Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1)=[O:38]
Reactant: O=C(O)c1cccc(F)c1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc5c(N)nn(C)c5c4)ccnc3NC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc5c(NC(=O)c6cccc(F)c6)nn(C)c5c4)ccnc3NC2=O)cc1
Temperature: 100 °C
Yield: 13.4 %

Procedure:
A solution of 5-[(3-amino-1-methyl-1H-indazol-6-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.23 mmol; 1.00 eq.),3-fluorobenzoic acid (35.80 mg; 0.26 mmol; 1.10 eq.), pybop (157.16 mg; 0.30 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (115.48 μl; 0.70 mmol; 3.00 eq.) was stirred at room temperature for 22 hr. Additional pybop was added and the reaction was heated to 100 degrees C. but the reaction did not go to completion. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 17 mg (26%) of 3-fluoro-N-(6-{[3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]oxy}-1-methyl-1H-indazol-3-yl)benzamide as a yellow solid. LC-MS (M+H=553, obsd.=553).
Reaction SMILES: [CH2:1]1[O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2]1.O.NN>O1CCCC1.[Rh].O.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH2:1]1[O:12][C:4]2[CH:5]=[C:6]([N:9]=[O:10])[CH:7]=[CH:8][C:3]=2[O:2]1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Agent: Cl[Fe](Cl)Cl
Agent: [Rh]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: O=Nc1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
1,2-Methylenedioxy-4-nitrobenzene (8.3 g, 0.05 mol) was dissolved in tetrahydrofuran (150 ml) with rhodium on carbon catalyst (0.2 g) at 0° C. and was treated dropwise with hydrazine hydrate (2.8 g, 0.055 mol). On completion of the addition, the mixture was stirred for 1 hour and then filtered through a HYFLO (Trade Mark) filter. The resulting solution was added dropwise to a chilled, stirred solution of iron (III) chloride hexahydrate (27.5 g, 0.1 mol) in water (150 ml). On completion of the addition, water (220 ml) was added and the green precipitate was filtered off, washed with water and dried overnight under high vacuum. 1,2-Methylenedioxy-4-nitrosobenzene was obtained as a green solid (3.7 g, 50% yield) by column chromatography eluting on silica with dichloromethane. M.p. 90°-92° C. M+ (CI):152 (M+ +H)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:13]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:12][N:11](C(OCC[Si](C)(C)C)=O)[C:8]2=[CH:9][CH:10]=1)(=[O:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:13]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:12][NH:11][C:8]2=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(S(C)(=O)=O)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(S(C)(=O)=O)cc32)C1
Reaction time: 1 h
Yield: 107.2 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-(methylsulfonyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (133 mg, 0.27 mmol) was dissolved in tetrahydrofuran (3 mL). Thereafter, tetra-n-butylammonium fluoride (1 M tetrahydrofuran solution, 0.5 mL) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 1 hour. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to obtain tert-butyl 5-(methylsulfonyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (102 mg, quant.) in the form of a white amorphous product.
Reaction SMILES: [CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7](=[O:14])[C:8]3[CH2:13][S:12][CH2:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7](=[O:14])[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)NC1=C(CSC1)C(=O)N2
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc2c(cc1C)Nc1cscc1C(=O)N2
Reaction time: 8 h

Procedure:
To a slurry of 18.8 g. of 6,7-dimethyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 150 ml. of pyridine, stirred in an ice bath, is added 10.1 g. of N-chlorosuccinimide portionwise over 15 minutes. The mixture is heated on a steam bath for 30 minutes, poured into one liter of water and allowed to stand overnight. The solid is filtered, washed with water, 1 N hydrochloric acid, three times with water and diethyl ether and dried giving the desired final product, mp. 233°-238° C. (dec.).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[Cl:18][C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[N:21][N:22]([CH2:25][C:26](O)=[O:27])[C:23]=1[CH3:24]>>[Cl:18][C:19]1[C:20]([C:29]([F:31])([F:30])[F:32])=[N:21][N:22]([CH2:25][C:26]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13][CH2:14]2)=[O:27])[C:23]=1[CH3:24]
Reactant: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)n1

Procedure:
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 5.50 g) is reacted analogously to Example IV-1 with [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (4.82 g). This gives, after chromatographic purification, ethyl 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (6.00 g, 65%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)[CH2:9]1)C1C=CC=CC=1.CCN(CC)CC.C(Cl)(=O)OC(Cl)C>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[N:18][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[N:14][CH:15]=1
Reactant: COc1cnc(C2CCN(Cc3ccccc3)C2)nc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cnc(C2CCNC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.8 %

Procedure:
To a solution of 2-(1-benzyl-pyrrolidin-3-yl)-5-methoxy-pyrimidine (100 mg, 0.37 mmol) and Et3N (37.6 mg, 0.37 mmol) in CH2Cl2 (2 mL) was added 1-chloroethyl carbonochloridate (63.8 mg, 0.45 mmol) dropwise at 0° C. The mixture was stirred at rt for 2 h. The reaction mixture was concentrated to afford crude 5-methoxy-2-(pyrrolidin-3-yl)pyrimidine (100 mg), which was used for next step without purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]=2[C:4]#[N:5])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Reactant: NC1CCCCC1
Product: N#Cc1c(NC2CCCCC2)cccc1-c1ccccc1
Temperature: 100 °C

Procedure:
The product of example la above, 2-fluoro-6-phenylbenzonitrile, (0.1 g, 0.51 mmol), and cyclohexylamine (1 mL) were combined in a sealed tube that had been flushed with argon. The tube was heated in an oil bath to 100° C. for 1.6 hours. The excess cyclohexylamine was evaporated, and the residue was flash chromatographed on silica gel eluted with 0-2% ethyl acetate in hexane, and then recrystallized from methylene chloride/hexane to give the title product as a white crystalline product. mp 125-126° C.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18].[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C1C=CC=CC=1>[Cl:18][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn2c(O)ccnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cnn2c(Cl)ccnc12
Temperature: 80 °C
Yield: 25.1 %

Procedure:
To a stirred suspension ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.95 g, 4.6 mmol) in POCl3 (8.0 mL, 86 mmol) was added dimethyl aniline (0.8 μL, 0.006 mmol) and the mixture was heated at 80° C. for 2 hours. The mixture was slowly poured onto ice, and the pH was carefully adjusted to ˜7 with 1N NaOH, then to pH 10 with solid Na2CO3. The mixture was then extracted with dichloromethane (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness. Trituration of the solids with hexanes gave ethyl 7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (260 mg, 25%) as a tan solid. ESI-MS m/z calc. 225.0, found 226.5 (M+1)+; Retention time: 0.87 minutes (3 min run).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:22][CH2:23][N:24]1[CH2:28]CC[CH2:25]1)(=O)=O)(C)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH:36]1([CH:35]([OH:42])[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=Cc1ccccc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN2CCCC2)c2ccccc2)c(C(C)C)c1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-(1-pyrrolidinyl)propiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g), and benzaldehyde (4.6 cc), 1,2-diphenyl-4-(1-pyrrolidinyl)-2-buten-1-ol (Z) hydrochloride (9.9 g) is obtained, after recrystallisation from a mixture of 2-propanol and isopropyl ether (40/60 by volume), in the form of white crystals melting at 106° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:17][CH2:16][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC=C(C(=O)OC)c1cccc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1cccc(Cl)c1CBr
Temperature: 25 °C

Procedure:
27.0 g of methyl α-(3-chloro-2-methylphenyl)-β-methoxy-acrylate and 21.5 g of N-bromosuccinimide were stirred in 300 ml of anhydrous tetrachloromethane. After 1 g of Porofor N had been added, the mixture was refluxed for 4 hours. After cooling to room temperature (=25° C.), the succinimide was removed. The combined organic phases were washed with water, dried over sodium sulfate and concentrated. This gave 23 g of the title compound as colorless crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[S:10][C:9]2=[C:11]([C:14]([OH:16])=O)[N:12]=[CH:13][N:8]2[CH:7]=1>C1(C)C=CC=CC=1>[Br:5][C:6]1[S:10][C:9]2=[C:11]([C:14]([Cl:3])=[O:16])[N:12]=[CH:13][N:8]2[CH:7]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncn2cc(Br)sc12
Yield: 100.4 %

Procedure:
Thionyl chloride (0.1 ml, 1.37 mmol) was added dropwise to a solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (97 mg, 0.39 mmol) in toluene (10 ml), and the mixture was heated under reflux for 1.5 hr. The excessive amount of thionyl chloride was removed at the atmospheric pressure, and the solvent was then removed by distillation under the reduced pressure to give 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid chloride (104 mg, quantitative) as a light brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH3:25].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][O:18][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CN1CCC[C@H]1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), (S)-(−)-2-hydroxymethyl-1-methylpyrrolidine (69 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 78 mg (0.31 mmol, 79%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:22])[N:6]=1)[CH2:3][CH3:4].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[NH:30]1[C:26]2=[N:27][CH:28]=[CH:29][C:24]([NH:1][C@H:2]([C:5]3[N:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:13](=[O:21])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[F:22])[N:6]=3)[CH2:3][CH3:4])=[C:25]2[CH:32]=[CH:31]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ccnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (27 mg, 0.091 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 4-chloro-1H-pyrrolo[2,3-b]pyridine (21 mg, 0.14 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 5A).
Reaction SMILES: CC1(C)S[C@@H]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H](NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H:44]([NH:50]C)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1>>[N:50]1[CH:44]=[C:16]([CH:15]2[CH2:14][CH2:13][CH2:11][N:10]2[CH3:7])[CH:17]=[CH:18][CH:19]=1
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Product: CN1CCCC1c1cccnc1

Procedure:
Penicillin & Gentamicin
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[C:4]([Cl:21])[CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]3[CH2:11][CH2:10][C:9]4([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[C:8]3=[O:17])=[C:4]([Cl:21])[CH:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC4(CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 63.5 %

Procedure:
Purge with N2 a mixture of 2-(4-bromo-2,6-dichloro-benzyl)-2-aza-spiro[4.5]decan-1-one (0.14 g, 0.36 mmol) and 4-methoxycarbonyl phenylboronic acid (0.19 g, 1.05 mmol) in toluene (10 mL) and 2M sodium carbonate (1.25 mL). Treat the reaction with Pd(PPh3)4 (0.041 g, 0.035 mmol) and heat to 90° C. for 4 hours under N2. Cool the reaction and dilute with ethyl acetate, and then wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.102 g (64%) of the titled product. Rf=0.51 (1/1 hexanes/ethyl acetate). MS (m/z): 446
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=O>>[Cl:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[N:16]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3Cl)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2-chloro-3-(trifluoromethyl)benzoic acid: MS (APCI): m/z 471 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([CH3:23])[S:21][CH:22]=2)=[CH:14][CH:13]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+:26]>C(O)C>[CH3:1][C:2]([CH3:24])([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([CH3:23])[S:21][CH:22]=2)=[CH:14][CH:13]=1)[C:3]([O-:5])=[O:4].[Na+:26]
Reactant: CCOC(=O)C(C)(C)CCCOc1ccc(-c2csc(C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccc(OCCCC(C)(C)C(=O)[O-])cc2)cs1

Procedure:
In 5 ml of ethanol was dissolved 1.40 g of ethyl 2,2-dimethyl-5-[p-(2-methyl-4-thiazolyl)phenoxy]pentanoate obtained in EXAMPLE 5. The solution was added to an aqueous sodium hydroxide solution (0.4 g of sodium hydroxide in 5 ml of water) and the mixture refluxed for 10 hours. After cooling, the precipitated crystals was washed with water to obtain the desired product, sodium 2,2-dimethyl-5-[p-(2-methyl-4-thiazolyl)phenoxy]pentanoate as white crystals.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CCO>[OH-].[Na+].O>[CH:6]1([CH2:5][C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:3]2[CH2:2][O:20]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
tert-Butyl (2S,3S)-4-chloro-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (1 g, 3.28 mmol) was dissolved in a solution of 0.71 N NaOH in EtOH (5.6 mL, 3.95 mmol, 1.2 eq). After stirring for 1 h, the mixture was concentrated to give a residue, which was dissolved in water and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (0.84 g, 95%). 1H NMR: 0.83 (m, 1H), 0.95 (m, 1H), 1.10-1.42 (m, 5H), 1.45 (s, 9H), 1.68 (m, 5H), 1.76 (m, 1H), 2.72 (m, 2H), 2.83 (m, 1H), 3.55 (m, 1H), 4.38 (m, 1H). MS (E/Z): 270 (M+H+).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:12][CH2:11][CH:10]2[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)([CH2:6][CH2:7][N:8]([CH3:13])[CH2:9]2)[CH2:4]1>C(O)(=O)C>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:5]23[CH2:4][C:3](=[O:2])[CH2:12][CH2:11][CH:10]2[CH2:9][N:8]([CH3:13])[CH2:7][CH2:6]3)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C23CCN(C)CC2CCC(OC)(OC)C3)c1
Solvent: CC(=O)O
Product: COc1cccc(C23CCN(C)CC2CCC(=O)C3)c1
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Ketal 49 (Example 31) (50 mg, 0.158 mmol) was dissolved in 2 mL of 3 N acetic acid and stirred for 4 h. Basification (pH 8.5), extraction with CHCl3 (2×5 mL), drying, and evaporation gave 29 mg (68%) of 41 as an oil. Attempted distillation resulted in decomposition and 41 failed to form a crystalline methiodide: NMR δ 7.27 (t, J=7 Hz, 1H), 6.77 (m, 3H), 5.96 (m, 1H), 3.78 (s, 3H), 2.27 (s, 3H); IR 1715, 1595, 1578 cm-1 ; mass spectrum m/e (rel intensity) 271 (100), 215 (43), 164 (48), 71 (55), 70 (41). C17H18NO2 requires 271.1572; found 271.1563.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=2)[CH:11]=1>CC#N>[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=2)[C:11]=1[Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(-c2ccc(CC(=O)O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CC#N
Product: Nc1c(Br)c(-c2ccc(CC(=O)O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of NBS (32 mg, 0.179 mmol) in CH3CN (1 mL) was added to a mixture of [4-(7-amino-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-acetic acid (70 mg, 0.179 mmol) in CH3CN (3 mL). After stirring at room temperature for 1 h, the solvent was evaporated in vacuo and the residue was purified by prep-LC to afford titled compound (22.9 mg, 27%). LC/MS RT=3.44 min. Mass calculated for, M+H 474.05, observed 474.05.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.[Br:15]Br>O>[Br:15][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(I)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(I)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
Dissolving 20 g (81 mmol) of 4′-iodo acetophenone into 200 milliliter of acetic acid, and adding 12.8 g (81 mmol) of bromine while cooling with ice, stirred at the temperature of 15° C. for 3 hours. After the color of bromine disappeared, adding water and separating the precipitated solids by filtration, thereby obtained 27 g of crude 2-bromo-4′-iodo acetophenone.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[N+](=[CH2:15])=[N-]>CCOCC>[Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:15])=[O:7]
Reactant: O=C(O)c1ccccc1CCBr
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccccc1CCBr

Procedure:
2-(2-Bromoethyl)-benzoic acid (11.4 g, 50 mmol) is added to a solution of diazomethan in ether at 0° C. The reaction mixture is concentrated in vacuo, and the residue purified by chromatography to give the desired compound as a colourless oil.