Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C)C=O.O>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][CH2:32][C:33]#[N:34])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: N#CCBr
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NCC#N)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 55.9 %

Procedure:
To the solution of the product from Example 205 (10 mg, 0.023 mmol) in N,N-dimethylformamide (0.2 mL) was added bromoacetonitrile (2.5 μL, 0.035 mmol) and potassium carbonate (5 mg, 0.035 mmol). The mixture was stirred while heating at 100° C. in a microwave reactor for 1 h. After cooling to 25° C., the orange solution was diluted with water and the pH of the aqueous layer was adjusted to pH 5 with acetic acid. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel eluting with 1% methanol/dichloromethane to give the title compound as a yellow solid (6.0 mg, 55%). MS (ESI−) m/z 465 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99 (d, J=6.62 Hz, 6 H) 1.58 (m, 2 H) 1.68 (m, 1 H) 4.46 (m, 4 H) 6.92 (m, 1 H) 7.16 (m, 2 H) 7.49 (m, 1 H) 7.61 (d, J=9.19 Hz, 1 H) 8.56 (dd, J=7.90, 1.65 Hz, 1 H) 8.89 (m, 1 H) 14.00 (br s, 1 H) 15.39 (br s, 1 H). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.62 Hz, 6 H) 1.48 (m, 2 H) 1.64 (m, 1 H) 4.31 (m, 4 H) 6.49 (t, J=6.62 Hz, 1 H) 6.99 (m, 2 H) 7.13 (m, 2 H) 8.35 (dd, J=7.72, 1.84 Hz, 1 H) 8.51 (dd, J=4.41, 1.84 Hz, 1 H) 15.73 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24].[N+:25]([O-])([OH:27])=[O:26]>C(Cl)(Cl)Cl>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:5]([CH3:14])[C:4](=[O:15])[C:3]([N+:25]([O-:27])=[O:26])([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[C:2]2=[O:1])[CH2:7][CH2:8]1
Reactant: O=[N+]([O-])O
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Solvent: ClC(Cl)Cl
Product: CON1CCC2(CC1)C(=O)C(c1c(C)cc(C)cc1C)([N+](=O)[O-])C(=O)N2C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2.2) (150 mg, 0.454 mmol) in chloroform (5 ml) at −5° C. was added fuming nitric acid (0.038 ml, 57.8 mg, 0.917 mmol) in chloroform (0.5 ml) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for three days, poured on ice water (10 ml), the layers were separated, the water phase extracted with ethyl acetate (3×20 ml), the combined organic phases washed with water (15 ml) and brine (15 ml), dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:3). Yield: 90 mg of 8-methoxy-1-methyl-3-nitro-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (title compound P1.13) as a white solid, mp 127-129° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].[C:13](=O)([O-])[O-].[Na+].[Na+].ClC[CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O-:25])=[O:24]>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][O:25][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4]
Reactant: Cn1c(=O)[nH]c2nc[nH]c2c1=O
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2ncn(COC(=O)C(C)(C)C)c2c1=O
Reaction time: 8 h
Yield: 25.6 %

Procedure:
To a mixture of 1-methylxanthine (844 mg, 5.08 mmoles) and sodium carbonate (538 mg, 5.08 mmoles) in 20 ml of dry DMF under nitrogen was slowly added over a period of 1 hour a solution of chloromethylpivalate (828 μl, 5.59 mmole) in 6 ml DMF at room temperature and the reaction mixture stirred overnight. The mixture was filtered, the filtrate evaporated to dryness and the residue triturated with 50 ml of 10 vol. %. EtOH/CHCl3. The solids obtained were starting material and the organic phase was chromatographed (10 vol. % EtOH/CHCl3) on silica gel plates. Two products were observed by eluting with 125 ml of 10 vol. % EtOH/CHCl3 and the band Rf, 0.48 obtained as 365 mg of the desired product. The other band proved to be the 3,7-disubstituted material.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].N1C=CC=CC=1.O>ClCCl>[Br:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:8][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH:18]=1
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1ccc(Br)cc1N
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cc1NC(=O)OC(C)C
Reaction time: 5.5 h
Yield: 96.4 %

Procedure:
Add isopropyl chloroformate (104 mL, 104 mmol, 1.0 M in toluene) dropwise to a solution of methyl 2-amino-4-bromobenzoate (14.5 g, 63.0 mmol) and pyridine (10.3 mL, 126.0 mmol) in dichloromethane (210 mL) at room temperature under nitrogen and stir for 5.5 h. Pour the reaction into water (500 mL) and separate the layers. Extract the aqueous layer with dichloromethane (2×100 mL) and combine the organic extracts and wash with 2 N HCl, saturated sodium bicarbonate and brine (100 mL each), then dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale orange solid (19.2 g, 96%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(Cl)cc1
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
5-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 5-(4-chlorophenyl)-2-(4-(2-dimethylamino-ethyloxy)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][C:3]1=[O:12]>CO.O>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]1=[O:12]
Reactant: COC(=O)c1ccn(C)c(=O)c1
Solvent: CO
Solvent: O
Product: Cn1ccc(C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a stirred solution of methyl 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (1 g, 1.0 eq) in 25 mL MeOH was added a solution of LiOHH2O (755 mg, 3.0 eq) in 5 mL water at rt. The reaction was then stirred at rt for 2 h. Then the solvent was removed in vacuo, and water was added to the residue, followed by addition of 3N HCl (aq) to adjust pH=1˜3. The product was collected by filtration and washed with water to give the product as white solid (540 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.56 (brs, 1H), 7.80 (d, J=7.2 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 6.53 (d, J=6.8 Hz, 1.6 Hz, 1H), 3.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.C[CH2:22][N:23](C(C)C)C(C)C.CN>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([NH:23][CH3:22])[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Agent: CN
Solvent: C1COCCO1
Product: CNc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
The crude 4-chloro-2-(methylsulfonyl)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]pyrimidine (1.09 g, 3.31 mmol) was dissolved 1,4-dioxane (30 mL). Hunig's base (2.88 mL, 16.53 mmol) and methylamine (6.61 mL, 13.22 mmol) were added, and the solution was stirred at room temperature overnight. Additional methylamine (2 mL) was added. The reaction was concentrated, then diluted with 30 mL EtOAc and washed with 0.1 N HCl (30 mL). The aqueous was back extracted with EtOAc and the organics were combined and washed with saturated NaCl, dried over MgSO4, filtered and concentrated. Purfication on Biotage 25 g SNAP column with a gradient of 0 to 50% EtOAc in Hexane over 35 minutes afforded the title compound (760 mg) as a clear oil. LC-MS (ES) m/z=281 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][C:3]=1[O:22][CH3:23].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31]>>[CH:18]1([C:10]2[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]3=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[C:3]([O:22][CH3:23])[CH:4]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Br
Reactant: Oc1ccccc1F
Product: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Oc1ccccc1F

Procedure:
Prepared according to a procedure analogous to that described for synthesis of Example 171, except using 1-(4-bromo-3-methoxy-phenyl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine and 2-fluoro-phenol. 1H NMR (400 MHz, CDCl3): δ=2.01-2.11 (m, 1H), 2.14-2.25 (m, 1H), 2.46-2.55 (m, 2H), 2.59-2.71 (m, 2H), 3.83 (t, J=8.6 Hz, 1H), 3.95 (s, 3H), 6.95-7.04 (m, 3H), 7.07-7.22 (m, 5H), 7.33 (d, J=2.0 Hz, 1H). MS (ES+): m/z 404.94 (100) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: COC(=O)c1cnccc1-c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4-chloro-2-fluorophenyl)nicotinate (1 g, 3.76 mmol) in MeOH (10 mL) and water (10 mL) was added NaOH (0.602 g, 15.06 mmol) and the solution stirred at room temperature for 2 h. The volatile organic solvent was evaporated under reduced pressure. The reaction mixture was cooled to 0° C. and acidified with 50% aqueous HCl. The precipitated so formed was collected by vacuum filtration to yield 4-(4-chloro-2-fluorophenyl)nicotinic acid (0.3 g, 1.192 mmol, 30% crude yield) as an off-white solid which was carried directly into the next step. 1H NMR (400 MHz, CD3OD) δ 9.12 (s, 1H), 8.78 (d, J=5.20 Hz, 1H), 7.29-7.48 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].C([Li])CCC.[CH:16]1([CH:19]2[CH2:22][C:21](=[O:23])[CH2:20]2)[CH2:18][CH2:17]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH:16]1([CH:19]2[CH2:22][C:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][CH:9]=[O:10])([OH:23])[CH2:20]2)[CH2:18][CH2:17]1
Reactant: O=C1CC(C2CC2)C1
Reactant: O=CNc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CNc1ccccc1C1(O)CC(C2CC2)C1
Temperature: -100 °C
Reaction time: 2.5 h

Procedure:
In a sulfonation flask, 7.8 g (0.039 mol) N-(2-bromophenyl)form amide was dissolved in a mixture of 100 ml dry tetrahydrofuran. The solution was cooled to −100° C. and 60 ml (0.096 mol) of n-butyllithium solution (1.6M in hexane) was added over a period of 1 hour in such at manner that the internal temperature remained constant at −100° C. (±2° C.). After stirring for 2.5 hours at −100° to −110° C., 5.3 g (0.048 mmol) of 3-cyclopropylcyclobutan-1-one (prepared as described in Example 7), dissolved in 30 ml of dry tetrahydrofuran, were added over a period of 30 minutes in such a manner that the internal temperature remained constant at −100° C. (±2° C.). After stirring for 3 hours at −78° C., the temperature was elevated to 0° C. in ca. 30 minutes. Concentrated ammonium chloride solution and ethyl acetate were added and the organic phase was washed several times with water. After drying and evaporation of the solvent in a water jet vacuum, the crude material was obtained. Purification was achieved by flash chromatography over silica gel (eluant: hexane/ethyl acetate 1:1). Yield: 2.55 g (23% of theory) of N-[2-(3-cyclopropyl-1-hydroxycyclobutyl)-phenyl]formamide in the form of a resin.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:49])([F:48])[F:47])=[CH:19][N:18]=2)=[C:12]([O:50][CH2:51][CH3:52])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1COCC1.CO.O.[OH-].[Li+].O>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:47])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:50][CH2:51][CH3:52])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@@H](C(=O)O)CC3)c3c2C(=O)N(C)C3)n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Ethyl cis-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-ethoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (Example 244, 72.0 mg, 0.096 mmol) was taken up in THF (0.13 mL, 1.60 mmol) and MeOH (0.13 mL, 3.20 mmol). This was treated with a solution of lithium hydroxide, monohydrate (20.2 mg, 0.48 mmol) in H2O (0.13 mL, 7.2 mmol) and was allowed to stir at rt for 30 hrs. The reaction was concentrated in vacuo to a solid and was purified by CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→5% MeOH in DCM] to afford 68.6 mg (99%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.43 (d, J=9.09 Hz, 1 H), 8.34 (s, 1H), 7.88 (d, J=8.34 Hz, 1 H), 7.26 (d, J=8.84 Hz, 1 H), 7.03 (t, J=2.02 Hz, 1 H), 6.90 (dt, J=8.21, 2.21 Hz, 1 H), 4.51 (s, 2 H), 4.03-4.17 (m, 6 H), 3.27 (s, 2 H), 3.18 (s, 3 H), 2.74 (br. s., 1 H), 2.61-2.70 (m, 1 H), 2.30 (d, J=12.38 Hz, 2 H), 1.66-1.82 (m, 6 H), 1.41 (t, J=6.95 Hz, 3 H), 1.28 (t, J=7.07 Hz, 6 H). MS (ES+): m/z 720.22/721.26 (100/98) [MH+]. HPLC: tR=1.62 min (Micromass TOF: polar—3 min).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)C=CC=CC=1.[Cl:25]CCCl.ClC(OC(Cl)C)=O>CO>[ClH:25].[O:12]([CH:10]1[CH2:11][NH:8][CH2:9]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: ClCCCl
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: Cl
Product: c1ccc(OC2CNC2)cc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A 50 mL flask was charged with 1-(diphenylmethyl)-3-phenoxyazetidine (328 mg, 1.04 mmol; which may be prepared as described in Step 2) and 1,2-dichloroethane (4.6 mL). 1-Chloroethyl chloroformate (164 μL, 1.35 mmol) was added and the reaction mixture was stirred at 70° C. for 1.5 h. After cooling to room temperature, MeOH (4.6 mL) was added and the reaction mixture was stirred at 70° C. for 1.5 h. The reaction mixture was concentrated to dryness. The crude product was triturated in pentane to give the title compound (204 mg, quantitative) as pale yellow crystals. This product was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH:15]=[O:16].[CH3:24][C:25](=[O:28])[CH:26]=[CH2:27]>COCCOC.C(OCC)(=O)C.O>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])([CH2:27][CH2:26][C:25](=[O:28])[CH3:24])[CH:15]=[O:16]
Reactant: C=CC(C)=O
Reactant: O=CC(c1ccccc1F)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(=O)CCC(C=O)(c1ccccc1F)c1ccccc1F
Temperature: -50 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (26.9 g) is added to a solution of bis(2-fluorophenyl)acetaldehyde (30.8 g) in 1,2-dimethoxyethane (135 cc), and butenone (19.9 cc) is then added dropwise and after cooling to -50° C. The reaction mixture is stirred for 12 h at -50° C. and then for 6 hours at 25° C. and diluted with ethyl acetate (250 cc) and water (200 cc). The organic phase is washed with water (3×200 cc) and then with saturated sodium chloride solution (200 cc), dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 5.5 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90:10). 2,2-Bis(2-fluorophenyl)-5-oxohexanal (9 g) is obtained in the form of a yellow oil. A solution of this compound (6.65 g) in toluene (100 cc) containing para-toluenesulphonic acid (1.5 g) is heated to reflux for 3 hours, washed with water (2×100 cc) and then with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 4 cm, height 30 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90:10) and collecting 15-cc fractions. Fractions 21 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 4,4-bis(2-fluorophenyl)cyclohexenone (2.83 g) in the form of a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:27])[NH:22]2.N1CCCCC1.C(O)(=O)C>C(O)C>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:1][C:3]1[NH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:21](=[O:27])[NH:22]2
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1CCC(=O)O)CCCC3)C(=O)N2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.2 g of 4-methyl-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed in 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and dried under vacuum to give 6.2 g (80% yield) of 3-[2-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5](C#N)=[CH:4][C:3]=1[CH3:11].[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].[NH4+].[CH3:18][N:19](C)C=O>O>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N:13]2[N:14]=[CH:18][NH:19][NH:12]2)=[CH:8][C:9]=1[CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C#N)cc(C)c1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(N2N=CNN2)cc(C)c1Br
Temperature: 140 °C

Procedure:
4-Bromo-3,5-dimethyl benzonitrile (3.0 g, 14.3 mmol), sodium azide (2.32 g, 35.7 mmol) and ammonium chloride (2.3 g, 42.84 mmol) are suspended in dry N,N-dimethylformamide and heated at 140° C. for 7 hours. The mixture is allowed to cool to room temperature, diluted with water and the precipitated solid collected by filtration, washed with water and dried to give the title compound (yield 1.74 g). The mother liquor was saturated with sodium chloride and repeatedly extracted with ethyl acetate. The organic extracts were combined and the solvent removed to give a second crop of title compound (yield 1.39 g, total yield 3.13 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([N+:36]([O-])=O)=[C:31]([F:39])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Sn](Cl)Cl>CCOC(C)=O.C(O)C.O>[NH2:36][C:32]1[C:31]([F:39])=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:34][C:33]=1[F:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c([N+](=O)[O-])c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(N)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 55.4 %

Procedure:
A solution of 5-cyclopropyl-6-(N-(3,5-difluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.65 g, 1.16 mmol) and tin (II) chloride (0.66 g, 3.49 mmol) in EtOAc (10 mL) and ethanol (10 mL) was heated under reflux for 2 h. The reaction mixture was diluted with EtOAc and water and the suspension was filtered through celite. The organic layer was dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.34 g, 55%) as a white solid. LCMS (m/z, ES+)=530.2 (M+H+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Cl:48][C:49]1[C:50]([O:61][CH3:62])=[C:51]([C:55]([O:59][CH3:60])=[C:56]([Cl:58])[CH:57]=1)[C:52](O)=[O:53].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:52](=[O:53])[C:51]3[C:55]([O:59][CH3:60])=[C:56]([Cl:58])[CH:57]=[C:49]([Cl:48])[C:50]=3[O:61][CH3:62])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: COc1c(Cl)cc(Cl)c(OC)c1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(Cl)c(OC)c1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,5-dichloro-2,6-dimethoxybenzoic acid (9.0 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.