Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:17])[C:13]=1[C:14]([NH2:16])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:17])[C:13]=1[C:14](=[S:19])[NH2:16]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)c1c(Cl)cncc1Cl
Solvent: c1ccncc1
Solvent: O
Product: NC(=S)c1c(Cl)cncc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
Into a 3000-mL three-necked round bottom flask equipped with a condenser, mechanical stirrer under an atmosphere of nitrogen was added pyridine (1500 mL), then 3,5-dichloro-4-pyridine-carboxamide (92.9 g., 0.486 mole) (which dissolved), and tetraphosphorus decasulfide (237 g., 0.535 moles)(which had almost dissolved then a bright yellow precipitate formed and an exotherm heated the mixture to 60° C.). The slurry was allowed to stir for 1 hr (temperature had dropped to 45° C.) and then the temperature was then raised and when it reached 100° C. all of the solids had dissolved and continued heating to 118° C. and was maintained at 115° C. for 4 hr. The mixture was poured into water (3750 mL) carefully as gas began to evolve and the temperature of the aqueous solution rose to approximately 45° C. and was allowed to sit at room temperature over two nights. To the resulting mixture was added water (6000 mL) and was extracted with methylene chloride (3×2000 mL), washed with water (3×1000 mL) and the solvent removed in vacuo to give a brownish yellow liquid, with much pyridine present. The vacuum pump was connected to the rotary evaporator to remove the residual pyridine. The residue (brown solid) was triturated with diethyl ether (3×1500 mL), treated with decolorizing carbon and the solvent removed in vacuo to give a solid which contained pyridine. The yellow solid was slurried in water (2×200 mL) and dried in vacuo at 60° C. to give 63.2 g of a light yellow solid (62.8% yield): mp 186-187° C.; TLC[50/50 ethyl acetate/hexanes] showed amide at Rf=0.31 and thioamide Rf=0.53; 1H NMR (DMSO-d6) d 10.6 (s, b, 1H), 10.0 (s, b, 1H), 8.6 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].CO.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(CC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1cccc(CC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]propionate (1.378 g, 3.309 mmol), sodium hydroxide (0.26 g, 6.62 mmol), methanol (10 ml), water (5 ml) and tetrahydrofuran (10 ml) was stirred overnight at room, temperature. The reaction solution was concentrated and diluted with water, acidified with 1N hydrochloric acid and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]propionic acid as a liquid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:10]([NH:11][C:12]([C:14]2[C:15](=[O:32])[N:16]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[C:22]([C:23]=2[OH:24])=[CH:21][CH:20]=[CH:19][N:18]=3)=O)=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].NS(C1C=C(Br)C=CC=1NC(C1C(=O)N(CC2C=CC=CC=2)C2C(C=1O)=CC=CN=2)=O)(=O)=O>>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][N:18]=2)[C:23]([OH:24])=[C:14]([C:12]2[NH:11][C:10]3[CH:9]=[CH:8][CH:7]=[N:6][C:5]=3[S:2](=[O:4])(=[O:3])[N:1]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NS(=O)(=O)c1ncccc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Agent: NS(=O)(=O)c1cc(Br)ccc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: O=c1c(C2=NS(=O)(=O)c3ncccc3N2)c(O)c2cccnc2n1Cc1ccccc1

Procedure:
The title compound was prepared according to the procedure of Example 84D substituting the product of Example 100A for the product of Example 84C to give after purification by reverse phase HPLC (water/acetonitrile/0.1% NH4OAc gradient) the title compound as a white solid (0.053 g, 10%). MS (ESI−) m/z 432 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 5.70 (m, 2H), 7.25 (m, 7H), 7.50 (dd, J=7.91, 4.60 Hz, 1H), 7.80 (dd, J=8.46, 4.41 Hz, 1H), 8.17 (d, J=8.46 Hz, 1H), 8.60 (m, J=5.79, 1.88, 1.88 Hz, 1H), 8.68 (dd, J=4.41, 1.10 Hz, 1H), 8.82 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C:5]=1[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])([O-])=O.C(OC1C=C(C=CC=1[N+]([O-])=O)C(OCC=C)=O)C=C.N>>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C:5]=1[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17]
Reactant: C=CCOC(=O)c1cccc([N+](=O)[O-])c1C(=O)OCC=C
Agent: C=CCOC(=O)c1ccc([N+](=O)[O-])c(OCC=C)c1
Agent: N
Product: C=CCOC(=O)c1cccc(N)c1C(=O)OCC=C

Procedure:
The above nitro compound was reduced by the method described in example 1, for the reduction of allyl 3-allyloxy-4-nitrobenzoate, except using an aqueous solution of ammonia in place of sodium bicarbonate in the work-up, to give diallyl 3-aminobenzene-1,2-dicarboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.C([O:21][C:22](=O)[C:23]([Cl:26])([Cl:25])[Cl:24])C>C1(C)C=CC=CC=1>[CH3:16][NH:15][C:13](=[O:14])[C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:22](=[O:21])[C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)C(Cl)(Cl)Cl)cc2)ccn1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
4-(4-aminophenoxy)-N-methylpicolinamide (35 g, 0.144 mol) was mixed with ethyl-2,2,2-trichloroacetate (50 ml, 0.27 mol) in toluene (350 ml) at ambient temperature. The mixture was then heated to 100° C. under distillation mode for 2-3 hours. The organic solvent was degassed under reduced pressure to obtain oil. This oil was triturated with hexane (500 ml) to obtain (49 g) of the desired solid.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1.[NH2:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[O:25][C:24]([CH2:26][N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1>>[CH3:29][N:27]([CH2:26][C:24]1[O:25][C:21]([CH2:20][S:19][CH2:18][CH2:17][NH:16][C:3]2[NH:8][C:7](=[O:9])[C:6]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][N:4]=2)=[CH:22][CH:23]=1)[CH3:28]
Reactant: CSc1ncc(-c2ccccc2)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CN(C)Cc1ccc(CSCCNc2ncc(-c3ccccc3)c(=O)[nH]2)o1
Yield: 79.2 %

Procedure:
A mixture of 2-(methylthio)-5-phenyl-4(3H)-pyrimidinone (1.09 g) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (2.14 g) was heated at 140° for 4 h. The cooled residue was chromatographed (silica/ethyl acetate-methanol, 1:1) to give a product which was crystallised from methyl acetate-light petroleum (b.p. 60°-80°) yielding the title compound (1.52 g) m.p. 116°-118°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29](O)=[O:30])=[CH:19][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C1(CN)CC1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:46][CH2:45][CH:44]5[CH2:42][CH2:43]5)=[O:30])=[CH:19][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NCC2CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (0.07 g, 0.15 mmol) and HATU (0.07 g, 0.18 mmol) in DMF (4.0 mL) was added N,N-diisopropyl-ethylamine (0.024 g, 0.032 mL, 0.18 mmol). After 30 min, cyclopropylmethanamine (0.016 g, 0.23 mmol) was added. After 18 h the reaction mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with EtOAc then the combined organic phase was washed with water and brine, dried (MgSO4). filtered and concentrated. The residue was purified by chromatography (silica, 24 g Analogix column, 30-100% EtOAc in hexanes, gradient over 40 min) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(cyclopropylmethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.049 g, 0.096 mmol, 63%) as a white solid. 1H NMR (CDCl3) δ: 9.25 (s, 1H), 8.47 (d, J=8.8 Hz, 1H), 8.30-8.39 (m, 2H), 7.49 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 5.73 (s, 2H), 4.17 (s, 3H), 3.59 (t, J=8.2 Hz, 2H), 3.42-3.54 (m, 2H), 1.22 (dd, J=13.1, 6.5 Hz, 1H), 0.95 (t, J=8.0 Hz, 2H), 0.66 (d, J=7.5 Hz, 2H), 0.40 (d, J=4.3 Hz, 2H), −0.04 (s, 9H)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:30](=[O:53])[CH2:31][C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[S:40][C:41]([CH2:44][O:45]C3CCCCO3)=[N:42][N:43]=2)[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][CH2:44][C:41]1[S:40][C:39]([C:35]2[CH:34]=[C:33]([C:32]3[CH2:31][C:30](=[O:53])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)=[N:43][N:42]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nnc(COC3CCCCO3)s2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nnc(CO)s3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,3,4]thiadiazol-2-yl]-phenyl}-propionic acid tert-butyl ester (0.23 g) (Example K30) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.02 g).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][NH2:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:21])=[O:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:38]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=480.1 (M+H)+
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[Br:9])(=[O:3])[CH3:2]>C(O)C>[Br:9][C:8]1[CH:7]=[CH:6][O:5][C:4]=1[CH:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1occc1Br
Solvent: CCO
Product: CC(O)c1occc1Br
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
2-Acetyl-3-bromofuran (1.6 g, 8.5 mmoles), made by the method of YA. L. Goldfarb, M. A. Marakathina and L. I. Belen'kii, Chem. of Heterocyclic Compounds, USSR, 6, 132 (1970) was dissolved in 15 ml of ethanol and NaHB4 (0.096 g, 26 mmoles) added at room temperature. After stirring for 1.5 hours, 3-bromo-2-(1-hydroxy-ethyl)-furan (1.60 g) was isolated as a yellow oil that was purified by chromatography with silica gel to yield 0.94 g (58%) of the pure product, NMR (CDCl3, δ) 7.33 (1H, d, J = 2Hz), 6.4 (1H, d, J = 2Hz), 5.13 (1H, q), 2.33 (1H, d), 1.57 (3H, d, J = 7Hz).
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[C:13]([CH:18]=[O:19])[C:14](F)=[C:15]([F:16])[C:10]=2[O:9][N:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C@H:28]1[O:33][C@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>C(#N)CCC.O.[Cl-].[Na+].O.C(OCC)(=O)C>[F:1][CH:2]([F:20])[CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[C:13]([CH:18]=[O:19])[C:14]([N:30]3[CH2:29][C@@H:28]([CH3:27])[O:33][C@H:32]([CH3:34])[CH2:31]3)=[C:15]([F:16])[C:10]=2[O:9][N:8]=1)=[O:6]
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: O=Cc1cc2c(C(=O)NCC(F)F)noc2c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCC#N
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2c(C=O)cc3c(C(=O)NCC(F)F)noc3c2F)C[C@@H](C)O1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
N-(2,2-Difluoroethyl)-6,7-difluoro-5-formylbenzo[d]isoxazole-3-carboxamide (Intermediate 243, 2.86 g, 9.86 mmol) was dissolved in butyronitrile (50 mL) and water (2.5 mL). Potassium carbonate (1.362 g, 9.86 mmol) and (2R,6R)-2,6-dimethylmorpholine (1.481 mL, 11.83 mmol) were added and the reaction was stirred at 90° C. for 4 hours. The crude reaction mixture was diluted with water, brine and ethyl acetate. The mixture was washed 2× with brine. The aqueous layer was back-extracted with ethyl acetate. The organic layers combined, dried over MgSO4 and concentrated. The residue was dissolved in DCM and purified by silica gel column chromatography using a gradient of DCM to ethyl acetate. Fractions were combined and concentrated to give the title compound.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:15]([C:17]1[O:18][C:19]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)=[O:16])=[O:8])C>O.O1CCCC1.CO>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:19]2[O:18][C:17]([C:15]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]3[C:7]([OH:8])=[O:6])=[O:16])=[CH:21][CH:20]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of lithium hydroxide monohydrate (0.027 g, 0.64 mmol) in water (1 mL) was added to a solution of (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid ethyl ester (0.085 g, 0.2 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL). The mixture was stirred overnight at room temperature and then the solvents were evaporated under reduced pressure. Water and ethyl acetate were added, and the mixture was acidified to pH 2 with 1 M HCl and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated. The residue was triturated with ether. The ether and dissolved impurities were removed by Pasteur pipette to give (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid (66 mg, 83%) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([N:27]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:22]1.C(OC1C(OC2CCCCO2)=CC=C2C=1C=NN2C1CCCCO1)CC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:78]([O:81][C:82]1[C:90]([OH:91])=[CH:89][CH:88]=[C:87]2[C:83]=1[CH:84]=[N:85][NH:86]2)[CH2:79][CH3:80].CN.C(O)C>O1CCCC1>[CH2:78]([O:81][C:82]1[C:90]([O:91][C@@H:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([NH2:27])[CH2:22]2)=[CH:89][CH:88]=[C:87]2[C:83]=1[CH:84]=[N:85][NH:86]2)[CH2:79][CH3:80]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](O)C1
Reactant: CCCOc1c(O)ccc2[nH]ncc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCOc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
Under a nitrogen atmosphere, triphenylphosphine (164 mg, 0.624 mmol), the trans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (128 mg, 0.520 mmol) obtained in Example 385, (b) and diisopropyl azodicarboxylate (113 μl, 0.572 mmol) were added at 0° C. to a solution of the 4-propoxy-1H-indazol-5-ol (100 mg, 0.520 mmol) obtained in Example 634 in tetrahydrofuran (4 ml). After 30 minutes, the resulting mixture was heated to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform and washed with a 1M-aqueous sodium hydroxide solution. The aqueous layer was re-extracted with chloroform and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). To the oil thus obtained was added a 30%-methylamine-ethanol solution at room temperature, and the resulting mixture was refluxed. After 2 hours, the mixture was concentrated under reduced pressure at room temperature, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain cis-3-[(4-propoxy-1H-indazol-5-yl)oxy]cyclohexanamine (82.3 mg, 55%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[N:20]>C1C(O)=CC=CC=1C>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[NH:20])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: N#CN1CCCCC1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2N)cc1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2NC(=N)N2CCCCC2)cc1

Procedure:
A mixture of 2-amino-4'-methanesulphonylbiphenyl hydrochloride (2.3 g), N-cyanopiperidine (1.3 g) and m-cresol (10 ml) was heated at 90°-95° C. for 10 hours to give N-(4'-methanesulphonyl-2-biphenylyl)piperidine-1-carboxamidine (m.p. 128°-129° C.) which was recrystallised from hexane.
Reaction SMILES: C(OC([NH:8][N:9]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:10])=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[C:18]([Si:15]([CH3:16])([CH3:17])[O:14][CH2:13][CH2:12][CH2:11][N:9]([CH3:10])[NH2:8])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(CCCO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(N)CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N′-[3-(t-Butyl-dimethyl-silanyloxy)-propyl]-N′-methyl-hydrazinecarboxylic acid t-butyl ester (120 mg, 377 μmol) was at 0° C. combined with dichloromethane (2 mL) and trifluoroacetic acid (2 mL) to give a light yellow solution. The reaction mixture was stirred for 2 h at 0° C. and subsequently concentrated in vacuo to give the title compound as yellow oil, which was used without further purification in the next step.
Reaction SMILES: C([NH:9][C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[CH:15][C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]1=2)=[S:11])(=O)C1C=CC=CC=1.[OH-].[K+]>O>[C:10]([N:12]1[C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=2)(=[S:11])[NH2:9]
Reactant: O=C(NC(=S)N1c2ccccc2C=Cc2ccccc21)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=S)N1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.3 %

Procedure:
3.56 g (0.01mole) of 5-(N-benzoyl thiocarbamoyl)-5H-dibenz(b,f)-azepine is suspended into 37.5 ml of cold water. 3.6 ml of 30% aqueous potassium hydroxide is added and the suspension is heated to boilling. A yellow solution is produced, out of which the reaction product (5-thiocatbamoyliminostilbene) starts to separate after 15 minutes. After boiling for 2.5 hours the suspension is cooled to 25° C. and the desired product is separated by filtration, washed profusely with cold water (25° C.), until the pH of rinsing water is adjusted to about 5. After drying at 50° C., 2.38 g of 5-thiocarbamoyl-5H-dibenz(b,f)-azepine is obtained (m.p. 192°-194° C.). After recrystallization from benzene a product with a 197°-197.5° C. melting point is obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Product: COc1cc2ncc(NC3CCCCC3)nc2cc1OC
Temperature: 135 °C
Yield: 69 %

Procedure:
To 0.3 g (1.34 mmol) of 2-chloro-6,7-dimethoxyquinoxaline is added approx. 1 mL of cyclohexylamine. The mixture is heated overnight at 105° C. and a further 10 hours at 135° C. The mix is partitioned between CH2Cl2 and saturated NaHCO3. The organic layer is dried (MgSO4) and concentrated. The resulting syrup is chromatographed (1:1EtOAc:CH2Cl2) to provide 0.265 g of the product as a lt. brown solid in 69% yield (m.p. 188-189.5). Anal. calcd for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.82., H, 7.28: N, 14.45.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28]Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:17][CH2:28][CH2:27][CH2:26][NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2cc1O
Reactant: CC(C)(C)OC(=O)NCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2cc1OCCCNC(=O)OC(C)(C)C
Yield: 99.6 %

Procedure:
A mixture of 3.8 g (12.88 mmol) ethyl 7-bromo-3-hydroxynaphthalen-2-carboxylate, 3.0 g (15.5 mmol) 1-(tert.-butoxycarbonylamino)-3-chloropropane (prepared according to Helv. Chim. Acta 76 (1993), 1644), 2.0 g (14.5 mmol) potassium carbonate, and a catalytic amount of potassium iodide in 20 ml dry DMF was stirred at 90° C. for 6 h. It was poured into water, extracted three times with ethyl acetate, and the combined organic layers were washed three times with water, dried over sodium sulfate, and concentrated in vacuo. The intermediate was purified by chromatography on silica gel with toluene/acetone 9:1 to give 5.8 g (100%) of a yellow oil, which solidified rapidly upon standing.