Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:7].[BH4-].[Na+]>C(OC(=O)C)C>[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)c2cc(Cl)ccc2N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(O)c2cc(Cl)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a methanol (10 ml) solution of 2-amino-4′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.9 g) was added sodium borohydride (0.28 g). The mixture was stirred for 30 minutes at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and dried over anhydrous Na2SO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give the object 2-amino-5-chloro-α-(4-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.85 g) as a colorless oily product.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[OH:16]S([O-])=O.[Na+].[OH-].[Na+].Cl>O>[OH:16][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2
Reactant: O=S([O-])O
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1ccc2cccc(O)c2c1
Yield: 99.5 %

Procedure:
A solution of 8-amino-2-naphthalenesulfonic acid (Aldrich, 2.40 g, 10.8 mmol) and 3.9M aq. NaHSO3 solution (20.0 mL, 77.0 mmol) in water (10.0 mL) was refluxed for 15 h. The reaction mixture was then basified with 30% aq. NaOH solution (430 mg, 10.8 mmol) and refluxed for 4 h. The reaction mixture was neutralized with conc. HCl and then concentrated in vacuo. The remaining solid was azeotroped with 1:1 MeOH/PhMe (3×) to give the title compound (2.41 g, 95%). 1H NMR (DMSO-d6) δ 9.43 (br s, 1H), 8.36 (s, 1H), 7.96 d, J=8.4 Hz, 1H), 7.88-7.78 (m, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H); MS(ESI−) m/z 222.3 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12](/[C:15](=[N:28]\[OH:29])/[CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(=O)CO)cc3)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(/C(CO)=N\O)cc3)c2)CCOCC1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in Example 69, 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-hydroxyacetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-hydroxyacetophenone oxime in 59% yield, m.p. 145°-146° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.Cl.N[C@H](C([C:20]1([NH2:43])[C:26](=[O:27])[N:25]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:21]1=[O:42])=O)C>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:43][C@H:20]([C:26]([NH:43][CH:20]2[C:21](=[O:42])[N:22]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:23]3[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=3[N:25]([CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C:26]2=[O:27])=[O:27])[CH3:21])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white solid (melting point=116-126° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.54 and 0.40 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][C:19]([N:6]1[CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1Cc2ccccc2Cc2ccccc21
Temperature: 95 °C

Procedure:
In a 100 ml round bottom flask equipped with magnetically stirring, thermometer, reflux condenser and addition funnel, 6,11-dihydro-5H-dibenz[b,e]azepine (1.0 g, 5,1 mmol, prepared in a similar way as described in Coll. Czech. Chem. Commun., 23, 1958, 1330) was dissolved in dry toluene (25 ml). 3-Chloropropionyl chloride (0.78 g, 6,1 mmol) was added slowly. When addition was complete, the reaction mixture was heated at 95° C. for 30 minutes and then allowed to cool to room temperature. With stirring, 0.2N sodium hydroxide (2.5 ml) was added. More toluene (50 ml) was added and the phases were separated. The organic phase was washed with 0.2N sodium hydroxide (10 ml) until pH>10, and then with water (3×10 ml) and brine (10 ml). After drying (MgSO4), the solvent was evaporated in vacuo affording 3-chloro-1-(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)-1 -propanone as an oil which was obtained in quantitative yield and used for further reactions without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.O>CS(C)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[CH:23][CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: BrCc1ccccn1
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccn3)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (2S,4R)-1-[2-(3-acetyl-5-hydroxy-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 579 (60.0 mg, 0.122 mmol) in DMSO (2.5 mL) was treated with cesium carbonate (160 mg, 0.490 mmol). After stirring at RT for 5 min, 2-(bromomethyl)pyridine (31.0 mg, 0.122 mmol) was added to the reaction mixture and stirring was continued at RT for 16 h. Water was then added to the mixture to form a solid precipitate which was filtered off, washed with water and dried in vacuo. Purification by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) afforded after lyophilization of the purified fractions the title compound as a white solid. MS (LC/MS): 580/581 [M+H]+; tR (HPLC conditions k): 3.00 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([CH2:29][OH:30])=[C:24]([NH:26][CH2:27][CH3:28])[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:4]([CH3:33])=[N:3]1.[H-].[Na+].I[CH3:37]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([CH2:29][O:30][CH3:37])=[C:24]([NH:26][CH2:27][CH3:28])[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:4]([CH3:33])=[N:3]1
Reactant: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1COC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 155.1, 0.086 mmol) in DMF (0.5 ml) was treated with 55% NaH in oil (0.086 mmol) and the RM was stirred for 10 min at rt, then was added iodomethane (0.086 mmol) and the RM was stirred for 2 h at rt. The RM was quenched with water, diluted with DMF, filtered and purified by preparative HPLC. The pure fractions were basified with NaHCO3, concentrated and extracted with CH2Cl2 (3×) and with EtOAc. The combined organic layers were dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a film. (HPLC: tR 2.24 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.08 (m, 2H), 7.98-7.91 (m, 2H), 7.64-7.61 (m, 1H), 6.90 (s, 1H), 5.32 (t, 1H), 4.53 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.28 (s, 3H), 3.20 (qt, 2H), 1.97 (s, 3H), 1.23 (t, 3H))
Reaction SMILES: [C:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1c(OC)cc(C(C)=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C(C)=O)cc(OC)c1OCCCC(=O)O
Yield: 86 %

Procedure:
Following the method of Preparation 3, 0.179 g (0.577 mmol) of 4-(4-acetyl-2,6-dimethoxyphenoxy)butanoic acid, ethyl ester is treated with potassium carbonate, producing an off-white solid. Recrystallization from ethyl acetate/hexane gives 4-(4-acetyl-2,6-dimethoxyphenoxy)butanoic acid as white crystals (0.14 g, 88%): m.p. 122°-24° C.; IR (KBr) 1735, 1660 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 283 (M+ +H). Analysis calculated. for C14H18O6 : C, 59.57; H, 6.43; O, 34.01. Found: C, 59.34; H, 6.40; O, 34.26.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH:29]1([O:28][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OC3CCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(OC3CCCC3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{[4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 120 mg (69%). HPLC-MS: m/z: 459.1 (M+H)+; Rt: 2.86 min.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CC(OCc2ccccc2)CC(C)(C)N1
Solvent: CCO
Product: CCOC(=O)CN1C(C)(C)CC(OCc2ccccc2)CC1(C)C

Procedure:
A mixture of 4-benzyloxy-2,2,6,6,-tetramethylpiperidine and 1.67 parts of ethyl α-bromoacetate in 30 parts of ethyl alcohol was heated under reflux conditions for 115 hours. The ethyl alcohol solvent was removed by distillation under reduced pressure and the residue fractionally distilled to give 4-benzyloxy-1-ethoxycarbonylmethyl-2,2,6,6-tetramethylpiperidine having a boiling point of 145°-6° C. at 0.2 m.m. of Hg. and the following elemental analysis by weight:
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[C:10]([O:12]C(C)C)=[O:11])[C:3]([O:5]C(C)C)=[O:4].[OH-].[K+].Cl>C1COCC1.O>[OH:1][C@@H:2]([C@@H:9]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=1)[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: CC(C)OC(=O)[C@@H](O)[C@@H](CCCc1ccc(OC(F)(F)F)cc1)C(=O)OC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](O)[C@@H](CCCc1ccc(OC(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 110.9 %

Procedure:
To a solution of diisopropyl (2S,3R)-2-hydroxy-3-{3-[4-(trifluoromethoxy)phenyl]propyl}butanedioate (6.98 g; 16.6 mmol; 1.0 eq.) in THF/water (3/1; 140 mL) was added potassium hydroxide (5.59 g; 99.6 mmol; 6.0 eq.). The reaction mixture was then stirred for 14 h at RT. The aq. layers were acidified with an aqueous solution of HCl to pH 2, extracted with EtOAc. The combined organic layers were then dried over MgSO4 and evaporated to give the title compound as an oil (6.19 g), used in the next steps without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:16])[CH3:15])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH:14]([N:11]1[C:12]2[C:8](=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=2)[CH:9]=[N:10]1)([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)c2cnn(C(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc3c2cnn3C(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
1-Isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid methyl ester (0.5 g, 1.62 mmol) was dissolved in methanol (30 mL) and 2N aqueous NaOH (3 mL) was added. The reaction mixture was stirred at room temperature overnight, then partitioned between 1N aqueous HCl and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to provide 0.48 g (100%) of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:13][C:14]2[C@H:15]3[CH2:20][CH:17]([CH2:18][CH:19]=2)[C:16]3([CH3:22])[CH3:21])[CH2:4][C@H:3]1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:28]=1)=[O:25].Br[CH2:41][C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])=[O:43]>CN(C)C(=O)C>[C:44]([C:42]([CH2:41][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:13][C:14]2[C@H:15]3[CH2:20][CH:17]([CH2:18][CH:19]=2)[C:16]3([CH3:21])[CH3:22])[CH2:4][C@@H:3]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:28]=2)=[O:25])[C:2]1=[O:1])=[O:43])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(CC3=CCC4C[C@H]3C4(C)C)c3ccccc3NC2=O)c1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(CC3=CCC4C[C@H]3C4(C)C)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
Step 2 of Example 1 was repeated except that 1-[(3R)-2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea was used instead of 2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, that bromomethyl-tert-butylketone was used instead of 2-bromo-2′-methylacetophenone, and that N,N-dimethyl acetamide was used instead of tetrahydrofuran as solvent, to thereby obtain the title compound.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH3+:6].[CH3:10][N:11]([CH3:14])[C:12]#[N:13]>O>[I:2][C:3]1[CH:4]=[C:5]([NH:6][C:12](=[NH:13])[N:11]([CH3:14])[CH3:10])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C#N
Reactant: [NH3+]c1cccc(I)c1
Agent: Cl
Solvent: O
Product: CN(C)C(=N)Nc1cccc(I)c1
Temperature: 130 °C
Yield: 81 %

Procedure:
46.00 g (0.21 mol) of 3-iodoaniline were admixed with 100 ml of 15% strength hydrochloric acid. The 3-iodoanilinium hydrochloride formed was filtered off with suction, recrystallized from water and dried under reduced pressure (yield: 52.57 g=98%). The total amount of the anilinium salt was mixed with 14.42 g (0.205 mol) of dimethylcyanamide and heated at 130° C. for 10 minutes on an oil bath. After the reaction had abated, the reaction mixture was cooled, admixed with 100 ml of water and the water-soluble constituents were filtered off. The aqueous solution was extracted twice with 100 ml each time of diethyl ether, adjusted to a pH of 10-12 using KOH and subsequently extracted three times with 100 ml of dichloromethane. The CH2Cl2 extracts were dried over magnesium sulfate and the solvent was then taken off under reduced pressure. This left 48.2 g of N′-(3-iodophenyl)-N,N-dimethylguanidine as a colorless solid (yield: 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=1)=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=1)=[N:1]2
Reactant: NC(=O)COc1ccc(C=O)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCC(N)=O)cc3)nc2c1
Yield: 27.3 %

Procedure:
2-Amino-4,6-dimethoxy-benzamide (150 mg, 0.764 mmol), 2-(4-formyl-phenoxy)-acetamide (137 mg, 0.764 mmol), sodium hydrogen sulfite (150 mg, 58.5%) and p-toluenesulfonic acid monohydrate (15 mg) in N,N-dimethyl acetamide (15 mL) were heated to 150° C. overnight. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and washed with methanol to yield 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (74 mg, 27.2%). Selected data: MS (m/z): 356.09; MP 309-311° C. HPLC purity: 88.57%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=2)=[O:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30]([C:29]2[CH:33]=[CH:34][C:26]([C:24]([NH:23][C:20]3[CH:21]=[N:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[O:25])=[N:27][CH:28]=2)=[O:31])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(NC(=O)c2ccc(C(=O)O)cn2)cn1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: COc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to 6-methoxypyridin-3-amine via Procedure G. Crude methyl 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 196 mg of 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinic acid via Procedure G. The crude product was recrystallized to yield pure N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-(6-methoxypyridin-3-yl)pyridine-2,5-dicarboxamide. MS (Q1) 460 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:16][C:17]([OH:19])=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(C1NC=CN=1)(C1NC=CN=1)=O.[C:33]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[CH2:34]C([O-])=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH2:16][C:17](=[O:19])[CH2:34][C:33]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a solution of N-CBZ L-aspartic acid 1-methyl ester (1.00 g, 3.55 mmol) in dry tetrahydrofuran (17 mL) is added carbonyl diimidazole (634.1 mg, 3.91 mmol). The mixture is stirred at room temperature for 6 hr then the magnesium salt of mono-tert butyl malonate (1.339 g, 3.91 mmol) (prepared according to Angew. Chem. Int. Ed. Engl. 1979, 18(1), 72-74) is added. The mixture is stirred at room temperature for another 20 h, then concentrated in vacuum. The residue is partitioned between ether (60 mL) and 0.5 N HCl (60 mL). The organic layer is washed with saturated NaHCO3 solution (50 mL) then dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 35 g of silica gel, eluted with EtOAc:Heptane (1:1) to afford (S)-2-Benzyloxycarbonylamino-4-oxo-hexanedioic acid 6-tert-butyl ester 1-methyl ester (1.17 g, 87%).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:22][C:23]([NH:25]C(C)(C)C)=[S:24])[C:17](OCC)=O)=O)C1C=CC=CC=1.[ClH:30]>C(OCC)C>[ClH:30].[ClH:30].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[CH2:17][S:24][C:23]([NH2:25])=[N:22]1
Reactant: CCOC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=S)NC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: NCCCC[C@H]1CSC(N)=N1

Procedure:
The process is performed as in Example 9, starting with 0.59 g of ethyl (2S)-6-{[(benzyloxy)-carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]-amino}hexanoate in 6 cm3 of 6N hydrochloric acid. After concentration of the reaction medium under the same conditions, the foam obtained is taken up 3 times in diethyl ether and the phases are separated each time after settling has taken place, and the remaining insoluble material is then taken up in 10 cm3 of acetonitrile. The resulting crystalline product is spin-filtered, washed with hot acetonitrile and then dried under reduced pressure (5 kPa) at a temperature in the region of 20° C. 0.34 g of (−)-(4S)-4-(4-amino-butyl)-4,5-dihydro-1,3-thiazol-2-ylamine dihydro-chloride in the form of cream-colored crystals melting at 170° C.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)(=O)C>[F:1][CH:2]([F:16])[C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[N:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:27]=1
Reactant: CSc1ccc(C(=O)CC(=O)C(F)F)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(SC)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of 4,4-difluoro-1-[4-(methylthio)phenyl]-butane-1,3-dione (2.4 g) and 4-methoxyphenylhydrazine hydrochloride (1.9 g) in acetic acid (10 ml) was stirred at 100° C. for 1 hour. The solvent was evaporated and the residue was purified by column chromatography on silica gel (30 g) eluting with toluene. The purified oily product was crystallized from ethanol to give crystals of 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (2.5 g).