Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NCc1ccncc1)C(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A solution of N'-t-butyl-N'-benzoylhydrazine (0.5 g, 0.00026 mol) in 10 ml of toluene was treated with 50% sodium hydroxide (0.6 g) followed by isonicotinyl chloride hydrochloride (0.47 g, 0.0026 mol). The mixture was stirred at 23° C. overnight. The solids were removed by filtration and washed with water followed by ether to afford N'-t-butyl-N-isonicotinyl-N'-benzoylhydrazine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][SH:5].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Cl>O.CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][S:5][NH:18][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)(=[O:17])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1F
Reactant: COCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCSNS(=O)(=O)c1ccccc1
Reaction time: 3 h

Procedure:
3.6 of 2-methoxyethyl-mercaptan is added dropwise to a mixture of 3.5 g of 55% sodium hydride and 80 ml of dimethylformamide. To this mixture 8.0 of 2-fluorophenylsulfonamide are added. The reaction mixture is stirred for 3 hours at a temperatur of 115°-120° C. After cooling the mixture is poured into water. To this mixture 10% of hydrochlorid acid are added, and the product is extracted with ethyl acetate. The organic phase is evaporated and the residue is purified by chromatography. Yield: 6.7 g of 2-methoxyethylthio-phenylsulfonamide, m.p. 119°-121° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])=[O:29])=[CH:18][CH:17]=2)[CH3:15])[CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].I[CH3:39]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:30])=[O:29])=[CH:18][CH:17]=2)[CH3:15])[CH2:10][CH2:11][O:12][CH3:39])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(CN(CCO)c1cccc(C#N)c1)c1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(CC(C)c1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Part A. N-[3-(cyano)phenyl]-N-[2-[2'-(1,1-dimethylethylaminosulfonyl)[1,1'-biphenyl]-4-yl]propyl]-N-2-(hydroxy)ethylamine (1.00 gm, 2.89 mmol) was dissolved in 100 mL of anhydrous THF followed by the addition of NaH (60% dispersion in mineral oil, 0.23 gm, 5.78 mmol). Once the evolution of gas ceased, iodomethane was added (0.411, 0.18 mL, 2.89 mmol) and the solution was allowed to stir overnight at room temperature. The solution was quenched with dilute HCl, and the volatiles removed in vacuum. N-[3-(Cyano)phenyl]-N-[2-[2'-(1,1-dimethylethylaminosulfonyl)[1,1'-biphenyl]-4-yl]propyl]-N-2-(methoxy)ethylamine was isolated after HPLC purification on Vydac C-18 column eluting with solvent A (acetonitrile:water:TFA 80:20:0.2) and solvent B (water:TFA 99.8:0.2) used as a gradient, as a clear oil (0.100 gm, 7%). MS m/e 506.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].Br[C:21]1[N:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>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]>[OH:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:25][N:26]=3)=[C:3]([C:17]([NH2:19])=[O:18])[N:4]=2)=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(O)c1ccc(Br)nc1
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(Nc3ccc(C(C)(C)O)cn3)s2)cc1

Procedure:
The title compound was prepared as described in Example 1, Step 2 using 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (150 mg, 0.54 mmol), 2-(6-bromopyridin-3-yl)propan-2-ol (for preparation, see WO 2004/050024 A2 Example 120 Step A) (117 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.032 mmol), X-PHOS (77 mg, 0.16 mmol), potassium carbonate (82 mg, 0.60 mmol), and tert-amyl alcohol (1.2 ml) as starting materials. 1H NMR (500 MHz, d6-DMSO) δ 11.25 (s, 1H), 8.42 (d, 1H), 7.88 (d, 2H), 7.82 (dd, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.55 (d, 2H), 7.14 (d, 1H), 5.13 (s, 1H), 5.11 (s, 1H), 1.44 (s, 6H), 1.43 (s, 6H). LRMS (APCI) calc'd for C21H25N4O3S [M+H]+ 413.2, found 413.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:16][C:4]1[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
Iron powder (293 mg, 5.2 mmol) was added to a solution of tert-butyl 5-bromo-3-nitropyridin-2-ylcarbamate (167 mg, 0.52 mmol) in acetic acid (2.5 mL). The mixture was stirred at 60° C. for 1 h 20 min before cooling to rt. The mixture was then diluted with ethyl acetate, and solids were removed by filtration through celite. The filtrate was washed with water followed by saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide tert-butyl 3-amino-5-bromopyridin-2-ylcarbamate (96.3 mg, 0.33 mmol, 64% yield) as a gray solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, 1H), 7.20 (d, 1H), 6.95 (br s, 1H), 4.42 (br s, 2H), 1.51 (s, 9H); MS (EI) for C10H14BrN3O2: 232, 234 (Br isotopes, MH+-t-butyl).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2,3-dichlorobenzaldehyde (20 g, 114 mmol) in concentrated sulfuric acid (100 mL) was added cautiously fuming nitric acid (5.4 mL, 8.16 g, 130 mmol). The resulting solution was stirred for 1 hour, then poured onto an ice/water slurry and the precipitate collected by filtration. This was dissolved in diethyl ether (400 mL), and the solution washed with water and saturated sodium carbonate, then dried (MgSO4) and concentrated. The residue was re-dissolved in the minimum amount of hot diethyl ether, then poured quickly into vigorously stirred petrol (1 L). After stirring for a further 10 minutes, the precipitate was collected by suction filtration and dried under vacuum to yield 2,3-dichloro-6-nitrobenzaldehyde, 9.98 g (40%), essentially free of isomers.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([CH2:14][C:15](O)=[O:16])[N:7]3[C:6]=2[CH:24]=1.[CH3:25][NH2:26].Cl>O1CCCC1>[CH3:25][NH:26][C:15](=[O:16])[CH2:14][C:13]1[N:7]2[C:8]([N:9]([CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:24][C:6]=32)=[N:11][C:12]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN
Reactant: Cc1ccc2c(c1)n1c(CC(=O)O)c(-c3ccccc3)nc1n2C
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nc2n(C)c3ccc(C)cc3n12
Reaction time: 2 h

Procedure:
A suspension of 1.5 g (0.0047 mol) of 6,9-dimethyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran, 1.22 g (0.0075 mol) of N,N'-carbonyldiimidazole are added thereto and the mixture is stirred for 2 h. The solution obtained is treated with an excess of dry gaseous methylamine and stirred for several hours. The solvent is evaporated under reduced pressure. The residue is taken up in water and the solid residue is isolated by filtration. After drying, the product is purified by silica gel column chromatography, eluting with a dichloromethane/methanol 95/5 mixture. The product obtained is then treated with a hydrochloric acid solution. The precipitate is collected by filtration and treated with an excess of ammonium hydroxide up to a pH of 9 to 10. A solid is isolated which is washed with water and dried. 0.79 g of product is obtained. Melting point: 251°-253° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:23])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:5]
Reactant: C[C@H](O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 47.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), (S)-1-aminopropan-2-ol (7.84 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.9 min) to provide (R/S)-2-hydroxy-N—((S)-2-hydroxypropyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18 mg, 0.033 mmol, 47.1% yield) as a mixture of diastereomers. LCMS=489.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.09-8.20 (2 H, m), 7.55-7.86 (7 H, m), 5.15 (1 H, s), 3.80-3.94(1 H, m, J=9.11, 6.67, 6.67, 4.62 Hz), 3.09-3.37 (2 H, m), 1.14 (3 H, dd, J=6.27, 1.21 Hz); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[NH:23][CH:22]=[N:21]2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:32][O:33][CH2:34][CH2:35]Br>CS(C)=O.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[N:23]([CH2:35][CH2:34][O:33][CH3:32])[CH:22]=[N:21]2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:5]
Reactant: O=C(NCC1(O)CCCCCC1)c1cc(-n2nc[nH]c2=O)ccc1Cl
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COCCn1cnn(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.9 %

Procedure:
A slurry of 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide (44.4 mg, 0.122 mmol) and Cs2CO3 (66.0 mg, 0.202 mmol) were stirred in DMSO (0.813 mL) at ambient temperature for 20 minutes. 2-Bromoethyl methyl ether (17.0 mg, 0.122 mmol) was added and the reaction stirred at ambient temperature for 48 hours. The reaction was diluted with water (15-fold) and the aqueous extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate, and concentrated in vacuo. The crude was purified by reverse phase HPLC reverse phase HPLC using a (25–65% gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water) (to give the title compound (18 mg). LCMS (m/z) 423.5 M+1.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:29]=[CH:28][C:18]([O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]([CH3:26])([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:28][CH:29]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc([C@H]2CC[C@H](N)CC2)cc1
Reaction time: 7 h

Procedure:
A mixture of 1.9 g of ethyl trans-2-{4-[4-(benzylamino)cyclohexyl]phenoxy}-2,2-dimethylacetate in the base form (4.8 mmol) and of 0.1 g of 10% palladium-on-charcoal in ethanol (75 ml) is placed under hydrogen atmosphere at 40° C. and stirred for 7 h. The reaction mixture is filtered through celite. The solvent is evaporated under reduced pressure and ethyl trans-2-[4-(4-aminocyclohexyl)phenoxy]-2,2-dimethylacetate is obtained (0.660 g) in the form of a yellow oil which is dissolved in ethanol (5 ml). The solution is acidified with a solution (9N) of HCl in ethanol and the solid thus obtained is filtered off (0.530 g, 72%). Melting point: 240-242.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([OH:18])=O)[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([Cl:21])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
5.00 g (19.18 mmol) (4′-chloro-4-methylbiphenyl-3-yl)acetic acid (EP 2029531 A1 and US 2009/298828 A1) were dissolved in 36.51 g (306.84 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for four hours and then concentrated under reduced pressure. Drying under fine vacuum gave 5.4 g (100% of theory) of the title compound as a brownish oil.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[N:5]([CH2:14][CH2:15][CH3:16])[C:4]2[N:17]=[C:18](OS(C(F)(F)F)(=O)=O)[CH:19]=[CH:20][C:3]1=2.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1>>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[N:5]([CH2:14][CH2:15][CH3:16])[C:4]2[N:17]=[C:18]([C:32]3[CH:33]=[N:29][NH:30][CH:31]=3)[CH:19]=[CH:20][C:3]1=2
Reactant: CCCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Reactant: c1cn[nH]c1
Product: CCCN1c2ncccc2C(=O)N(C)c2ccc(-c3cn[nH]c3)nc21

Procedure:
The title compound (mp 206°-207° C.) was prepared from 5,11-dihydro-5-methyl-11-n-propyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-stannyl)pyrazole in a manner analogous to that described in Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:28][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)(=[O:32])[CH3:31]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A162) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[C:17]1(C)C=CC=C[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH:17]([C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1)=[CH2:18]
Reactant: Cc1ccccc1
Reactant: CC1(C)c2ccccc2-c2ccc(I)cc21
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: CCO
Product: C=Cc1ccc2c(c1)C(C)(C)c1ccccc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
8.19 g (25.6 mmole) of 2-iodo-(9,9-Dimethyl)-fluorene, 5.18 g (28.1 mmole) of dibutyl vinylborate, 0.26 g of Pd(PPh3)4, 60 ml of toluene, 30 ml of ethanol, and 60 ml of a 2M sodium carbonate aqueous solution were fed into a 300-ml round-bottomed flask, and the whole was stirred at 80° C. for 8 hours in a stream of nitrogen. After the completion of the reaction, the reaction liquid was extracted with toluene. The organic layer was washed with water and dried with magnesium sulfate, followed by evaporation to dryness under reduced pressure. The resultant was purified by means of silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to yield 3.5 g of 2-vinyl-(9,9-Dimethyl)-fluorene (62.1% yield). 1.05 g (4.77 mmole) of the obtained 2-vinyl-(9,9-Dimethyl)-fluorene and 10 ml of THF were fed into a 100-ml round-bottomed flask, and the whole was cooled to −5° C. in a stream of nitrogen. 6.21 ml of a 0.5M 9-BBN solution were slowly added dropwise to the resultant, and the whole was stirred at 0° C. for 2 hours. After that, 4.8 ml of a 3N aqueous solution of NaOH, 130 mg of PdCl2(dppf), and 956 mg (2.144 mmol) of 2,2′-diodo-(9,9-Dimethyl)-fluorene were added to the resultant, and the whole was stirred at 60° C. for 7 hours. After the completion of the reaction, the reaction liquid was extracted with toluene. The organic layer was washed with water and dried with magnesium sulfate, followed by evaporation to dryness under reduced pressure. Then, the resultant was recrystallized with toluene/hexane. After the obtained crystal had been removed by filtration, the remainder was purified by means of mother liquor silica gel column chromatography (eluent: hexane/ethyl acetate=5/1→1/1), recrystallized with toluene, dried in a vacuum, and subjected to sublimation purification to yield 272 mg of Compound 21 (20% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:23]3[CH2:24][CH2:25][N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][CH2:22]3)[N:10]=2)[CH:7]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Agent: Cl
Product: Clc1ccc2nc(CN3CCN(c4ccccc4)CC3)cn2c1
Yield: 58 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.296 g) and 1-phenylpiperazine hydrochloride (Aldrich; 0.333 g) are converted to 0.279 g of the title compound after chromatography on silica gel and crystallization from dichloromethane/ethyl ether/hexane; mp 128.5-130.5° C.; MS m/z 326, 328; IR (mineral oil) 1217, 1073, 1501, 921, 1600 cm-1 ; 1H NMR (CDCl3) δ2.74, 3.24, 3.77, 6.85, 6.92, 7.12, 7.26. 7.52. 8.13.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)[CH3:2].[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[I:11])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCOC(=O)c1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(I)c(N)c1
Temperature: 85 °C

Procedure:
To a solution of ethyl4-iodo-3nitrobenzoate (Compound 30, 9.45 g, 29.4 mmol) in ethyl acetate (200 ml) and tin(II) chloride dehydrate (33.1 g, 147 mmol). Reaction was heated to 85° C. for 1 h, cooled to 25° C., quenched with NaHCO3(S), filtered off white solid, and then organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1.C1COCC1.N1CCC1>C(N(CC)CC)C>[F:20][C:21]1([F:25])[CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22]1
Reactant: FC1(F)CNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: C1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CC(F)(F)C3)s2)noc1C(F)(F)F
Yield: 49 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 3,3-difluoroazetidine hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine (containing and additional 1.1 eq to neutralize the azetadinyl hydrochloride salt) and azetidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried and then chromatographed on silica gel with EtOAc/hexanes (25 then 50%) as eluant to afford product as a colorless solid (43 mg, 49%). 1H NMR (CDCl3) 2.37 (s, 3H), 4.68 (br, 4H), 4.19 (br, 2H), 7.53 (s, 2H). 19F NMR −100.6, −63.1. LC/MS 6.42 min, [M+1]+ 353.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 4.05 g. (0.0126 mole) of ethyl 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetate, 15 ml. of 1N sodium hydroxide solution and 2 ml. of ethanol is refluxed for 30 minutes. The solution is cooled, diluted with water and filtered. The filtrate is acidified with dilute hydrochloric acid. The precipitated solid is collected and recrystallized from methanol-water to give a white crystalline solid, 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid, m.p. 135-136° C. Analysis: Calcd. for C15H14ClNO3 : C, 61.76; H, 4.83; N, 4.82% Found: C, 61.68: H, 4.86; N, 4.89%