Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[S:17][C:16]([CH2:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][CH:14]=1)=O>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:11]([C:13]1[S:17][C:16]([CH2:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][CH:14]=1)=[O:10])([CH3:3])[CH3:2]
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a stirred solution of isopropylamine (130 mg, 2.2 mmol) in dioxane (3 mL) under argon and at room temperature was added trimethylaluminium (0.65 mL of a 2M solution in toluene, 1.3 mmol). After 1 h, a solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (170 mg, 0.55 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. overnight. The reaction mixture was then cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 6% methanol in dichloromethane then heptane:ethyl acetate=100:0 to 1:4) gave the title compound (30 mg, 16%) as a white solid. MS: m/e=336.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14]1([C:20]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:23])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(C(C)=O)C.[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([OH:12])(=[O:21])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14]1([C:20]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:23])=[O:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1

Procedure:
In accordance with the procedure of Example 2, 3-nitrobenzenesulfonyl chloride is reacted with benzoin in methyl ethyl ketone and aqueous NaOH. The resultant sulfonate melts at 92°-96° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[C:20](=[O:21])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C.Cl.CCOCC.CCOCC>[ClH:1].[CH3:4][N:3]([CH2:5][C@H:6]1[C@H:20]([OH:21])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:2]
Reactant: CN(C)CC1CCc2onc(-c3ccccc3)c2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)C[C@@H]1CCc2onc(-c3ccccc3)c2[C@H]1O
Reaction time: 1 h

Procedure:
6,7-Dihydro-5-dimethylaminomethyl-3-phenyl- 1,2-benzisoxazol-4(5H)-one hydrochloride (7.5 g) was dissolved in 100 ml ethanol and treated with 5.0 g sodium borohydride. After stirring for 1 hour the reaction mixture was distributed between 5% HCl and ether. The aqueous phase was then made basic with solid sodium bicarbonate and extracted with ether. Concentration under reduced pressure gave the product as a mixture of trans and cis isomers which was chromatographed by preparative HPLC (ethyl acetate/CH3CN/diethylamine; 90:10:1) to give 3.31 g of the pure trans isomer. The hydrochloride was formed in HCl/ether and then recrystallized from methanol/ether to give 2.90 g of trans-5-(dimethylaminomethyl)-4-hydroxy-3-phenyl -4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride, m.p. 231°-232° C.
Reaction SMILES: NC1([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][C:16]3[C:21]4[C:22]([CH3:26])([CH3:25])[CH2:23][O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])CCC1.[NH2:27][C:28]1([C:31](NC2C=NC(OC3C4C(C)(C)COC=4C=CC=3)=CC=2)=[O:32])[CH2:30][CH2:29]1>>[CH3:25][C:22]1([CH3:26])[C:21]2[C:16]([O:15][C:12]3[N:11]=[CH:10][C:9]([N:8]4[C:31](=[O:32])[C:28]5([CH2:30][CH2:29]5)[NH:27][C:6]4=[O:7])=[CH:14][CH:13]=3)=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CCC4)cn3)c21
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CC4)cn3)c21
Product: CC1(C)COc2cccc(Oc3ccc(N4C(=O)NC5(CC5)C4=O)cn3)c21
Yield: 49 %

Procedure:
The title compound (5 mg, 49% yield) was made in a similar fashion to the preparation of Example 11 replacing 1-amino-N-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}cyclobutanecarboxamide (Intermediate 70) with 1-amino-N-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}cyclopropanecarboxamide (Intermediate 73, 9 mg).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(OC(=O)C(C1C=CC(S(C)(=O)=O)=C(Cl)C=1)CC1CCCC1)C.[OH-].[K+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: CCOC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
The mixture of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester and 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (937 mg) was dissolved in ethanol (30 mL). This solution was then treated with a solution of potassium hydroxide (733 mg, 13.1 mmol) in water (7 mL). The resulting yellow solution was stirred at 25° C. for 3 h and then concentrated in vacuo to remove ethanol. The aqueous residue was treated with a 1N aqueous hydrochloric acid solution until the pH=2. The product was then extracted into methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (787 mg, 82% for two steps) as a white solid: mp 123.9-126.2° C.; FAB-HRMS m/e calcd for C15H19ClO4S(M+H)+ 331.0771, found 331.0776.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: O=C(Cl)c1ccccn1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Cl)cc21)c1ccccn1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and picolinoyl chloride in a similar manner as described in Example 14 to give an off-white solid (62% yield). 1H-NMR (DMSO-d6): δ 10.93 (s, 1H), 8.78 (d, 1H), 8.61 (m, 1H), 8.12 (m, 1H), 8.02 (m, 1H), 7.61 (m, 1H), 7.43 (m, 1H), 7.26 (d, 1H), 7.01 (dd, 1H), 5.34 (m, 1H), 2.64 (m, 2H), 2.00 (m, 3H), 1.82 (m, 1H); MS m/z 348 (M+Na).
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH:23]=[O:24]>C1COCC1>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH:23]([OH:24])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C=CCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=CCCCCC(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A flame-dried round-bottomed flask was charged with magnesium turnings (1.23 g, 50.75 mmol) and stirred under vacuum for 15 minutes and then applied under nitrogen atmosphere. THF (70 mL) was added followed by 1,2-dibromoethane (381 mg, 2.03 mmol), and the mixture was brought to the boiling point for 1 minute, then and cooled down to room temperature. A solution of 6-bromohexene (8.28 g, 50.75 mmol) in THF (30 mL) was transferred via cannula to the magnesium flask and the mixture was refluxed overnight and cooled to −78° C. A solution of 2-naphthaldehyde (6.10 g, 39.04 mmol) in THF (30 mL) was transferred via cannula to the Grignard reagent and the mixture was slowly warmed to 0° C. over 3 hours and kept at that temperature for 2 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution and THF was evaporated in vacuo. The aqueous residue was poured into a separating funnel containing water and the compound was extracted with diethyl ether (2×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (10% to 15% ethyl acetate in hexane), affording the title compound 181 in 89% yield (8.33g). 1H NMR: (300 MHz, CDCl3) δ: 7.85-7.78 (m, 4H), 7.51-7.44 (m, 3H), 5.85-5.72 (m, 1H), 5.02-4.91 (m, 2H), 4.87-4.82 (m, 2H), 2.08-2.01 (m, 2H), 1.94-1.80 (m, 2H), 1.53-1.23(m, 4H). MS (ESI)=223 (MH+—H2O).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(O)CCC>[Cl:26][C:22]1[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(Cl)n1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCCCO
Product: O=C(Nc1cccc(Cl)n1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (9 g) is added, at a temperature between 60° and 68° C., to a solution of 2-amino-6-chloropyridine (3.9 g) and triethylamine (6.1 g) in dioxane (200 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 5 hours and 45 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (500 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (9.5 g) is thereby obtained, which is dissolved in boiling butan-1-ol (140 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 16 hours. The crystals formed are separated by filtration, washed 3 times with butan-1-ol (30 cc in total) and 3 times with diethyl ether (150 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(6-chloro-2-pyridyl)-3-(3-pyridyl)-1H, 3H-pyrrolo[1,2-c]thiazole-7-carboxamide (5,6 g) in the form of cream-coloured crystals, m.p. 186° C., is thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:25][CH2:26][CH2:27][OH:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([CH2:25][CH2:26][CH2:27][O:28][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=1)(=[O:44])=[O:43])[CH2:18][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH3:24]
Reactant: CCOC(=O)C(CCCO)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCCOS(=O)(=O)c1ccc(C)cc1)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
190 mg (0.47 mmol) of 1-tert-Butyl 6-ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(3-hydroxypropyl)hexanedioate (5b) were dissolved in 10 mL dichloromethane at 0° C. Then, 284 mg (391 microL, 2.8 mmol) triethylamine and 179 mg (0.94 mmol) p-toluene sulfonyl chloride were added at 0° C. and the mixture was stirred at this temperature for 3 h. After stirring for 18 h at r.t. the solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate gradient) to give (S)-2-tert-Butoxycarbonylamino-5-[3-(toluene-4-sulfonyloxy)-propyl]-hexanedioic acid 1-tert-butyl ester 6-ethyl ester as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:29][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccc(F)cc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-fluoro-phenyl)-C-phenyl-methylamine (CA [55095-26-6]).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][C:13]([OH:15])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18]1>>[C:24]1([CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:18]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)Cc1ccccc1C1CCCC1
Product: O=C(Cc1ccccc1C1CCCC1)N[C@H]1CCN(CCc2ccccc2)C1
Yield: 21.9 %

Procedure:
2-Cyclopentylphenylacetic acid (0.39 g) and (S)-3-amino-1-(2-phenylethyl)pyrrolidine (0.3 g) were reacted under the same conditions as in Example 23 to give N-((S)-1-(2-phenylethyl)pyrrolidin-3-yl)-2-cyclopentylphenylacetamide (0.13 g), melting point 117-119° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[N:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[N:4]=1.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1>C(O)(=O)C>[N:18]1([C:14]2[CH:13]=[C:12]([C:9]3[N:6]4[N:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:20])=[N:4][C:5]4=[N:11][CH:10]=3)[CH:17]=[CH:16][CH:15]=2)[CH:23]=[CH:27][CH:26]=[CH:25]1
Reactant: Nc1cccc(-c2cnc3nc(C(F)(F)F)cnn23)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: FC(F)(F)c1cnn2c(-c3cccc(-n4cccc4)c3)cnc2n1
Temperature: 130 °C
Yield: 62 %

Procedure:
A mixture of 3-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenylamine and 2,5-dimethoxytetrahydrofuran in acetic acid was heated at 130° C. for 20 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10% Et2O/isohexane) to give 40 mg (62%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 6.41 (2H, t, J 2.2 Hz), 7.18 (2H, t, J 2.2 Hz), 7.51 (1H, ddd, J 8.3, 2.5, 1.1 Hz), 7.62 (1H, t, J 8.3 Hz), 7.92 (1H, dt, J 8.8, 1.1 Hz), 8.21 (1H, t, J 2.2 Hz), 8.66 (1H, s), 8.81 (1H, s); MS (ES+) m/z 330 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([N:31]3C(=O)C4=CC=CC=C4C3=O)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CN>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:26]=[C:27]([NH2:31])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: CN
Product: CCCc1nc2c(C)cc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
Prepared analogously to Example 1b from methyl 4'-[(2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazol-1-yl)methyl]-biphenyl-2-carboxylate and methylamine.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CO.O>[CH3:23][N:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: Oc1ccc(CCN[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCc1ccc(O)cc1)[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a stirred solution of trans-4-[2-(4-phenylcyclohexylamino)ethyl]phenol (380 mg, 1.3 mmol) in MeOH (5 mL), H2O (0.5 mL), and CH2Cl2 (5 mL) was added ρformaldehyde (200 mg, 6.5 mmol). After stirring for 15 minutes NaBH(OAc)3 (340 mg, 1.6 mmol) was added, and the reaction mixture was stirred for 12 hours. Additional NaBH(OAc)3 (138 mg, 0.65 mmol) was added, and the mixture was stirred for 2 days. NaBH(OAc)3 (138 mg, 0.65 mmol) was added, and stirring was continued for 6 hours. Solid NaOH was added to give a clear solution, which was concentrated under reduced pressure. Purification by flash chromatography (silica, 89:10:1 CH2Cl2:MeOH:NH4OH) and formation of the HCl salt gave trans-4-{2-[methyl(4-phenylcyclohexyl)amino]ethyl}phenol (380 mg, 64%), as an off-white solid: mp 97-105° C.; IR (KBr): 2941, 1614, 1517 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.42 (s, 1H), 7.35-7.15 (m, 5H), 7.10 (br d, J=8 Hz, 2H), 6.77 (br d, J=8 Hz, 2H), 3.49-2.94 (m, 6H), 2.80-2.70 (m, 2H), 2.56-2.48 (m, 1H), 2.30-2.11 (m, 2H), 1.89 (br d, J=11.5 Hz, 2H), 1.75-1.50 (m, 4H); CI—MS (methane) (m/z): 310 [M+H]+; HPLC: method A, 5.99 minutes (99.4%); method B, 10.68 minutes (99.1%); Anal. Calcd for C21H27NO.HCl.0.25H2O: C, 71.98; H, 8.20; N, 4.00. Found: C, 71.60; H, 8.31; N, 3.86.
Reaction SMILES: Br[CH:2]([Br:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[N:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>CC(C)=O>[Br:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]=[N:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Reactant: CCCCCC(Br)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCCCCOc1ccc(N=Nc2ccccc2)cc1
Reaction time: 4.5 h

Procedure:
A mixture of 454 g. (1.86 mol) of dibromohexane, 128.5 g of potassium carbonate and about 0.2 g of potassium iodide in 460 ml of acetone is heated to the boil. A solution of 36.9 g. (0.186 mol) of p-hydroxyazobenzene in 330 ml of acetone is then added in several portions. In order to prevent delays in boiling, the mixture is stirred constantly. After about 4.5 hours, the reaction is terminated, the still-hot solution is filtered, and a little dye is washed out of the filtered-off inorganic salts using a little acetone. The acetone is removed from the solution under slightly reduced pressure. The excess dibromohexane is subsequently removed in an oil-pump vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:17]([N:18]([C:20](=[O:26])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH3:19])[CH2:16][N:15]([C:27](OC(C)(C)C)=O)[CH2:14][CH2:13][N:12]2[C:34](=[O:37])[C:35]=1[OH:36])=[O:8].ClCCl.F[C:46](F)(F)[C:47](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:17]([N:18]([CH3:19])[C:20](=[O:26])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:16][N:15]([CH:27]3[CH2:47][CH2:46]3)[CH2:14][CH2:13][N:12]2[C:34](=[O:37])[C:35]=1[OH:36])=[O:8]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(CNC(=O)c2nc3n(c(=O)c2O)CCN(C(=O)OC(C)(C)C)CC3N(C)C(=O)C(=O)N(C)C)cc1Cl
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)c2nc3n(c(=O)c2O)CCN(C2CC2)CC3N(C)C(=O)C(=O)N(C)C)cc1Cl

Procedure:
The compound of Step 2 was stirred in dichloromethane/trifluoroacetic acid (8/2 v/v) for 1 hour, then concentrated under reduced pressure and triturated with diethyl ether. A portion of this material was purified by prep RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording title compound as a white solid. 1H NMR (400 MHz, CD3CN) δ 12.40 (bs, 1H), 9.78 (bs, 1H), 7.43 (s, 1H), 7.28-7.21 (m, 2H), 5.37-5.29 (m, 2H), 4.58 (dd, J=14.6 Hz, J=6.86 Hz, 1H), 4.47 (dd, J=14.6 Hz, J=6.41 Hz, 1H), 4.01-3.3.92 (m, 3H), 3.78-3.69 (m, 1H), 3.22-3.12 (m, 1H), 3.08 (s, 3H), 2.93 (s, 3H), 2.91 (s, 3H), 2.28 (s, 3H); MS (ES) C22H27ClN6O5 requires 490. Found: 491 (M+H+). N-(2-{[(3-chloro-4-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepin-10-yl)-N,N′,N′-trimethylethanediamide has been resolved into its enantiomers by semipreparative chiral SFC using the following conditions:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:4]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:27][C:28]#[N:29].[OH-].[K+]>C(O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27](=[CH:15][C:14]1[CH:17]=[CH:18][C:11]([N:4]2[C:5]([C:7]([F:10])([F:9])[F:8])=[CH:6][C:2]([CH3:1])=[N:3]2)=[CH:12][CH:13]=1)[C:28]#[N:29]
Reactant: N#CCc1cc(F)ccc1F
Reactant: Cc1cc(C(F)(F)F)n(-c2ccc(C=O)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)n(-c2ccc(C=C(C#N)c3cc(F)ccc3F)cc2)n1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a stirred mixture of 4-(3-methyl-5-trifluoromethyl-pyrazol-1-yl)-benzaldehyde (127 mg, 0.50 mmol) and 2,5-difluoro-phenylacetonitrile (77 mg, 0.50 mmol) in ethanol (4 mL) was added 0.5 mL of aqueous 6N KOH at room temperature. The mixture was stirred for 2 hours and the resulting precipitate was collected by filtration to give 2-(2,5-difluoro-phenyl)-3-[4-(3-methyl-5-trifluoromethyl-pyrazol-1-yl)-phenyl]-acrylonitrile (170 mg, 87% yield) as a white solid: 1H-NMR (CDCl3) δ 2.45 (s, 3H), 6.51 (s, 1H), 7.1 (m, 2H), 7.3 (m, 1H), 7.6 (d, 2H, J=9), 7.67 (s, 1H), 8.0 (d, 2H, J=9) ppm. ESMS calculated for C20H12F5N3: 389.1; Found: 390.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:21]([N:25]([CH2:26][C:27](=[O:28])[NH2:29])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)(C)NCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N(CC(N)=O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-(tert-butylamino)acetamide (207925-15-3) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=397.5 [MH+].