Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O-:9])=O)=[N:4][N:3]=1.[K+].C(Cl)(=O)C(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[C:27](=[CH:28][C:29]([O:33][C@H:34]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=4)[C@@H:35]([NH2:37])[CH3:36])=[CH:30][CH:31]=3)[CH:26]=[N:25]2)=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.N>C1COCC1.CCOC(C)=O.C(#N)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:32]3[C:27](=[CH:28][C:29]([O:33][C@H:34]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=4)[C@@H:35]([NH:37][C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)=[O:9])[CH3:36])=[CH:30][CH:31]=3)[CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1nnc(C(=O)[O-])o1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nnc(C)o2)c1
Temperature: 2.5 °C

Procedure:
Potassium 5-methyl-[1,3,4]oxadiazole-2-carboxylate (31.8 mg, 0.19 mmol) was mixed with acetonitrile (195 μl). A slurry was formed. The mixture was cooled to 0-5° C. oxalyl chloride (14.99 μl, 0.17 mmol) was added and the reaction was stirred for 1 h at 0-5° C. (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 25 mg, 0.06 mmol) was dissolved in dry THF (400 μl). N,N-diisopropylethylamine (65.6 μl, 0.38 mmol) was added. The THF solution was cooled to 0-5° C. The acid chloride slurry was drop wise added to the amine solution. The reaction was stirred at 0-5° C. After 1.5 h the reaction was poured into a mixture of EtOAc and diluted ammonia (ca 5%). The mixture was shaken, the organic layer collected. The water phase was washed twice with EtOAc. The combined organic layers were dried over sodium sulphate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[O-][CH2:15][CH3:16].[Na+]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[C:15]1([CH:16]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC[O-]
Reactant: O=C(c1ccc(Cl)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)C(=Cc1ccccc1)c1ccc(Cl)cc1
Yield: 68 %

Procedure:
4'-Chloro-2,2,2-trifluoroacetophenone (R. Fuchs, J. Org. Chem. 22, 993-994 (1957)) is reacted with benzyl-triphenylphosphonium chloride in the presence of an ethanolic solution of sodium ethoxide. The product is crystallized from hexane. 1-Phenyl-3,3,3-trifluoro-2-(4-chlorophenyl)-propene is obtained with a yield of 68%; m.p.: 63-66° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:22][O:23][CH3:24])[C:12]([NH:14][C@H:15]2[C@@H:18]([CH2:19][OH:20])[NH:17][C:16]2=[O:21])=[O:13])[N:10]=1)=[O:4].N1C=CC=CC=1.[Cl:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl.CN(C)C=O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:22][O:23][CH3:24])[C:12]([NH:14][C@H:15]2[C@@H:18]([CH2:19][O:20][C:33](=[O:34])[CH2:32][Cl:31])[NH:17][C:16]2=[O:21])=[O:13])[N:10]=1)=[O:4]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CO)c1csc(NC(=O)CCl)n1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1COC(=O)CCl)c1csc(NC(=O)CCl)n1

Procedure:
In a mixture of 17 ml of methylene chloride and 6 ml of N,N-dimethylformamide is dissolved 172 mg of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-hydroxymethyl-2-oxoazetidine (syn-isomer), followed by addition of 0.2 ml of pyridine. While the mixture is cooled with ice-sodium chloride mixture and stirred, 0.12 ml of chloroacetyl chloride is added dropwise. The mixture is stirred under cooling for 30 minutes and the solvent is distilled off. To the residue are added aqueous sodium chloride and ethyl acetate, and the mixture is shaken well. The organic layer is separated and washed with aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is crystallized from ether. Recrystallization from chlorform-methanol gives colorless crystals of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-chloroacetoxymethyl-2-oxoazetidine (syn-isomer), m.p. 225°-227° C. (decomp.).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14](S(C)(=O)=O)[CH2:15]S(C)(=O)=O)[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH:14]2[C:10]([C:11]#[N:12])([CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CC(CN(CCC#N)Cc1ccccc1)S(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: N#CC12CC1CN(Cc1ccccc1)C2
Reaction time: 2 h
Yield: 49 %

Procedure:
N-Benzyl-N-(2-cyanoethyl)-2,3-dimethanesulfonylpropylamine (32.25 g, 85.2 mmol) was dissolved in benzene (800 ml), cooled to -10°, and treated with sodium hexamethyldisilazide (170 ml of a 1M solution in tetrahydrofuran, 170 mmol). After 2 hours, the reaction mixture was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatographic purification (eluant: 4:1 hexane:ethyl acetate) gave the title product as a yellow oil (8.23 g, 41.5 mmol, 49% yield. 1H NMR (CDCl3): 7.26 (m, 5H), 3.59 (s, 2H), 3.11 (d, J=9 Hz, 1H), 2.94 (d, J=9 Hz, 1H), 2.54 (d, J=9 Hz, 1H), 2.47 (dd, J=10, 4 Hz, 1H), 2.03 (m, 1H), 1.57 (m, 1H), 1.10 (dd, J=8, 5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:44]1([NH2:49])[CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:49][CH:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: NC1CCCC1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(NC4CCCC4)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 92 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with cyclopentylamine yielded the title compound (92% yield) as a yellow waxy solid. MS (ISP): m/z=658.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)C1=Nc2cc(Cl)ccc2C(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Ethyl 7-chloro-4-quinolone-2-carboxylate (1.0 g, 4 mmol) is stirred with sodium hydride (0.144 g, 6 mmol) in DMF (50 mL) for 1 h at 40° C. N-Phenyl (trifluoromethylsulfon)imide (2.0 g, 5.6 mmol) is added and, after an hour, 1-tert-butoxycarbonylpiperazine (3.0 g, 6 mmol). The reaction mixture is stirred at 50° C. for 15 h, concentrated, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography with CH2Cl2-MeOH yielding the title product as a colorless solid.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]([C:8]1[C@H:9]2[CH2:17][C@@H:16]3[O:18][C@:15]3([CH3:19])[C@@H:10]2[CH:11]([OH:14])[O:12][CH:13]=1)=[O:7].[Cl:20][CH2:21][C:22]([N:24]=[C:25]=[O:26])=[O:23]>CCCCCC.C(OCC)(=O)C>[CH3:4][O:5][C:6]([C:8]1[C@H:9]2[CH2:17][C@@H:16]3[O:18][C@:15]3([CH3:19])[C@@H:10]2[C@@H:11]([O:14][C:25](=[O:26])[NH:24][C:22](=[O:23])[CH2:21][Cl:20])[O:12][CH:13]=1)=[O:7]
Reactant: COC(=O)C1=COC(O)[C@@H]2[C@@H]1C[C@@H]1O[C@@]12C
Reactant: O=C=NC(=O)CCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1=CO[C@H](OC(=O)NC(=O)CCl)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
A dichloromethane solution containing 100 mg of a known (4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-1-hydroxy-7-methylcyclopenta[c]pyrane-4-carboxylic acid methylester was cooled with ice followed by addition of chloroacetylisocyanate (45 ml) and stirring for 15 hours at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ethyl acetate eluate in the form of (1R,4aS,6S,7R,7aR)-1-(chloroacetylcarbamoyloxy)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c]pyrane-4-carboxylic acid methylester (137 mg, yield: 91%). The physicochemical properties of this compound are described in Table 8, Compound No. 40.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C([O-])=O.N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(OC)cc1OC
Reaction time: 0.33 h

Procedure:
83 g of 2,4-dimethoxybenzaldehyde and 66 g of monoethyl malonate are dissolved in 100 ml of dry pyridine and, after addition of 1 ml of piperidine and 40 g of molecular sieves, refluxed until evolution of CO2 has ceased. The reaction mixture is cooled and then poured onto crushed ice, and the pH is adjusted to 1-2 with concentrated hydrochloric acid, while stirring. Stirring is continued for 20 minutes, and the product which has separated out is filtered off with suction, washed with 1 N hydrochloric acid and water and dried in a desiccator. Yield: 100.2 g, melting point 58° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][O:5][CH2:4][NH:3]1.[C:8]([NH:15][CH2:16][CH2:17][C:18](O)=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[CH3:1][C:2]1([CH3:7])[CH2:6][O:5][CH2:4][N:3]1[C:18](=[O:19])[CH2:17][CH2:16][NH:15][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC1(C)COCN1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)N1COCC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 139.5 %

Procedure:
To a mixture of 4,4-dimethyloxazolidine (287 μl; 2 mmol; 1 eq) and boc-beta-alanine (416.3 mg; 2.2 mmol; 1.10 eq) in DCM (30 ml), are added triethylamine (832 μl; 6 mmol; 3 eq) and 2-chloro-1-methylpyridinium iodide (1533 mg; 6 mmol; 3 eq). The mixture is stirred for 2 days at RT. The reaction is followed by TLC cyclohexane/EtOAc 1:1). The reaction mixture is then washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layer is dried over Na2SO4, filtered and concentrated to give 760 mg of an orange oil, which is purified by flash chromatography (cyclohexane/EtOAc gradient, from 9/1 to 1/1 over 30 min). The title product is isolated as a white-off solid (420.5 mg; 77%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[N:10][CH:9]=[C:8]2[C:13]([O:15][CH3:16])=[O:14].[F-:17]>C1C=CC=CC=1>[F:17][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[N:10][CH:9]=[C:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: [F-]
Reactant: COC(=O)c1cnnc2c(CCl)cccc12
Solvent: c1ccccc1
Product: COC(=O)c1cnnc2c(CF)cccc12

Procedure:
A mixture of 0.35 g of 58B, 3.0 g of Amberlyst A26 fluoride resin and 5 ml of benzene was stirred vigorously at mild reflux in a nitrogen atmosphere overnight. The resulting mixture was filtered, and the filtrate was stripped of solvent. The residue was chromatographed over silica gel, using a 1:99 v:v mixture of ethyl acetate and methylene chloride as eluent, to give 58, as a yellow solid, m.p.: 104°-105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:13])=[C:5]2[OH:23].[C:24](NC1C=C2C(C(O)=C(C(NCC3C=CC(Cl)=CC=3)=O)C=N2)=CC=1)(=[O:26])[CH3:25].NC1C=C2C(C(O)=C(C(NCC3C=CC(Cl)=CC=3)=O)C=N2)=CC=1>>[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:13])=[C:5]2[OH:23])(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Reactant: Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Product: CC(=O)Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1

Procedure:
This compound is prepared from 6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide using a procedure similar to that used to prepare 7-(acetylamino)-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide from 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide. The product is obtained as a tan powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:13](C)[CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:19][CH2:18][CH2:17][C:5]=13.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:19][CH2:18][CH2:17][C:5]=13
Reactant: CN1CCc2ccc(Cl)c3c4c(n(c23)CC1)CCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1ccc2c3c1c1c(n3CCNCC2)CCC1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
To a solution of 8-chloro-3-methyl-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (1.0 g, 3.64 mmole) in dichloroethane (200 mL) was added 1-chloroethyl chloroformate (2.0 mL, 18.35 mmole) and refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (200 mL) and refluxed for another 3 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The dark residue was dissolved in methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 3% methanol in dichloromethane) provided 0.70 g of the title compound as a white solid. 0.12 g of the above solid was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 226-228° C. MS (ES) m/z 261.09 ([M+H]+), MS (ES) m/z 302.12 ([M+ACN+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:23]=[CH:24][C:25]=1[NH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cn1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)cn1
Temperature: 40 °C
Yield: 100.4 %

Procedure:
A mixture of 5-[3-(benzyloxy)-4-nitrophenoxy]-2-(methylsulfonyl)pyridine (28.0 g), calcium chloride (0.78 g), iron (powder, 19.0 g), ethanol (500 mL) and water (110 mL) was refluxed for 5 h. The mixture was cooled to 40° C. and filtered through a celite pad. The filtrate was concentrated in vacuo to remove ethanol. The residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=2:1, volume ratio) to give the title compound (26.0 g, 100%) as light brown crystals. MS 371 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1.C(#N)C.C(=O)=O.[B]1OC2C(=CC=CC=2)O1.O>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[Br:1][C:2]1[CH:25]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]([C@H:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.9 %

Procedure:
To a solution of methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (6.15 g, 15.03 mmol, 1 equiv) in toluene (200 mL) was added (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,2,3]oxazaborole (9.0 mL of a 1M solution in toluene, 9.02 mmol, 0.6 equiv). The solution was cooled to −25° C. (acetonitrile/CO2) and catechol borane (8.7 mL of a 50% solution in toluene, 36.1 mmol, 2.4 equiv) was added. The cooling bath temperature was maintained between −15° C. and −25° C. for 4 h. The reaction was then diluted with EtOAc (35 mL) and 10% aqueous solution of K2CO3 (35 mL) and then allowed to warm to ambient temperature. The quenched solution was stirred for 45 min and then added to water. Extract with ether (×3). Combined ether extracts dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-70% EtOAc/hexane) to provide (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate as a pale yellow glass (5.68 g, 92%). 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 1H), 5.54 (d, J=5.2 Hz, 1H), 4.51 (d, J=5.0 Hz, 1H), 3.81 (s, 3H), 3.73-3.14 (m very broad, 4H), 2.62 (s, 3H), 1.60-1.54 (m, 4H), 1.11 (s, 6H); LCMS (ESI, M+1): 411.05.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:8]=2)[CH:6]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH:13]([C:11]1[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[N:3]=[CH:4]2)[N:12]=1)([CH3:15])[CH3:14]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-isopropyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.66) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.125 g, 59%). MS (ISP) 425.3 [(M+H)+]; mp 274.5° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N+:16]([CH2:19][CH2:20][CH3:21])([O-:18])=[O:17].C1CCN2C(=NCCC2)CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH:19]([N+:16]([O-:18])=[O:17])[CH2:20][CH3:21])[CH2:9][C:8]2=[O:13])=[CH:14][CH:15]=1
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Reactant: CCC[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Reaction time: 24 h

Procedure:
To a solution 1-(4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (2.0 g, 10 mmol) in 1-nitropropane (8.68 g, 97.5 mmol) was added DBU (1.48 g, 9.75 mmol). After stirring for 24 hours, the reaction mixture was concentrated under vacuum. The residual material was purified by silica gel column chromatography eluting with 1% methanol in CH2Cl2. The appropriate fractions were combined and concentrated to afford the title compound as mixture of diastereomers. The diastereomers co-eluted with a retention time of 3.01 min. The HPLC method was performed on a Hewlett-Packard Zorbax SB-C8 column (75×4.6 mm, 3.5 micron) eluting with 5%-100% CH3CN (0.1% TFA) in H2O (0.1% TFA). ES MS M+1=295.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:14])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=O.[C:15]1([NH:21][C:22]([NH2:24])=[S:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25]>CN(C)C=O>[ClH:25].[NH:21]([C:22]1[S:23][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([OH:14])[C:8]([OH:13])=[C:9]([CH:12]=2)[C:10]#[N:11])[N:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1cc(C(=O)CBr)cc(O)c1O
Reactant: NC(=S)Nc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2csc(Nc3ccccc3)n2)cc(O)c1O
Reaction time: 5 h

Procedure:
3.8 g of 5-(bromoacetyl)-2,3-dihydroxybenzonitrile dissolved in 25 ml of N,N-dimethylformamide are treated with N-phenylthiourea and stirred at 100° for 5 hours. Thereafter, the solvent is removed by evaporation. The residue is treated with 200 ml of 1N sodium carbonate solution and extracted three times with 100 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 30 g of silica gel with ethyl acetate. The thus-obtained crude product is treated with 40 ml of 1N hydrochloric acid, evaporated and crystallized from acetone. There is obtained 5-(2-anilino-4-thiazolyl)-2,3-dihydroxybenzo- nitrile hydrochloride of m.p. 245°-247°.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:14]2[NH:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].[CH3:24]I>COCCOC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:14]2[C:10](=[N:11][C:12]([CH3:24])([CH3:15])[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1nc2cccc(NCc3c(C)cc(F)cc3C)c2[nH]1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(F)cc(C)c1CNc1cccc2c1=NC(C)(C)N=2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
4-(2,6-Dimethyl-4-fluorobenzylamino)-2-methylbenzimidazole (0.1 g, 0.35 mmol) was dissolved in 1,2-dimethoxyethane (3 ml). Solid sodium hydroxide (25 mg, 0.63 mmol) and tetrabutylammonium bromide (5 mg, 0.016 mmol) were added. The mixture was stirred 15 minutes at ambient temperature. Methyl iodide (60 mg 0.42 mmol) was added and the reaction mixture was stirred at ambient temperature for 2.5 h. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using methylene chloride: ethyl acetate (50: 50) as eluent. 80 mg (76%) of the title compound was obtained.