Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:19]3[S:18][C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])=[N:21][CH:20]=3)=[CH:23][CH:24]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (0.11 ml) was added to a solution of methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 150 mg) in DCM (3 ml) and the reaction mixture was stirred for 5 minutes. 4-tert-butylbenzoyl chloride (0.125 ml) was then added and the reaction mixture was stirred for 1 h. The reaction mass was quenched with water. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to get dark brown solid which was purified by silica gel column chromatography (EtOAc:CHCl3, 2:8) to get off white solid. The solid was crystallized in CHCl3/pet ether to give the title compound. Yield: 160 mg (72%) white solid. 1HNMR (DMSO-d6, 300 MHz): δ 10.38 (s, 1H), 8.76 (d, 1H), 8.41 (s, 1H), 7.94 (d, 2H), 7.91 (d, 2H), 7.8 (d, 2H), 7.58 (d, 2H), 4.33 (m, 1H), 3.69 (s, 3H), 2.27 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 494 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=O.[F:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[F:17][CH2:18][CH2:19][N:20]1[C:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[C:3]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: FCCNc1ccccc1
Reactant: O=C1C(Br)CCCC1C(=O)N1CCCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: O=C(C1CCCc2c1c1ccccc1n2CCF)N1CCCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
A mixture of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20; prepared according to example 3(b)) (500 mg, 1.7 mmol) and (2-fluoro-ethyl)-phenyl-amine (24) (890 mg, 3.5 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (2 mL) and dry zinc chloride (682 mg, 5 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with 2 N HCl (20 mL), water (2×20 mL) and aqueous potassium carbonate solution (2×20 mL) then dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 151 mg (27%) of [9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (non-radioactive imaging agent 6) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 21.6, 21.8, 24.7, 26.5, 26.9, 27.4, 37.3, 43.1 (d, JCF=45 Hz), 47.0, 82.1 (d, JCF=173 Hz), 108.5, 108.9, 118.6, 119.4, 121.0, 126.8, 136.2, 172.7.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH3:16][NH:17][C:18]([NH:20][C:21]#[N:22])=[NH:19].Cl>O>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:21]([NH:20][C:18]([NH:17][CH3:16])=[NH:19])=[NH:22])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNC(=N)NC#N
Agent: Cl
Solvent: O
Product: CNC(=N)NC(=N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To 22.9 g (0.1 mole) of 3,5-di(trifluoromethyl)aniline and 12.6 g (0.1 mole) of 1-methyl-3-cyanoguanidine is added 10 ml of concentrated hydrochloric acid and 20 ml of water. The solution is heated on a steam bath for 1 hour at which time a solid precipitates out. The reaction mixture is cooled to room temperature, made strongly alkaline with 40% NaOH and extracted with ether. The ether layer is dried over potassium carbonate, and evaporated in vacuo to obtain an oil. The residue is triturated with 500 ml heptane and the solid which forms is recrystallized from methylene chloride to obtain 1-[3,5-di(trifluoromethyl)phenyl]-5-methylbiguanide.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[O:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1>C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:30]3([OH:33])[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine (1 g, 2.92 mmol) in THF (10 mL) at room temperature was added isopropylmagnesium chloride (5.11 mL, 10.23 mmol). After 1 h stirring at room temperature, another equal amount of isopropylmagnesium chloride was added and the resulting mixture was stirred at room temperature overnight. To the solution was added dropwise dihydro-2H-pyran-4(3H)-one (0.540 mL, 5.84 mmol) and stirring was continued for 1 h. Reaction was quenched with saturated NH4Cl and extracted with DCM. Purification by Biotage produced the product. MS (ESI, pos. ion) m/z: 364.0. IC50 (uM) 0.04172.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5](=[O:17])[NH:6][C@@H:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:8]([O:10]CC)=[O:9].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:5](=[O:17])[NH:6][C@@H:7]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)N(CCO)CCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)N(CCO)CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl (2S)-2-[3-(2-hydroxyethyl)-3-phenethylureido]-4-methylvalerate (Compound No. 1-31, 1.00 g) is dissolved in a mixed solvent of tetrahydrofuran (3.5 ml)-ethanol (2.8 ml). A 2 N aqueous lithium hydroxide solution (1.7 ml) is added thereto under ice cooling, and the mixture is stirred under ice cooling for 25 minutes and further at room temperature for one hour. A 5% aqueous citric acid solution is added to the reaction mixture, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.02 g (quantitatively) of the titled compound (Compound No. 15-1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C:30]1([C:39](O)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1)=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:39]([C:30]3([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31]3)=[O:40])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCc2ccccc21
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CCc2ccccc21
Yield: 70.6 %

Procedure:
Preparation of example 149 from the title compound of Example 7 (hydrochloride) (52 mg, 0.17 mmol), 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2,3-dihydro-1H-indene-1-carboxylic acid (72 mg, 0.26 mmol), triethylamine (0.071 mL, 0.51 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (99 mg, 0.26 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (63 mg, 0.12 mmol) as a yellow powder in 69% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]([O:20][CH2:21][O:22][CH3:23])[CH:6]=1.[Li]CCCC.[B:29](OC)([O:32]C)[O:30]C.Cl>C1COCC1.O>[CH3:23][O:22][CH2:21][O:20][C:7]1[CH:8]=[C:9]([C:11]([CH3:18])([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[B:29]([OH:32])[OH:30]
Reactant: COB(OC)OC
Reactant: CCCCCCC(C)(C)c1cc(OCOC)cc(OCOC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(C)(C)c1cc(OCOC)c(B(O)O)c(OCOC)c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
1,3-Bis(methoxymethoxy)-5-(1,1-dimethylheptyl)-benzene (50) (1 equiv.) was dissolved in dry THF (10 mL). The solution was cooled to −10° C. and n-BuLi (1.1 equiv. using 1.6 solution in hexanes) was added dropwise. The mixture was stirred for an additional 1.5 h, then it was cooled to −78° C. and (MeO)3B (5 equiv.) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water, stirred for 30 min and the pH was adjusted to 4 with dilute aqueous HCl. The mixture was extracted with EtOAc, the organic layer was dried (MgSO4) and the solvent was evaporated. Purification by flash column chromatography (hexane-acetone) gave the title compound in 81% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]1[C:23]([CH:24]=O)=[CH:22][N:21]=[C:20]([CH3:26])[C:19]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6]([N:8]([CH2:17][C:18]1[C:23]([CH2:24][NH:37][C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)=[CH:22][N:21]=[C:20]([CH3:26])[C:19]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ncc(C=O)c(CN(CCCCCC(=O)O)C(=O)OC(C)(C)C)c1OCc1ccc(C#N)cc1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(CN(CCCCCC(=O)O)C(=O)OC(C)(C)C)c1OCc1ccc(C#N)cc1
Yield: 752.9 %

Procedure:
The reductive amination of 6-{tert-butoxycarbonyl-[3-(4-cyano-benzyloxy)-5-formyl-2-methyl-pyridin-4-ylmethyl]-amino}-hexanoic acid (52) (0.9 g, 0.2 mmol) and 4-aminobenzonitrile (1.6 g, 13.5 mmol), as described in Example 21, gave 6-(tert-butoxycarbonyl-{3-(4-cyano-benzyloxy)-5-[(4-cyano-phenylamino)-methyl]-2-methyl-pyridin-4-ylmethyl}-amino)-hexanoic acid (53) (0.9 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][O:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:35]4[CH2:36][CH2:37][CH:33]([O:32][CH3:31])[CH2:34]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: COC1CCNC1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCC(OC)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 3-methoxypyrrolidine. LCMS (M+H)+=531.2/533.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5]([C:17]([O:19][CH3:20])=[O:18])=[C:4]([CH:21]([CH3:23])[CH3:22])[N:3]=1.[C:24](=O)(OC1C=CC=CC=1)[O:25]C1C=CC=CC=1.N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:7]3[CH2:8][O:9][C:24](=[O:25])[NH:1][C:2]=3[N:3]=[C:4]([CH:21]([CH3:23])[CH3:22])[C:5]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)c1c(C(C)C)nc(N)c(CO)c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)COC(=O)N2

Procedure:
41.3 g (0.13 mol) of the compound from Example IV are dissolved in 325 ml of toluene and heated to reflux with 33.4 g (156 mmol) of diphenyl carbonate and 21.7 g (143 mmol) of 1,8-diazabicyclo-[5.4.0]-undec-7-ene for 30 min. The mixture is cooled and treated with 300 ml of water and 150 ml of ethyl acetate. The aqueous phase is extracted with 300 ml of ethyl acetate and the combined organic phases are washed twice with 200 ml of 0.1M NaOH and once with 200 ml of saturated sodium chloride solution, dried using sodium sulphate and concentrated in vacuo. The residue which remains is chromatographed in a column (φ 20 cm) on 1.6 kg of silica gel 230-400 mesh using a mixture of petroleum ether/ethyl acetate (3:1) to (1:1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2cc(Cl)ccc21
Reactant: CC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) and from 3-amino-2-benzoyl-5-chloro-1-(ethoxycarbonyl)indole (step 1) and acetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:26]1(B(O)O)[CH2:30][CH2:29][CH2:28][CH:27]=1>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:26]2[CH2:30][CH2:29][CH2:28][CH:27]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)C1=CCCC1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccccc2C1
Yield: 85 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (800 mg, 1.78 mmol) and cyclopenten-1-ylboronic acid (796 mg, 7.11 mmol) in dioxane (20 mL) is added Pd(PPh3)4 (412 mg, 0.36 mmol) and 2M aqueous solution of CsCO3 (5.34 mL, 10.7 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 2.7 h. After concentration in vacuo, the residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-40% EtOAc in heptane) to give a pure product (131) as a brown solid (589 mg, 85%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1N
Yield: 116 %

Procedure:
Prepared from [4-(2-fluoro-phenylethynyl)-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example F10) (713 mg, 2 mmol) by reduction with SnCl2.2H2O (2.26 g, 10 mmol) according to the general procedure G (method b). Obtained as an orange solid (757 mg).
Reaction SMILES: II.FC(F)(F)C(O[I:8](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[O:34][N:33]=2)=[CH:28][CH:27]=1>C(Cl)Cl>[I:8][C:31]1[CH:30]=[C:29]([C:32]2[CH:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[O:34][N:33]=2)[CH:28]=[CH:27][C:26]=1[O:25][CH3:24]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)no1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(OC)c(I)c2)no1
Reaction time: 8 h

Procedure:
Iodine (0.147 mL, 2.85 mmol) and [bis(trifluoroacetoxy)iodo]benzene (1.224 g, 2.85 mmol) were added successively to a solution of methyl 3-(4-methoxyphenyl)isoxazole-5-carboxylate (1.021 g, 4.38 mmol) in CH2Cl2 (13.2 mL) at 25° C. and the reaction was stirred overnight. After this time the solvent was removed in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 2088 mL, gradient to 40% EtOAc in hexanes over 2448 mL) to afford methyl 3-(3-iodo-4-methoxyphenyl)isoxazole-5-carboxylate, as a colorless oil. LCMS calc.=359.97. found=359.81 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 8.24 (d, J=2.1 Hz, 1H); 7.78 (dd, J=8.5, 2.2 Hz, 1H); 7.19 (s, 1H); 6.89 (d, J=8.5 Hz, 1H); 3.99 (s, 3H); 3.93 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[OH-].[Na+]>C(O)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[N:7]=2)=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared as in Example 1(B)(c), 198.1 mg, 0.44 mmol) in absolute ethanol (2.2 mL) was treated with a 1N aqueous sodium hydroxide solution (910 μL, 0.91 mmol). The reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove absolute ethanol. The resulting residue was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and extracted with ethyl acetate (1×150 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting white residue was washed well with cold water and dried to afford {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid (150 mg, 81%) as a white solid: mp 100–102° C.; FAB-HRMS m/e calcd for C19H20Cl2N2O3S (M+H)+ 427.0650, found 427.0633.
Reaction SMILES: [OH:1][C:2]([CH2:7][F:8])([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C>CC(N(C)C)=O.O.CO.CCOCC.C(Cl)Cl>[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([NH:26][C:3](=[O:4])[C:2]([OH:1])([CH3:6])[CH2:7][F:8])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(O)(CF)C(=O)O
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: C
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(O)(CF)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-fluoromethylpropionic acid (0.78 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto water, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water, and brine. After drying (Na2SO4) the ethyl acetate was removed by evaporation to give an amber foam. Trituration with ether/methylene chloride yielded the title tertiary carbinol (0.75 g, 52%) as a light tan solid; mp=189°-192° C. 1H-NMR (300 MHz, d6 -DMSO): 1.31 (s, 3H, CH3), 4.38 (dd, J=72 and 9.4 Hz, 1H, CH2F), 4.58 (dd, J=72 and 9.3 Hz, 1H, CH2F), 6.29 (s, 1H, OH), 7.58-7.68 (m, 4H, ArH, 7.89-8.02 (m, 5H, ArH), 10.16 (S, 1H, NH). MS (CI, CH4): 338(+1, 100). Analysis for C16H16FNO4S.0.1 H2O: Calculated: C, 56.66; H, 4.81 ; N, 4.13 Found: C, 56.40; H, 4.74; N, 4.02
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[O:16]([NH2:18])[CH3:17]>CO>[CH3:17][O:16][N:18]=[C:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: CON
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Solvent: CO
Product: CON=C1CCN(c2ccc(N)cc2)CC1
Yield: 63.5 %

Procedure:
A solution of 1-(4-aminophenyl)-4-piperidone (300 mg, 1.58 mmol) and methoxylamine hydrochloride (250 mg, 3.0 mmol) in methanol (5 mL) was heated at reflux for 30 min. The solvent was evaporated, water added and extracted with ethyl acetate. The combined organic layers were washed with water and brine then dried over sodium sulfate. Concentration to dryness afforded 1-(4-amino-phenyl)-piperidin-4-one O-methyl-oxime (220 mg, 64%) as a semisolid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])=[C:4]([N+:18]([O-])=O)[CH:3]=1>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH:8][C:9]2[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(Nc2ccc(F)cc2[N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Nc2ccc(F)cc2N)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Palladium on carbon (10%) (0.54 g) was added to a solution of (4-fluoro-2-nitro-phenyl)-(2,4,6-trimethyl-phenyl)-amine (5.32 g, 19.4 mmol) in ethyl acetate (40 mL) under nitrogen at room temperature in a 500 mL round-bottomed flask. The flask was evacuated under high vacuum (<2 mm Hg) and purged with hydrogen six times at room temperature, then it was attached to a balloon filled with hydrogen. After the reaction mixture was stirred at room temperature for 4.0 h under 1 atmosphere of hydrogen, the balloon was removed and a stream of nitrogen was bubbled through the reaction mixture for 10 min. The reaction mixture was filtered through a pad of celite and solvents were removed in vacuo to afford the title compound as a red solid (4.74 g, 100% yield). The purity of this compound was determined to be 98% by LC/MS. 1H NMR (CDCl3, 300 MHz) δ 6.93 (s, 2H), 6.52 (dd, J=9.8, 2.7 Hz, 1H), 6.32 (td, J=8.6, 2.7 HZ, 1H), 6.22 (dd, J=8.7, 5.7 Hz, 1H), 2.32 (s, 3H), 2.12 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 159.8, 156.7, 138.2 (d, J=10.5 Hz), 137.6, 133.5, 132.3, 129.5, 117.3 (d, J=9.5 Hz), 105.1 (d, J=22 Hz), 102.9 (d, J=25.5 Hz), 20.8, 18.0; Mass spec.: 245.14 (MH+)