Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.C([O-])(=O)C.[Na+].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[C:19]([OH:24])[N:18]=1>O>[NH2:16][C:17]1[N:18]=[C:19]([OH:24])[C:20]2[CH:2]=[CH:1][NH:23][C:21]=2[N:22]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: CCOC(CBr)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(O)c2cc[nH]c2n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of 136.7 g of bromoacetaldehyde diethylacetal, 347 mL of water, and 17.3 mL of concentrated HCl was heated to about 90° C. with vigorous stirring for about 30 minutes, at which time a clear solution was obtained. The solution was cooled to ambient temperature and 68.3 g of sodium acetate was added. The resulting solution was added, with stirring, to a suspension of 100 g of 2,4-diamino-6-hydroxypyrimidine and 34.2 g of sodium acetate in 739 mL of water, which had been heated to 70°-85° C. The reaction was allowed to proceed for 2 hours at 70°-85° C., at which time the reaction was complete. The mixture was cooled to 0° C. and stirred for about 1.5 hours. The mixture was then filtered and the collected product was washed with 500 mL of water and 500 mL of acetone, and dried, affording 72.3 g (79%) of 2-amino-4 -hydroxy-7H-pyrrolo[2,3-d]pyrimidine, mp>300° C. NMR δ6.03 (s, 2H), 6.13 (m, 1H), 6.56 (dd, J=3.3, 2.3 Hz, 1H), 10.23 (br s, 1H), 10.93 (br s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].CN.[CH2:14]([N:16](CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:16][CH3:14])=[O:7]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1cccc(CCl)c1
Temperature: 25 °C

Procedure:
A solution of 3-chloromethylbenzoyl chloride (7.4 g, Aldrich) in DCM (35 ml) was added dropwise at 0° C. over 30 minutes to a stirred mixture of 30% aqu. methylamine (4.5 ml) and triethylamine (3.6 g) in DCM (50 ml). When addition was complete, the mixture was allowed to warm to room temperature over 1 hour with stirring. Further methylamine (0.5 ml) was added and the mixture stirred for a further 10 minutes, then washed with water, 1N aqu. HCl, 1N aqu. NaOH and brine, dried over MgSO4 and evaporated in vacuo to give the desired product as a colourless oil which solidified to a white solid on standing.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.[BH3-]C#N.[Na+].[C:20](O)([C:22]([F:25])([F:24])[F:23])=O>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:20][C:22]([F:25])([F:24])[F:23].[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH:13]([F:14])[F:15])[NH:6]2
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: O=C(O)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1Cl)CC(C(F)F)N2
Product: N#Cc1ccc2c(c1Cl)CC(C(F)F)N2CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %
Yield: 40 %

Procedure:
To an ice-cold suspension of 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile (0.010 g, 0.044 mmol) in TFA (1 mL) was added NaCNBH3 (0.028 g, 0.44 mmol) in portions. After 10 min, the cold bath was removed and the mixture stirred at rt. After 1.5 h, additional NaCNBH3 (0.014 g, 0.22 mmol) was added and the mixture was stirred at rt another 20 min. The mixture was concentrated to dryness in in vacuo at 45° C. The residue was partitioned between EtOAc and 0.2N NaOH. The organic phase was washed with a sat'd NaHCO3 solution and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by radial chromatography (10-100% CH2Cl2-hexanes) to afford 4-chloro-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole-5-carbonitrile (0.004 g, 29% yield) (MS (ES) m/z 311 (M+1)) and 4-chloro-2-(difluoromethyl)-2,3-dihydro-1H-indole-5-carbonitrile (0.004 g, 40% yield) (MS (ES) m/z 229 (M+1)).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](=O)[CH3:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:12])[CH:24]=[CH:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(C=Cc1ccc2ccccc2c1)c1ccc2ccccc2c1

Procedure:
Synthesised according to example 1.59.1, using 2-naphthaldehyde (10.9 g, 64.03 mmol) and 1-(naphthalen-2-yl)ethanone (11.9 g, 64.03 mmol); yellow solid; yield: 18.8 g (95%);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[C:5]=1[NH2:12].[CH2:14](N(CC)CC)[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)(=O)C>C1(C)C=CC=CC=1.Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]2[O:11][C:14]([CH3:15])=[N:12][C:5]=12)=[O:13]
Reactant: COC(=O)c1ccc(Br)c(O)c1N
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Br)c2oc(C)nc12
Temperature: 25 °C

Procedure:
To a solution of 2-amino-4-bromo-3-hydroxy-benzoic acid methyl ester (Example 6.3) (2.46 g) in toluene (250 ml) was added sequentially triethylamine (1.53 ml), pyridinium p-toluenesulfonate (“PPTS”) (0.75 g) and acetyl chloride (0.78 ml). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with aqueous hydrochloric acid (1M) (100 ml) and ethyl acetate (200 ml). The phases were separated and the organic extract was washed with aqueous hydrochloric acid (1M) (150 ml) and brine (150 ml) and then dried over sodium sulfate. The solids were removed by filtration and the filtrate was concentrated to give 7-bromo-2 methyl-benzo[d]oxazole-4-carboxylic acid methyl ester (2.94 g). 1H-NMR (400 MHz, CDCl3): 7.87 (d, 1H), 7.52 (d, 1H), 4.04 (s, 3H), 2.77 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@:11]3([CH3:25])[N:12]=[C:13]([NH:16]C(=O)C4C=CC=CC=4)[S:14][CH2:15][C@H:10]3[CH2:9][O:8][C:6]=2[CH:7]=1.N1C=CC=CC=1.CO[NH3+].[Cl-]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@:11]3([CH3:25])[N:12]=[C:13]([NH2:16])[S:14][CH2:15][C@H:10]3[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: C[C@]12N=C(NC(=O)c3ccccc3)SC[C@H]1COc1cc(F)ccc12
Agent: CO[NH3+]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@]12N=C(N)SC[C@H]1COc1cc(F)ccc12
Temperature: 50 °C
Yield: 70.2 %

Procedure:
A mixture of rel-N-((4aR,10bS)-8-Fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-yl)benzamide from step F5 (1.27 g, 3.56 mmol), pyridine (1.0 mL, 12.36 mmol), and hydroxylamine methyl ether hydrochloride (1.0 g, 12.0 mmol) in ethanol (100 mL) was heated at 50° C. for 24 h. The mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using silica gel column chromatography (5-10% MeOH/dichloromethane) to afford rel-(4aR,10bS)-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-amine (644 mg, 2.50 mmol, 70% yield) as a viscous yellow oil. LCMS (M+H)+=253.1. 1H NMR (500 MHz, chloroform-d) δ 7.59 (dd, J=8.8, 6.6 Hz, 1H), 6.73-6.65 (m, 1H), 6.51 (dd, J=10.1, 2.6 Hz, 1H), 4.40 (dd, J=11.4, 2.8 Hz, 1H), 4.21 (dd, J=11.4, 5.7 Hz, 1H), 3.15-3.02 (m, 2H), 2.14 (dddd, J=8.4, 5.7, 3.7, 2.9 Hz, 1H), 1.60 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:21]([Cl:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]([C:32]3[N:36]([CH3:37])[C:35]([CH3:38])=[N:34][CH:33]=3)=[O:31])[CH:19]=2)[N:14]=1>C1COCC1>[Cl:12][C:13]1[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:21]([Cl:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]([C:32]3[N:36]([CH3:37])[C:35]([CH3:38])=[N:34][CH:33]=3)([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:31])[CH:19]=2)[N:14]=1
Reactant: Cc1ncc(C(=O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)n1C
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(O)(c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)c2cnnn2C)n1C
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (125 mg, 1.5 mmol) was added THF (10 mL) and the colorless solution was cooled to −45° C. Then, n-BuLi (2.5 M in hexanes, 0.6 mL, 1.5 mmol) was added affording a suspension. The suspension was stirred between −40° C. and −10° C. for 30 minutes, then a THF solution of (2,4-dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (500 mg, 1.26 mmol, Intermediate 18: step b, in 5 mL THF) was introduced and the mixture was allowed to warm up to room temperature. After 1 hour, the reaction mixture was heated to 40° C. for 3 hours and then quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (3×50 mL) and then with DCM (3×50 mL). The individual organic portions were washed with brine, dried over MgSO4, filtered, combined and concentrated to dryness. Chromatography on silica gel (5% MeOH-DCM increasing to 10% MeOH) provided material which was re-purified by preparative TLC (5% 2 M-NH3-MeOH-EtOAc) to provide the title compound as light tan solid. 1H NMR (500 MHz, CDCl3) δ 8.45-8.36 (m, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.66-7.46 (m, 4H), 7.46-7.30 (m, 2H), 7.01 (s, 1H), 5.94 (s, 1H), 3.91 (s, 3H), 3.34 (s, 3H), 2.17 (s, 3H). MS (ESI): mass calcd. for C24H20Cl2N6O, 478.1, m/z found 479.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH2:3][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Product: CC(C)(CN1CCCCC1)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with piperidine to provide the title compound: C13 NMR (100 MHz, CDCl3) 23.8, 25.6, 26.6, 57.0, 60.9, 69.2, 118.3, 134.4; MS m/z 253.3 (M+1).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=O)[C:19](=[O:22])[C:18]=3[O:23]C)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:25][NH2:26]>CO.C(Cl)(Cl)Cl.C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:18](=[O:23])[C:19](=[O:22])[C:20]=3[NH:26][CH3:25])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Reaction time: 2 h

Procedure:
A solution of 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.25 g.) in warm methanol/chloroform (50:50 v/v) (50 ml.) was treated with 14 ml. of a solution of methylamine in ethanol (33% w/v) and the resulting solution allowed to stand at room temperature for 2 hours. Concentration of the reaction mixture gave a crystalline solid (0.21 g.) which was collected and washed with a small volume of methanol to give 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methylaminocyclobutene-3,4-dione, obtained as the hemihydrate, m.p. 263°-268° (decomp.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3(O)CCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(Cl)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A 250-mL single-neck round bottomed flask equipped with a magnetic stirrer was charged with methyl 4-chlorosalicylate (25.0 g, 134 mmol) followed by concentrated sulfuric acid (73 mL) and the resulting suspension cooled to 0° C. using an ice bath. Concentrated nitric acid (6.20 mL, 147 mmol) was then added and the reaction stirred for 1 h at 0° C. After this time, the reaction was poured into ice and the resulting precipitate collected by vacuum filtration. The filter cake was washed with water (20 mL) and then re-crystallized from hot ethanol (100 mL) to afford methyl 4-chloro-3-nitrosalicylate in 52% yield (16.0 g) as white solid: 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=2.7 Hz, 1H), 8.11 (d, J=2.7 Hz, 1H), 4.03 (s, 3H); MS (ESI) m/z 232 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].Cl.[O-:14][C:15]#[N:16].[K+]>>[CH3:1][C:2]([CH3:12])([CH3:11])[CH:3]([NH:4][C:15]([NH2:16])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#C[O-]
Reactant: CC(C)(C)C(N)c1ccccc1
Agent: Cl
Agent: [K+]
Product: CC(C)(C)C(NC(N)=O)c1ccccc1

Procedure:
In a manner simnilar to that described for Intermediate 16B, 2,2-dimethyl-1-phenylpropan-1-amine was reacted with HCl and potassium cyanate to provide 1-(2,2-dimethyl-1-phenylpropyl)urea. MS: [M+H]+ m/z 207.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[F:25][C:26]([F:39])([O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:27]([Cl:30])([Cl:29])[Cl:28].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][C:26]([F:25])([F:39])[C:27]([Cl:28])([Cl:29])[Cl:30])=[CH:38][CH:37]=3)=[O:20])=[CH:23][CH:24]=1)[CH:6]=[N:5]2
Reactant: Nc1ccc(OC(F)(F)C(Cl)(Cl)Cl)cc1
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)C(Cl)(Cl)Cl)cc1

Procedure:
A solution of 4.35 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propanoyl chloride (previously prepared from 1.5 g of the corresponding acid) in 15 ml of acetonitrile was added to a mixture prepared from 1.20 g (4.35 mmol) of 4-(1,1-difluoro-2,2,2-trichloroethoxy)aniline, 0.66 g (6.5 mmol) of triethylamine and 10 ml of acetonitrile. The mixture was warmed at reflux for a period of 2.5 hours and then poured over ice and aqueous NaOH added. The resulting precipitate was filtered and dried and then recrystallized from methylcyclohexane. This left 2.2 g (84 percent of theoretical) of the above-named product as a brown solid, m.p. 139°-141° C. (Compound 36)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[N+:15]([O-])=O)C.COC1C=CC2OCC(=O)NC=2C=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][CH2:5][C:4](=[O:3])[NH:15][C:8]=2[CH:9]=1
Reactant: CCOC(=O)CSc1ccc(OC)cc1[N+](=O)[O-]
Agent: COc1ccc2c(c1)NC(=O)CO2
Product: COc1ccc2c(c1)NC(=O)CS2

Procedure:
Prepared from ethyl[(4-methoxy-2-nitrophenyl)thio]acetate (Intermediate 53, 3 g, 11 mmol) according to procedure described for preparation of Intermediate 48. Silica gel chromatography with hexanes/ethyl acetate (3:2) afforded desired product, 2 g (93%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13]Cl)[C:4]=2[O:3]1.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>>[CH2:16]([O:18][P:19]([CH2:13][CH2:12][O:11][C:10]1[C:4]2[O:3][C:2]([CH3:15])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:23])[O:20][CH2:21][CH3:22])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: CC1(C)Cc2cccc(OCCCl)c2O1
Product: CCOP(=O)(CCOc1cccc2c1OC(C)(C)C2)OCC

Procedure:
68.2 g. (0.3 mole) 2,3-dihydro-2,2-dimethyl-7-(2'-chloro-ethoxy)-benzofuran (prepared according to Examples 1 or 2) and 49.86 g. (0.3 mole) triethylphosphite are stirred at 140°-146° C. for 60 hours and heated. When the reaction is completed the obtained yellowish brown oily product is purified by vacuum distillation by distilling off the volatile contaminations at 0.5 torr. The cuts are collected until 148° C. and the distillation residue is a pure product according to gas chromatographic analysis. The product is a pale yellow oily liquid, nD24.5 =1.5101 (compound No. 1).
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6](O)=O.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C1CCCCC1>[C:1]1(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:16]1([OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCCCCCCO
Reactant: O=C(O)CCCCC(=O)O
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
Instead of pure adipic acid, dicarboxylic acid solution (DCS) has also been used as a starting material for the preparation of 1,6-hexanediol. It is obtained as a waste product in the oxidation of cyclohexane with air to give cyclohexanone and cyclohexanol, by extraction of the oxidized mixture with water.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](Cl)=[O:33]>>[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([C:32]([N:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C@H:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:9]2)=[O:33])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1
Reactant: C1CCNC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(F)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCCC2)[C@H](c2ccc(F)cc2)C1

Procedure:
The title compound, MS: m/e=489.3 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(4-fluoro-phenyl)-piperidin-4-one, pyrrolidine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[N:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:29]2[CH2:28][CH2:27][N:26]([C:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:15]4[CH:16]=[CH:17][N:12]=[CH:13][N:14]=4)[CH2:19][CH2:20]3)=[O:25])[CH2:31][CH2:30]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N2CCN(C(=O)C3CCN(c4ccncn4)CC3)CC2)cc1
Yield: 46.2 %

Procedure:
A solution of 4-cyanobenzoyl chloride (298 mg) in dichloromethane (10 ml) was added to a stirred mixture of 1-[1 (4-pyrimidinyl) piperidin-4-ylcarbonyl] piperazine (412.5 mg) and triethylamine (0.28 ml) in dichloromethane (15 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between dichloromethane and water. The organic phase was washed with water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography using 0.5 % methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-cyanobenzoyl)-4-[l-(4-pyrimidinyl)-4-piperidylcarbonyl]piperazine (280 mg), mp 192-193° C.;
Reaction SMILES: [C:1]([N:4]1[CH:16]2[CH:5]1[C:6]1([OH:23])[O:17][N:14]([CH2:15]2)[C:13]2[C:8](=[C:9]([OH:20])[CH:10]=[C:11]([CH:18]=[O:19])[CH:12]=2)[CH:7]1[CH2:21][OH:22])(=[O:3])[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[C:24]1([NH:30][C:31](=[O:32])[O:22][CH2:21][CH:7]2[C:6]3([OH:23])[O:17][N:14]([CH2:15][CH:16]4[CH:5]3[N:4]4[C:1](=[O:3])[CH3:2])[C:13]3[C:8]2=[C:9]([O:20][C:31](=[O:32])[NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=[C:11]([CH:18]=[O:19])[CH:12]=3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(=O)N1C2CN3OC(O)(C(CO)c4c(O)cc(C=O)cc43)C21
Solvent: CN(C)C=O
Product: CC(=O)N1C2CN3OC(O)(C(COC(=O)Nc4ccccc4)c4c(OC(=O)Nc5ccccc5)cc(C=O)cc43)C21
Reaction time: 0.5 h

Procedure:
To a solution of 11-acetyl-6,9-dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (18 mg) in dimethylformamide (1.0 ml) was added a mixture of phenyl isocyanate (12.5 μl) in dimethylformamide (1.25 ml) in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath and then stirred for additional 1 hour at ambient temperature. The mixture was evaporated in vacuo and subjected to preparative thin layer chromotography, which was developed with a mixture of chloroform and methanol (15:1, v/v) to afford 11-acetyl-4-formyl-9-hydroxy-6-(N-phenylcarbamoyloxy)-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl N-phenylcarbamate (12 mg).
Reaction SMILES: C[O:2][C:3](=[O:57])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:16][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:14][C:13]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)=[CH:6][C:5]=1[O:55][CH3:56].[OH-].[Na+]>C1COCC1.CCO>[CH3:56][O:55][C:5]1[CH:6]=[C:7]([CH2:10][O:11][C:12]2[C:13]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=3)=[CH:14][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:57])=[O:2]
Reactant: COC(=O)c1ccc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 2-methoxy-4-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-2′yloxymethyl]-benzoic acid methyl ester (0.352 g, 0.44 mmol, 1 eq) in THF/EtOH (3/2) (10 mL) was added 1M NaOH (4 mL) and the reaction was stirred at rt overnight. It was then concentrated in vacuo, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane +1% Formic acid) to afford the title compound (0.342 g, 865) as a white foam. 1H NMR (DMSO-d6) δ 12.50 (bs, 1H); 8.59 (t, 1H); 7.99-7.92 (m, 6H); 7.80-7.68 (m, 4H); 7.37 (d, 1H); 7.26-7.10 (m, 5H); 6.38 (s, 1H); 6.30 (d, 1H); 4.21 (s, 2H); 3.58 (s, 3H); 3.26 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.28 (m, 8H); IR (KBr) 3350, 2950, 2850, 1720, 1640, 1620, 1550, 1495, 1475, 1415, 1320, 1160, 1150, 1120, 1095, 1080, 1030 cm−1; mass spectrum [(+)APCI], m/z 778 (M+H)+; Anal. Calcd. for C44H41F6NO5: C, 67.95; H, 5.31; N, 1.80, Found: C, 67.22; H, 5.22; N, 1.74.