Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18](COCC[Si](C)(C)C)[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[C:1]([NH:5][C:6]([C:17]1[NH:18][C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1

Procedure:
Using essentially the same procedure as Example 25, Step B–C, but using t-butyl isocyanate (0.016 mL, 0.14 mmol) in Step B, 4,5-di-(4-chlorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)imidazole (23 mg, 0.055 mmol) from Example 25, Step A was converted to the SEM intermediate and then to the title compound with TBAF. HPLC/MS: 388 (M+1), 390 (M+3); Rt=2.45 min.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][CH:17]([C:19]2[C:20]([CH3:31])=[N:21][O:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)[OH:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:41]=[CH:42][C:43]([C:27]3[CH:26]=[CH:25][C:24]([C:23]4[O:22][N:21]=[C:20]([CH3:31])[C:19]=4[CH:17]([OH:18])[CH2:16]/[CH:15]=[CH:14]/[C:11]4[CH:10]=[CH:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:13][CH:12]=4)=[CH:29][CH:28]=3)=[CH:44][CH:45]=2)[CH2:38][CH2:39]1)[CH3:33]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccc(Cc2ccccc2)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccc(Cc5ccccc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using (E)-4-(4-benzyl-phenyl)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42](Cl)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.C(OCC)(=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]2[C:11](=[O:12])[NH:10][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=2)=[O:43])[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCCC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (675 mg; 2.345 mmol) in THF (18 mL) is added N,N-diisopropylethylamine (0.81 mL; 4.65 mmol) and 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester (609 mg; 2.45 mmol). The reaction mixture is left stirring at room temperature for 18 hours. After this time, the reaction mixture is diluted with ethyl acetate and washed with water then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 464 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorobenzamide was dissolved in dichloromethane, after which 1.5 eq. of oxalyl chloride were added and the mixture was heated to reflux for 16 hours. The reaction mixture was then concentrated under high vacuum and reacted in step b without any further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc2ccccc2n1C1CCNCC1
Reactant: Fc1ccc(SCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2ccccc2n1C1CCN(CCCSc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
To a stirred solution of 1-(3-bromopropylsulfanyl)-4-fluorobenzene (0.2 g) and 2-butyl-1-piperidin-4-yl-1H-benzimidazole (0.3 g) in DMF (5 ml) was added K2CO3 (0.6 g) and KI (0.05 g). The mixture was heated at 100° C. for 1 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (9:1 DCM:MeOH) to yield 0.3 g of the title compound as colourless crystals. Mp. 159-161° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[F:25]>>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][C:19]=1[F:25]
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1ccc(O)cc1F
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F
Yield: 83.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 182 using Compound 83 (250 mg, 1.08 mmol) and 4-amino-3-fluoro-phenol (276 mg, 2.17 mmol) to provide 185 (290 mg, 83% yield) as a solid. LC-MS (M+H=322, obsd.=322).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]2[N:22]=[CH:23][S:24][C:20]=2[CH:19]=1>>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[Br:1])[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Br
Reactant: Nc1ccc2ncsc2c1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2ncsc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 97(e), (140 mg, 0.47 mmol) and 6-aminobenzothiazole (86 mg, 0.57 mmol, Lancaster) provided, after purification by silica gel chromatography (gradient: 0-30% EtOAc in hexane), the title product as an off-white solid. MP 214-215° C. MS (ESI, pos. ion) m/z: 427 (M+1).
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH:4]([CH3:6])[CH3:5].CCCCCBr.[CH3:14][C:15](=[CH:18][CH2:19][CH3:20])[CH:16]=[O:17].Cl>CCOCC>[CH3:5][CH:4]([CH2:3][CH2:2][CH:16]([OH:17])[C:15]([CH3:14])=[CH:18][CH2:19][CH3:20])[CH3:6]
Reactant: CCC=C(C)C=O
Reactant: CC(C)CCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CCCCCBr
Product: CCC=C(C)C(O)CCC(C)C
Temperature: 10 °C
Yield: 76 %

Procedure:
69.5 g (2.9 g atoms) of magnesium are placed in 500 ml of absolute ether. Subsequently, a solution of 438 g of isoamyl bromide, which contains ca 1.5% n-amyl bromide in accordance with gas chromatography, in 1.2 l of absolute ether is added dropwise so that the exothermic reaction maintains the ether constantly at the boiling point. After completing the addition, the mixture is held at reflux temperature for a further 30 minutes. The Grignard solution is thereupon cooled to 10° C. Then, 236.5 g (2.41 mol) of 2-methyl-2-pentenal in 600 ml of absolute ether are added dropwise within 40 minutes, the temperature being held between 10° and 20° C. during the addition. In order to complete the reaction, the mixture is held at reflux temperature for a further 1 hour. The mixture is subsequently added to ice, decomposed with aqueous hydrochloric acid, the ethereal solution is washed neutral with sodium carbonate solution and saturated sodium chloride solution and then dried. The crude product (480 g) remaining after distillation of the solvent is fractionally distilled over a Widmer column and gives 312 g of 2,6-dimethyl-6-nonen-5-ol (III) of boiling point 62° C./0.05 mm Hg; nD25 =1.4479, which contains 1.5% of 4-methyl-3-decen-5-ol in accordance with gas chromatography (Carbowax, 130° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([CH3:19])=[C:15]([CH:18]=1)[CH:16]=[O:17]>>[CH3:19][C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: Cc1ccc(Br)cc1C=O
Reactant: OB(O)c1ccncc1
Product: Cc1ccc(-c2ccncc2)cc1C=O

Procedure:
Pyridine-4-boronic acid (14 mg, 96 μmol) is coupled to aryl bromide 230 (19 mg, 96 μmol) using Method A to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[CH3:17]OS(OC)(=O)=O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:17])([O-:3])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1O
Product: COc1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
After the 3-nitro-4-hydroxybiphenyl is formed as described above, it is then reacted with dimethylsulfate to form 3-nitro-4-methoxybiphenyl, which is then reduced to form 3-amino-4-methoxybiphenyl. The 3-amino-4-methoxybiphenyl is precipitated by the addition of hydrochloric acid solution, forming the desired 3-amino-4-methoxybiphenyl hydrochloride.
Reaction SMILES: S[C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1.C(=O)(O)[O-].[Na+]>[N+]([O-])(O)=O>[N:3]1[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][C:5]2=[N:6][CH:2]=1
Reactant: Sc1nc2cccccc-2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: c1ccc2ncnc-2cc1

Procedure:
With reference to Journal of the American Chemical Society, vol. 76, pages 3352 and 3353 (1954), 23 g of 2-mercaptocycloheptimidazole as synthesized in Synthetic example 1 (b) was added to 210 ml of 10% nitric acid, and stirred with heating to the inner temperature of 80° to 90° C. for one hour. The reaction solution was neutralized with sodium bicarbonate and extracted with chloroform (250 ml×2). The chloroform layer was dried over anhydrous sodium sulfate and concentrated to 50 ml under reduced pressure, and then 200 ml of hexane was added. Deposited crystals were collected by filtration and dried.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)O[CH2:27][CH2:26][O:25]1.[OH-].[Na+]>CN(C)C=O>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([CH2:27][CH2:26][OH:25])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: O=C1OCCO1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2CCO

Procedure:
A mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (0.50 g), ethylene carbonate (0.16 g), N,N-dimethylformamide (20 ml) and a catalytic amount of sodium hydroxide powder was boiled under reflux for 1 hour. The mixture was evaporated under reduced pressure and the residue was triturated with water (30 ml). The mixture was filtered to give a solid which was purified by flash column chromatography on silica using ethyl acetate/industrial methylated spirit (9:1) as the mobile phase to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]ethanol, m.p. 144.5-145° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>O.CC(C)=O>[C:10]1([CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:5]1[C:4]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH3:9])=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=1
Reactant: Oc1cccnc1O
Reactant: Cc1ccccc1N
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1NC1=CC(=O)C(=O)N=C1Nc1ccccc1C
Reaction time: 2 h
Yield: 27 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), o-methylaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml of water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(o-tolylamino)-2,3-pyridindione in a red powder. The yield was 27%-45%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH2:14]([O:16][C:17](=[O:22])[C:18](Br)([CH3:20])[CH3:19])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Cl.[Cl-].[Na+].O.O>C(#N)C>[CH2:14]([O:16][C:17](=[O:22])[C:18]([O:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([C:9](=[O:11])[CH3:10])=[CH:6][C:7]=1[CH3:8])([CH3:20])[CH3:19])[CH3:15]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1cc(O)c(C)cc1C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1cc(OC)c(C(C)=O)cc1C
Temperature: 0 °C
Yield: 65.2 %

Procedure:
A suspension of 416 mg (2.3 mmol) 1-(4-hydroxy-2-methoxy-5-methyl-phenyl)-ethanone, 0.69 ml (4.6 mmol) 2-bromo-2-methyl-propionic acid ethyl ester, 1.58 g (4.9 mmol) cesium carbonate and a trace of potassium iodide in 25 ml acetonitrile was heated under reflux conditions for 14 h. The mixture was poured onto 1 M HCl solution/ice water 1/1 and extracted two times with ethyl acetate. The combined extracts were washed with brine/ice water and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 450 mg (1.5 mmol, 66%) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cc(F)cc(F)c1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Fc1cc(F)cc(-c2cc(-c3cncc(Cl)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-3,5-difluorobenzene (Apollo, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.51 (tt, J=9.3, 2.4 Hz, 1 H), 7.61-7.74 (m, 2H), 7.93 (s, 1H), 8.41 (t, J=2.1 Hz, 1H), 8.82 (d, J=2.4 Hz, 1 H), 9.06 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+, 295 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([CH2:16][NH2:17])[OH:15].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH2:16][CH2:14][OH:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a chilled solution (−10° C.) of 4-chloro-3-nitrobenzoyl chloride (1.85 g, 8.4 mmol) in anhydrous THF (60 mL) was added dropwise a solution of ethanolamine (0.48 mL, 8.0 mmol) in THF (20 mL) followed by TEA (1.1 mL, 8.0 mmol). After stirring 1 h while temperature was maintained at −10° C., the solution was combined with a 1:1 mixture of ice and satd NaHCO3 (100 mL) and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give 4-chloro-N-(2-hydroxyethyl)-3-nitrobenzamide (1.74 g, 89%) as a white solid, which was used without purification. TLC (3:22 MeOH/DCM Rf 0.36).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1I.NC1C=CC(O)=CC=1Cl.CI>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[Cl:9]
Reactant: COc1ccc(I)c(Cl)c1
Reactant: Sc1ccccc1Br
Agent: Nc1ccc(O)cc1Cl
Solvent: CI
Product: COc1ccc(Sc2ccccc2Br)c(Cl)c1

Procedure:
Prepared from 2-bromo-benzenethiol and 2-chloro-1-iodo-4-methoxy-benzene (prepared from 4-amino-3-chloro-phenol by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753 followed by alkylation with methyl iodide according to the general procedure by Uozumi et al. J. Org. Chem. 1993, 58, 1945-1945)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[NH:19]1[CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:19]2[CH2:22][CH2:21][CH2:20]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CNC1
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 97.8 %

Procedure:
A solution of 1.07 g (4.0 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester and 0.461 ml (6.8 mmol) of azetidine in 10 ml of tetrahydrofuran is heated at reflux for 90 minutes. After evaporation of the tetrahydrofuran the residue is distributed between water and ethyl acetate, the organic phase separated and washed with water and brine, dried over Na2SO4 and concentrated yielding 1.19 g of 5-azetidin-1-yl-2-nitro-4-trifluoromethyl-benzoic acid methyl ester as yellow powder, m.p. 127-136° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[CH:8]2.N[C@H:33]1CCCCN[C:34]1=O>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:34][CH2:33][CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:9]=[CH:8]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Reactant: N[C@H]1CCCCNC1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (Example 16; 300 mg, 0.677 mmol) in dichloromethane (3 mL) was added (S)-3-aminoazepan-2-one (prepared according to Example 4; 173 mg, 1.35 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with 80% ethyl acetate/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxoazepan-3-yl)-1H-indazole-6-carboxamide (Ic) (290 mg, 94%). Mass spec: 457 (M+1). 1H NMR (CDCl3) δ 9.11 (br, 1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 6.14 (br, 1H), 4.78 (ddd, 1H), 4.22 (d, 2H), 3.34 (m, 1H), 3.24 (m, 1H), 2.35 (m, 1H), 2.26 (m, 1H), 2.07 (m, 1H), 1.89 (m, 2H), 1.57 (m, 1H), 1.42 (m, 1H), 0.93 (d, 6H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH:16]2[CH2:18][CH2:17]2)=[CH:14][C:13](=[O:19])[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH:16]2[CH2:18][CH2:17]2)=[CH:14][C@H:13]([OH:19])[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C=C(C2CC2)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C=C(C2CC2)[C@H]1CO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-cyclopropyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 237, 2.97 g, 7.78 mmol) following the procedure described for Intermediate 8. The desired product was obtained as a tan oil (2.74 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1C=O.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[OH:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:27][N:24]1[CH2:25][CH2:26][CH:21]([N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:22][CH2:23]1
Reactant: O=Cc1ccccc1O
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-Hydroxybenzaldehyde (0.122 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 16 mg; HRMS (FAB30, NBA) (M+H)+ 459.2633, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.2, tr 5.81 min.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[I:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1([C:34]([OH:36])=O)[CH2:33][CH2:32]1.CCN(CC)CC.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C.C1COCC1>[I:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1([C:34]([NH2:7])=[O:36])[CH2:33][CH2:32]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1(c2ccccc2I)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1(c2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
HOBt (1.89 g, 14.0 mmol) and EDCl.HCl (2.69 g, 14.0 mmol) were added to a solution of 1-(2-iodophenyl)cyclopropanecarboxylic acid (I10) (3.11 g, 10.8 mmol) in DMF (6 mL), THF (29 mL) and Et3N (9.4 mL, 54 mmol). After 15 minutes ammonium carbonate (7.95 g, 86.4 mmol) was added and the resulting mixture was stirred at room temperature for 20 hours. The volatiles were removed in vacuo and water (150 mL) was added to the residue resulting in the formation of a suspension. The suspension was sonicated for several minutes, filtered and the filter cake dried to give the title compound I11 as an off white solid (2.55 g, 82%); 1H NMR (300 MHz, d6-DMSO) δ 7.87 (d, J=7.6 Hz, 1H), 7.36-7.38 (m, 2H), 7.02-7.08 (m, 1H), 6.96 (brs, 1H), 6.05 (brs, 1H), 1.52 (brs, 2H), 0.96 (brs, 2H). LCMS-B: rt 5.800 min; m/z 288 [M+H]+.