 15.4 %

Procedure:
A mixture of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (115 mg, 0.35 mmol), (1-Ethoxy-cyclopropoxy)-trimethylsilane (360 mg, 2.0 mmol), AcOH (0.2 ml, 3.5 mmol), NaCNBH3 (110 mg, 1.75 mmol) and 4 Å molecular sieves (100 mg) in MeOH (5 ml) was heated to reflux for 18 hours. The mixture was cooled, concentrated in vacuo and partitioned between 2M NaOH (10 ml) and DCM (10 ml). The organic phase was separated and the aqueous phase extracted with DCM (2×10 ml). The combined organic phases were concentrated in vacuo and purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:1) to provide the title compound as a clear colourless oil (20 mg, 0.054 mmol, 15%). 1H NMR (400 MHz, CDCl3) δ 0.15 (m, 2H), 0.29 (m, 2H), 1.68 (m, 1H), 1.70-1.90 (m, 6H), 1.85 (s, 3H), 2.00-2.10 (m, 4H), 2.60 (m, 4H), 2.65 (s, 2H), 2.68 (m, 2H), 3.50 (t, 2H), 3.76 (m, 2H), 4.01 (t, 2H), 6.85 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 373.2844 [MH]+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](O)[CH3:25]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:24][CH3:25])=[O:15]
Reactant: Sc1ccccn1
Reactant: CCO
Reactant: O=C(O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCCCSc1ccccn1

Procedure:
2-Mercaptopyridine (5.84 g) and 6-bromocaproic acid (9.75 g) were dissolved in ethanol (50 ml), and the solution was heated under reflux for 14 hours. After cooling, the reaction mixture was added with water, and adjusted to pH 8 with aqueous sodium carbonate. The deposited oily product was extracted with ethyl acetate, and then purified by silica gel column chromatography (developing solvent: chloroform/ethyl acetate) to obtain 13.6 g of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][N:14]=[CH:13]1>>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:20][CH2:19][CH2:18][CH2:17][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NCCCn1ccnc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)c(F)c1
Temperature: 96 °C
Yield: 68.1 %

Procedure:
Starting with 31.8 g (0.2 mol) of 1,2-difluoro-4-nitrobenzene and 37.5 g (0.3 mol) of 3-imidazol-1-ylpropylamine, and after purification by recrystallization from refluxing 96° C. ethanol, 36.0 g of orange-yellow crystals melting at 144° C. (Kofler) were obtained, the elemental analysis of which, calculated for C12H13N4O2F, was:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.[I-].[K+]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:10])[Cl:11])[CH:7]=1)[CH2:13][Br:32]
Reactant: Cc1cc(F)cc(C(Cl)=C(Cl)Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: Fc1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1

Procedure:
To a solution of 3-fluoro-5-(trichlorovinyl)toluene (2.39 g) and dibenzoyl peroxide (0.2 g) in 60 ml of benzene at reflux, N-bromosuccinimide (2.21 g) is added in portions. The mixture is heated at reflux until the solution gives a negative reaction with potassium iodide. The reaction mixture is concentrated and the residue triturated with 100 ml of hexane. The precipitated succinimide is collected by filtration and the filtrate concentrated and then chromatographed on silica gel (hexane) to give the desired benzyl bromide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=O)=[C:22]([O:35][CH3:36])[CH:21]=1.C(O)(C(F)(F)F)=[O:38].CCN(CC)CC>CS(C)=O>[CH3:36][O:35][C:22]1[CH:21]=[C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:24][C:23]=1[CH2:26][C:27](=[O:38])[CH2:28][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(N)ccc1CCC(=O)N1CCCC1
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(Nc2nccc(Nc3cnc4ccccc4c3)n2)ccc1CC(=O)CN1CCCC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (0.5 g, 1.8 mmol, 1.0 eq.) and 3-(4-amino-2-methoxy-phenyl)-1-pyrrolidin-1-yl-propan-1-one (0.47 g, 2.0 mmol, 1.1 eq. Step B) in 0.5 mL of DMSO was added a 1/1 (v/v) mixture of TFA/Et3N (337 μl, 1.8 mmol, 1.0 eq.). The reaction was heated to 100° C. and stirred for 16 h. The mixture was cooled, concentrated and purified by column chromatography (0-5% MeOH in CH2Cl2 with 1% of NH4OH (aq.)). Triturated with CH2Cl2 to provide the title compound. MS m/z=469.6 (M+H)+ Calc'd for C27H28N6O2: 468.56.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][N:7]1[C:11](=O)[CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[NH:8]1.[OH-].[Na+].CN([CH:22]=[O:23])C>>[CH3:6][N:7]1[C:11]([Cl:3])=[C:10]([CH:22]=[O:23])[C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1[nH]c(C(F)(F)F)cc1=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
21.35 g of phosphorus oxychloride was dropwise added to 4.72 g of DMF at 10° C. or lower. After the temperature of the reaction solution was returned to room temperature, the reaction mixture was stirred for 1 hour, and 10.71 g of 1-methyl-3-trifluoromethyl-5-pyrazolone was added thereto. The resulting mixture was heated up to 110° C., and stirred for 7 hours. After having been left to be at 70° C. the reaction mixture was poured into ice water. After pH of the mixture was made to be about 4 with an aqueous solution of sodium hydroxide added thereto, and precipitated crystals were taken out through filtration and dried to obtain 10.55 g of 1-methyl-3-trifluoromethyl-5-chloropyrazole-4-carbaldehyde.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[C:12]([OH:20])=[N:13][C:14]([C:17](O)=[O:18])=[N:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O>[C:1]1([CH:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]([NH:10][C:11]2[C:12]([OH:20])=[N:13][C:14]([C:17]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:18])=[N:15][CH:16]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Step A product, 3-1-a, (300 mg, 0.86 mmol), methyl 2-aminoacetate (129 mg, 1.03 mmol) and DIEA (222 mg, 1.7 mmol) in DMSO (10 mL) was added with TBTU (330 mg, 1.03 mmol) and stirred at room temperature for overnight. The reaction mixture was poured into ice water (100 mL). The solids were filtered and purified by pre-HPLC to afford the product as a white solid, 3-1-b, (60 mg, 17%). LC-MS (M+H)+ 421.0
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[OH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.O>C(Cl)Cl>[S:1]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)OCCc1ccccn1
Yield: 12 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride solution prepared in (a) was reacted as in Example 12 with 16.7 g (0.136 mole) of 2-(β-hydroxyethyl)pyridine using 54.9 g (0.544 mole) of triethylamine in 100 ml of methylene chloride. Water, 150 ml, was added to the reaction mixture with agitation and the layers was separated. The organic layer was discarded, pH of the aqueous layer was adjusted to 8 with sodium carbonate. The mixture was extracted with three 200 ml portions of methylene chloride. The organic extracts were washed twice with 200 ml portions of water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 7.1 g of a brown, viscous oil which solidified on standing. The solid was recrystallized from methylene chloride-petroleum ether (bp range 30°-60° C.) to give 3.2 g (12%) of title compound as white needles, mp 89°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.CN(C)CCCN=C=NCC.[C:33]([O:36][CH:37]1[C:41]2=[N:42][C:43]3[C:44](=[N:45][CH:46]=[C:47]([NH2:49])[CH:48]=3)[N:40]2[CH2:39][CH2:38]1)(=[O:35])[CH3:34]>CN(C)C=O>[C:33]([O:36][CH:37]1[C:41]2=[N:42][C:43]3[C:44](=[N:45][CH:46]=[C:47]([NH:49][C:19]([C:6]4[N:7]([CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=5)[C:8]5[C:4]([CH:5]=4)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)=[O:20])[CH:48]=3)[N:40]2[CH2:39][CH2:38]1)(=[O:35])[CH3:34]
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: CC(=O)OC1CCn2c1nc1cc(N)cnc12
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCn2c1nc1cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc12
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
A solution of 0.25 g (0.87 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid, prepared in step 1.1, 0.166 g (0.87 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and 0.117 g (0.87 mmol) of N-1-hydroxybenzotriazole in 3 ml of dimethylformamide is stirred at 20° C. for 15 minutes. The reaction mixture is subsequently admixed with 0.245 g (1.04 mmol) of 6-acetoxy-7,8-dihydro-6H-pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridin-3-amine (compound IV-b), in solution in 3 ml of dimethylformamide. The reaction mixture is subsequently stirred at 20° C. for 16 hours and then concentrated under reduced pressure, poured into 50 ml of water and extracted with three times 50 ml of ethyl acetate. The organic phases are combined, then washed with twice 20 ml of saturated sodium hydrogen carbonate solution, once with 20 ml of water and then once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. The product thus purified is finally triturated in hot diisopropyl ether and filtered while hot to give 0.27 g of the expected product.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].CS([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O)(=O)=O.O.[NH3:17]>O.[N+]([O-])([O-])=O.[Ag+]>[CH:11]1[C:10](=[N:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:17])=[CH:11][CH:10]=2)[CH:9]=[CH:14][C:1](=[O:3])[CH:2]=1
Reactant: CS(=O)(=O)Nc1ccccc1O
Reactant: N
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 3 h
Yield: 76 %

Procedure:
150 ml of ethanol was added to 3.7 g of 2-methylsulfonylaminophenol of the following structural formula: ##STR108## and 5.24 g of a compound of the following structural formula: ##STR109## stirred at room temperature, and then a solution of 3.4 g of silver nitrate in 15 ml of water was added dropwise. 15 ml of a 28% ammonia water was added thereto, further a solution of 1.5 g of silver nitrate in 10 ml of water was added dropwise, and the reaction was effected at 30°-40° C. for 3 hours. After completion of the reaction, it was extracted with chloroform, the solvent was distilled off, and the residue was purified by column chromatography using chloroform to obtain 5.27 g (yield 76% based on the theoretical yield) of a purified product of an indoaniline type dye of the following structural formula: ##STR110## The dye thus obtained had a melting pont of 135°-137° C. and a maximum absorption wavelength (chloroform) of 640 nm.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]([CH2:21][C:22](=O)[CH2:23][CH3:24])[C:11]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:21]=[C:22]([CH2:23][CH3:24])[N:13]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:19]=4[CH3:20])[C:11]3=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(=O)CN(C(=O)Nc1cnccc1C)c1ccc2ncsc2c1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cn(-c2ccc3ncsc3c2)c(=O)n1-c1cnccc1C
Yield: 28.5 %

Procedure:
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-1-(2-oxo-butyl)-urea (I-168b: 185 mg, 0.522 mmol) in toluene (15 mL) was refluxed at 120° C. for 20 hours. The reaction was monitored by TLC (5% MeOH in chloroform). The reaction mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography on silica gel (2.5% methanol in chloroform) to afford 50 mg of the product (28.57% yield).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH2:8])=[N:5][N:4]=1.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]([F:10])([F:9])[C:3]1[O:7][C:6]([NH:8][C:18](=[O:19])[CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5][N:4]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1nnc(C(F)(F)F)o1
Product: O=C(Nc1nnc(C(F)(F)F)o1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 149-150° C. and MS: m/e=347.2 (M+) was prepared in accordance with the general method of example 44a from 5-trifluoromethyl[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22]([C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][C:31]=1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1)[CH2:23][CH2:24][CH3:25]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:29]2[N:28]=[N:27][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[C:31]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:36][CH:37]=3)[CH:30]=2)[CH:10]([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOCC1CN(C(=O)OC(C)(C)C)CCC1O
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2COCOC)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-3-methoxymethoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.4 mmol, 0.111 g) in 3 mL of THF was added 60% NaH in mineral oil (2.0 mmol, 0.05 g) at room temperature. The mixture was stirred for 10 mins, then a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.2 mmol, 0.07 g) in THF was added. The mixture was refluxed for 1 h, then, stirred at room temperature overnight. The mixture was quenched with water, extracted with ethyl acetate, the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure, the resulting residue was chromatographed using 10% ethyl acetate in hexane to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-3-methoxymethoxymethyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:3][CH2:2]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:11][CH2:10]2)[O:3][CH2:2]1
Reactant: O=C1CCN(CCC2CCOCO2)CC1
Reactant: NCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(CNC2CCN(CCC3CCOCO3)CC2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of 128NLS50 (1.73 g, 8.13 mmol) in methanol (100 mL) was added dropwise 4-fluorobenzylamine (0.93 mL, 8.13 mmol) and acetic acid. Sodium cyanoborohydride (2.15 g, 40 mmol) was added slowly to the mixture at 0° C. and stirring was continued at rt overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and 1M NaOH, the aqueous layer extracted twice with dichloromethane and the combined organic layers dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by a short silica gel column chromatography eluting with 0-30% methanol in dichloromethane gave the title compound (1.51 g, 58%) as a colourless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=O)=O)=CC=1>>[CH2:25]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCc2ccccc2)cc1
Product: c1ccc(COCCOCCOC2CCOCC2)cc1
Yield: 85.3 %

Procedure:
Using tetrahydro-4-pyranol (0.784 mL, 8.23 mmol) and 2-[2-(benzyloxy)ethoxy]ethyl 4-methylbenzenesulfonate (1.92 g, 5.48 mmol) synthesized in Reference Example 6 (6a), the desired title compound (1.31 g, yield 85%) was obtained by the same method as in Reference Example 2 (2a).
Reaction SMILES: [CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCC(C)CCCCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)CCCCCOc1ccc(O)cc1

Procedure:
A flask was charged with 23.37 g of optically active 4-benzyloxyphenyl 6-methyloctyl ether, 2.33 g of 10% Pd/C and 230 ml of ethanol, and the mixture was reacted at room temperature until it reacted with a theoretical amount of hydrogen. After completion of the reaction, the catalyst was removed by filtration and the organic solvent was distilled under reduced pressure to obtain a crude product. The crude product was refined to obtain 16.91 g of the intended phenol.