Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N+:26]([O-])=O)=[CH:4][CH:3]=1.[H][H]>CN(C)C=O.[Ni]>[NH2:26][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(-c2ccc(C)cc2)c(S(=O)(=O)N=CN(C)C)c1
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(-c2ccc(C)cc2)c(S(=O)(=O)N=CN(C)C)c1

Procedure:
A solution of 28 g (0.07 mole) of methyl 4-(4-methylphenyl)-3-nitro-5-dimethylaminomethyleneaminosulfonyl-benzoate in 200 ml of dimethylformamide is hydrogenated with 3 g of Raney nickel at 50° and with hydrogen under a pressure of 50 atmospheres, for 10 hours in an autoclave. After filtering, the filtrate is introduced into ice-water and the precipitate is filtered off and recrystallized from dimethylformamide/MeOH.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][OH:12])=[O:8])(=[O:4])=[O:3].C(Cl)Cl.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>C(N(CC)CC)C>[NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][O:12][Si:21]([CH3:23])([CH3:22])[CH3:20])=[O:8])(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccccc1C(=O)OCCO
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCOC(=O)c1ccccc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
To a slurry of 12.25 g of 2-aminosulfonylbenzoic acid, 2-hydroxyethyl ester, 125 ml of dry methylene chloride, and 7.7 ml of triethylamine was added dropwise over 10 minutes 6.3 ml of trimethylsilyl chloride (exotherm to 36° C.). The resulting solution was allowed to stand at ambient temperature for 18 hours and then washed with saturated sodium chloride solution, dried (MgSO4), and the solvent removed under reduced pressure to give an oil which was chromatographed on silica gel eluting with 25% EtOAc:hexane to give a colorless oil which slowly crystallized. Trituration with hexane gave 8.0 g of white crystals, m.p. 72°-76° C.
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[N:14][CH:15]=2)[CH:5]=1.CN(C=O)C.[N+:29]([C:32]([CH3:41])=[CH:33]NC1C=CC=CN=1)([O-:31])=[O:30]>O>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:20][C@@H:19]([CH:21]([CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH3:41])[NH2:22])[O:18][C:17]3=[O:23])=[N:14][CH:15]=2)[CH:5]=1
Reactant: NC[C@H]1CN(c2ccc(-c3cccnc3)cn2)C(=O)O1
Reactant: CC(=CNc1ccccn1)[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=CC(N)[C@@H]1CN(c2ccc(-c3cccnc3)cn2)C(=O)O1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
100 mg (0.37 mmol) of the compound from Example XXVIII (free base; prepared by dissolving in water, NH3(aq) addition to pH 11, extraction with CH2Cl2, drying over MgSO4 and concentrating) are initially introduced into 1 ml of DMF under argon and 200 mg (1.11 mmol) of 2-(2-nitro-prop-1-en-1-yl-amino)-pyridine are added and the mixture is stirred overnight. It is treated with water, extracted 3× with ethyl acetate, and the organic phase is washed with satd. NaCl solution and dried over MgSO4. It is concentrated and the residue is purified by column chromatography on silica gel (eluent CH2Cl2 :MeOH=100:5). 126 mg (96% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:25][CH3:26])[C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[C:12]2=[O:23])=[CH:5][N:4]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:6]([N:7]([CH2:25][CH3:26])[C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:23])=[CH:5][N:4]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1
Reactant: CCN(C(=O)CCC1CCN(C(=O)OC(C)(C)C)C1=O)c1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)CCC1CCNC1=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 3-(3-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(ethyl)amino)-3-oxopropyl)-2-oxopyrrolidine-1-carboxylate (0.076 g, 0.17 mmol) in dry CH2Cl2 (0.33 mL), TFA (0.33 mL) was added at room temperature under N2. The reaction was stirred at room temperature for about 90 minutes. Saturated aqueous NaHCO3 (about 10 mL) was carefully added until reaction mixture became basic. The product was extracted with CH2Cl2 (3×10 mL), dried and concentrated. The residue was purified by silica gel chromatography by eluting with 0%-15% MeOH/CH2Cl2 to afford the title compound F131 as a white foam (0.041 g, 66%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].CCN(CC)CC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([O:15][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:6][C:2]=1[C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)s1
Temperature: 50 °C
Yield: 70 %

Procedure:
A solution (0.1 M) of ethyl 5-bromo-4-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate in THF was treated with trimethylsilylacetylene (1.3 eq.), Et3N (1.5 eq.), CuI (0.04 eq.) and PdCl2(PPh3)2 (0.01 eq.). The solution was heated at 50° C. for 3 h. After cooling down, it was filtered through a pad of celite and washed with AcOEt. The organic layer was washed with brine and dried then concentrated and the residue was purified by flash chromatography on silica gel (1:19 AcOEt/petroleum ether) to afford the title compound (70%) as a solid.
Reaction SMILES: [N-]=C=O.[CH:4]([NH:6][CH:7]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[C:10](=[O:16])[CH2:9][CH2:8]1)=O.C(Cl)(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[O:16]=[C:10]1[C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH:7]([N+:6]#[C-:4])[CH2:8][CH2:9]1
Reactant: O=CNC1CCC(=O)c2sccc21
Agent: O=C(Cl)Cl
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]C1CCC(=O)c2sccc21

Procedure:
Alternatively, formula (Ia) isocyanate can be prepared by reacting the N-formyl-4,5,6,7-tetrahydro-7-oxobenzo-[b]thiophen-4-amine of formula (IIIa) with phosgene in the presence of a tertiary amine, e.g. triethylamine, in an inert solvent such methylene chloride and other chlorinated hydrocarbons at a temperature between about 0° and 50° C and preferably between 15° and 30° C to obtain 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanide of formula (IV), which is then oxidized with dimethylsulfoxide (DMSO) in the presence of anhydrous p-toluenesulfonic acid (pTSA) at a temperature between about 25° and 75° C, and preferably 25° and 50° C. The above-described reaction sequence may be graphically illustrated as follows: ##SPC3##
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([C:26]#[N:27])=[CH:21][CH:20]=3)[CH:12]=1>>[O:4]([CH2:3][CH2:2][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:26]#[N:27])=[CH:21][CH:20]=2)[CH:25]=[C:17]1[C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCOc1ccccc1
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Product: N#Cc1ccc2c(c1)cc(-c1cccnc1)n2CCOc1ccccc1

Procedure:
(2-Bromo-ethoxy)-benzene and 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8) are processed according to the method described in Example 57 to give 1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, MeOD) δ ppm 4.19 (t, J=5.2 Hz, 2H), 4.67 (t, J=5.1 Hz, 2H), 6.63 (d, J=7.8 Hz, 2H), 6.77 (s, 1H), 6.84 (t, J=7.5 Hz, 1H), 7.10-7.17 (m, 2H), 7.53 (dd, J=8.6, 1.8 Hz, 1H), 7.55-7.60 (m, 1H), 7.77 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 8.08-8.13 (m, 1H), 8.63 (dd, J=4.9, 1.6 Hz, 1H), 8.79 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 340.1453 [(M+H)+ Calcd for C22H18N3O: 340.1450].
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(OCC)(=O)C>[CH3:18][S:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])(=[O:21])=[O:20]
Reactant: COC(=O)c1ccccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Methyl anthranilate (11.73 g, 77.6 mmol) was dissolved in pyridine (25 mL, 309 mmol). Mixture was cooled to 0° C. Methanesulfonyl chloride (6.60 mL, 85.3 mmol) was added to the mixture drop-wise. Reaction mixture was warmed to room temperature and held with stirring overnight. Mixture was diluted with ethyl acetate. Material was washed twice with water and three times with 1N hydrochloric acid. Organic layer was dried (magnesium sulfate), filtered and then concentrated. Residue was triturated with 50% diethyl ether in hexanes. Solids were filtered off, washed with 50% diethyl ether-hexanes, washed with hexanes and then dried under high vacuum. Title compound was obtained as an off-white solid in 88% yield. MS m/e (M−H)−=227.9.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([S:8](=[O:19])(=[O:18])[N:9]([CH3:17])[CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:7]=1.C1(C)C=CC=CC=1.[CH3:27][N:28]=[C:29]=[O:30]>C(OCC)(=O)C>[CH3:1][N:2]([C:3]1[S:4][C:5]([S:8](=[O:19])(=[O:18])[N:9]([CH3:17])[CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:7]=1)[C:29]([NH:28][CH3:27])=[O:30]
Reactant: CN=C=O
Reactant: CNc1nnc(S(=O)(=O)N(C)Cc2cccnc2)s1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNC(=O)N(C)c1nnc(S(=O)(=O)N(C)Cc2cccnc2)s1

Procedure:
To a solution of 5.7 g. of 2-methylamino-5-[N-methyl-N-(3-pyridylmethyl)sulfamoyl]-1,3,4-thiadiazole (from Preparation 4) in 100 ml. of toluene was added 3 g. of methyl isocyanate. The mixture was heated at reflux for about 5 hours. The mixture was cooled and concentrated in vacuo to yield a semisolid residue. A sample of the semisolid subjected to thin layer chromatography in ethyl acetate showed three spots. The semisolid was chromatographed on a silica gel column using ethyl acetate. The eluate corresponding to the second spot material was collected. The eluate was concentrated to dryness in vacuo, leaving a residue. The residue was recrystallized from ethyl acetate to yield white crystals having a melting point of about 169°-170° C., and weighing about 2.2 g. The product was identified by NMR spectrum and elemental analyses as 1,3-dimethyl-1-[5-[N-methyl-N-(3-pyridylmethylsulfamoyl]-1,3,4-thiadiazol-2-yl]urea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[N:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[C:13]=[S:14]>C1C=CC=CC=1.C(N(CC)CC)C>[F:27][C:25]([F:26])([F:28])[C:17]1[CH:16]=[C:15]([NH:12][C:13]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=2)=[S:14])[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[N:18]=1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc(NC(=S)Nc2cc(C(F)(F)F)nc(C(F)(F)F)c2)cc1
Yield: 72.9 %

Procedure:
A mixture of 4-aminobenzotrifluoride (1.48 g) and 4-isothiocyanato-2,6-bis(trifluoromethyl)pyridine (2.5 g, 0.01 mole) in dry benzene (25 ml) containing several drops of triethylamine was heated under reflux for 7 hours. Removal of the solvent and triethylamine gave the title compound as a colorless solid 2.9 g, m.p. 125°-132° C. Crystallization from benzene furnished a sample, m.p. 132° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[O:13][C@@H:12]([CH2:14][OH:15])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].OO.C([OH:22])C>[OH-].[NH4+]>[NH2:1][C:2]1[N:6]([C@H:7]2[O:13][C@@H:12]([CH2:14][OH:15])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[N:5]=[CH:4][C:3]=1[C:16]([NH2:17])=[O:22]
Reactant: CCO
Reactant: N#Cc1cnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Agent: OO
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of (25) (4.60 g) in ammonium hydroxide (35 mL) was added 30% hydrogen peroxide (2 mL). The mixture was stirred in a pressure bottle at room temperature for 18 h, the pressure bottle was cooled, opened carefully and the volatile products were evaporated to dryness. The residue thus obtained was co-evaporated with ethanol (3×20 mL). The crude product on crystallization with ethanol/water gave pure compound 3.5 g (71%): 1H NMR (DMSO-d6) δ3.57 (m, 2H, C5′CH2), 3.86 (q, 1H, C4′H), 4.11 (q, 1H, C3′H) 4.43 (q, 1, C2′OH), 5.63 (d, 1H, J=3.99 Hz, C1′H), 6.51 (br s, 2H, NH2), 6.71 and 7.26 (2br s, 2H, CONH2) and 7.69 (s, 1H, C3H). Anal. Calc. for C9H14N4O5 (258.23): C, 41.86; H, 5.46; N, 21.69. Found: C, 41.57; H, 5.40; N, 21.61.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[OH-].[Na+]>[Pd].O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cncc(-c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.38 kg of 5-bromonicotinic acid, 1.10 kg of 4-fluorobenzeneboronic acid and 0.40 kg of Pd/activated carbon (5%) are introduced into 8.5 liters of water. The black suspension is rendered alkaline using 1.39 kg of 32% sodium hydroxide solution and warmed to 100° C. After 4 hours, the mixture is subjected to conventional work-up, giving 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: [BrH:1].C(O)(=O)C.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1>C(OCC)C>[BrH:1].[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 70 ml of a 25% hydrogen bromide-acetic acid solution was suspended 8.02 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane, and 2.96 g of dimethylsulfoxide sulfoxide was added thereto under ice cooling. The mixture was stirred at room temperature for 1.5 hours. Then, 140 ml of diethyl ether was added to the reaction mixture, and crystals precipitated were collected by filtration and recrystallized from methanol to obtain 8.55 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane hydrobromide
Reaction SMILES: [CH3:1][P:2]([O-:9])[O:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:10][C:11]([O:13][CH:14]([C:17]#[N:18])[CH:15]=[CH2:16])=[O:12]>>[C:11]([O:13][CH:14]([C:17]#[N:18])[CH2:15][CH2:16][P:2]([CH3:1])(=[O:9])[O:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:12])[CH3:10]
Reactant: C=CC(C#N)OC(C)=O
Reactant: CC(C)CCOP(C)[O-]
Product: CC(=O)OC(C#N)CCP(C)(=O)OCCC(C)C
Temperature: 72 °C
Reaction time: 2.75 h
Yield: 102.3 %

Procedure:
235.0 g of isopentyl methanephosphonite are heated to 72° C. under nitrogen. 0.5 g of tert.-amyl perpivalate is added to the solution, and 63.9 g of acrolein cyanohydrin acetate, in which 3.6 g of tert.-butyl pereodecanoate are dissolved, are added dropwise, with vigorous stirring at 72° C., within 2.75 hours. After reaction is complete, the mixture is stirred at 72° C. for 5 min, and 154.8 g of isopentyl methanephosphonite are distilled out. (Recovery: 94.8%). 143.8 g of 93.6% pure isopentyl (3-acetoxy-3-cyanopropyl)methylphosphinate (yield=97.9%) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.S(Cl)([Cl:19])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:19])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
1.52 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid was dissolved in 10 ml of chloroform, 0.55 ml of thionyl chloride was dropwise added, and 0.05 ml of DMF was added, followed by reflux for 30 minutes. After the reaction liquid was stood to cool, the solvent was distilled off under reduced pressure to obtain crude product of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride. Then, a mixed solution comprising the above crude product and 5 ml of toluene was dropwise added to a mixed solution comprising 0.5 ml of ethanethiol, 1.11 ml of triethylamine and 20 ml of chloroform under cooling with ice, followed by stirring for 5 minutes and reaction at room temperature for 14 hours. The reaction solvent was distilled off under reduced pressure, and 50 ml of water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 3/1) to obtain 1.4 g of the desired product in the form of light red crystals (melting point: 94° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>O1CCOCC1>[CH2:9]([O:11][C:12]([NH:14][C:15]([NH:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=1)=[S:16])=[O:13])[CH3:10]
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cc(Br)ccn1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 4-bromopyridin-2-amine (10.4 g, 60.1 mmol) in dioxane (242 ml) is added ethoxycarbonyl isothiocyanate (7.88 g, 6.8 ml, 60.1 mmol) at 25° C. The resulting mixture is stirred for 4 hours at 25° C. The solvent is evaporated, the solid yellow residue diluted with ethyl acetate and washed with water and brine. The organic layer is separated, dried over magnesium sulfate and the solvent is removed in vacuo affording 1-ethoxycarbonyl-3-(4-bromo-pyridin-2-yl)-thiourea (17.37 g, 95%) as a yellow solid. mp.: 107-110° C. MS: m/z=304.0, 305.9 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8]Cl)[N:7]=1.[C:10]1([CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:21]2[CH2:22][CH2:23][CH:18]([O:17][CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:19][CH2:20]2)[N:7]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A stirred mixture of 2-amino-4-chloromethylthiazole hydrochloride (0.7 g), 4-(diphenylmethoxy)piperidine (0.78 g) and triethylamine (1.82 ml) in N,N-dimethylformamide (7.8 ml) was heated at 40° C. to 45° C. for 5 hours. After cooling to ambient temperature, the reaction mixture was filtered. The filtrate was poured into water (50 ml) and extracted with ethyl acetate (80 ml×2). The extract was washed with a saturated aqueous solution of sodium chloride (30 ml) and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (30 g) and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.78 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18](=[O:24])[N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:16]=2)=[CH:8][CH:7]=1.[I-].[Na+].[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.ClCCl>C(#N)C>[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18](=[O:24])[N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:16]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cc1coc(-c2ccc(OCCCCl)cc2)n1)N1CCCC1
Reactant: CC1CCCN1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nc(CC(=O)N3CCCC3)co2)cc1
Yield: 50 %

Procedure:
To a solution of 2-[4-(3-chloropropoxy)phenyl]-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole ax64 (0.51 g, 1.46 mmol, 1 eq) in acetonitrile (10 ml) is added sodium iodide (0.022 g, 0.15 mmol, 0.1 eq) and 2-methylpyrrolidine (0.25 ml, 2.92 mmol, 2 eq). The mixture is stirred at reflux overnight. The mixture is poured into dichloromethane and washed with water. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. The crude product is purified by chromatography over silica gel (eluent: dichloromethane/methanol/ammonia 95:4.5:0.5) to give 0.29 g of 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole 52 as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[N:15]>ClCCl.C(N(CC)CC)C>[NH2:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH:11][S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(N)c1ccc(CCN)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)c1ccc(CCNS(=O)(=O)c2ccc(C#N)cc2)cc1

Procedure:
4-(1-Amino-1-methylethyl)phenethylamine (A18, 2.132 g) was treated with 4-cyanophenylsulphonyl chloride (2.63 g) in dichloromethane (35 ml) and triethylamine (1.8 ml) to give N-{2-[4-(1-amino-1-methylethyl)phenyl]ethyl}-4-cyanobenzenesulphonamide, as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)CNc1ccccc12
Reactant: Fc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC2(CC1)CN(c1ccccc1)c1ccccc12
Reaction time: 45 h

Procedure:
A mixture of 2.1 g of 1'-methylspiro[indoline-3,4'-piperidine] (Example 1b), 3 g of 50% sodium hydride and 12 ml of fluorobenzene in 18 ml of dimethyl sulfoxide is stirred at 65°-70° C. for 45 hours. The well stirred mixture is poured into water and extracted thrice with ether. The combined ether extracts are dried briefly before forming, the hydrochloride salt. The salt is collected, basified and then extracted into ether, giving a yellowish oil which is crystallized from hexane, producing off-white crystals, mp 90°-92° C. of 1'-methyl-1-phenylspiro[indoline-3,4'-piperidine].