Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([OH:24])[C:18]([CH3:26])([CH3:25])[CH2:17]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:27]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH2:28]>O1CCCC1>[C:7]([O:15][CH:16]1[CH2:17][C:18]([CH3:26])([CH3:25])[N:19]([O:24][CH2:28][CH2:27][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[C:20]([CH3:22])([CH3:23])[CH2:21]1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CP(=O)(OCC)OCC
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(CCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)OCC
Temperature: 25 °C

Procedure:
To a suspension of 0.12 gram of potassium tert-butoxide in 25 ml of dry tetrahydrofuran is added 3.0 grams of 4-benzoyloxy-1-hydroxy-2,2,6,6-tetramethylpiperidine. After stirring the solution under nitrogen at room temperature for ten minutes, 1.78 grams of diethyl vinylphosphonate are added. After stirring the reaction mixture at room temperature under nitrogen for 24 hours, the solvent is removed under reduced pressure. The residue is partitioned between water and methylene chloride. The organic phase is washed with water, then brine and finally dried over anhydrous magnesium sulfate followed by evaportion. Purification of the residue by liquid chromatography affords the title compound as a colorless liquid. Analysis by nmr, ir and ms gives data consistent with the structure of the title compound.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=O)[CH2:17]Br)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[C:9]3=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8]3)=[CH:4][CH:3]=[CH:2][N:1]4[CH:17]=2)=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1cnc2c(c1)CCCC2
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cn3cccc4c3c2CCC4)cc1
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrahydroquinoline (35 g) was dissolved in 500 ml of toluene. To this solution was added 4-chlorophenacyl bromide (61.4 g) gradually and refluxed for 1 hour. The reaction mixture was cooled to room temperature, and depositing crystals were collected by filtration (86 g). These solids were dissolved in 500 ml of N,N-dimethylformamide. To this solution was added, molecular sieves 3A (50 g) and triethylamine (44 ml), then the reaction mixture was heated at 100° C. for 1 hour. The reaction mixture became dark brown. The dark brown solution that obtained after removing insoluble matter by filtration was concentrated under reduced pressure. The resultant brown solids were recrystallized from ethanol (300 ml), and the title compound was obtained as colorless leaflets (50 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[CH:42]([CH2:48][NH:49][CH3:50])[CH2:41]2.[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55]>>[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55].[CH3:54][O:55][C:39]1[C:38]([O:37][CH3:36])=[C:45]([O:46][CH3:47])[CH:44]=[C:43]2[C:40]=1[CH2:41][CH:42]2[CH2:48][NH:49][CH2:50][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19].[CH3:36][O:37][C:5]1[C:4]([O:3][CH3:2])=[C:11]([O:12][CH3:13])[CH:10]=[C:9]2[C:6]=1[CH2:7][CH:8]2[CH2:14][NH:15][CH2:16][CH2:17][C:18](=[O:19])[N:20]1[CH2:21][CH2:22][C:23]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:24]=2[CH2:25][CH2:26]1
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Reactant: CNCC1Cc2cc(OC)c(OC)cc21
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3c1cc(OC)c(OC)c3OC)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by the product of Preparation 11. Conversion to a salt is carried out in the presence of fumaric acid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.O1CCC[CH2:42]1>CO>[CH3:42][CH:24]1[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]2[CH:36]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:11]=3)[CH:16]=[CH:17][C:18]=2[N:25]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3c2ccccc2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCC(C)N3c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Methyl 8-(4-(2-butoxyethoxy)phenyl)-1-phenyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (230 mg) was dissolved in tetrahydrofuran (15 ml) and methanol (15 ml), after which an aqueous 1N sodium hydroxide solution (5 ml) was added. The mixture was stirred for 3 hours at 90° C. After adding water at 0° C., the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 8-(4-(2-butoxyethoxy)phenyl)-1-phenyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (220 mg) as a yellow amorphous material.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7].[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 72.2 %

Procedure:
A mixture of methyl 2-(3-(2-methoxyethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.25 mmol) in methanol (4.5 mL) and 1N sodium hydroxide aqueous solution (3.7 mL, 3.7 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and washed with water, dried in vacuo to afford 69 mg of 2-(3-(2-methoxyethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 71.9%. LC-MS (M+1)=383.2.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([CH3:15])[C:8]2[S:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)C=C.[BH4-].[Na+]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:15][C:13]1[C:8]2[S:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=[C:5]([OH:4])[CH:14]=1
Reactant: C=CCOc1cc(C)c2c(c1)OCCS2
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(O)cc2c1SCCO2
Temperature: 40 °C

Procedure:
The allyl ether from stage (i) (1.40 g, 6.3 mmol) was dissolved in THF (63 mL) and treated with sodium borohydride (1.19 g, 31.5 mmol) followed by palladium tetrakis(triphenylphosphine) (730 mg, 0.63 mmol), and the mixture was heated to 40° C. overnight. After cooling to room temperature the THF was evaporated and the residue was partitioned between 2M NaOH (25 mL) and diethyl ether (25 mL). The aqueous layer was separated and the organic layer re-extracted with 2M NaOH (25 mL). The combined aqueous layers were acidified with concentrated hydrochloric acid to pH 7–8 and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (MgSO4) and evaporated to a brown oil (10.73 g, 93%) of the desired title phenol; δH (CDCl3, 400 MHz) 2.17 (3H, s), 3.07 (2H, m), 4.33 (2H, m), 6.20 (1H, s), 6.31 (1H, s); MS m/z (TS+) 183 (MH+).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[NH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C=O.C(O)(=O)C>CO>[CH3:1][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Sodium cyanoborohydride (0.19 g) was added portionwise to a suspension of 6-(1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.74 g), 36% aqueous formaldehyde (0.34 ml), acetic acid (1 ml) and methanol (3 ml) at room temperature. After stirring for 0.5 hours at the same temperature, the resultant precipitates were collected by filtration, washed with methanol, dried, and recrystallized from 70% aqueous ethanol to give 0.66 g of 6-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[NH:4][CH:5]([CH3:29])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[O:27][CH3:28].[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[NH:4][CH:5]([CH3:29])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:42][S:39]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[Cl:32])(=[O:41])=[O:40])=[O:23])=[CH:20][C:19]=1[O:27][CH3:28]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(CC(C)NC(=O)N(C)C)cc12
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cc1cn(C)c2ccc(CC(C)NC(=O)N(C)C)cc12

Procedure:
Using a similar procedure to that described in Example 2, part c, except starting from 4-[5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]- 3-methoxybenzoic acid, and using 2-chlorophenylsulfonamide instead of 2-methylphenylsulfonamide, the title compound was obtained (88%) as a white solid; mp 131°-136° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23]Br)[C:8]=1[CH2:25][CH2:26][CH3:27])[CH3:2].[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:39][C:34]2[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=2[CH2:36][CH2:37][CH3:38])[C:8]=1[CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCOCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 73.8 %

Procedure:
A mixture of 1.89 g (0.004 mole) of [4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acid ethyl ester, 0.80 g (0.004 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, and 1.14 g (0.0082 mole) of potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 35% ethyl acetate-hexane to give 1.69 g (72% yield) of [4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:44]=[CH:45][CH:46]=1)[CH2:34]B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[CH2:34][C:33]1[CH:44]=[CH:45][CH:46]=[C:31]([O:30][CH3:29])[CH:32]=1
Reactant: COc1cccc(CB2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(Cc2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Yield: 25.5 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.57 mmol) was treated with 2-(3-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (211 mg, 0.85 mmol), sodium carbonate (2M, 1.28 mL, 2.56 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (70 mg, 0.09 mmol) according to the method described in Example 3 to give 70 mg (26% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: CN(C)C1N=C2C=CC(N)=CN2N=1.[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:42])[C:23]=1[C:24](=[O:41])[NH:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([N:35]3[CH2:40]COC[CH2:36]3)[N:34]=2)[CH:31]=1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:42])[C:23]=1[C:24](=[O:41])[NH:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([N:35]([CH3:36])[CH3:40])[N:34]=2)[CH:31]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: CN(C)c1nc2ccc(N)cn2n1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N(C)C)nn2c1

Procedure:
Using N*2*,N*2*-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2,6-diamine, this compound was prepared following the same method as for the synthesis of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester. White solid (64 mg, 48%). Mp.: 194° C. MS: m/z=358 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:31][CH3:32])=[C:28]([Pb+3])[CH:29]=1.CN(C1C=CC=CN=1)C.Cl>ClCCl.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:31][CH3:32])=[C:26]([CH:4]2[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]2=[O:8])[CH:25]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: CC1(C)CCC(=O)CC1=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(Br)cc1C1C(=O)CCC(C)(C)C1=O
Temperature: 80 °C
Yield: 46.6 %

Procedure:
To a mixture of 4,4-dimethylcyclohexane-1,3-dione (6.28 g, 45 mmol), 5-bromo-2-ethylphenyl lead triacetate (28 g, 49 mmol) and dimethylaminopyridine (27.4 g, 0.22 mol) under nitrogen are added anhydrous chloroform (300 ml) and toluene (75 ml). The reaction mixture is heated at 80° C. for 2 hours and then allowed to cool to room temperature overnight. 2M Aqueous hydrochloric acid (750 ml) and dichloromethane (500 ml) are added and the mixture is filtered through diatomaceous earth, washing through with more dichloromethane (250 ml). The two layers are separated and the aqueous phase is extracted with dichloromethane (500 ml). The organic layers are combined and washed with 2M aqueous hydrochloric acid (1000 ml) and then brine (1000 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by preparative normal phase chromatography to give 2-(5-bromo-2-ethylphenyl)-4,4-dimethylcyclohexane-1,3-dione (6.78 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C@@H:24]([N:26]=[N+]=[N-])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1.O.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C@H:12]1[C@@H:24]([NH2:26])[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N=[N+]=[N-])[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](N)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
(S,S)-1-Benzyloxycarbonyl-2-(1-azidoethyl)-4-tert-butyloxycarbonylpiperazine (8.1 g) was dissolved in 255 mL of 9:1 THF-water and triphenylphosphine (10.9 g) was added. The mixture was heated to 75° C. and stirred at this temperature overnight. The reaction mixture was cooled, diluted with 286 mL of CH2Cl2, poured into 250 mL of 1N HCl, and extracted with 750 mL of CH2Cl2. The aqueous phase was basified to pH>10 by addition of 5N NaOH, then extracted with 5×750 mL of EtOAc. The combined organic extracts were washed with 750 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography using 90:10 ethyl acetate-methanol to yield 3.07 g of the title compound. Mass spectrum (ESI) 308.3 (M−55).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:31])[CH:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][CH:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:7]([NH:6][OH:5])=[O:31])(=[O:19])=[O:18])=[CH:25][CH:24]=1)[C:28]#[C:29][CH3:30]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)NOC(C)(C)C)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)NO)c2ccc(O)cc2)cc1
Yield: 9 %

Procedure:
A 450 mg (1.007 mmol) portion of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(4-hydroxyphenyl)acetamide was stirred in neat TFA at room temperature for 72 h. TFA was removed in vacuo. The residue was chromatographed on preparative TLC, eluting with 1% HOAc and 10% MeOH in dichloromethane to provide 33.8 mg (9%) of 2-({[4-(2-butynyloxy)phenyl]-sulfonyl}amino)-N-hydroxy-2-(4-hydroxyphenyl)acetamide as a white solid. Electrospray Mass Spec 391.4 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:48])=[O:5].[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:48])=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)[C@@H](C)C2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)[C@@H](C)C2
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A solution of 2-({2-{[(2S)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (216 mg, 0.315 mmol) in dioxane (5 mL) and a 2M aqueous NaOH solution (10 mL) was heated at 80° C. for 5 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL) and a saturated NaCl solution (10 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[(2S)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a yellow solid (106 mg, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=5.49 Hz, 3H), 2.27 (s, 6H), 2.60 (d, J=15.57 Hz, 1H), 3.09 (d, J=14.28 Hz, 1H), 3.25-3.50 (m, 2H), 3.80 (s, 3H), 4.71-4.86 (m, 1H), 6.24 (dd, J=3.11, 1.65 Hz, 1H), 6.89 (t, J=9.25 Hz, 1H), 6.98 (s, 2H), 7.25-7.43 (m, 1H), 7.57 (s, 1H), 8.03 (s, 1H), 8.10 (s, 1H), 8.49 (d, J=8.24 Hz, 1H), 8.63 (s, 1H), 10.53 (s, 1H), 11.33 (s, 1H); ESIMS (M+H)+=533.36; Optical rotation −13.1 (1 mg/mL MeOH, rt).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH:25]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:32])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=C(O)C1CCCCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCCCC2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was coupled with cyclohexanecarboxylic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 464.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:11](=[CH2:13])=[N-:12]>CCOCC>[N+:11](=[CH:13][C:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])=[N-:12]
Reactant: O=C(Cl)CC1CCCCC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)CC1CCCCC1

Procedure:
A solution of 19.8 g of cyclohexylacetyl chloride (b.p. 98°-100°/23 mm Hg) in 150 ml of dry ether is slowly added at 0°-5° with cooling in an ice-water bath to a vigorously stirred solution of 11 g of diazomethane in 500 ml of ether. The excess diazomethane and ether is distilled off under reduced pressure and cyclohexylmethyl diazomethyl ketone is obtained as residue; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.45μ, 3.52μ, 4.75μ and 6.12μ; the product is processed without any further purification. A solution of 20 g of cyclohexalmethyl diazomethyl ketone in 100 ml of ether is added in one portion, with stirring, to a solution of 32 g of triphenylphosphine in 450 ml of ether. After stirring for 30 minutes at room temperature, the solvent is evaporated under reduced pressure. The 1-cyclohexyl-3-(triphenylphosphoranylidene-hydrazono)-acetone obtainable as oily residue crystallises in the cold from ether; m.p. 58°-62°; ultra-violet absorption spectrum: λmax 314 mμ, 262-275 mμ and 223 mμ (in ethanol and in potassium hydroxide/ethanol), and λmax 257-275 mμ and 230 mμ (in hydrogen chloride/ethanol); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.43μ, 3.56μ, 4.76μ, 6.15μ and 6.67μ.