Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:13]([O-])([O-])=O.[K+].[K+].BrC[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=3)=[C:28]([C:33]([O:35][CH3:36])=[O:34])[CH:29]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4.5 g of 2-butyl-4-chloro-5-formylimidazole and 6.75 g of K2CO3 in 200 ml of anhydrous DMF under nitrogen atmosphere is added under stirring with a solution of 8.1 g of methyl 4'-bromomethyl-1,1'-biphenyl-2-carboxylate in 10 ml of anhydrous DMF. The mixture is stirred at room temperature for 2 hours then concentrated under reduced pressure to 50 ml, poured into 500 ml of H2O and extracted with CH2Cl2. The organic phase is washed with H2O, dried over Na2SO4 and evaporated to dryness under reduced pressure. 9 of an orange oil are obtained which is used without further purification. 1H NMR (CDCl3), δ: 0.89 (t, 3 H); 1.45 (m, 2 H); 1.72 (m, 2 H); 2.66 (m, 2 H); 3.62 (s, 3 H); 5.59 (s, 2 H); 7.02-7.88 (m, 8 H); 9.76 (s, 1 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].N1C=C[C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)=CC=1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:29]3[C:28]4[C:32](=[CH:33][CH:34]=[CH:35][C:27]=4[CH3:24])[NH:31][C:30]3=[O:36])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[CH3:15][C:14]1[C:8]2[C:7](=[O:18])[NH:6][CH2:11][CH2:10][C:9]=2[NH:12][C:13]=1[CH:16]=[C:29]1[C:28]2[C:32](=[CH:33][CH:34]=[CH:35][C:27]=2[CH3:24])[NH:31][C:30]1=[O:36]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(C)c43)c(C)c2C1=O
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1C)C(=O)NCC3)C(=O)N2
Yield: 64.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 542-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (48 mg, 64.9%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:27]1(O)[CH2:32]CCC[CH2:28]1>CCO.CCO.CCO.CCO.[Ti]>[NH2:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:22][CH2:32][CH2:27][CH2:28][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(N)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: Nc1cccc2c1C(=O)N1CCC[C@H]1c1c(C(=O)OC3CCCCC3)ncn1-2
Reaction time: 24 h

Procedure:
A mixture of 10.0 g (28.2 mmol) of tert.butyl (S)-8-amino-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 2.6 g (11.1 mmol) of a tetraethyl orthotitanate and 60 ml of cyclohexanol is stirred at 130° for 24 hours, a small amount of solvent being distilled off three times in vacuo. The mixture is subsequently evaporated in vacuo, the residue is taken up in 60 ml of chloroform, the chloroform solution is treated with water, stirred for a further 1 hour, filtered over siliceous earth and then the organic phase is separated. The organic phase is dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate and subsequently recrystallized from ethyl acetate. There is obtained cyclohexyl (S)-8-amino-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 211°-212°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH3:40][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:8]2[C:14]([CH3:40])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c(Br)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2c(c(C)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Temperature: 130 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a mixture of 1-benzo[1,3]dioxol-5-ylmethyl-3-bromo-2-(4-chloro-phenyl)-4-(2,2-dimethyl-propionyloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (from Example 38(a))(180 mg, 0.29 mmol) in DMF (2.5 mL) was added tetramethyltin (207 mg, 1.16 mmol) and Pd(PPh3)2Cl2 (30 mg, 0.044 mmol). Resulting mixture was stirred at 130° C. for 2 h. Reaction mixture was diluted with EtOAc and filtered. Filtrate was washed with water and brine, dried over MgSO4, filtered, and concentrated to give the title product 161 mg. MS-(+)-ion: M+1=549.14.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17](=[O:29])[CH:18]([CH3:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH:18]([CH3:28])[C:17]([OH:29])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: CC(Cc1ccc(OCc2cccc(SC3CCC3)n2)c(Cl)c1)C(=O)O
Yield: 78.6 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (50 mg, 0.25 mmol) obtained in Step C of Preparation Example 37 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (60 mg, 0.28 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([CH3:20])=[C:15]([OH:19])[C:16]=2[CH2:17][OH:18])=[O:8])=[CH:5][CH:4]=1)#[N:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([CH3:20])=[C:15]([O:19][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[C:16]=2[CH2:17][OH:18])=[O:8])=[CH:21][CH:22]=1)#[N:2]
Reactant: Cc1ncc(CNC(=O)c2ccc(C#N)cc2)c(CO)c1O
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1ncc(CNC(=O)c2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 35 %

Procedure:
The coupling of 4-cyano-N-[5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-benzamide (71) (580 mg, 3.0 mmol) and α-bromo-p-tolunitrile (580 mg, 3.0 mmol), as described in Example 3, gave 4-cyano-N-[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-benzamide (72) (433 mg, 39% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCC(c3ccccn3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C2CCNCC2)nc1
Reaction time: 24 h
Yield: 100.3 %

Procedure:
To 1-Benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 ml), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and 50 ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (Hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9 H),1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 (s, 1H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H).7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100w) of 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).
Reaction SMILES: CO[C:3]([N:5]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]1=[O:11])=O.NC[CH2:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17]>C(=O)([O-])O.[Na+]>[O:10]=[C:9]1[CH:8]=[CH:7][C:6](=[O:11])[N:5]1[CH2:3][CH2:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17]
Reactant: CC(C)(CCN)C(=O)O
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(CCN1C(=O)C=CC1=O)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of 1.39 g (8.95 mmol) of N-methoxycarbonylmaleimide in 44 ml of saturated sodium hydrogencarbonate solution were added, at 0° C., 1.5 g (8.95 mmol) of 4-amino-2,2-dimethylbutyric acid, and the mixture was stirred for 40 min. Subsequently, the cooling bath was removed and the reaction mixture was stirred for a further 1 h. While cooling with ice, the reaction mixture was then adjusted to pH 3 by adding sulphuric acid, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. 1.17 g (79% purity, 49% of theory) of the title compound were obtained.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:9]=2[O:8][CH:7]=[CH:6]1.C(N(CC)CC)C.O>CN(C)C=O>[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:2][C:3]#[N:4])[CH2:17][CH2:16]3)[C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: C1=COc2c(cccc2N2CCNCC2)O1
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN1CCN(c2cccc3c2OCCO3)CC1
Yield: 99 %

Procedure:
A solution of bromoacetonitrile (2.38 g, 19.86 mmol), benzodioxin-5-ylpiperazine (5.1 g, 19.86 mmol) and triethylamine (11.05 mL, 79.4 mmol) in dimethylformamide (50 mL) was stirred under a nitrogen atmosphere at 70° C. for 3 days. Water (300 mL) was added and the product extracted into ethyl acetate (6×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator gave the desired compound as a light yellow oil which solidified on standing (5.1 g, 99% yield). The compound was isolated as its hydrochloride salt by treatment in ethyl acetate with ethereal HCl to yield a light yellow solid, mp=193-194° C.; MS (+) ESI m/z=260 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]([O:14][CH3:15])=[C:12](Cl)[N:11]=[CH:10][N:9]=1>O>[Cl:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: COc1c(Cl)ncnc1Cl
Solvent: O
Product: COc1c(Cl)ncnc1N1CCNCC1
Yield: 103.9 %

Procedure:
Piperazine (6.00 g, 70 mmol, 6.25 eq) is dissolved in water (30 ml), and to this solution is added 4,6-dichloro-5-methoxypyrimidine (2.00 g, 11.2 mmol, 1.0 eq). The mixture is stirred vigorously at room temperature for 2.0 h, during which 4,6-dichloro-5-methoxypyrimidine is gradually dissolved. The aqueous phase is extracted with CH2Cl2 (25 ml*2). The extracted liquids are combined, dried over anhydrous sodium sulfate and filtered by vacuum filtration, and concentrated to give a light yellow oily crude product (2.66 g).
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=O)C=1.C(O)(C)(C)C.[C:17]([O:20][C@:21]1([C@:41]2([CH3:42])[C@H:27]([C@H:28]3[C@H:38]([C@@H:39]([F:43])[CH2:40]2)[C@:36]2(C)[C:31](=[CH:32][C:33](=[O:45])[C@@H:34]4C[C@@H:35]42)[CH:30]=[CH:29]3)[CH2:26][CH2:25]1)[C:22](=[O:24])[CH3:23])(=[O:19])[CH3:18].[CH2:46]([Cl:49])[CH2:47]Cl>C(OCC)(=O)C>[C:17]([O:20][C@:21]1([C@:41]2([CH3:42])[C@H:27]([C@H:28]3[C@H:38]([C@@H:39]([F:43])[CH2:40]2)[C@:36]2([CH3:35])[C:31](=[CH:32][C:33](=[O:45])[CH2:34][C@@H:47]2[CH2:46][Cl:49])[C:30]([Cl:1])=[CH:29]3)[CH2:26][CH2:25]1)[C:22](=[O:24])[CH3:23])(=[O:19])[CH3:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCCl
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)C[C@H](CCl)[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Reaction time: 48 h

Procedure:
A solution of 4.0 g. of m-chloroperbenzoic acid in 10 ml. of tert.-butanol is combined with 700 mg. of 17-acetoxy-11β-fluoro-1α,2α -methylene-4,6-pregnadiene-3,20-dione in 60 ml. of ethylene chloride. The solution is allowed to stand for 48 hours at room temperature, then diluted with ethyl acetate, and washed in succession with sodium bisulfite solution and water. Yield: 510 mg. of 17-acetoxy-6α,7α -epoxy-11β-fluoro-1α,2α -methylene-4-pregnene-3,20dione, which is introduced into 10 ml. of glacial acetic acid saturated with gaseous hydrogen chloride. After 22 hours, the solution is poured into ice/water. The thus-precipitated product is vacuum-filtered, washed with water, taken up in methylene chloride, and dried over sodium sulfate. The thus-produced crude 17-acetoxy-6-chloro-1α-chloromethyl-11β-fluoro-4,6-pregnadiene-3,20-dione (380 mg.) is agitated in 5 ml. of collidine for 6 hours at 140° C. After cooling, the solution is diluted with ether and washed repeatedly in succession with 2N hydrochloric acid and water. The ether phase is dried over sodium sulfate. The crude product is purified by preparative layer chromatography (system: ether/chloroform 8+2), thus obtaining 175 mg. of 17-acetoxy-6-chloro-11β-fluoro-1α,2α -methylene-4,6-pregnadiene-3,20-dione; m.p. 250°-252° C. UV: ε282 = 16,650.
Reaction SMILES: OCC1C=CC=C[C:4]=1[C:9]1[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.CCOC(/N=N/C(O[CH2:37][CH3:38])=O)=O>C1COCC1>[C:38]1([C:12]2[CH:13]=[C:9]([CH2:4][O:18][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)[S:10][C:11]=2[C:14]([F:15])([F:16])[F:17])[CH:37]=[CH:12][CH:13]=[CH:9][CH:4]=1
Reactant: OCc1ccccc1-c1ccc(C(F)(F)F)s1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2cc(-c3ccccc3)c(C(F)(F)F)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 184 %

Procedure:
A solution of 1.95 g (7.5 mmol) of 2-hydroxymethyl-4-phenyl-5-trifluoromethyl-thiophene (from Step A), 925 mg (7.6 mmol) of 4-hydroxybenzaldehyde and 3.0 g (11.4 mmol) of triphenylphosphene in 40 mL of THF at 0° C. was treated with 2.0 g (11.4 mmol) of diethylazodicarboxylate. The resulting mixture was warmed to rt, stirred for 2 h, then concentrated. Chromatography on a Biotage 75S cartridge using 9:1 v/v heptane/EtOAc as the eluant afforded 2.5 g of impure title compound. Chromatography on a Biotage 40M cartridge using 19:1 v/v hexanes/EtOAc (1 L), then 4:1 v/v hexanes/EtOAc (1 L) as the eluant afforded 1.65 g (60%) of the title compound: 1H NMR (500 Mhz) δ 5.32 (s, 2H), 7.10 (d, J=8.5, 2H), 7.12 (s, 1H), 7.41-7.43 (5H), 7.85-7.90 (2H), 9.92 (s, 1H).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH3:23])([CH3:22])[CH2:15][N:16]2[C:19](=[O:21])[CH3:20])=[CH:12][CH:11]=1.[CH3:24][C:25]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)([CH3:30])[C:26](OC)=[O:27]>ClCCCl.C1COCC1>[C:19]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([N:9]3[C:26](=[O:27])[C:25]([CH3:30])([CH3:24])[N:31]([CH2:32][C:33]4[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=4)[C:4]3=[O:3])[CH:18]=2)[C:14]([CH3:23])([CH3:22])[CH2:15]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reactant: COC(=O)C(C)(C)NCc1ccncc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.26 g (36.7 mmol) of diphosgene were initially charged at −20° C. in 80 ml of 1,2-dichloroethane, and 3.0 g (14.5 mmol) of 1-(6-amino-3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone, dissolved in 80 ml of 1,2-dichloroethane, were added dropwise. After stirring at RT for 2 h and reflux for 1 h, the mixture was concentrated fully. The remaining residue was dissolved in 80 ml of THF, added to a solution of 3.06 g (14.7 mmol) of methyl 2-methyl-2-[(pyridin-4-ylmethyl)amino]propionate in 80 ml of THF, and heated under reflux for 8 h. The residue remaining after evaporation was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 4.69 g.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Br:9][C:10]1[CH:46]=[C:45]([CH3:47])[C:13]([O:14][C:15]2[C:20]([N+]([O-])=O)=[C:19](/[CH:24]=[CH:25]/[N:26](C)C)[N:18]=[C:17]([N:29]([C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:16]=2)=[C:12]([CH3:48])[CH:11]=1>O.C1COCC1>[Br:9][C:10]1[CH:46]=[C:45]([CH3:47])[C:13]([O:14][C:15]2[C:20]3[NH:26][CH:25]=[CH:24][C:19]=3[N:18]=[C:17]([N:29]([C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[N:16]=2)=[C:12]([CH3:48])[CH:11]=1
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2cc[nH]c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of Na2S2O4 (40.04 g, 230 mmol) in water (100 ml) was added to a solution of (E)-tert-butyl 4-(4-bromo-2,6-dimethylphenoxy)-6-(2-(dimethylamino)vinyl)-5-nitropyrimidin-2-yl(4-cyanophenyl)carbamate (28.0 g, 45.9 mmol) in THF (300 ml). The mixture was stirred at room temperature of 2 days. The reaction mixture was concentrated. The residue was washed with water and extracted with ethyl acetate. The organic layer was concentrated and the product was obtained by crystallization from a mixture of water and methanol (18.15 g (mmol, 74%). 1H NMR (CDCl3, 400 MHz) δ 1.33 (s, 9H), 2.05 (s, 6H), 6.73 (d, J=3.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.21 (s, 2H), 7.49 (d, J=8.8, 2H), 7.55 (d, J=3.8 Hz, 1H), 9.09 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].[PH2:12](=[O:14])[OH:13]>>[CH2:5]([O:4][CH2:1][CH2:2][CH2:3][PH:12](=[O:13])[OH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[PH2]O
Reactant: C=CCOCc1ccccc1
Product: O=[PH](O)CCCOCc1ccccc1

Procedure:
The title compound was prepared from allylbenzyl ether and 50% aqueous phosphinic acid by an analogous procedure to that described in J. Inorg. Nucl. Chem., 1965, 27, 697.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[O:9][N:8]=1.[C:17]([O:21][C:22]([NH:24][C:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=NS(C(F)(F)F)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:38]([O:37][C:35]([NH:34][C:25]([N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[C:10]1[O:9][N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:11]=1)=[N:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: c1ccc(-c2cc(C3CCCN3)on2)nc1
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCCC1c1cc(-c2ccccn2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
2-[3-(Pyrid-2-yl)isoxazol-5-yl]pyrrolidine (Method 12) (1.5 g, 7 mmol) was added to a solution of N,N′-di(tertbutyloxycarbonyl)-N″-(trifluoromethylsulphonyl)guanidine (2.59 g, 6.6 mmol) and triethylamine (0.975 ml) in DCM and the mixture stirred at ambient temperature for 8 hours. The mixture was then washed with water, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/methanol (100:0 increasing in polarity to 98:2) to give the title compound (2.3 g, 70%).
Reaction SMILES: C([Cl:4])(C)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([OH:24])[C@@H:13]2[O:20][C@@H:19]3[C@@H:15]([O:16][C:17](C)(C)[O:18]3)[C@@H:14]2[OH:23])=[CH:8][C:7]=1[CH2:25][C:26]1[CH:35]=[CH:34][C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=1>CO>[ClH:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[C@H:13]([OH:20])[C@@H:14]([OH:23])[C@H:15]([OH:16])[CH:19]([O:18][CH3:17])[O:24]2)=[CH:8][C:7]=1[CH2:25][C:26]1[CH:35]=[CH:34][C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=1
Reactant: CC1(C)O[C@@H]2O[C@@H]([C@@H](O)c3ccc(Cl)c(Cc4ccc5c(c4)OCCO5)c3)[C@@H](O)[C@@H]2O1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
A solution of 0.35M HCl in CH3OH was prepared by adding AcCl (25 μL, 0.35 mmol) to CH3OH (1.0 mL) at 0° C., and stirring for 15 min. Compound 136 (50 mg, 0.11 mmol) was treated with this solution for 2 h at 80° C. in a sealed vial. The reaction mixture cooled to room temperature, and quenched with K2CO3 until basic. The mixture was diluted with CH2Cl2, filtered, and concentrated in vacuo. The crude was purified by preparative HPLC (reverse phase) to provide the title compound (22 mg, 48%) as a white solid.