Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Sn](CCCC)(CCCC)CCCC)[CH:6]=[CH:7][CH:8]=1.[CH2:22]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44](Br)[CH:45]=2)[NH:40][CH:39]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:45]=2)[NH:40][CH:39]=1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(CO)c1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(-c3cccc(CO)c3)cc12
Yield: 51.8 %

Procedure:
3-Hydroxymethylphenyltri-n-butylstannane (2.016 g, 5.076 mmol) (see Preparation 25) and 3-(1-benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-bromo-1H-indole (1.902 g, 4.602 mmol) (see Preparation 35B) were reacted together in the presence of tri-o-tolylphosphine, triethylamine and palladium (II) acetate using a procedure similar to that described in Example 1. This yielded the title compound as a white foam (1.050 g). Found: C,75.58; H,6.51; N,5.88; C28H28N2O3.1/12CH2Cl2 requires: C,75.36; H,6.34; N,6.26%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12](=[CH2:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1CCCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[C:8](/[CH:11]=[C:12](\[CH3:20])/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(Br)cc1N
Reactant: C=C(C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C/C(=C\c1ccc(C#N)c(N)c1)C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Under argon, a mixture of 2.0 g (10.15 mmol) of 2-amino-4-bromobenzonitrile, 2.165 g (2.5 ml, 15.23 mmol) of tert-butyl 2-methylacrylate, 93 mg (0.10 mmol) of tris(dibenzylideneacetone)-dipalladium, 41 mg (0.20 mmol) of tri-tert-butylphosphine and 2.4 ml (11.17 mmol) of N,N-di-cyclohexylmethylamine in 20 ml of dioxane was heated to 120° C. and stirred at this temperature overnight. The reaction was checked (TLC, mobile phase cyclohexane/ethyl acetate 9:1), and another 10 mg of tris(dibenzylideneacetone)dipalladium, 10 mg of tri-tert-butylphosphine and 500 μl of tert-butyl 2-methylacrylate were then added and the mixture was stirred at 120° C. for a further 4 h. The reaction mixture was then filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethylacetate 9:1→4:1). This gave 1.375 g of the title compound (52% of theory).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:25]=[C:24]([C:35](Cl)=[O:36])[CH2:23]2)=[CH:18][CH:17]=1>C(Cl)Cl>[N:2]1([NH:1][C:35]([C:24]2[CH2:23][CH:22]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:25]=2)=[O:36])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Reactant: NN1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCCCC1)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Under nitrogen atmosphere N-aminopiperidine (0.6 mL, 5.6 mmoles) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL). The resulting mixture was ice-cooled down to 0° C. and a solution of 5-(4-chlorophenyl-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3carboxylic acid chloride obtained in step (c) in methylene chloride (15 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature (approximately 25° C.) overnight. Afterwards the reaction mixture was washed with water, followed by a saturated aqueous solution of sodium bicarbonate, then again with water, dried over sodium sulfate, filtered and evaporated to dryness in a rotavapor. The resulting crude solid was crystallized from ethanol. The crystallized solid was removed via filtration and the mother liquors were concentrated to yield a second fraction of crystallized product. The two fractions were combined to give a total amount of 1.7 g (57% of theoretical yield) of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide having a melting point of 183-186° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(F)ccc1-c1ccc(F)cc1
Temperature: 165 °C
Yield: 51.9 %

Procedure:
A microwave reaction vessel was charged with 2-chloro-5-fluoronitrobenzene (0.878 g, 5.0 mmol), 4-fluorophenylboronic acid (0.770 g, 5.5 mmol), sodium carbonate (1.590 g, 15.0 mmol), palladium diacetate (0.045 g, 0.2 mmol), tetrabutylammonium bromide (1.612 g, 5.0 mmol) in water (10 mL). The mixture was heated to 165° C. in a microwave reactor for 10 mins. The reaction was cooled to room temperature and poured into diethyl ether and 0.1N aqueous sodium hydroxide. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-30% methylene chloride/hexanes) to give the desired product as a yellow solid (0.61 g, 52%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (dd, 1H, J=8.1, 2.7 Hz), 7.44-7.30 (m, 2H), 7.30-7.21 (m, 2H), 7.16-7.07 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cccc(Nc2ccccc2)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(Nc2ccccc2)c1NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of 3-methyl-N1-phenylbenzene-1,2-diamine (381 mg, 1.92 mmol) in anhydrous DCM (10 mL) were added (R)-2-tertbutoxycarbonylaminopropionic acid (399 mg, 2.11 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (404 mg, 2.11 mmol) and the mixture was stirred at RT for 2 h. After this period of time, additional amounts of (R)-2-tertbutoxycarbonylaminopropionic acid (145 mg, 0.77 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol) were added. Stirring was continued for 20 h and then additional amounts (R)-2-tertbutoxycarbonylaminopropionic acid (545 mg, 2.88 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) were added. Stirring was continued for 24 h and then the crude mixture was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording [(R)-1-(2-methyl-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an orange oil (456 mg, 64%). LCMS: RT 3.69 min [M+H]+ 370.2
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=NC#N)[C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2].[Pd:26].[OH-].[K+].C(N[C@H](C(O)=O)CS)(=O)C>C1COCC1>[C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2].[Pd:26]
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=NC#N)N2
Agent: [Pd]
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(C=N2)CCCCC1
Reaction time: 1 h

Procedure:
Crude 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide (1.0 g) containing residual Pd (5100 ppm) was suspended in THF (5 mL). Upon addition of aqueous 1M KOH (5 mL), a clear orange solution was obtained. N-Acetylcysteine (1.3 g) was added, the mixture was stirred for 1 hour, and filtered. Ten percent aqueous HCl (3 mL) was added dropwise to the filtrate causing precipitation of a white solid. The solution was filtered, the solid washed with methanol, and the washed solid dried to give 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol])-2′-ylidenecyanamide (0.6 g; 60% yield; 96 ppm Pd).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23].CCCCCC>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of 4-(4-hydroxy-butyl)-benzoic acid methyl ester (300 mg, 1.44 mmol) in DMF (4 mL) was added imidazole (147 mg, 2.16 mmol) followed by TBDMS-Cl (324 mg, 2.16 mmol). The reaction stirred at room temperature for 2 hours, monitoring by TLC (3:1 Hexane:ethyl acetate). After consumption of the starting material, the reaction was diluted with ethyl acetate and washed with water (3×) and saturated sodium bicarbonate (1×). The organic layer was dried over sodium sulfate, filtered, and concentrated down to obtain a yellow oil (360 mg, 77% yield). This crude oil was taken on to the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:14][CH2:13]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:26])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: C1CNC1
Agent: Cl
Agent: [Li+]
Product: O=C(c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1)N1CCC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and azetidine hydrochloride (84 mg, 0.90 mmol). Yield: 41 mg (47%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[N:22][N:23]3[CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br-:37].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>O.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[C:21]([Br:37])=[N:22][N:23]3[CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Br-]
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1cccc2c1cnn2CCN1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1cccc2c1c(Br)nn2CCN1CCCC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 2-[4-(benzyloxy)phenyl]-N-[1-(2-pyrrolidin-1-ylethyl)-1H-indazol-4-yl]acetamide (Example 3, 0.200 g, 0.440 mmol) and NaOH (0.400 g, 10.0 mmol) in H2O (6 mL) was added in methanol (6 mL) was placed in an ice-water bath for 15 minutes before pyridinium tribromide (0.470 g, 1.47 mmol) in MeOH (1.5 mL) was added. The reaction mixture was stirred at 0° C. for 5 hours after which the pH was adjusted to 7 with diluted HCl. The mixture was extracted with ethyl acetate, and the combined organic layer washed with H2O and concentrated under reduced pressure. The residue was purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.60 (m, 4H), 2.43 (m, 4H), 2.85 (t, 2H, J=6.44), 3.68 (s, 2H), 4.48 (t, 2H, J=6.44), 5.10 (s, 2H), 7.00 (d, 2H, J=8.47), 7.29–7.48 (m, 7H), 7.55 (s, 2H), 7.64 (s, 1H), 10.05 (s, 1H); MS (DCI/NH3) m/z 533 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:29]=[N:28][NH:27][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][C:7]2=[O:26].[CH3:30][C:31]1([NH2:35])[CH2:34][S:33][CH2:32]1>CN(C)C=O>[CH3:30][C:31]1([NH:35][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:19]4[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=4)[N:14]=[C:15]([O:17][CH3:18])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:5]=2[NH:27][N:28]=[CH:29]3)=[O:26])[CH2:34][S:33][CH2:32]1
Reactant: COc1cc(-c2nc3c(Cl)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: CC1(N)CSC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2c(Cl)cc3cn[nH]c3c2C(=O)NC2(C)CSC2)n(-c2ncccc2Cl)n1
Temperature: 60 °C
Reaction time: 72 h
Yield: 44.7 %

Procedure:
To a solution of 500 mg (1.16 mmol) of the above 5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of N,N-dimethylformamide is added 396 mg (3.49 mmol) of 3-methyl-thietan-3-ylamine. The reaction is stirred at 60° C. for 72 hours and then concentrated in vacuo. The residue is taken-up with water and ethyl acetate. The phases are separated and the aqueous layer is washed three times with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 1:2) affords 276 mg (44%) of the product as a white solid; LC/MS:532/534 (M+H)+, m.p.: 162-165° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:28][C:27]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:38][CH2:37][C:27]2[N:28]=[C:29]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[S:30][C:26]=2[CH3:25])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(N3CCOCC3)sc2C)cc1
Product: Cc1sc(N2CCOCC2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Yield: 87.7 %

Procedure:
3-[4-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (272 mg, 0.806 mmol) and toluene-4-sulfonic acid 2-(5-methyl-2-morpholin-4-yl-thiazol-4-yl)-ethyl ester (522 mg, 1.36 mmol) were reacted according to Standard procedure A. Purification using radial chromatography (CH2Cl2/EtOAc 98:2 to 75:25) gave the title compound as a white solid (387 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 1.14 (d, 6H, J=5.9 Hz), 1.32 (s, 9H), 2.16 (s, 3H), 2.39 (t, 2H, J=7.6 Hz), 2.77 (t, 2H, J=7.6 Hz), 2.84 (t, 2H, J=7.1 Hz), 3.28 (t, 4H, J=4.9 Hz), 3.70 (t, 4H, J=4.9 Hz), 4.08 (t, 2H, J=7.1 Hz), 4.25 (d, 2H, J=5.4 Hz), 4.83 (heptet, 1H, J=4.9 Hz), 6.66 (dd, 1H, J=2.4, 8.3 Hz), 6.72 (d, 1H, J=2.4 Hz), 6.98 (d, 1H, J=8.3 Hz). MS (ES) m/e 548.3 [M+1].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1
Reactant: ClCCCOC1CCCCO1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCOC1CCCCO1
Yield: 93.3 %

Procedure:
2-(3′-Chloropropoxy) tetrahydro-2H-pyran (Aldrich) (9 g, 0.05 mol) was added to a solution of sodium iodide (37.8 g, 0.25 mol) in acetone (250 mL) with stirring. The resultant slurry was refluxed for 48 hours. The mixture was cooled, evaporated to a solid mass and transferred to the top of a short column of neutral alumina. The column was washed with CH2Cl2 (1 L) and CH2Cl2 was removed using a rotary evaporator. The product was obtained as yellow liquid (12.6 g, 93%). 1H NMR δ: 1.62-1.86 (m, 6 H, ring CH2), 2.07 (m, 2 H, CH2—CH2—I), 3.27 (m, 2 H, CH2—I), 3.38-3.54 (m, 2 H, CH2—O), 3.74-3.89 (m, 2 H ring O—CH2), 4.58 (t, 1 H, J=3.2 Hz, ring CH); λmax/nm (εmax/dm3 mol−1 cm−1) 267 (1500); HRMS (EI+) calc. for C8H15IO2: 269.0049. found 269.0039.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C(N(CCCC)CCCC)CCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 56.9 %

Procedure:
To a mixture of 314 mg (purity: 96.0%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 828 mg (5.50 mmol) of 2-cyclopropyl-6-methylphenol were added tributylamine (2.76 g) and 334 mg (5.56 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 288 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 57%) and 2.5 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.5%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9](Br)[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4].[CH2:17]([O:19][C:20](=[O:35])[CH2:21][Sn](CCCC)(CCCC)CCCC)[CH3:18]>CN(C=O)C.[Br-].[Zn+2].[Br-].CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:35])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4]
Reactant: COC(=O)n1c(C)cc2c(Br)c(Cl)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)CC(=O)OCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [Br-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(Cl)ccc2c1cc(C)n2C(=O)OC
Temperature: 80 °C

Procedure:
4-Bromo-5-chloro-2-methyl-indole-1-carboxylic acid methyl ester (1.99 g, 6.57 mmol) and tributylstannanyl-acetic acid ethyl ester (3.22 g, 8.55 mmol) are dissolved in dry DMF (55 ml) under an atmosphere of argon. Zinc(II) bromide (1.92 g, 8.55 mmol) and dichlorobis(tri-o-tolylphosphin)palladium (0) (1.03 g, 1.31 mmol) are added. The reaction mixture is heated to 80° C. for 18 hours. TLC analysis indicates complete consumption of the starting material. The reaction mixture is cooled to RT and poured on a saturated aqueous solution of NH4Cl. After addition of EtOAc (30 ml), the mixture is filtered through a pad of Celite. The organic layer is washed with saturated aq. NaCl solution, dried over Na2SO4 and concentrated. The residue is purified by FCC (hexane/EtOAc 4:1) to yield the desired compound, still contaminated with tin residues. The mixture is dissolved in a 1:1 mixture of 1 M NaOH/EtOAc (200 ml in total) and stirred at RT for 18 hours. The organic layer is separated, washed once with concentrated aqueous NaCl solution, and then dried over Na2SO4. Concentration yields a solid residue which is purified by FCC (hexane/EtOac 4:1) to afford the desired compound, still slightly contaminated. A further round of purification with an automated preparative HPLC system (Gilson HPLC, Xterra 5 mikron, gradient 10% to 100% MeCN in H2O, 30 min) affords the pure title compound. 1H NMR (DMSO, 400 MHz) δ 1.20 (t, J=6.6 Hz, 3H), 2.59 (s, 3H), 4.01 (s, 2H), 4.03 (s, 3H), 4.11 (q, J=6.6 Hz, 2H), 6.68 (s, 1H), 7.32 (d, J=9 Hz, 1H), 7.96 (d, J=9 Hz, 1H); ES-MS: 332.1 [M+Na]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:2]2[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)nc1
Product: Nc1ccc(-c2ccccc2)nc1
Yield: 71 %

Procedure:
Obtained (71% yield) following the procedure described in Intermediate 39, starting with 6-bromopyridin-3-amine and phenylboronic acid.
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][N:4]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:5]1[C:6]([O:8]C(C)(C)C)=[O:7]>ClCCl.FC(F)(F)C(O)=O>[CH3:17][C:2](=[CH2:1])[CH2:3][N:4]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:5]1[C:6]([OH:8])=[O:7]
Reactant: C=C(C)CN1C(=O)CC[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)CN1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-dimethylethyl 1-(2-methyl-2-propen-1-yl)-5-oxoprolinate (0.099 g, 0.41 mmol) was dissolved in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) and stirred overnight at room temperature. The solvent was evaporated (azeotroping with toluene to remove traces of trifluoroacetic acid) to give crude 1-(2-methyl-2-propen-1-yl)-5-oxoproline as a brown oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C[O:19][C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([N:28]2[CH:32]=[C:31]([C:33]3[CH:34]=[N:35][N:36]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:37]=3[CH2:38][CH3:39])[N:30]=[CH:29]2)[CH:22]=1>>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([CH3:17])=[C:2]([NH:1][C:20](=[O:19])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([N:28]3[CH:32]=[C:31]([C:33]4[CH:34]=[N:35][N:36]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:37]=4[CH2:38][CH3:39])[N:30]=[CH:29]3)[CH:22]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: Cc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4C)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 157 was prepared from N-(3-amino-5-tert-butyl-2-methyl-phenyl)-methanesulfonamide and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 611 [C34H38N6O3S+H]+.