Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:10](=[O:26])[C:11]([CH:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH2:14][N+:15]([O-])=O)[C:12]([CH:13]=1)=[C:5]23.P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:10](=[O:26])[C:11]([CH:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:14]#[N:15])[C:12]([CH:13]=1)=[C:5]23
Reactant: CCOC(=O)C(C#N)C1(C[N+](=O)[O-])C(=O)N2CCOc3cc(Cl)cc1c32
Solvent: O
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCOC(=O)C(C#N)C1(C#N)C(=O)N2CCOc3cc(Cl)cc1c32
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of ethyl 2-(8-chloro-2,3-dihydro-6-nitromethyl-5-oxopyrrolo[1,2,3-de]-1,4-benzoxazine-6-yl)-2-cyanoacetate (3 g) in pyridine (30 ml) was added phosphorous trichloride (1.6 g) on an ice bath, and stirred at room temperature for 4.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After removal of solvent, the title compound was obtained as dark reddish oil (0.9 g, 33%) by purification.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]([CH:10]([F:12])[F:11])([F:9])[F:8])([F:4])([F:3])[F:2].[Br:13]Br.C(=O)=O>>[C:1]([CH:5]([O:6][C:7]([CH:10]([F:11])[F:12])([F:8])[F:9])[Br:13])([F:4])([F:3])[F:2]
Reactant: FC(F)C(F)(F)OCC(F)(F)F
Reactant: BrBr
Agent: O=C=O
Product: FC(F)C(F)(F)OC(Br)C(F)(F)F
Temperature: 475 °C

Procedure:
CF3CH2OCF2CF2H (110 g.) was reacted with bromine (125 g.) by passing a mixture of the two diluted with a stream of nitrogen through a 12 inch × 1 inch glass tube heated to 475° C. The effluent product was condensed in a "Dry Ice" trap and purified by fractional distillation and preparative gas chromatography to give CF3CHBrOCF2CF2H., b.p. 80° C., nD25 1.3155. This product analyzed as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(Cl)(=O)C([Cl:17])=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([Cl:17])=[O:13])=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: O=C(Cl)c1cc2cc(F)ccc2[nH]1
Reaction time: 24 h

Procedure:
5-Fluoroindole-2-carboxylic acid is dissolved in oxalylchloride and stirred 24 hr at 20°-25° in the dark. The reaction mixture is concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)[CH3:2].[CH2:18]=O.[CH:20]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])(=[O:24])=[O:23])=[CH2:21]>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:18][CH:20]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:32])([F:34])[F:33])(=[O:23])=[O:24])[CH2:21][N:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=1)=[O:17])[CH3:2]
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)CNc1cccc(C(F)(F)F)c1
Reactant: C=O
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 343d, (3-trifluoromethyl-phenylamino)-acetic acid ethyl ester (CAS Reg. No. 2445-84-3) was reacted with paraformaldehyde and 1-ethenesulfonyl-2-trifluoromethyl-benzene (example 243c) to give the title compound as off-white solid. MS (ESI): m/z=496.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>ClC1C=CC=CC=1Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[S:9]([OH:12])(=[O:11])=[O:10]
Reactant: Nc1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(Br)cc1S(=O)(=O)O
Temperature: 180 °C

Procedure:
A mixture containing 31 g (180 mmol) of 4-bromoaniline and 9.7 ml (220 mmol) of sulphuric acid in 200 ml of 1,2-dichlorobenzene is heated at 180° C. for 6 hours. The reaction medium is allowed to cool to room temperature and is then filtered. The residue is washed with dichloromethane.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]([CH2:18]CO)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].Cl[CH2:22][Cl:23]>>[Cl:3][CH2:6][CH2:7][N:8]([CH2:18][CH2:22][Cl:23])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccccc1)N(CCO)CCO
Reactant: ClCCl
Product: O=C(Nc1ccccc1)N(CCCl)CCCl
Reaction time: 4 h

Procedure:
26.44 ml of thionyl chloride are added, at 0° C., to a solution of 0.173 mol of the product obtained in Step 1 in 100 ml of dichloromethane. After reacting for 4 hours at reflux and then for 12 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:45]1[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2.O>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2]>[N+:55]([C:52]1[C:51]2[N:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:45]([C:2]#[N:3])=[CH:54][CH:53]=1)([O-:57])=[O:56]
Reactant: O=[N+]([O-])c1ccc(Br)c2cccnc12
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c2ncccc12
Temperature: 100 °C
Yield: 73.1 %

Procedure:
Zn(CN)2 (739 mg, 6.3 mmol), DIPEA (0.41 ml, 2.37 mmol), X-phos (225 mg, 0.47 mmol) and Pd2 (dba)2 (90 mg, 0.16 mmol) were added to a degassed (with argon) solution of 5-bromo-8-nitroquinoline 470 (400 mg, 1.58 mmol) in DMF (4 ml) and the mixture was heated at 100° C. in microwave for 20 min. After cooling, the mixture was poured into water and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (96:4) as the eluent to give the title compound (230 mg, 63%).
Reaction SMILES: CN1CCN=C1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Br:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.[CH3:35][N:36]([N:38]=C1C=CC(N)=CC1)[CH3:37].C(Cl)CCl>CN(C=O)C.O>[CH3:35][N:36]([N:38]=[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Br:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH2:8]1)[CH3:37]
Reactant: CN1CCN=C1c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Br)cc1
Reactant: CN(C)N=C1C=CC(N)=CC1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Br)=CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of 2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 77, 60 mg, 0.16 mmol) and 4-(dimethylaminoimino)phenylamine (51 mg, 0.31 mmol) in DMF (4 mL) and H2O (1 mL), EDC (120 mg, 0.62 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (40 mg). MS 528.2 and 530.2 (M+H, Cl+Br pattern).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.CN(C)[CH2:14][CH2:15]CN=C=NCC.C(O)C>ClCCl.CN(C)C1C=CN=CC=1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 50 °C

Procedure:
To a suspension of 23.38 g (94.2 mmol) of 6-iodonicotinic acid in 100 ml of dichloromethane was added a solution of 19.86 g (103.6 mmol) of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride in 250 ml of dichloromethane. To this suspension was added 12.40 g (15.8 ml, 269.3 mmol) of ethanol (95%) and 1.15 g (9.4 mmol) of 4-dimethylaminopyridine. The resulting solution mixture was then heated at 50° C. in an oil bath for 24.5 hours, concentrated in vacuo, partitioned between 200 ml of water and 250 ml of ethyl ether, and the layers were separated. The aqueous phase was washed with 2×150 ml-portions of ethyl ether. All organic phases were combined, washed once with 75 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a yellow solid. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) yielded the title compound as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(Cl)c1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 309 under basic conditions (aq. NaOH/EtOH). 1H NMR (DMSO-d6, 300 MHz) δ 1.10-1.40 (m, 3H), 1.45-1.60 (m, 2H), 2.25-2.45 (m, 2H), 2.55-2.80 (m, 1H), 4.30 (m, 4H), 4.50 (m, 1H), 6.70 (d, J=8.0 Hz, 1H), 7.00 (m, 3H),7.10 (m, 1H), 7.25 (d, J=16.0 Hz, 1H), 7.48 (d, J=8.0 15.5 Hz, 1H), 7.90 (d, J=15.5 Hz, 1H). MS (ESI) m/z 458 (M+H)+. Anal. calcd. for C23H21ClNO5SNa.1.3 H2O: C, 54.69; H, 4.73; N, 2.45. Found: C, 54.67; H, 4.71; N, 2.77.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:23])[CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:23])[CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: CC1Cc2c(c3ccc(Br)cc3n2C)CN1C(=O)OC(C)(C)C
Reactant: O=C1CN(CCc2ccc(Cl)cc2)CCN1
Product: CC1Cc2c(c3ccc(N4CCN(CCc5ccc(Cl)cc5)CC4=O)cc3n2C)CN1C(=O)OC(C)(C)C
Yield: 58.9 %

Procedure:
tert-Butyl 7-bromo-3,5-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.316 mmol) and 4-(4-chlorophenethyl)piperazin-2-one (75 mg, 0.316 mmol) were reacted following the procedure for Example 2 (step f) to provide the title compound (100 mg, 59%) as a white solid: ESI MS m/z 537 [M+H]+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:33][CH2:32][C@H:31]([N:34]4[CH:38]=[N:37][CH:36]=[N:35]4)[CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.C(OCC)(=O)C>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:33][CH2:32][C@H:31]([N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)[CH2:30]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4cncn4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](n2cncn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.6 %

Procedure:
783 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] were suspended in 1.5 ml of anisole, and 7.5 ml of trifluoroacetic acid and 0.24 ml of trifluoromethanesulfonic acid were added to the resulting suspension, whilst ice-cooling, after which the mixture was stirred at room temperature for 1.5 hours. A cycle consisting of removing the solvent by evaporation under reduced pressure, washing the residue with hexane to remove anisole, adding diethyl ether to the mixture to solidify the product and milling the product, after which the mixture was decanted was repeated several times to obtain a powder. The whole of this powder was mixed with 40 ml of ethyl acetate and with an aqueous solution of sodium hydrogencarbonate, and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated by evaporation under reduced pressure, to give 713 mg of the title compound, as a powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C=O.ClCCl.[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>[CH2:16]([NH:15][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:5]2[C:6]([N:8]=1)=[N:7][C:2]([C:32]#[C:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:3][N:4]=2)=[O:14])[CH3:17]
Reactant: C#Cc1ccccc1
Reactant: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc2ncc(C#Cc3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
98.1 mg of 1-(3-chloropyrido[2,3-b]pyrazin-6-yl)-3-ethylurea (0.39 mmol), 10.1 mg copper(I) iodide (0.05 mmol) and 193 μl of triethylamine (1.38 mmol) were initially charged in 2 ml of anhydrous dimethylformamide under nitrogen as a protective gas. Subsequently, 29.1 mg of dichlorobis(triphenylphosphine)palladium(II) (0.04 mmol) and 54 μl of phenylacetylene (0.49 mmol) were added, and the mixture was stirred at room temperature for 16 h. For workup, the mixture was diluted with dichloromethane and added to dilute hydrochloric acid. The precipitated solid was filtered off with suction, and the organic phase was washed with dilute hydrochloric acid and distilled water. After phase separation, the organic solvent was removed under reduced pressure. The further purification was effected by column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[CH:11]([C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[S:16][CH:17]=1)=O.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5]2[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]3[CH:11]([C:13]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[S:16][CH:17]=3)[C:4]=2[C:3]1=[O:9]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1csc([N+](=O)[O-])c1
Product: CC1(C)CCC2=C(C1=O)C(c1csc([N+](=O)[O-])c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 4-formyl-2-nitrothiophene and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[CH:4]=[N:3]1.[Br-:10].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)C.O>[Br:10][CH2:8][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: [Br-]
Reactant: CC(=O)c1cnn(C)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cn1cc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-(1-methyl-1H-pyrazol-4-yl)ethanone (28.5 g, 230 mmol) in dichloromethane (400 mL) was diluted with absolute ethanol (100 mL) and treated portion-wise with pyridinium tribromide (95%, 77.3 g, 230 mmol). The reaction was stirred at room temperature for 3 hours, during which time it solidified; the mixture was diluted with dichloromethane (300 mL) and water (400 mL), treated with sodium sulfite (5 g) and stirred for 10 minutes. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with water (200 mL), collected by filtration, washed again with water, and dried to afford the product as an off-white solid. Yield: 41.6 g, 205 mmol, 89%. 1H NMR (500 MHz, CDCl3) δ 7.97-7.98 (m, 1H), 7.95 (br s, 1H), 4.17 (s, 2H), 3.95-3.96 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:26][CH:14]4[CH2:15][N:16]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:17][CH:13]4[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:26][CH:14]4[CH2:15][N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH:13]4[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(CC(=O)OC(C)(C)C)CC4C3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(CC(=O)O)CC4C3)cc12
Reaction time: 1 h

Procedure:
A solution of Example 293A (0.685 g, 1.423 mmol) and trifluoroacetic acid (2.74 mL, 35.6 mmol) in dichloromethane (12 mL) was stirred for 18 hours. The mixture was concentrated and the residue was dissolved in 5 mL dichloromethane and treated with 8 mL 2M hydrogen chloride in ether. The suspension was sonicated, diluted with ether, and stirred for 1 hour. The solid was filtered, washed with ether and vacuum oven-dried to give the title compound as a hydrochloride salt. MS (trifluoroacetic acid salt via HPLC) (ESI+) m/z 426.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[NH:8][C:6]1=[O:7])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].Cl[CH:23]([P:27]([O:32][CH2:33][CH3:34])(=[O:31])[O:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26]>>[CH2:1]([O:3][CH2:4][N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:26][CH2:25][CH2:24][CH2:23][P:27](=[O:31])([O:32][CH2:33][CH3:34])[O:28][CH2:29][CH3:30])[CH:11]=[N:10][C:9]=2[N:8]([CH3:16])[C:6]1=[O:7])[CH3:2]
Reactant: CCCC(Cl)P(=O)(OCC)OCC
Reactant: CCOCn1c(=O)[nH]c2nc[nH]c2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCOCn1c(=O)c2c(ncn2CCCCP(=O)(OCC)OCC)n(C)c1=O

Procedure:
4 g (0.018 mol) of 1-ethoxymethylxanthine were stirred at 70° C. for 6 hours with 3 g of potassium carbonate and 4.9 g (0.0214 mol) of diethyl chlorobutanephosphonate. The solution was filtered and concentrated, and the residue which remained was chromatographed (eluent: dichloromethane/methanol 20:1).
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:14][C:15]([CH3:17])=[CH2:16])[CH2:3][CH2:4][N:5]([C:9]([CH3:13])([C:11]#[CH:12])[CH3:10])[C:6](=[O:8])[O-:7].Br[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.[CH3:32]CN(CC)CC>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>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:12]#[C:11][C:9]([N:5]([CH2:4][CH2:3][C:2]([OH:1])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][C:15]([CH3:17])=[CH2:16])[C:6](=[O:7])[O:8][CH3:32])([CH3:10])[CH3:13])=[CH:26][CH:27]=1
Reactant: CCN(CC)CC
Reactant: C#CC(C)(C)N(CCC(O)(CC(=C)C)c1ccccc1)C(=O)[O-]
Reactant: Fc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=C(C)CC(O)(CCN(C(=O)OC)C(C)(C)C#Cc1ccc(F)cc1)c1ccccc1
Yield: 73 %

Procedure:
A microwave vial equipped with a flea stir bar was charged with 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-methylbut-3-yn-2-yl)carbamate (37 mg, 0.11 mmol), 1-bromo-4-fluorobenzene (39 mg, 0.22 mmol), Cul (2 mg, 0.011 mmol), Pd(PPh3)2Cl2 (4.7 mg, 0.007 mmol) and Et3N (1.5 mL). The mixture was sparged with N2 for 5 min and heated at 100 C for 2 h in the microwave. The mixture was concentrated and the residue was redissolved in EtOAc (90 mL), washed with 5% aq HCl (15 mL), satd aq NaHCO3 (15 mL) and brine (15 mL), and dried over Na2SO4. Removal of the solvent left an orange oil (46 mg) which was applied to a 2-g silica SPE cartridge and eluted sequentially with 0, 10, 25, 50 and 100% EtOAc in hexanes (15 mL of each) to give five fractions. Fractions 2 and 3 were pooled and concentrated to afford methyl 4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamate (35 mg, 73%) as an oil. LC-MS Method 1 tR=2.33 min, 406 (M−18).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[CH2:8][CH2:9][N:10]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:12]=[N:11]1.[CH3:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:37]>CN1CCCC1=O>[OH:34][C:31]1[CH:32]=[CH:33][C:28]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:20]=[CH:21][C:16]([N:13]4[CH:12]=[N:11][N:10]([CH2:9][CH2:8][NH:37][C@@H:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH3:35])[C:14]4=[O:15])=[CH:17][CH:18]=3)[CH2:23][CH2:24]2)=[CH:29][CH:30]=1
Reactant: O=c1n(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)cnn1CCBr
Reactant: C[C@@H](N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C[C@@H](NCCn1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1ccccc1
Temperature: 60 °C
Yield: 75.7 %

Procedure:
Reaction under N2 atmosphere. Na2CO3 (0.01 mol) was added to a mixture of 2-(2-bromoethyl)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H -1,2,4-triazol-3-one (0.0054 mol) in 1-methyl-2-pyrrolidinone (25 ml). This mixture was stirred at 60° C. A solution of (+)-(R)-α-methylbenzenemethanamine (0.0065 mol) in 1-methyl-2-pyrrolidinone (25 ml) was added dropwise and the resulting reaction mixture was stirred overnight at 60° C. The reaction mixture was cooled, poured out into ice-water and the resulting precipitate was filtered off, washed with water, then dried. This fraction was recrystallized from 2-propanol, filtered off and dried, yielding 1.98 g (77%)of (R)-2,4-dihydro4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-[(1-phenylethyl)amino]ethyl]-3H-1,2,4-Triazol-3-one (interm. 19).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]#[N:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]#[N:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol), K2CO3 (8.5 g, 61.6 mmol) and 2-chloroacetonitrile (5.5 g, 73 mmol) in acetonitrile (250 ml) was heated at reflux for 24 hours. The in,solubles were filtered off and rinsed with methylene chloride (DCM). During concentration of the solvents on the rotary evaporator, crystals appeared. The crystals were collected and weighed 5.79 g. The product in the mother liquor was further purified by flash chromatography over a silica gel column (SiO2, 70 g; eluted with DCM, and 1% CH3OH in DCM). The second crop of product thus obtained weighed 5.2 g. The total yield was 10.9 g. The sample was recrystallized once more form ethanol, m.p. 130°-132° C.