Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])[N:5]=[N:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=3[Cl:14])[N:5]=[N:4][N:3]=2)=[CH:20][CH:21]=1
Reactant: Clc1cccc(-n2nnnc2Cl)c1Cl
Reactant: Clc1ccc(C2CCCN2)cc1
Product: Clc1ccc(C2CCCN2c2nnnn2-c2cccc(Cl)c2Cl)cc1
Yield: 10.1 %

Procedure:
The compound from Example 75B (0.1 g) was reacted with 2-(4-Chloro-phenyl)-pyrrolidine (0.1 g) according to the method of Example 75C to provide 0.016 g of the title compound as a white solid. MS (ESI/NH3) m/z 395 (M+H)+; 1H NMR (δ, DMSO-d6) 1.78-1.9 (m, 4H), 3.3-3.6 (m, 2H), 4.8-5.0 (m, 1H) 6.8-6.9 (m, 1H), 7.05-7.19 (m, 4H), 7.60-7.65 (t, 1H), 7.79-7.85 (d, 1H), 7.99-8.1 (d, 1H).
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].C(OC([N:15]1[CH2:22][CH2:21][C@:20]2([CH3:26])[C:23]([CH3:25])([CH3:24])[C@H:16]1[CH2:17][C:18]1[C:30](N)=[CH:29][CH:28]=[CH:27][C:19]=12)=O)(C)(C)C>O1CCOCC1.CO>[F:1][C:30]1[C:18]2[CH2:17][C@@H:16]3[C:23]([CH3:25])([CH3:24])[C@:20]([CH3:26])([C:19]=2[CH:27]=[CH:28][CH:29]=1)[CH2:21][CH2:22][NH:15]3
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@]2(C)c3cccc(N)c3C[C@@H]1C2(C)C
Agent: N#[O+]
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)[C@H]2Cc3c(F)cccc3[C@]1(C)CCN2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of nitrosonium tetrafluoroborate (0.25 g) in dioxane (2 mL) is added to a solution of (2R,6S)-10-amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.10 g) in dioxane (2 mL). The solution is heated to 50° C. and stirred at this temperature overnight. The reaction solution is diluted with methanol and then concentrated under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to yield the title product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:15]=[C:16]([C:30]2([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:17]=[C:18]([F:29])[C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:29][C:18]1[CH:17]=[C:16]([C:30]2([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[CH:15]=[C:14]([F:13])[C:19]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCOCC3)cc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3(O)CCOCC3)cc2F)n1
Yield: 72 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 4-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol (1.8 equiv.) at to give methyl 6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinate in 72% yield. LC/MS=368.0 (MH+), Rt=0.75 min.
Reaction SMILES: C(O)C.Cl.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:15][CH:16]([NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29]C(=O)C)[C:17]([Cl:20])([Cl:19])[Cl:18]>O>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:15][CH:16]([NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:17]([Cl:19])([Cl:20])[Cl:18]
Reactant: CC(=O)Oc1ccccc1C(=O)NC(Oc1ccc2ccccc2c1)C(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(NC(Oc1ccc2ccccc2c1)C(Cl)(Cl)Cl)c1ccccc1O
Yield: 52.5 %

Procedure:
50 ml of ethanol and 1 ml of concentrated hydrochloric acid were added to 4.2 g of N-(1'-β-naphthoxy-2',2',2'-trichloroethyl)-2-acetoxybenzamide synthesized in Preparation Example 5. The whole was refluxed for about three hours. After cooling, the reaction mixture was poured into water and the resulting crystals were recrystallized from N-hexane/benzene (2:1) to obtain 2.0 g of N-(1'-β-naphthoxy-2',2',2'-trichloroethyl)-2-hydroxybenzamide as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([OH:18])[C:6](=[CH:16][CH:17]=1)[CH:7]=[N:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:15].[OH:20][C:21]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O>C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([OH:18])[C:6](=[CH:16][CH:17]=1)[CH:7]=[N:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[N:15]=[CH:23][C:22]1[C:21](=[CH:28][C:27]([OH:29])=[CH:26][CH:25]=1)[OH:20]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CN(C)c1ccc(C=N[C@@H]2CCCC[C@H]2N)c(O)c1
Solvent: CCO
Product: CN(C)c1ccc(C=N[C@@H]2CCCC[C@H]2N=Cc2ccc(O)cc2O)c(O)c1
Temperature: 60 °C

Procedure:
To a solution of 2.5 g (9.56 mmol) (R,R)-N-mono(4-dimethylaminosalicylidene)-1,2-cyclohexanediamine in 225 ml of ethanol is added dropwise at room temperature over the course of 45 minutes a solution of 1.321 g (9.56 mmol) 2,4-dihydroxybenzaldehyde in 225 ml ethanol. The reaction solution is heated at 60° C. for 4 h. After cooling to room temperature the resultant reddish brown solution is concentrated to dryness. The crude product (ca. 5 g) is resolved by column chromatography (ethyl acetate/methanol 9:1). Yield: 1,09 g (300%), yellowish orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH3:11].[Br:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O>[BrH:12].[Cl:1][C:2]1[C:10]2[C:5]([N:6]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=[CH:8][CH:9]=2)=[N:4][C:3]=1[CH3:11]
Reactant: BrCCc1ccccc1
Reactant: Cc1[nH]c2ncccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: Cc1nc2n(CCc3ccccc3)cccc-2c1Cl
Yield: 50.2 %

Procedure:
A solution of 28.4 mg (0.17 mmol) of 3-chloro-2-methyl pyrrolo [2,3-b]pyridine and 36 mg (0.2mmol) of (2bromoethyl)benzene in 0.4 ml of dimethylformamid was heated at 80° C. for 20 h. The solvent was evaporated. The solid that formed was treated with ethyl acetate and isolated by filtration to give 30 mg (50%) of 3 -chloro-2-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridine hydrobromide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH3:20][C:21]1[C:26]([CH:27]=O)=[CH:25][N:24]=[C:23]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[C:3]2[N:10]=[C:27]([C:26]3[C:21]([CH3:20])=[N:22][C:23]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[N:24][CH:25]=3)[NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c2nc(-c3cnc(NCCCC4CCN(C)CC4)nc3C)[nH]c2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a 2 L Erlenmeyer flask were added 3,5-dimethyl-benzene-1,2-diamine.2HCl (54.85 g, 262.3 mmol) and Na2S2O5 (64.82 g, 341.0 mmol), as well as 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde (prepared as in Example 3 above) (72.5 g, 262.3 mmol) in DMF (725 mL). After addition of triethylamine (73.1 mL, 524.6 mmol), the resultant mixture was warmed on a hot plate with stirring to 90° C. and held at this temperature for 2 hours. The resultant mixture was then concentrated to near dryness and partitioned between dichloromethane (0.7 L) and 1 N NaOH (1 L). The resultant mixture was stirred for 1 hour and then filtered to isolate the voluminous solid which had formed. The solids were dried and then partitioned between chloroform (700 mL) and saturated aqueous NaHCO3 (700 mL). The layers were separated, the organic layer was dried over sodium sulfate and concentrated to a residue. The residue was recrystallized in hot heptane/ethyl acetate (1.8:1,840 mL total volume) with initial hot filtration (˜1 g of oily residues removed) and final filter cake washing with heptane/ethyl acetate (3:1, 250 mL total volume) to yield the title compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([C:6](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]#[N:8])=[O:5]
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: N#CCC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: N#CC(=CNc1ccccc1)C(=O)c1ccccc1Cl
Yield: 52.2 %

Procedure:
A solution of 2-chlorobenzoylacetonitrile (1.0 g, 5.6 mmol, 1.0 eq) and diphenylformamidine (1.10 g, 5.6 mmol, 1.0 eq) in 50 mL of toluene was heated to 85° C. overnight. The heat source was removed and desired product slowly began to precipitate from solution. The resulting solid was filtered and dried to provide the desired product (826 mg, 52%). HPLC (4 minute 10-90 gradient) tR 3.13 min; MS m/z 283.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[N:54]([C@@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH3:58])=[C:55]=[O:56]>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:55](=[O:56])[NH:54][C@@H:57]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH3:58])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@H](C)c3ccccc3)O[C@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-2-({(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (35 mg) was dissolved in 2 mL DCM and ((R)-1-isocyanato-ethyl)-benzene (5 equiv) added and reaction stirred at room temperature for 2 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+2% MeOH). The resulting compound was hydrolyzed according to General Procedures B to give the title compound (28 mg). LCMS (m/z): 886.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6](Cl)[N:5]=[C:4]([CH3:14])[N:3]=1.[C:15]1([N:21]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][NH:34][CH3:35]>CN(C)C=O>[CH3:14][C:4]1[N:5]=[C:6]([N:34]([CH3:35])[CH3:33])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:26][C:23]2[CH:24]=[CH:25][N:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:22]=2)[N:3]=1
Reactant: O=c1ccn(-c2ccccc2)[nH]1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Oc2ccn(-c3ccccc3)n2)nc(C)nc1N(C)C
Reaction time: 20 h

Procedure:
A mixture of methyl (4,6-dichloro-2-methyl-pyrimidin-5-yl )-acetate (5.43 g, 23 mmol), 1-phenyl-1H-pyrazol-3-on (3.73 g, 23 mmol) and potassium carbonate (5.5 g, 40 mmol) in dimethylformamide (30 ml) is heated at +120° C. for 30 minutes. Addition of dimethylamine (10 ml of a 25% aqueous solution) at room temperature, stirring for 20 hours and workup gives the intermediate methyl 2-[2-methyl-4-dimethylamino-6-(1-phenyl-1H-pyrazol-3-yloxy)-pyrimidin-5-yl]-acetate as an oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24]([OH:26])=O)[C:14]4=[O:31])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24]([NH:32][C:33]3[CH:37]=[CH:36][O:35][N:34]=3)=[O:26])[C:14]4=[O:31])[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C4CCC4)CC3)cc2c1=O
Reactant: Nc1ccon1
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(N3CCN(C4CCC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[6-[4-(cyclobutyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[6-[4-(cyclobutyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 1.74 (m, 2H), 1.96 (m, 2H), 2.07 (m, 2H), 2.28 (s, 3H), 2.55 (m, 4H), 2.83 (m, 1H), 3.39 (m, 4H), 7.20 (s, 1H), 7.46 (m, 1H), 7.53 (d, 1H), 7.67 (m, 2H), 7.85 (s, 1H), 7.91 (s, 1H), 7.99 (d, 1H), 8.26 (s, 1H); Mass Spectrum: M+H+ 485.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:18]([OH:19])[C@H:17]([CH3:20])[O:16][C@H:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[C@H:4]1[OH:21].[H][H].ClCCl.CO>CO.[Pt](=O)=O>[CH3:1][O:2][C@@H:3]1[C@H:18]([OH:19])[C@H:17]([CH3:20])[O:16][C@H:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[C@H:4]1[OH:21]
Reactant: CO[C@H]1[C@H](O)[C@@H](Oc2ccc([N+](=O)[O-])cc2)O[C@@H](C)[C@H]1O
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CO
Product: CO[C@H]1[C@H](O)[C@@H](Oc2ccc(N)cc2)O[C@@H](C)[C@H]1O

Procedure:
3.81 g (12.73 nmmol) of p-nitrophenyl 3-O-methyl-β-L-fucopyranoside are dissolved in methanol and, after addition of platinum dioxide, hydrogenated in a hydrogen atmosphere at a slight overpressure. After filtering off the catalyst and precipitating with ether, 3 g (88%) of the target product are obtained. [TLC: dichloromethane/methanol 9:1 Rf =0.53].
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].O>CN(C=O)C>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:8]=[C:7]2[I:13]
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Reactant: CN(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCn1nc(I)c2cc(OC(F)F)ccc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 5-(difluoromethoxy)-3-iodo-1H-indazole (1 g, 3.2 mmol) in DMF (25 mL) was added K2CO3 (1.8 g, 12.8 mmol) and 3-chloro-N,N-dimethylpropan-1-amine (1.1 g, 6.4 mmol), after the addition, the reaction mixture was stirred at 80° C. for 4 hour. After cooling to room temperature, H2O (25 mL) was added and product extracted with ethyl acetate (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with dichloromethane/CH3OH=10:1) to give 3-(5-(difluoromethoxy)-3-iodo-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (1.1 g, 78.5%) as yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.46-7.42 (m, 1H), 7.27-7.17 (m, 2H), 6.87-6.29 (t, 1H, J=73.8 Hz), 4.47-4.41 (m, 2H), 2.24-2.18 (m, 8H), 2.08-2.03 (m, 2H). LCMS: (M+H)+=396.
Reaction SMILES: [Na].[C:2]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:28])[CH:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20](=[O:28])[CH:21]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:2]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:18]
Reactant: Oc1ccc(C2=CCCCCCC2)cc1
Reactant: CCCCCC(Br)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)OCC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 2.1 g of sodium in 180 ml of absolute ethanol are added with stirring 15.0 g of p-(1-cyclooctenyl)-phenol. After stirring has continued for a further 30 minutes, 28.5 g of 2-bromo-heptanoic acid ethyl ester are slowly added dropwise to this solution and the mixture is maintained at 50° C for 24 hours. Upon removal of the solvent in vacuo, the residue is partitioned at 0° C between ether and 2N sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and evaporated in vacuo, to yield the oily α-[p-(1-cyclooctenyl)-phenoxy]-heptanoic acid ethyl ester of the formula ##STR7##
Reaction SMILES: [CH2:1]=[CH:2]C(=C)C.[CH3:6][O:7][C:8]([O:12][CH2:13][C:14]#[CH:15])([CH2:10][CH3:11])[CH3:9].BrCC>CCCCCC>[CH3:6][O:7][C:8]([CH3:9])([O:12][CH2:13][C:14]#[C:15][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: C=CC(=C)C
Reactant: C#CCOC(C)(CC)OC
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC(C)(CC)OC
Temperature: -38 °C
Reaction time: 0.42 h
Yield: 89.1 %

Procedure:
890 mg (127 mmol) of granulated lithium were added within 5 minutes to 100 ml (4.0 mol) of liquid ammonia at −40° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 5.94 g (86.6 mmol) of isoprene was added portion wise within 10 minutes, whereas the solution gets white at the end of the addition. The mixture was stirred for 25 minutes at −38° C. 9.1 g (69.5 mmol) of 2-methoxy-2-prop-2-ynyloxy-butane (97.4% GC) were added with a dropping funnel to the reaction mixture at −38° C. within 25 minutes. The reaction mixture was held at −38° C. for about 1 hour. 14 g (128.5 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1 hour and 30 minutes. 50 ml of water was added to the reaction mixture at 40° C., and the mixture was stirred until all salt was dissolved. The mixture is transferred into a separatory funnel and the layers were separated. The aqueous layer is extracted with 127 ml of n-hexane. The organic layers were dried over 0.5 g of anhydrous sodium sulphate and concentrated under reduced pressure (40° C., 60 mbar), and the crude product (1-(1-methoxy-1-methyl-propoxy)-pent-2-yne) was analyzed by GC. 10.54 g of crude 1-(1-methoxy-1-methyl-propoxy)-pent-2-yne were obtained with a purity of 87.1% (yield 77.6% based on 2-methoxy-2-prop-2-ynyloxy-butane).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:60])=[C:54]([CH:56]=[CH:57][C:58]=2[F:59])[NH2:55])[CH:38]=[CH:37][N:36]=1.[F:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[S:69](Cl)(=[O:71])=[O:70]>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:60])=[C:54]([NH:55][S:69]([C:63]3[CH:64]=[C:65]([F:68])[CH:66]=[CH:67][C:62]=3[F:61])(=[O:71])=[O:70])[CH:56]=[CH:57][C:58]=2[F:59])[CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline (900 mg, 2.196 mmol) and 2,5-difluorobenzenesulfonyl chloride (0.355 mL, 2.64 mmol) the title compound of Step H was obtained as a light yellow solid (774 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=5.5 Hz, 1H), 7.48-7.57 (m, 4H), 7.29 (t, J=8.8 Hz, 1H), 6.57 (d, J=5.5 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]+.
Reaction SMILES: CS[C:3]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([N:9]([OH:11])[CH3:10])=[O:8].O[O:26][S:27]([O-:29])=O.[K+].[CH3:31]O>O>[CH3:31][S:27]([C:3]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([N:9]([OH:11])[CH3:10])=[O:8])(=[O:29])=[O:26]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1ccc(CCCc2ccccc2)cc1C=CC(=O)N(C)O
Agent: [K+]
Solvent: O
Product: CN(O)C(=O)C=Cc1cc(CCCc2ccccc2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In methanol (15 ml) is placed 2-methylthio-5-(3-phenylpropyl)-N-hydroxy-N-methylcinnamamide (0.35 g, 1.02 mmol) prepared according to Example 27. In 3 ml of water is placed oxone (0.94 g, 1.54 mmol) which is added to the methanol solution and stirred at room temperature for 3 days. The reaction mixture is poured into 80 ml of water, then extracted twice with 75 ml portions of ethyl acetate. The organic layers are washed
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.[Cl:13]Cl>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([Cl:13])=[CH:11][NH:10][N:9]=1
Reactant: ClCl
Reactant: Clc1ccccc1-c1cc[nH]n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccccc1-c1n[nH]cc1Cl
Temperature: 25 °C
Yield: 44.5 %

Procedure:
6.8 g (0.038 mol ) of 3-(2'-chlorophenyl)-1H-pyrazole, prepared as in Example 9, are dissolved, at temperature and with stirring, in 30 ml of acetic acid. 2.9 g (0.0409 mol) of chlorine are then introduced into the reaction mixture. Stirring is maintained for 1 hour at room temperature and then the acetic acid is driven off under reduced pressure. The residue is taken up in methylene chloride and this organic solution is washed with an aqueous bicarbonate solution, then with water and then dried over Na2SO4 before being concentrated to dryness. The residue is chromatographed on a silica column (eluent: heptane/ethyl acetate 60/40). 3.6 g of 3-(2'-chlorophenyl)-4-chloro-1H-pyrazole (compound 96) are obtained, which is of honey-like consistency (yield 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O.[CH2:20]([N:22]([CH2:29][CH3:30])[CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25]O)[CH3:21]>C1C=CC=CC=1>[ClH:18].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([O:15][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][N:22]([CH2:29][CH3:30])[CH2:20][CH3:21])=[O:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Reactant: CCN(CC)CC(C)(C)CO
Solvent: c1ccccc1
Product: CCN(CC)CC(C)(C)COC(=O)c1ccc(-c2ccc(F)cc2)o1
Product: Cl
Reaction time: 48 h

Procedure:
5-(p-Fluorophenyl)-2-furoic acid (18.6 g., 0.09 mole) is added with rapid stirring to thionyl chloride (31.5 ml.) at room temperature, heated until solution occurs (about 1/4 hr.) and then is refluxed for 2 hr. The mixture is stripped of excess thionyl chloride in vacuo, benzene (100 ml.) is added, and again stripped of solvent. The reside is treated with a solution of 3-diethylamino-2,2-dimethylpropanol (14.5 g. 0.09 mole) in benzene (490 ml.) is refluxed for 3 hr., cooled, is diluted with petroleum ether (300 ml.), and is stored for 2 days at room temperature. The benzene-petroleum ether solution is decanted, the residue dissolved in H2O (750 ml.) and the solution adjusted to pH 8 with saturated aqueous Na2CO3 (75 ml.). The product is extracted from the aqueous phase with benzene (860 ml.) in portions and the extract dried for hours over MgSO4 and activated charcoal. The solution is filtered and the filtrate adjusted to pH 3 with ether-HCl (cooled in ice bath). Petroleum ether (400 ml.) is added and the product oiled out of solution. The benzene-petroleum ether solution is decanted and the product washed twice with anhydrous ether (scratching induced crystallization). The solid is recrystallized from isopropanol (200 ml.) to yield 16.9 g. (49%). A sample is recrystallized from isopropanol, m.p. 134°-138°.