Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:13])[C:4]2([CH3:12])[O:10][C:7]([CH3:11])([C:8]=1Br)[CH:6]=[CH:5]2.[CH:14]([O-:17])([CH3:16])[CH3:15].[Li+].CCCCCC.C(OCC)(=O)C.CCCCCC.P([O-])(O)(O)=O.[Na+]>O1CCCC1.O>[Br:1][C:2]1[C:3](=[O:13])[C:4]2([CH3:12])[O:10][C:7]([CH3:11])([C:8]=1[O:17][CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:5]2
Reactant: CC(C)[O-]
Reactant: CC12C=CC(C)(O1)C(Br)=C(Br)C2=O
Agent: O=P([O-])(O)O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)OC1=C(Br)C(=O)C2(C)C=CC1(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
A solution of 2.74 g (8.9 mmol) of 3,4-dibromo-1,5-dimethyl-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one (prepared according to Organic Lett. 4(12), 1997 (2002)) dissolved in 10 ml of tetrahydrofuran is added dropwise at ambient temperature to a solution of 5.4 ml (10.7 mmol) of 2M lithium isopropanolate diluted with 10 ml of tetrahydrofuran. The mixture is stirred for 3 hours at ambient temperature until the starting material has reacted completely (TLC monitoring: hexane/ethyl acetate/hexane 4:1). The reaction solution is then treated at a temperature of 0° C. with a 10% sodium dihydrogen phosphate solution (20 ml) and water (30 ml) and extracted three times with ethyl acetate. Drying over sodium sulfate and concentration by evaporation are carried out. For further purification, the dark oil so obtained is purified by chromatography over silica gel with 5% ethyl acetate in hexane. 1.73 g (68% of theory) of pure 3-bromo-1,5-dimethyl-4-isopropoxy-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one are isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30](O)=[O:31])=[N:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:40][CH2:41][CH2:42][NH:43][CH3:44])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:33]([O:40][CH2:41][CH2:42][N:43]([CH3:44])[C:30]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:11]=1)=[O:31])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35]
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Yield: 48.1 %

Procedure:
5-Benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-02) (2 g, 48.09%) was synthesized as a yellow liquid from 5-benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (7-02) (3 g, 6.72 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8-a) (1.39 g, 7.399 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][S:25][C:19]=2[C:18](=O)[CH2:17]1)=[O:15])[CH3:12]>C1COCC1.CCOC(C)=O>[CH2:11]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][S:25][C:19]=2[C:18](=[CH2:1])[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1CCc2ccsc2C(=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OCC)CCc2ccsc21
Reaction time: 0.5 h

Procedure:
MePPh3 Br (785 mg, 2.2 mmol) was dissolved in 7 mL THF and treated with KHMDS (408 mg, 2.04 mmol). After stirring for 30 minutes, the product of step d) (350 mg, 1.5 mmol) was added as a solution in 3 mL THF. After stirring for 1 hour, the reaction was diluted with EtOAc and washed with water. The organic layer was concentrated and the product was purified by silica gel chromatography (EtOAc/Hex-gradient) to give 188 mg of the subtitle compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:11]=1>C(#N)C>[Br:1][C:15]1[C:10]([F:9])=[N:11][C:12]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)COc1cccc(F)n1
Solvent: CC#N
Product: CC(C)(C)COc1ccc(Br)c(F)n1
Temperature: 70 °C
Yield: 51.8 %

Procedure:
N-bromosuccinimide (8.29 g, 46.6 mmol) was added to a solution of 2-fluoro-6-(neopentyloxy)pyridine (7.11 g, 38.8 mmol) in acetonitrile (80 mL) at rt. The reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (100% hexanes) to obtain 3-bromo-2-fluoro-6-(neopentyloxy)pyridine (5.27 g, 20.11 mmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].CCOP(Cl)(OCC)=O.[N+:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[C-:25].CC(C)([O-])C.[K+]>CN(C=O)C.C(O)(=O)C>[CH3:1][C:2]1[C:3]2[N:4]([CH:25]=[N:24][C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cc1nc2ccccc2nc1O
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1c(C)nc1ccccc12
Yield: 54.4 %

Procedure:
3-Methyl-2-quinoxalinol (2.84 g, 18 mmol) was dissolved in dry DMF (40 ml) and charged with sodium hydride (55% oil dispersion, 1.0 g, 23 mmol). The resulting solution was cooled under nitrogen to -20° C., whereafter chlorodiethylphosphate (3.3 ml, 23 mmol) was added. The reaction mixture was allowed to reach room temperature, and was then added a -30° C. cold solution of ethyl isocyanoacetate (2.6 g, 23 mmol) and potassium t-butoxide (2.6 g, 23 mmol) in dry DMF (25 ml). The mixture was stirred for 45 min. at ambient temperature, whereafter acetic acid (3 ml) was added. The crystalline precipitate was collected by filtration, rinsed with DMF and water and dried, yielding 2.5 g of the title compound. M.p. 192°-193° C. (Compound 1)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[O:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][O:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]2[O:11][CH2:12][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][O:15]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCCCCC1COC(c2ccc(F)c(C#N)c2)OC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCC1COC(c2ccc(F)c(CN)c2)OC1

Procedure:
27.7 g of 2-(3-cyano-4-fluorophenyl)-5-pentyl-1,3-dioxane (obtainable from 3-cyano-4-fluorobenzaldehyde and 2-pentyl-1,3-propanediol) in 380 ml of dioxane are added dropwise, in the course of 2 hours, to a boiling suspension of 4.0 g of lithium aluminium hydride in 300 ml of the same solvent. When the addition is complete, heating is continued for a further hour and decomposition is then effected with water. The solution is filtered off from the precipitated hydroxide and evaporated down under reduced pressure. 2-(3-Aminomethyl-4-fluorophenyl)-5-pentyl-1,3-dioxane is obtained.
Reaction SMILES: ClCCl.CS(C)=O.C(N(C(C)C)CC)(C)C.[OH:17][C@@H:18]([C@@H:29]([NH:34][C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=[O:36])[CH2:30][CH2:31][CH2:32][CH3:33])[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[OH:28])=[O:20]>CS(C)=O>[O:20]=[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])[C:18](=[O:17])[C@@H:29]([NH:34][C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=[O:36])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)C(=O)N[C@H]1CCCCC1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
Under argon gas stream, to 10 ml of an anhydrous dimethylsulfoxide-dichloromethane (1:1) solution containing 1.38 g (8.6 mmol) of sulfur trioxide pyridine complex salt were successively added dropwise at 0° C. 1.47 ml (8.6 mmol) of diisopropylethylamine, and then, 5 ml of an anhydrous dimethylsulfoxide solution containing 350 mg (0.7 mmol) of (2S)-N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-1-(phenylmethoxycarbonyl)pyrrolidine-2-carboxamide, and the resulting mixture was stirred at the same temperature for 5 hours. After completion of the reaction, to the reaction mixture was added 25 ml of ice-water, and the resulting mixture was extracted with 30 ml of ethylacetate three times. The organic layers were combined, washed with 100 ml of a 10%-aqueous citric acid solution, 100 ml of a saturated aqueous sodium hydrogen carbonate solution, and then, 100 ml of a saturated NaCl solution, dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography to obtain 300 mg (Yield: 86.1%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH:12]1[CH:11]=[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])[CH:14]=[N:13]1
Reactant: O=[N+]([O-])c1cccc(-c2cn[nH]c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2cn[nH]c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A 5 mL ethyl acetate solution of 300 mg (1.59 mmol) of 4-(3-nitrophenyl)-1H-pyrazole was added to 30 mg of 5% Pd—C, and stirred under a hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through celite, and the filtrate was condensed and dried to give 252 mg of 3-(1H-pyrazol-4-yl)aniline (yield: 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([S:14](=[O:27])(=[O:26])[NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:10]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[NH:38])=[CH:36][C:30]=4[N:29]=3)[C:9]=2[OH:40])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[O-:48][C:49]#[N:50].[K+]>CO.O>[OH:40][C:9]1[C:10]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[NH:38])=[CH:36][C:30]=3[N:29]=2)=[CH:11][C:12]([S:14](=[O:27])(=[O:26])[NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:49]([NH2:50])=[O:48])[CH:3]=1
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCc4cccnc4)cc(-c4cccc(N)c4)c3O)nc2c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCc4cccnc4)cc(-c4cccc(NC(N)=O)c4)c3O)nc2c1
Yield: 72.6 %

Procedure:
2-[3′-Amino-2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.015 g, 0.023 mmol), prepared as in Example 10, was dissolved in a mixture of methanol and water and then triethylamine was added to bring the solution to pH 9. The mixture was heated with potassium cyanate (0.018 g, 0.23 mmol) for 12 hour at 40° C., concentrated by evaporation under reduced pressure and the crude product was purified by reversed phase HPLC (acetonitrile gradient) to give 2-[2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-3′-ureido-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.01 g). MS: found (M+H+) 599.5, (M−H+) 597.7, calc. 598.17.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[C:9]([OH:19])=[N:8]1)=[O:6]>[Pd].CCO>[CH3:1][NH:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=2)[C:9]([OH:19])=[N:8]1)=[O:6]
Reactant: CNc1ccccc1C(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CNc1ccccc1C(=O)n1nc(O)c2cc(N)ccc21

Procedure:
To 1.5 g. of 1-(2-methylaminobenzoyl)-5-nitro-1H-indazol-3-ol, prepared in Example 19, suspended in 500 ml. of absolute EtOH was added 1.0 g. of 5% Pd/C and the mixture was hydrogenated at 50 psi for 20 hours. The catalyst was filtered off, washed with absolute EtOH and the filtrate evaporated to afford a semi-solid. Recrystallization from EtOH afforded 0.48 g. (35.4%) of the amine as a tan amorphous powder; mp. 169°-170° C.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH:13]([O:24][CH3:25])[C:14]1[CH:23]=CC2C(=NC=CC=2)N=1>>[CH3:11][O:12][CH:13]([O:24][CH3:25])[C:14]1[CH:23]=[CH:4][C:3]2[C:2](=[N:9][C:8]([CH3:10])=[CH:7][CH:6]=2)[N:1]=1
Reactant: Cc1ccc(C=O)c(N)n1
Reactant: COC(OC)c1ccc2cccnc2n1
Product: COC(OC)c1ccc2ccc(C)nc2n1

Procedure:
From 2-amino-6-methylnicotinaldehyde, synthesized in an analogous manner to intermediate 5, the title compound was obtained as a white solid. (UPLC-MS 6) tR 0.62; ESI-MS 219.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10]CC)=[O:9])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1C=CC(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ethyl 2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamate (330 mg, 0.62 mmol) is dissolved in ethanol (10 ml) and, after the addition of 4N sodium hydroxide solution (4 mo), stirred for 3 hours at 50° C. Then the mixture is neutralized with 4N hydrochloric acid (4 ml), diluted with water and filtered off from the precipitate. It is then recrystallized from aqueous ethanol.
Reaction SMILES: FC1C=CC=CC=1[C:8](=[N:18][OH:19])[CH2:9][O:10][C@@H:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13].C1(C=CC(O)=CC=1)O>>[F:15][C:12]([F:13])([F:14])[C@@H:11]1[C@@H:16]2[C:8](=[N:18][O:19][CH2:17]2)[CH2:9][O:10]1
Reactant: C=C[C@H](OCC(=NO)c1ccccc1F)C(F)(F)F
Agent: Oc1ccc(O)cc1
Product: FC(F)(F)[C@H]1OCC2=NOC[C@@H]21
Temperature: 140 °C
Yield: 108.6 %

Procedure:
(S)-1-(2-Fluorophenyl)-2-((1,1,1-trifluorobut-3-en-2-yl)oxy)ethanone oxime (40.54 g) was dissolved in xylenes (400 mL) and hydroquinone (4.0 g) was added. The reaction mixture was heated to reflux (heating block temperature 140° C.) for 22 hrs, then cooled and evaporated. The residue was purified by silica gel column chromatography (1% to 30% EtOAc in hexanes) to obtain the title compound (28.76 g). 1H NMR (400 MHz, CDCl3) δ ppm: 3.71-3.81 (m, 1H), 4.04-4.35 (m, 3H), 4.51-4.62 (m, 1H), 5.38-5.54 (m, 1H), 7.07-7.26 (m, 2H), 7.32-7.42 (m, 1H), 7.54-7.67 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9](=[O:16])[CH:10]=[C:11]([CH2:14][OH:15])O[CH:13]=2)=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9](=[O:16])[CH:10]=[C:11]([CH2:14][OH:15])[NH:21][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(CO)occ1OCc1ccc(Cl)cc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: O=c1cc(CO)[nH]cc1OCc1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
5-(4-Chloro-benzyloxy)-2-hydroxymethyl-pyran-4-one (71, 8.00 g, 3.00 mmol) was suspended in ammonium hydroxide (200 mL) in an 80 mL sealed tube. The reaction was heated at 90° C. overnight. Upon cooling, the reaction was lowered to pH 10 with 6N HCl to provide a beige solid that was collected by filtration (72, 7.8 g, 98%).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([C:24]([F:27])([F:26])[F:25])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>ClCCl.O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].[Pd]>[C:1]1([CH2:7][O:8][CH:9]([C:24]([F:27])([F:25])[F:26])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2
Agent: [Pd]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [BH4-]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2
Reaction time: 1 h

Procedure:
To a solution of 5.9 g (16 mmol) of 2-(2-phenylmethoxy-3,3,3-trifluoropropyl)-6-nitro-3,4-dihydro-2H-1-benzopyran in 50 ml of dichloromethane and 25 ml of water are added 73 mg of Adogen 464, 660 mg of 5% palladium on carbon containing 50% of water, and then a solution of 1.1 g (28 mmol) of sodium borohydride in 10 ml of water. The mixture is stirred for 1 hour, then it is filtered and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using dichloromethane, 5.4 g of product are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]2[N:7]([CH2:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][C:31]=3[CH3:40])[C:8](=[O:28])[C@@H:9]([NH:20]C(=O)OC(C)(C)C)[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2].[ClH:43]>O1CCOCC1.CCOCC>[ClH:43].[NH2:20][C@@H:9]1[C:8](=[O:28])[N:7]([CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][C:31]=2[CH3:40])[C:6]2[CH:41]=[CH:42][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C@H:10]1[CH3:19]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Yield: 90 %

Procedure:
A rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (510 mg, 863 μmol) in 4 M HCl in dioxane (4.32 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (3S,4S)-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (410 mg, 90%) as a white solid. MS m/z 491 (MH)+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17]>C1COCC1>[C:1]([O:9][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C(ON1C(=O)CCC1=O)c1ccncc1
Yield: 98.7 %

Procedure:
A mixture of isonicotinic acid (3 g), N-hydroxysuccinimide (2.79 g) and N,N-dicyclohexylcarbodiimide (5.52 g) was stirred in THF (200 mL) for 16 hours. The solid was filtered off and the solvent evaporated under reduced pressure. The residue was triturated with ethyl acetate and more solid filtered off. The filtrates were concentrated under reduced pressure gave 2,5-dioxopyrrolidin-1-yl isonicotinate (5.27 g). MS: 221 [MH]+.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH:24]([F:26])[F:25]>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:19]([O:18][C:16]([N:11]1[CH2:12][CH:13]([O:15][CH:24]([F:26])[F:25])[CH2:14][N:10]1[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OC(C)(C)C
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(OC(F)F)CN1C(=O)OC(C)(C)C
Yield: 33.3 %

Procedure:
0.2 g of tetrabutylammonium fluoride and 5.6 g of potassium hydroxide powder are added to a solution of 6.9 g of 4-hydroxy-pyrazolidine-N,N'-dicarboxylic acid di-tert-butyl ester in 60 ml of tetrahydrofuran. At a maximum of 45° C., 8.0 g of chlorodifluoromethane are introduced. The reaction solution is then filtered, concentrated and purified by means of column chromatography to yield 2.7 g of the desired product, 4-difluoromethoxy-pyrazolidine-N,N'-dicarboxylic acid di-tert-butyl ester, in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][C:18]#[N:19])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[C:29]2[C:28]([N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH3:36])[CH2:31]3)=[N:27][CH:26]=[N:25][C:24]=2[NH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[C:29]4[C:21]([CH3:20])=[CH:22][NH:23][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:31][C@@H:32]2[CH3:36])=[N:17][C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CN=C(Nc1cccc(Cl)c1)Oc1ccccc1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(Cl)c4)[C@@H](C)C3)c12
Temperature: 85 °C
Yield: 46.5 %

Procedure:
The cyanocarbamimidate from step A (0.47 g, 1.7 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine from Example 1, step B (0.40 g, 1.7 mmol), and N,N-diisopropylethylamine (1 ml) were added to acetonitrile (10 ml). The mixture was heated at 85° C. in a sealed pressure tube for 4 hours. The solvent was evaporated, and the residue was purified by flash chromatography (80 g SiO2, 0-5% MeOH:CH2Cl2, 50 min) to give (S)—N-(3-chlorophenyl)-N′-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (0.32 g, 0.79 mmol, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][C:7]=1[F:8].C=O.[C:20](O)(=O)C>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[CH2:20][N:11]([C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9]2
Reactant: O=C(NCCc1ccc(F)c(Cl)c1)C(F)(F)F
Reactant: CC(=O)O
Agent: C=O
Agent: O=S(=O)(O)O
Product: O=C(N1CCc2cc(Cl)c(F)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[2-(3-Chloro-4-fluoro-phenyl)-ethyl]-2,2,2-trifluoro-acetamide (400 mg, 1.48 mmol) and paraformaldehyde (89 mg, 2.96 mmol) were added sequentially at 0° C. to a solution of acetic acid (3 mL) in sulfuric acid (2 mL). After stirring of the reaction mixture at room temperature for 16 hours, the clear colorless solution was poured into ice-water (20 mL). The mixture was extracted with EtOAc (2×30 mL) and the organic layer was washed with satd. aq. NaHCO3 (20 mL), H2O (2×25 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude title product together with a regioisomer (400 mg) as white solid.