Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=O)O[C:19](=O)[C:18]2=[CH:24][CH:25]=1)([O-:14])=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[CH2:22][C:17]2[C:18](=[CH:24][CH:25]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[CH2:19]1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)CN(CCc1ccc(Cl)cc1Cl)C2
Temperature: 150 °C
Reaction time: 2 h

Procedure:
2-(2,4-dichlorophenyl)ethanamine was suspended in toluene with 4-nitrophthalic anhydride (1 eq) and heated to 150° C. After 2 hours, the reaction was cooled and checked for completion by LC/MS. The solvent was then removed in vacuo and the resulting product was taken on to the next step without further purification. Rt 3.91 minutes, LC/MS m/z 365.1 (MH+).
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9].S(=Cl)=O.[C-:21]#[N:22].[Na+]>C(Cl)(Cl)Cl.CS(C)=O>[C:21]([CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])#[N:22]
Reactant: COc1ccc(-c2nc(CO)c(C)[nH]2)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: COc1ccc(-c2nc(CC#N)c(C)[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a stirred slurry of 15.3 g (0.06 mole) of 4-hydroxymethyl-2-p-methoxyphenyl-5-methyl-imidazole hydrochloride in 200 ml of chloroform are added 15 g (0.12 mole) of thionyl chlorine in CHCl3. Vigorous evolution of gas is observed during the addition. The reaction mixture is stirred at room temperature for 5 hours, during which time the slurry dissolves to form a pale pink solution. The solvent is then removed under reduced pressure and the solid residue taken up in fresh CHCl3. The solution is then filtered, ether is added until cloudy and then chilled. White crystals of 5-chloromethyl-2-p-methoxyphenyl-4-methyl-imidazole hydrochloride are precipitated, filtered and collected (91% yield), m.p. 203°-205° C (dec.). This chloromethyl derivative is dissolved in 75 ml of warm DMSO and added to a hot solution of 15 g (0.3 mole) of sodium cyanide in DMSO. The reaction mixture is stirred at room temperature for 16 hours and warmed to 60° C for 4 hours, then allowed to cool to room temperature and poured over 1 liter of ice and stirred. A yellow solid is precipitated, filtered and air-dried. Three recrystallizations from methylene chloride-hexane give the product, 4-cyanomethyl-2-(p-methoxyphenyl)-5-methyl-imidazole, as fluffy white crystals, m.p, 158°-160° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:4]=2[O:5][C:6]=1[CH3:7].C(O)(=O)C>C(O)C.O1CCOCC1.[Fe]>[NH2:12][C:8]1[C:4]2[O:5][C:6]([CH3:7])=[C:2]([Br:1])[C:3]=2[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1oc2c(N)cccc2c1Br
Yield: 98.9 %

Procedure:
To a solution of 3-bromo-2-methyl-7-nitrobenzo[b]furan (300 mg) and acetic acid (776 mg) in a mixture of ethanol (6 ml) and dioxane (1.5 ml) was added iron (722 mg) at 50° C. The mixture was refluxed for 1.5 hours and the insoluble material was filtered off. The filtratate was evaporated in vacuo with toluene. The residue was extracted with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and it was extracted with ethyl acetate from aqueous layer. The organic layer was combined and washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, and evaporated in vacuo to give 7-amino-3-bromo-2-methylbenzo[b]furan (262 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][CH2:3]1.Cl[C:14]1[N:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>CN(C)C=O>[CH3:1][C:2]1([CH3:12])[C:6]2[C:7]([O:11][C:14]3[N:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CC1(C)COc2cccc(O)c21
Solvent: CN(C)C=O
Product: CC1(C)COc2cccc(Oc3ncc([N+](=O)[O-])cn3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of 3,3-dimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 50, 724 mg) in dry N,N-Dimethylformamide (40 mL) potassium carbonate and 2-chloro-5-nitropyrimidine (774 mg, 4.85 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (40 ml) and extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with brine (2×50 ml), separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column SNAP 50 g and cyclohexane/ethyl acetate as eluents from 100/0 to 70/30 to afford the title compound (1.257 g) as a yellow oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.NC[C:16]([NH:18][C@@H:19]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[CH:29]([OH:31])[CH3:30])[CH2:20]1)=[O:17].[NH2:41][C@@H:42]1CC[C@@]2(C)[C@@H:44]([CH2:45][CH2:46][C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(O)C)[CH2:43]1.C(O)(=O)C1C=CC=NC=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:30][C@H:29]([OH:31])[C@@H:28]1[C@:32]2([CH3:40])[C@H:25]([C@H:24]3[C@H:35]([CH2:34][CH2:33]2)[C@:36]2([CH3:39])[C@H:21]([CH2:20][C@H:19]([NH:18][C:16]([C:45]4[CH:46]=[N:41][CH:42]=[CH:43][CH:44]=4)=[O:17])[CH2:38][CH2:37]2)[CH2:22][CH2:23]3)[CH2:26][CH2:27]1
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](NC(=O)CN)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1cccnc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C[C@H](O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](NC(=O)c5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 16 h

Procedure:
582 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added under an inert atmosphere to a solution of 960 mg of (20S) 3α-amino-5α-pregnane-20-ol, 813 mg of nicotinic acid, 30 ml of chloroform and 6 ml of pyridine and after 31/2 hours, another 291 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added to the mixture. The mixture was stirred for 16 hours and was evaporated to dryness. The residue was taken up in 30 ml of water and the solution was iced and vacuum filtered. The product was washed with water, dried at 80° C. under reduced pressure and was crystallized from methanol to obtain 920 mg of N-[(20S) 5α-pregnan-20-ol-3α-yl]-3-pyridinecarboxamide melting at 258° C. and having a specific rotation of [α]D20 =+14.5± 1° (c=1% in pyridine).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:33])[CH:19]([CH:20]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([Br:24])([Br:23])[Br:22])[CH:18]1[C:30]([OH:32])=[O:31].[C:34]([CH:36]([OH:50])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:38]=1)#[N:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:34]([CH:36]([OH:50])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:38]=1)#[N:35].[CH3:16][C:17]1([CH3:33])[CH:19]([CH:20]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([Br:23])([Br:24])[Br:22])[CH:18]1[C:30]([O-:32])=[O:31]
Reactant: CC1(C)C(C(=O)O)C1C(OS(C)(=O)=O)C(Br)(Br)Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Product: CC1(C)C(C(=O)[O-])C1C(OS(C)(=O)=O)C(Br)(Br)Br
Reaction time: 2 h

Procedure:
0.78 g of dicyclohexylcarbodiimide and 3 ml of methylene chloride were added to a solution of 1.8 g of the product of Step C, 20 ml of methylene chloride, 0.86 g of (S) α-cyano-3-phenoxy-benzyl alcohol and 0.1 g of 4-dimethylamino-pyridine. The mixture was stirred at 20° to 25° C. for 2 hours and the product formed was dried and the filtrate was evaporated to dryness under reduced pressure. A chromatography was carried out with elution with a hexane-ethyl acetate mixture (7-3) to obtain 2 g of α-cyano-3-phenoxy-benzyl 1R-[1α(S) 3α (S)] 2,2-dimethyl-3-[2,2,2-tribromo-1-methylsulfonyloxyethyl]-cyclopropane carboxylate with a specific rotation [α]D20 =1°±1° (c=1% in CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C@H:18]([CH3:27])[CH2:19][N:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)=[CH:15][C:14]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=O)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[CH:35]12[NH:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH2:36]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(N(CC)CC)C>[CH:38]12[N:41]([C:29](=[O:31])[C:28]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][C:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[C:17]4[C@H:18]([CH3:27])[CH2:19][N:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)([CH3:33])[CH3:32])[CH:35]([CH2:40][CH2:39]1)[CH2:36][CH2:37]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CN2CCC(=O)CC2)c1
Reactant: C1CC2CCC1N2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
To a solution of (S)-2-{2-(3,5-dimethylphenyl)-3-[1-methyl-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-indol-5-yl}-2-methylpropionic acid (148 mg in 2 mL dry methylene chloride) was added 58 mg 7-aza-bicyclo[2.2.1]heptane hydrochloride followed by 0.185 mL triethylamine and 173 mg of the PyBOP reagent and the mixture stirred at room temperature. After 14 hours, the mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water and brine and the organic portion dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 3:2) gave the title compound (128 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][C:34]4[CH:38]=[C:37]([CH3:39])[O:36][N:35]=4)([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:40][C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH2:33][C:34]5[CH:38]=[C:37]([CH3:39])[O:36][N:35]=5)([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:43]3[CH2:44][CH2:45][C@@H:41]([F:40])[CH2:42]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: Cc1cc(COC[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(Cl)nc2)C3)no1
Reactant: F[C@@H]1CCNC1
Product: Cc1cc(COC[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(N4CC[C@@H](F)C4)nc2)C3)no1

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-(5-methyl-isoxazol-3-ylmethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, CHCl3-d): δ 8.55 (d, 1H), 7.77 (dd, 1H), 7.49-7.37 (m, 3H), 7.14 (t, 2H), 6.41 (d, 1H), 6.35-6.20 (m, 2H), 5.40 (d, 1H), 4.62-4.48 (m, 2H), 4.19 (dd, 1H), 3.78-3.70 (m, 3H), 3.51 (d, 1H), 3.18-3.10 (m, 2H), 2.69-2.60 (m, 1H), 2.42 (d, 3H), 2.21 (d, 1H), 2.10 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([Si:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(Br)c(C=O)c1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 2-bromo-5-hydroxybenzaldehyde (4.66 g, 23.2 mmol), tert-butyldiphenylchlorosilane (7.73 mL, 30.6 mmol), and imidazole (2.37 g, 34.8 mmol) in DMF (50 mL) was stirred at 25° C. for 12 hours and 60° C. for 12 hours. The solvent was removed in vacuo and the residue partitioned between methylene chloride (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (10% ethyl acetate/hexane) to provide the title compound as a yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([Mg]Br)[CH:28]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:29]3[CH:28]=[C:27]([CH3:26])[CH:32]=[CH:31][N:30]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccnc([Mg]Br)c1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: Cc1ccnc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 1.96 mL 0.25M 4-methyl-2-pyridylmagnesium bromide. Yield: 17 mg of a white solid. LC-MSD, m/z for C22H16BrN3O2 [M+H]+=434.0, 436.0; HPLC retention time: 1.8 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(#N)C>[CH:12]1([NH:18][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NC1CCCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
2,4-Difluoronitrobenzene (2.00 g, 12.57 mmol) was dissolved in acetonitrile (20 mL) and cyclohexylamine (1.25 g, 12.57 mmol) and DIPEA (2.2 mL, 12.57 mmol) added. The reaction mixture was stirred at RT overnight. The resultant mixture was concentrated in vacuo to afford a bright yellow gum. This was purified by column chromatography (silica gel, gradient 0-10% EtOAc in cyclohexane) to afford the title compound as a bright yellow oil (2.4 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 8.20 (1H, dd, J=9.50, 6.22 Hz), 6.49 (1H, dd, J=11.75, 2.62 Hz), 6.31 (1H, ddd, J=9.51, 7.26, 2.61 Hz), 3.47-3.33 (1H, m), 2.11-1.98 (2H, m), 1.85-1.77 (2H, m), 1.72-1.60 (1H, m), 1.48-1.26 (5H, m)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(Cl)c2)s1
Reactant: NCc1ccccc1
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(NCc3ccccc3)c2)s1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
With stirring, a mixture of 5.24 g (16.4 mmol) of 2-chloro-4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine and 25 ml benzylamine is heated at 180° C. After 16 h, the reaction mixture is concentrated under reduced pressure, the residue is taken up in 100 ml of MTBE, the resulting precipitate is filtered off and the filtrate is concentrated again. The residue is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 4.75 g (88%) of the desired product; 1H-NMR(MeCN-d3) δ: 7.91 (d, 1H), 7.49 (m, 2H), 7.29 (m, 5H), 7.07 (m, 2H), 6.45 (d, 1H), 6.39 (s, 1H), 5.83 (br.s, 1H), 4.43 (d, 2H), 3.02 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][CH2:17][CH2:18]Br>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:17][CH3:18]
Reactant: CCCBr
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccccc1C#N

Procedure:
75 g (63 mmol) of 2-hydroxybenzonitrile, 174 g (1.26 mol) of potassium carbonate and 232.3 g (1.89 mol) of n-propyl bromide in 1 l of acetone are refluxed overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure.
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH3:37][Zn+]>C1COCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]5=[C:15]([CH3:37])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)CC1CCn2c1c(C)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Methyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.923 g, 1.54 mmol) was mostly dissolved in anhydrous THF (15.4 mL) to give a turbid suspension which was degassed with N2 for about 15 min. Bis(tri-t-butylphosphine)Pd(0) (0.071 g, 0.139 mmol) and 2.0 M methylzinc chloride in THF (2.318 mL, 4.64 mmol) were added at 25° C. The reaction mixture was sealed and heated at 70° C. to give a dark suspension. After 2 h at 70° C., the reaction mixture was cooled to 25° C., quenched with NaHCO3 (4 mL), stirred for 5 min, and filtered through a celite pad. The filtrate was diluted with MTBE, washed with H2O (twice), brine, and dried over MgSO4. The solvent was evaporated in vacuo to give a solid. The solid was dissolved in DCM/hexanes (1:1) and purified by silica gel column chromatography to give the titled compound (0.582 g) as a white solid. LCMS m/z=486.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.66 (m, 2H), 1.67-1.79 (m, 2H), 1.80-1.91 (m, 2H), 2.05-2.14 (m, 2H), 2.23 (s, 3H), 2.26-2.36 (m, 1H), 2.51 (dd, J=−15.92, 10.11 Hz, 1H), 2.82-2.90 (m, 1H), 2.94 (dd, J=15.79, 4.67 Hz, 1H), 3.32-3.43 (m, 1H), 3.73 (s, 3H), 3.75-3.80 (m, 1H), 3.92-4.01 (m, 1H), 4.02-4.10 (m, 1H), 5.09 (s, 2H), 6.86 (dd, J=8.72, 2.40 Hz, 1H), 7.04 (d, J=2.27 Hz, 1H), 7.10 (d, J=8.84 Hz, 1H), 7.47 (d, J=8.08 Hz, 1H), 7.61 (d, J=8.08 Hz, 1H), 7.71 (s, 1H).
Reaction SMILES: N1NN=NC=1C1NN=C2C=1C[C@@H]1C[C@@H]12.[CH2:15]1[C@H:17]2[CH2:18][C:19]3[C:23]([C@@H:16]12)=[N:22][NH:21][C:20]=3[C:24]([OH:26])=[O:25]>>[N:22]1[NH:21][C:20]([C:24]([OH:26])=[O:25])=[C:19]2[C@H:18]3[CH2:15][C@H:17]3[CH2:16][C:23]=12
Reactant: O=C(O)c1[nH]nc2c1C[C@@H]1C[C@H]21
Agent: C1c2c(n[nH]c2-c2nn[nH]n2)[C@H]2C[C@@H]12
Product: O=C(O)c1[nH]nc2c1[C@H]1C[C@H]1C2

Procedure:
(1aS, 5aS)-4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; and (1aS, 5as)-1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:25](=[O:26])[CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)Cc1cccs1
Product: Cc1noc(-c2sc(NC(=O)Cc3cccs3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and thiophen-2-yl-acetyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([CH3:34])[CH:22]=3)[CH2:16][O:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Na+].Cl>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([CH3:34])[CH:22]=3)[CH2:16][O:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC[C@@H](Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C#N)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@@H](Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Ethyl [(4-{[(1S)-1-[6-(4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate (0.886 g) was dissolved in THF (8.8 mL). Water (8.8 mL) and aq 2M NaOH (1.8 mL) were added and the mixture stirred at ambient temperature for 30 mins. The reaction mixture was acidified to pH 1 by the addition of aq 2M HCl and extracted with EtOAc (2×10 mL). The organic extracts were washed with brine (20 mL), dried (Na2SO4) and evaporated to give the title compound as a white foam (729 mg).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:30])[C:5]1[CH:6]=[C:7]([N:11]2[C:16]3[CH2:17][CH2:18][C:19](=[O:20])[C:15]=3[CH:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[NH:13][C:12]2=[O:29])[CH:8]=[CH:9][CH:10]=1.[CH3:31]I.O>O1CCCC1>[F:30][CH:4]([F:3])[C:5]1[CH:6]=[C:7]([N:11]2[C:16]3[CH2:17][CH2:18][C:19](=[O:20])[C:15]=3[CH:14]([C:21]3[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=3)[N:13]([CH3:31])[C:12]2=[O:29])[CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Sodium hydride (60% in mineral oil, 13 mg, 0.32 mmol) is added to a solution of 4-(1-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) in tetrahydrofuran. After 20 min methyl iodide (22 μL, 0.35 mmol) is added and the mixture is stirred at room temperature over night. Water is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 55 mg; ESI mass spectrum [M+H]+=394; Retention time HPLC: 0.74 min (005_CA01).