Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+:13].[OH-].[NH4+]>O>[NH2:13][C@H:2]([C:1]([OH:11])=[O:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 37 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A suspension of 14.74 g of wet immobilized cells of Example 14 in 30 ml of water containing 2.25 g of trans-cinnamic acid, 652 mg of ammonium chloride and 3.3 ml of concentrated ammonium hydroxide was adjusted to pH 9.5. The mixture was shaken at 37°C for 18 hours giving about 90% yield of L-phenylalanine, based on recovered cinnamic acid. The reaction solids were filtered and washed with water to give 14 g of wet immobilized cells containing 77% of their original phenylalanine ammonia-lyase activity. The L-phenylalanine was isolated from the filtrate using standard procedures.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][CH:8]=C[C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[N:29]=[CH:30][N:31]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:32]=4)[CH:25]=[C:26]([CH3:27])[C:21]=3[N:20]=[C:19]2[CH2:40][CH2:41][CH3:42])=[CH:13][CH:12]=1)(C)(C)C.F[C:44](F)(F)[C:45]([OH:47])=[O:46]>C(Cl)Cl>[CH2:40]([C:19]1[N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:44]([C:45]([OH:47])=[O:46])=[CH:8][CH:9]=[CH:10][CH:5]=3)=[CH:12][CH:13]=2)[C:22]2[CH:23]=[C:24]([C:28]3[N:29]=[CH:30][N:31]([CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:32]=3)[CH:25]=[C:26]([CH3:27])[C:21]=2[N:20]=1)[CH2:41][CH3:42]
Reactant: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15]C(=O)C)[C@H:11]([CH3:19])[O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([OH:15])[C@H:11]([CH3:19])[O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)O[C@H]1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1O[C@H](O[Si](C)(C)C(C)(C)C)CC[C@H]1O
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a solution of the acetate from step 2 herein (36 mg, 0.13 mmol) in dry MeOH (1.3 ml), at room temperature, was added 1N NaOH (0.14 ml, 1.1 eq.) and the solution was stirred for 45 minutes. It was then poured in H2O and the aqueous phase was extracted 3× with CH2Cl2. The combined organic extracts were dried over MgSO4, the solids were filtered and the solvent evaporated to give 30 mg (96%) of the pure titled alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:26]3[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCC(C)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 80 °C
Reaction time: 19.5 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (3.0 mL) was added 4-methylpiperidine (0.035 g, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 80° C. and stirring continued for 19.5 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(4-methylpiperidin-1-yl)-pyridin-3-yl)quinoline as a tan solid. Mass Spectrum (ESI) m/e=388.1 (M+1).
Reaction SMILES: Cl.[C:2]1([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].C(N(CC)CC)C.[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([N:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[CH3:9])[CH2:11][CH2:12]1)=[O:26]
Reactant: O=C(Br)CBr
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(N2CCN(C(=O)CBr)CC2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(2,3-Xylyl)piperazine hydrochloride (5 g; 25 mmol) is suspended in dichloromethane and triethylamine (7.6 ml; 54 mmol) is added. The mixture is cooled to 0° C. and bromoacetyl bromide (2.4 ml; 27 mmol) is added dropwise. The reaction is stirred for 30 minutes and then diluted in dichloromethane, washed with half-saturated sodium bicarbonate solution and dried over magnesium sulfate. The final product is purified by flash chromatography with a gradient of eluents (30/70 to 50/50; EtOAc-Pet. ether).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:20]([CH3:21])[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:13]=2[NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[O:11])[CH2:4][O:3]1>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[N:20]([CH3:21])[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:11]
Reactant: Cn1c(C(=O)NOC[C@H]2COC(C)(C)O2)c(Nc2ccc(I)cc2F)c2cnccc21
Solvent: CO
Product: Cn1c(C(=O)NOC[C@H](O)CO)c(Nc2ccc(I)cc2F)c2cnccc21
Yield: 18.5 %

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (71 mg, 0.13 mmol) was dissolved in methanol (0.5 ml) and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was then washed with methanol (15 ml) and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluant was collected and concentrated to give a residue. The residue was purified by flash chromatography (Si-PPC, dichloromethane:MeOH, gradient 100:0 to 90:10) followed by reversed phase HPLC (Phenomenex Luna 5 phenyl/hexyl, 0.1% TFA in water on a gradient of acetonitrile 100:0 to 40:60) to afford the title compound as a white solid (12 mg, 15%). LCMS (method A): RT=4.83 min, M+H+=501. 1H NMR (d4-MeOH, 400 MHz) 8.61 (s, 1H), 8.30 (d, J=6.0 Hz, 1H), 7.59 (d, J=6.0 Hz, 1H), 7.44 (dd, J=11.0 Hz, 1.8 Hz, 1H), 7.18-7.23 (m, 1H), 6.37 (dd, J=9.0 Hz, 9.0 Hz, 1H), 3.99 (s, 3H), 3.89-3.95 (m, 1H), 3.77-3.86 (m, 2H), 3.47-3.59 (m, 2H).
Reaction SMILES: [OH-].[K+].C([OH:7])(C)(C)C.[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([C:18]#[N:19])=[N:16][OH:17].Cl>O>[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](=[N:16][OH:17])[C:18]([NH2:19])=[O:7]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2C(=NO)C(N)=O)c1
Yield: 60 %

Procedure:
85% Potassium hydroxide (6.12 g, 92.8 mmol) and tert-butyl alcohol (15 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-hydroxyiminobenzyl cyanide (E/Z=15/85)(1.30 g, 4.64 mmol). The mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was neutralized with 6N hydrochloric acid, and water (100 ml) was added. The resulting mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from n-hexane/ethyl acetate to give 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyiminoacetamide (0.83 g, Yield: 60.0%, Z=at least 98%) as colorless crystals.
Reaction SMILES: [OH-].[K+].C(O)C.[SH:6][C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][CH:13]([CH3:15])[CH2:12][C:11]=2[CH:16]=1.[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>O>[CH:20]1([CH2:23][S:6][C:7]2[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]3[O:14][CH:13]([CH3:15])[CH2:12][C:11]=3[CH:16]=2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CC1Cc2cc(S)cc(C(=O)O)c2O1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1Cc2cc(SCC3CC3)cc(C(=O)O)c2O1

Procedure:
73 g of potassium hydroxide were dissolved in 84 ml of water in a 2-liter round-bottomed flask and 387 ml of absolute ethanol and 130.5 g of 5-mercapto-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were then added. 86 g of cyclopropylmethyl bromide were then quickly poured in and the contents were heated under reflux for 1 hour. After adding water, the contents were filtered and the solution was acidified by adding concentrated hydrochloric acid until a color change of Congo red was observed. The precipitate formed was drained, washed with water and dried at 40° C.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[C:16]=1[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH:1]1([NH:6][C:15]2[N:20]3[N:21]=[CH:22][N:23]=[C:19]3[N:18]=[C:17]([C:24]([F:26])([F:27])[F:25])[C:16]=2[CH2:28][CH2:29][CH3:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: CCCc1c(C(F)(F)F)nc2ncnn2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(C(F)(F)F)nc2ncnn2c1NC1CCCC1
Yield: 82.7 %

Procedure:
With stirring, a mixture of 0.13 g (1.5 mmol) of cyclopentylamine and 0.15 g (1.5 mmol) of triethylamine in 10 ml of methylene chloride was added to a mixture of 0.40 g (1.5 mmol) of 7-chloro-6-propyl-5-trifluoromethyl-[1,2,4]-triazolo-[1,5-α]-pyrimidine (cf. Ex. 5) in 20 ml of methylene chloride. The reaction mixture was stirred at room temperature for 16 h, work-up was carried out analogously to Ex. 3. This gave 0.39 g (1.24 mmol) of the title compound (melting point 179° C.).
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C
Yield: 936.7 %

Procedure:
In analogy to example 1 were reacted 6,36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol with 4,38 g (2 mmol) of lauroyl chloride and 2.02 g (2 mmol) of triethylamine in toluene to give 9,4 g (94%) dodecanoic acid 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[NH:8][C:7]2=[O:17].I[CH:19]([CH3:21])[CH3:20].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[N:8]([CH:19]([CH3:21])[CH3:20])[C:7]2=[O:17]
Reactant: CC(C)I
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaH (5.30 g, 0.132 mol) was added in portions to a solution of 5-chloro-6-nitroisoindoline-1,3-dione (20.0 g, 88.27 mmol) in 100 mL of anhydrous DMF at 0° C. under argon. The reaction mixture was then stirred at rt for 3 h. 2-Iodopropane (15.0 g, 106 mol) was added dropwise via a syringe at rt under argon. The resulted mixture was stirred for 6 h at rt, hydrolyzed by adding 200 mL of water. The precipitate was isolated, washed with water and dried under vacuum. The solid was purified by column chromatography (silica-gel, CH2Cl2/Acetone=19/1 v/v) to give a solid product.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[C:12]3[CH:13]=[CH:14][S:15][C:16]=3[CH2:17][C:10]=2[C:9]([C:18]2[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[CH:20][CH:19]=2)=[N:8]1.[ClH:30]>CO>[ClH:30].[S:15]1[CH:14]=[CH:13][C:12]2[C:11]3[NH:7][N:8]=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[C:10]=3[CH2:17][C:16]1=2
Reactant: CC(=O)Nc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sccc2-3)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Temperature: 100 °C
Yield: 84 %

Procedure:
N-{4-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-acetamide (0.21 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.42 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenylamine hydrochloride (0.12 g, 0.42 mmol) as yellow solid in 84% yield.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1.Br[CH:32]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH3:33]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:20])[CH:32]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)[CH3:33])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(COC(=O)Cc2cccc(Br)c2)cc1
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)C(C(=O)OCc2ccc(OC)cc2)c2cccc(Br)c2)cc1
Temperature: 25 °C

Procedure:
LHMDS (1.0M THF, 2.6 mL) was added dropwise to a −78° C. THF (4 mL) solution containing the intermediate from Step A (0.827 g, 2.47 mmol). After stirring 10 minutes a THF (4 mL) solution containing methyl 4-(1-bromoethyl)benzoate (0.6 g, 2.47 mmol) was added dropwise. The solution was allowed to warm to room temperature. After 1.5 hours the solution was partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with water, brine and dried over magnesium sulfate. The solution was filtered and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compounds as a 1.67/1 mixture of diastereomers. 1H NMR (400 MHz, CDCl3): selected data δ 5.16 (d, J=12.0 Hz); 5.01 (d, J=12.0 Hz); 4.82 (d, J=12.0 Hz); 4.64 (d, J=11.9 Hz); 1.34 (d, J=6.8 Hz); 1.02 (d, J=7.0 Hz). Minor diastereomer: LCMS1 4.08 min (M+Na)=519. Major diastereomer: LC1 4.19 min (M+Na)=519.
Reaction SMILES: CN[C:3]([C:5]1SC=C(C)C=1NC1C(Cl)=CN=C(Cl)N=1)=O.[CH3:20][NH:21][C:22]([C:24]1[S:25][CH:26]=[C:27]([CH3:53])[C:28]=1[NH:29][C:30]1[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH:37][C:38]2[CH:39]=[CH:40][C:41]3[CH2:47][N:46]([C:48](=[O:50])[CH3:49])[CH2:45][C:44](=[O:51])[NH:43][C:42]=3[CH:52]=2)[N:31]=1)=[O:23]>>[CH3:20][NH:21][C:22]([C:24]1[S:25][CH:26]=[C:27]([CH3:53])[C:28]=1[NH:29][C:30]1[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH:37][C:38]2[CH:39]=[CH:40][C:41]3[CH2:47][N:46]([C:48](=[O:50])[CH3:49])[CH2:45][C:44](=[O:51])[N:43]([CH2:3][CH3:5])[C:42]=3[CH:52]=2)[N:31]=1)=[O:23]
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C(C)=O)C3)ncc1Cl
Product: CCN1C(=O)CN(C(C)=O)Cc2ccc(Nc3ncc(Cl)c(Nc4c(C)csc4C(=O)NC)n3)cc21

Procedure:
Following a procedure analogous to Example 1741e, 4-acetyl-1-ethyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazopin-2-one and 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide were converted to 3-[2-(4-acetyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide: 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.2 (s, 1H), 7.8 (s, 1H), 7.38 (dd, 2H), 7.22 (d, 1H), 7.1 (d, 1H), 6.08 (d, 1H), 4.55 (s, 2H), 4.12 (s, 2H), 3.85 (br, 2H), 3.05 (d, 3H), 2.30 (s, 3H), 2.18 (s, 3H), 1.15 (t, 3H); MS (m/e): 528.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)C=O.[CH3:13][O:14][CH:15](OC)[O:16][CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:15]([O:16][CH3:17])[O:14][CH3:13])[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
A mixture of 5-chloro-2-nitro-benzaldehyde (0.0792 mol), trimethoxy-methane (0.126 mol) and PTSA (0.00079 mol) in methanol (80 mL) was refluxed until the 5-chloro-2-nitro-benzaldehyde had completely reacted. The mixture was cooled, Na2CO3 was added, and the reaction mixture was stirred for 5 min. The mixture was filtered and the filtrate was evaporated under reduced pressure to yield the title compound as a residue.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:11]1([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1.ClCCl>[CH:20]1([NH:19][C:18](=[N:17][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:8][N:7]=[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: ON=C1CCCCC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C1CCC(=NOC(=NC2CCCCC2)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
To a solution of cyclohexanone oxime (5.65 g, 0.05 mol) in dry THF (30 ml) is added finely powdered NaOH (0.2 g) and dicyclohexylcarbodiimide (11.34 g, 0.055 mol). The mixture is then stirred 5 h at room temperature under argon. The turbid mixture is thereafter diluted with dichloromethane (25 ml), filtered and evaporated under reduced pressure. The residue is stirred 10 minutes with acetonitrile (30 ml), the acetonitrile phase is then discarded, the oily residue is dissolved in dichloromethane (30 ml), filtered and evaporated to afford 14.27 g of the title compound as a slightly yellow liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[N:6]=1)=[O:4].S(Cl)(Cl)=O.[CH3:22]O>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:22])=[O:12])[CH:8]=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[N:6]=1)=[O:4]
Reactant: CO
Reactant: CNC(=O)c1cc(C(=O)O)cc(C(=O)NC)n1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cc(C(=O)OC)cc(C(=O)NC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Bis(N-methylcarbamoyl)pyridine-4-carboxylic acid (1 g) was mixed with methanol (50 ml), and to the mixture was added thionyl chloride (2 ml). After addition of thionyl chloride, the mixture was stirred at room temperature overnight. The mixture was then evaporated under reduced pressure, and water was added to the residue followed by extraction with chloroform. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, and evaporated to dryness. The residual crystals were recrystallized from toluene to give 0.4 g of methyl 2,6-bis(N-methylcarbamoyl)pyridine-4-carboxylate. m.p. 202°-203° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[CH2:1]([O:8][C:9]([NH:10][CH2:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=2)=[CH:19][CH:18]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNC(=O)OCc1ccccc1
Product: Cc1noc(-c2ccc(-c3cccc(C(=O)O)c3)cc2)c1CNC(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-carbamic acid benzyl ester and 3-carboxyphenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=2)[CH:5]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[N:7]=1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: N#Cc1ccc(-c2cc(Cl)nc(N)n2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(-c3ccc(C(N)=O)cc3)nc(N)n2)cc1F
Temperature: 110 °C
Yield: 35.4 %

Procedure:
A mixture of 4-(2-amino-6-chloro-4-pyrimidinyl)-2-fluorobenzonitrile (400 mg, 1.61 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (397.0 mg, 2.41 mmol), Pd(PPh3)4 (185 mg, 0.16 mmol), and Na2CO3 (427 mg, 4.02 mmol) in 1,4-dioxane (60 mL) and water (20.0 mL) was stirred and heated at 110° C. for 1 hour under nitrogen. The mixture was cooled to room temperature and concentrated, and the resulting residue was portioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (2×50 mL), and the combined organic layers were dried Na2CO3, filtered and concentrated to dryness. Purification by SiO2 chromatography using 4:1 petroleum ether/THF as eluent afforded the title compound (190 mg) as a white solid. LC-MS (ES) m/z=334 [M+H]+.
Reaction SMILES: [C:1]([N:4]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1C(=O)C2=CC=CC=C2C1=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.NN>C(O)C>[C:1]([N:4]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCCN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)N(CCCCN)c1ccccc1
Yield: 80.6 %

Procedure:
A mixture of N-[4-(N-acetyl-N-phenylamino)butyl]phthalimide (9.2 g), hydrazine monohydrate (10 ml) and ethanol (200 ml) was heated under reflux for 1 hour. The deposited crystals were separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 4-(N-acetyl-N-phenylamino)butylamine (4.55 g, 80.7%) as an oil.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH2:14][OH:15])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:4]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1COS(C)(=O)=O
Temperature: 2.5 °C

Procedure:
7.5 3.2 g of tert-butyl (2R,4S)-4-fluoro-2-hydroxymethylpyrrolidine-1-carboxylate are dissolved in 50 ml of CH2Cl2 with stirring, 3.1 ml of triethylamine are added, the mixture is cooled to 0-5° C., and a solution of 1.4 ml of methane-sulfonyl chloride in 10 ml of CH2Cl2 is subsequently added dropwise. The mixture is subsequently stirred at RT for 4 h. After aqueous work-up, the 4.1 g of tert-butyl (2R,4S)-4-fluoro-2-methanesulfonyloxymethylpyrrolidine-1-carboxylate) obtained are reacted further directly.