Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 100 °C

Procedure:
A mixture of 2,6-dichloro-9H-purine (5.0 g, 26.5 mmol), methyl 2-bromopropanoate (5.3 g, 31.7 mmol) and potassium carbonate (11.0 g, 79.4 mmol) in anhydrous DMF (100 mL) was heated at 100° C. for 15 h. Sat. aqueous sodium bicarbonate solution was added and reaction was extracted with ethyl acetate (150 ml×3). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (10 to 80% ethyl acetate in hexane eluant) to afford the title compound as a white solid. MS m/z 275.0 (M+1).
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:32][C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:25]=5[N:24]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[C:33]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][N:36]=1)#[N:34].CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:32][C:26]4[CH2:27][CH2:28][N:29]([C:39]([C:38]5[CH:42]=[CH:43][C:35]([C:33]#[N:34])=[N:36][CH:37]=5)=[O:40])[CH2:30][CH2:31][C:25]=4[N:24]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Reactant: N#Cc1ccc(C(=O)Cl)cn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(C#N)nc3)CC4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 28 mg, 44 μmol) in DMF (1 mL), was added 6-cyano-nicotinoyl chloride (Preparation 46, 20.9 mg, 141 μmol), and DIPEA (31 μL, 176 μmol). The reaction mixture was stirred at room temperature for 18 hours and then saturated aqueous sodium hydrogen carbonate solution (5 mL) was added. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method A to afford 10.3 mg of the title compound.
Reaction SMILES: CN(C)[S:3]([C:6]1[CH:7]=[C:8]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:9]([N:11]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:10])(=[O:5])=[O:4].[CH3:39]S(C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=O)=O>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][N:11]([C:9](=[O:10])[C:8]1[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=[C:6]([S:3]([CH3:39])(=[O:5])=[O:4])[CH:7]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1)c1cnccc1-c1cccnc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1OC

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-ylamino)-acetic acid methyl ester (example 178, intermediate) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). The product-containing fractions were pooled and evaporated. The remaining solid was purified by preparative HPLC (Gemini NX column) with a gradient of methanol:water (containing 0.05% formic acid) (80:20 to 98:2). Light yellow foam (32%). MS (ESI): m/z=524.108 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([NH2:13])=O)=[N:9][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:5]2=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>S1(CCCC1)(=O)=O.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]#[N:13])=[N:9][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:5]2=[N:6][CH:7]=1
Reactant: NC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1nn(Cc2ccccc2F)c2ncc(F)cc12
Temperature: 25 °C

Procedure:
17.3 g (60.0 mmol) of the compound obtained in Example 7 were heated to 103°-107° C. in 40.5 ml of sulpholane and 5.4 ml of acetonitrile. Thereafter, 6.9 g (45.0 mmol) of phosphorus oxychloride were slowly added dropwise while stirring, the dropping funnel was rinsed with 2.8 ml of acetonitrile, then the mixture was stirred at 107° C. for 1.5 h until conversion was complete (HPLC). Thereafter, the mixture was cooled to room temperature, and 2.8 ml of sulpholane/acetonitrile (5:1 vol/vol) and then 17.8 ml of water were added dropwise. The mixture was stirred for 0.5 h, a solution of 9.4 g of aqueous ammonia (28%) in 22.7 ml of water was added dropwise and the mixture was stirred for a further 2 h. The precipitated solids were filtered off with suction, washed three times with 20.5 ml each time of water and dried in a vacuum drying cabinet at 50° C. under a gentle nitrogen stream. This gave 14.7 g (91.9% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18][CH2:19][CH2:20]Br.O>CN(C)C=O>[CH3:17][O:18][CH2:19][CH2:20][N:14]1[CH2:15][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][CH2:12][C:13]1=[O:16]
Reactant: O=C1CCCC(c2ccccc2)CN1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CC(c2ccccc2)CCCC1=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.32 g, 8.03 mmol) was added to a solution of 6-phenylazepan-2-one (0.76 g, 4.02 mmol) in N,N-dimethylformamide (15 mL) at 0° C., followed by the addition of 2-bromoethyl methyl ether (0.837 g, 6.03 mmol), and the mixture was allowed to warm to ambient temperature. After 21 h, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. MS 248 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:34](=[O:35])[CH2:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(Cl)Cc1ccccc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)Cc5ccccc5)c4)CC3)cccc2n1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and phenylacetyl chloride.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([NH2:66])[CH:61]=2)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59]>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=2)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc(-c2cccc(N)c2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1OC
Temperature: 25 °C
Yield: 64.2 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,4′-Dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 64% yield: LCMS (ESI) m/z 432 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9].CCCCCC>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9]
Reactant: COC(=O)CCSCc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1
Solvent: CCCCCC
Solvent: CCO
Product: COC(=O)CCSCc1ccc(-c2nocc2NC(=O)O[C@H](C)c2ccccc2Cl)cc1
Yield: 49 %

Procedure:
Methyl 3-(4-{4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-isoxazolyl}benzylsulfanyl)propionate (110 mg, 0.232 mmol) was subjected to optical resolution by high performance liquid chromatography (HPLC) (hexane:ethanol=8:2) using CHIRALCEL OD column (2 cm I.D.×25 cm L; DAICEL CHEMICAL IND., LTD) to give the title compound (R form, 54 mg, 49%) along with its S form (55 mg, 50%). The optical purity was determined by HPLC analysis using an optically active column.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:21][CH:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[CH:29]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([S:32]([N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8]3[S:9][C:10]4[CH:16]=[C:15]([C:17]5[CH2:18][CH2:19][N:20]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:21][CH:22]=5)[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH2:5][CH2:6]2)(=[O:34])=[O:33])[CH2:31][CH2:30]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Product: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(S(=O)(=O)C5CC5)CC4)sc3c2)CC1

Procedure:
Example 22 was prepared from Compound 15A and cyclopropanesulfonyl chloride in a similar manner to the procedure described for Example 1. 1H NMR (599 MHz, DMSO-d6) δ ppm 7.93 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 6.23 (br. s., 1H), 5.35 (ddd, J=7.5, 3.7, 3.5 Hz, 1H), 3.96 (br. s., 2H), 3.50 (t, J=5.6 Hz, 4H), 3.35 (m, 2H), 3.00-3.14 (m, 2H), 2.60-2.69 (m, 3H), 2.15-2.26 (m, 2H), 1.98 (d, J=7.6 Hz, 2H), 1.70-1.82 (m, 2H), 0.94-1.10 (m, 7H). LC/MS (m/z)=526 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12].Br[CH2:14][CH2:15][CH2:16]Br.[H-]>CCCCC.CN(C=O)C.O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:11]#[N:12])[CH2:16][CH2:15][CH2:14]1
Reactant: N#CCc1ccccc1Br
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCC
Product: N#CC1(c2ccccc2Br)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaH (80% dispersion in mineral oil, 127 mmol) was washed several times with n-pentane and suspended in DMF (50 mL). A mixture of 2-bromophenylacetonitrile (51 mmol) and 1,3-dibromopropane (51 mmol) in DMF (50 mL) was added dropwise to the ice-cold mixture. The reaction mixture was stirred at room temperature for 3 h. Excess hydride was then decomposed by the cautious addition of H2O. Extraction with toluene, drying of the organic layer (MgSO4) and evaporation of the solvent afforded 1-(2-bromophenyl)-cyclobutanecarbonitrile that was refluxed with KOH (210 mmol) in ethyleneglycol (50 mL) for 4 h. The resulting solution was then allowed to cool to room temperature, toluene and H2O were added and the layers were separated. The aqueous layer was acidified and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to provide the desired product. The yield was 8.5 g (65%); 1H NMR (CDCl3) δ 1.80-1.93 (m, 1H), 2.20-2.40 (m, 1H), 2.54-2.65 (m, 2H), 2.86-2.96 (m, 2H), 7.07-7.15 (m, 1H), 7.29-7.37 (m, 2H), 7.53 (d, 1H)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:22][CH3:23].[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>O>[CH3:23][O:22][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1CSCCN1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCSCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
1,2-Dibromoethane (19.2 ml, 286 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (6.0 g, 22 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (14.4 g, 107 mmol) in DMF. The mixture was stirred at 85° C. for 2.5 hours, allowed to cool and insoluble material was removed by filtration. The solvent was removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol (93/7). The product was trituated with ethyl acetate to give 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (5.3 g, 63%). A mixture of 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (2.0 g, 5.3 mmol) in thiomorpholine (15 ml) was stirred at ambient temperature for 5 hours. The mixture was diluted with water and the resulting precipitate collected by filtration. The solid product was dissolved in methylene chloride, washed with brine and passed through phase separating paper. The solvent was removed by evaporation to give 6-methoxy-4-phenoxy-7-(2-thiomorpholinoethoxy)quinazoline (2.0 g, 94%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:20]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a cooled (0° C.) solution of 2,4-difluoroaniline, (1.5 g, 11.6 mmol) in DCM (50 mL) was added triethylamine (1.9 mL, 13.9 mmol) followed by 2-chloroacetyl chloride (1.0 mL, 12.8 mmol). The reaction was warmed to RT and stirred for 2 h. The reaction mixture was concentrated, redissolved in EtOAc (50 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 2.2 g of crude product which was further purified by flash column chromatography using 1:1 EtOAc:hexanes as the eluent. 2.0 g of 2-chloro-N-(2,4-difluorophenyl)acetamide, (yield: 84%) was isolated.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[S]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: c1ccc2c(c1)CCNC2
Agent: [S]
Solvent: Cc1ccccc1
Product: C1=NCCc2ccccc21
Yield: 96.5 %

Procedure:
30.0 g of 1,2,3,4-tetrahydroisoquinoline and 15.0 g of sulphur powder in 200 ml of toluene are refluxed for 6 hours. After cooling the precipitating sulphur is filtered off, the filtrate is extracted with 200 ml of 5% hydrochloric acid. The aqueous solution is made alkaline with 40% sodium hydroxide to pH=10, then extracted with 250 ml of chloroform. The chloroform extract is dried with sodium sulfate and evaporated in vacuo. As residue 28.5 g of 3,4-dihydroisoquinoline are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].[S:19]([CH2:23][CH2:24][CH2:25][S:26][CH2:27][C@@H:28]([C:30]([OH:32])=[O:31])[NH2:29])([OH:22])(=[O:21])=[O:20].C(N(CC)CC)C.C(Cl)(Cl)Cl.CO.O>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:29][C@H:28]([C:30]([OH:32])=[O:31])[CH2:27][S:26][CH2:25][CH2:24][CH2:23][S:19]([OH:22])(=[O:20])=[O:21])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H](CSCCCS(=O)(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CSCCCS(=O)(=O)O)C(=O)O

Procedure:
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) (121 mg, 0.49 mmole) (Aldrich Chem. Co., Milwaukee, Wis.) was added to a solution of S-(3-sulfopropyl)cysteine (SulfoCys, 100 mg, 0.41 mmole), (prepared by the method of U. T. Ruegg and J. Rudinger, J. Peptide Protein Res. 6, 447, 1974), and triethylamine (0.18 ml, 1.23 mmole) in 3 ml of 50% aqueous dioxane to form a reaction mixture. The reaction mixture was heated at 50°-55° C. for 1 hour to obtain a yellow solution. The reaction mixture was then cooled, diluted with 5 ml of water, and washed with ethylacetate (3×10 ml). The resultant aqueous layer was evaporated to dryness under vacuo by coevaporating with methanol twice. TLC (Silica gel 60, Merck & Co., Inc,) analysis of the residue produced by the evaporation, using a solvent system of chloroform/methanol/water (55:40:5), showed complete conversion of SulfoCys to BOC-SulfoCys.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[CH2:29][NH2:30].[CH:31](OCC)=[O:32]>>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]=[CH:4][C:3]=1[CH2:29][NH:30][CH:31]=[O:32]
Reactant: NCc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Reactant: CCOC=O
Product: Nc1c(CNC=O)cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A suspension of {5-amino-1-[2-(trityloxy)ethyl]pyrazol-4-yl}methylamine (19.7 g, 49.4 mmol) in ethyl formate (500 ml) was stirred at 50° C. for 3 hours. After evaporation of the solvent in vacuo, the residue was triturated with diisopropyl ether to give N-{5-amino-1-[2-(trityloxy)ethyl]pyrazol-4-yl}methylformamide (7.99 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:4]2[C:5]([O:7][C:8](=O)[NH:9][C:3]=12)=[O:6].[Cl:17][C:18]1[C:19]([N:24]2[C:28](C(Cl)=O)=[CH:27][C:26]([C:32]([F:35])([F:34])[F:33])=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[Cl:17][C:18]1[C:19]([N:24]2[C:28]([C:8]3[O:7][C:5](=[O:6])[C:4]4[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:2]([CH3:1])[C:3]=4[N:9]=3)=[CH:27][C:26]([C:32]([F:35])([F:33])[F:34])=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc([N+](=O)[O-])cc2c(=O)oc(=O)[nH]c12
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 100 °C

Procedure:
A mixture of 505 mg (1.63 mmol) of the title material from Step A, 344 mg (1.55 mmoles) of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride (which can be prepared according to Example 7) and 2 mL of pyridine was heated at 100° C. for 3 hours. The resulting mixture was cooled to 25° C. and partitioned between ethyl acetate and dilute aqueous HCl. The organic layer was washed three times with dilute aqueous HCl, dried over anhydrous magnesium sulfate and concentrated to give a brown solid that was used in the next step without further purification. 1H NMR (CDCl3): δ 8.86 (d, 1H), 8.60 (dd, 1H), 8.38 (d, 1H), 8.03 (dd, 1H), 7.59 (s, 1H), 1.95 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.[NH2:19][OH:20].Cl.[OH-].[Na+]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[N:19][OH:20]
Reactant: CC(C)C1CCCCCCCCC(C)(C)C=N1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(N)CCCCCCCCC(C)(C)C=NO
Yield: 94 %

Procedure:
The procedure is carried out as described in Example 1(b) but with the use of 118.7 g (0.5 mol) of 3,3-dimethyl-12-isopropyl-1-aza-cyclododecene, 35 g (0.5 mol) of hydroxylamine hydrochloride, 55 g of 37% hydrochloric acid, 200 ml of water and 50 g (1.25 mols) of solid sodium hydroxide. Distillation yields 127 g (0.47 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undecanal-oxime; b.p. 145° C./4 Pa; nD20 =1.4761.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[CH:25](=[S:27])[NH2:26]>C1COCC1>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:26]=[CH:25][S:27][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: NC=S
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3scnc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.7 %

Procedure:
To a solution of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.60 g, 1.5 mmol, Preparation #A.2) in THF (25 mL) was added methanethioamide (0.19 g, 3.0 mmol, prepared according to Euro. J. Med. Chem., 2004, 39, 867-872). The reaction mixture was stirred at ambient temperature for about 15 h. The solvent was removed under reduced pressure. The crude material was purified by silica gel flash chromatography using DCM/MeOH (gradient, 100:0 to 95:10). This residue was then repurified by silica gel flash chromatography using DCM/ACN (gradient, 90:10 to 0:100). The residue was dissolved in Et2O and solvent removed under reduced pressure to give a yellow solid. The solid was dried overnight under high vacuum to afford the title compound (0.095 g, 17%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.39 min; MS m/z: 358.2 (M+H.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8]C(C2C=CC(C)=CC=2)=O)[O:5][C@@H:4]([N:18]2[CH:25]=[C:24]([C:26]#[C:27][Si](C)(C)C)[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1.C[O-].[Na+]>CO>[C:26]([C:24]1[C:22](=[O:23])[NH:21][C:19](=[O:20])[N:18]([CH:25]=1)[C@@H:4]1[O:5][C@H:6]([CH2:7][OH:8])[C@@H:2]([F:1])[CH2:3]1)#[CH:27]
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 7 h

Procedure:
The product of Stage c), (0.53 g, 1.18 mmoles) was dissolved in methanol (17 ml) containing sodium methoxide (from 0.027 g, 1.18 mmoles of sodium metal) and the solution left standing at ambient temperature for 7 hours. The mixture was then neutralised with Dowex 50 (H+) resin, filtered and evaporated to dryness. The final residue was triturated with ether (2×7 ml) and recrystallised from ethanol to give the title compound.