Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH:15]S(C(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl.O1CCOCC1>CO>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:15])[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCC(N)c1ccccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 5-([1,1′-biphenyl]-2-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (270 mg; 0.69 mmol) in MeOH (4 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.35 ml; 1.40 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the colorless solid residue was further dried under HV to give the chlorhydrate salt of methyl 5-([1,1′-biphenyl]-2-yl)-5-aminopentanoate as a colorless solid. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 284.13 g/mol.
Reaction SMILES: [H-].[Na+].[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[C:11]=1[CH3:17])([CH3:6])([CH3:5])[CH3:4].Cl[C:21]1[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=1.Cl>O.C1COCC1>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:21]2[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)[C:11]=1[CH3:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1N
Reactant: N#Cc1cnc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1Nc1ncc(C#N)s1
Temperature: 25 °C

Procedure:
An oven dried flask under N2 was charged with NaH (60% dispersion, 210 mg, 5.25 mmol). 5 mL of anhydrous THF was added followed by 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-methyl-pyridin-2-ylamine (10-2, 0.602 g, 2.39 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.414 g, 2.86 mmol). The resulting solution was heated to reflux. After 19 hours additional NaH (19 mg, 0.48 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.069 g, 0.48 mmol) were added. After an additional 1 hour at reflux the reaction was allowed to cool to room temperature and diluted with water. The pH was adjusted to 7 with 1 M HCl. The resulting precipitate was filtered and washed with water to afford 10-3. 1H NMR (CDCl3) δ 8.41 (bs, 1H), 8.27 (d, 1H, J=5.2 Hz), 7.94 (s, 1H), 7.19 (d, 1H, J=5.2 Hz), 4.74 (s, 2H), 2.21 (s, 3H), 0.96 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C(OCC)C>[Cl:19][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1
Reactant: OCc1cc2ccccc2o1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: ClCc1cc2ccccc2o1
Reaction time: 1 h

Procedure:
Compound 4 (155.25 g) was dissolved in anhydrous ethyl ether (250 ml) containing dimethylformamide (1 ml). The reaction flask was placed into an ice bath, and when the solution temperature was between 0° C. and 4° C., thionyl chloride (124.3 g, 76.2 ml) was added dropwise, while stirring, over the period of 1 hour. The mixture was then stirred for another hour, washed with water (250 ml), 3% sodium bicarbonate solution (250 ml), and with water again (250 ml). The material was dried over magnesium sulfate, filtered, and the solvent evaporated. The product was distilled in vacuo, and the yield was approximately 117 g. The boiling point is about 78° C. at 1.5 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[SH:38].O>CN(C=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[S:38][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a stirred solution of 4-chloro-3-nitrocinnamide (275 mg, 0.814 mmol) from Example 32A in 1.0 mL of DMF was added potassium carbonate (169 mg, 1.22 mmol), followed by the dropwise addition of 2,4-dichlorothiophenol (146 mg, 0.815 mmol). The mixture was then stirred at room temperature for 60 minutes. Completion of the reaction was indicated by the TLC. Water was then added to precipitate the product. Filtration, washing with cold water, and drying in a vacuum oven afforded 350 mg (0.728 mmol, 89%) of the title compound as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.05 (s, 3H), 3.42-3.50 (br m, 4H), 3.50-3.64 (br m, 2H), 3.64-3.79 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.44 (d, J=15.3 Hz, 1H), 7.55 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H). MS (DCI/NH3) (M+H)+ at m/z 497, 499, 501. Analysis calculated for C21H19N3O4Cl2S1 0.82H2O: C, 50.94; H, 4.20; N, 8.49. Found: C, 50.91; H, 4.21; N, 8.69.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH:8](C(=O)C)[CH2:7][CH:6](C(=O)C)[CH:5]1[C:15]#[N:16].ClC1C=CC=[C:20]([C:24]([O:26]O)=[O:25])C=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH:4]1[CH:8]([O:26][C:24](=[O:25])[CH3:20])[CH2:7][CH:6]([O:26][C:24](=[O:25])[CH3:20])[CH:5]1[C:15]#[N:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C1CC(C(C)=O)C(CCCl)C1C#N
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CC(OC(C)=O)C(CCCl)C1C#N
Temperature: 50 °C
Yield: 76.8 %

Procedure:
A mixture of 0.46 g of 2-(2'-chloroethyl)-3,5-diacetyl-cyclopentanecarbonitrile, 2.05 g of meta-chloroperbenzoic acid and 15 ml of chloroform was heated at 50°C for 4 days. The reaction mixture was treated by the same procedure as set forth in Example 32 to afford 0.40 g of 2-(2'-chloroethyl)-3,5-diacetoxy-cyclopentanecarbonitrile as an oily substance. The product had the following characteristics: Infrared absorption (film method): 2250, 1740, 1430, 1370, 1230, 1045, 1020. Nuclear magnetic resonance (in CDCl3): about 5.3 (two multiplet, 2H, two methyne protons at the 3- and 5-position), 3.65 (triplet, J=7 cps, methylene protons adjacent to chlorine), 2.10 (two singlets, two acetoxy protons).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]C)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[C:17]([NH:21][C:13]([C:3]1[C:4](=[O:12])[NH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1c(O)c2ccccc2[nH]c1=O
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)NC(=O)c1c(O)c2ccccc2[nH]c1=O

Procedure:
8.76 g (0.04 mol) of methyl 4-hydroxy-2-oxoquinoline-3-carboxylate was stirred with 3.7 g (0.05 mol) of tert-butylamine in 60 ml of ethanol in a miniautoclave for 8 hours at 150° C. under autogenous pressure. After cooling, the crystals were removed by suction filtration, washed with ligroin and dried.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[K+].O>C(O)C>[O:15]=[C:14]([CH3:16])[CH:13]=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(-c2cccs2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)C=Cc1ccc(-c2cccs2)s1
Temperature: 16 °C

Procedure:
3.39 g of 5-formyl-2,2'-bithiophene and 2 ml of acetone was dissolved in 50 ml of ethanol. The temperature of the reaction solution was controlled at 12° C. and diluted KOH solution was dropped in. After the temperature of the mixture raised to 16° C. and the color thereof changed from dark yellow to orange red. After completion of the reaction in refrigerator for overnight, the reaction mixture was decomposed with water. The solid collected was recrystallized from alcohol. A yellowish crystal (2.23 g) was thus obtained. The melting point of the product was 204° C.
Reaction SMILES: I.[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[NH:26])SC)[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1>>[C@H:2]1([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23]([NH:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)=[NH:26])[CH:18]=3)[N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(N)CC1
Reactant: CSC(=N)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: I
Product: CN1CCC(NC(=N)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 16 described in example 151 from 1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea hydroiodide and 1-methylpiperidine-4-amine; MS: m/e=415.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]CC)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1
Reactant: CCOC(=O)c1noc(C2=CCC3(CCCC3)CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)noc1C1=CCC2(CCCC2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 4-methyl-5-(spiro[4.5]dec-7-en-8-yl)isoxazole-3-carboxylate (180 mg, 0.622 mmol) in ethanol (10 mL), 2M NaOH (aq) (0.311 mL, 0.622 mmol) was added and the reaction mixture was stirred at room temperature. The resulting mixture was diluted with water (30 mL) and acidified to pH 5-6 by the addition of 2M HCl (aq). The aqueous was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[O:25][CH3:26])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[OH:34][C@H:35]1[CH2:39][NH:38][C@H:37]([C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[CH2:36]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:38]1[CH2:39][C@H:35]([OH:34])[CH2:36][C@H:37]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[O:25][CH3:26]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccc(N2CCCCC2)cc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCCCC2)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.10 g of the compound obtained in Step 193-3 and (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (1.83 mmol) as starting materials, respectively 202 mg (Isomer A, brown amorphous) and 343 mg (Isomer B, brown amorphous) of two species of diastereoisomers of the title compound were obtained by a similar procedure to Step 4-2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](OCC)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[Na+]>CCOCC>[OH:12][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: CCOC(=O)c1ccc2ncccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: OCc1ccc2ncccc2c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
59.5 g (0.296 mole) of ethyl quinoline-6-carboxylate are stirred in 970 ml of ether at -70° C. with 750 ml (0.9 mole) of diisobutylaluminum hydride (DIBAL, 20% strength in toluene, 1.2 molar) overnight. The temperature is then allowed to rise to -35° C. and 310 ml of sodium chloride solution are added, whereupon the temperature slowly comes to 20° C. The mixture is stirred at 20° C. for 3 hours and the aluminum hydroxide is filtered off with suction and rinsed with ether/ethyl acetate. The organic phase is washed with 100 ml of sodium chloride solution, dried over Na2SO4 and evaporated. Crude yield: 40 g
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1ccc2ccccc2n1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3ccc4ccccc4n3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with quinoline-2-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=487.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CCC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CCC4)cc3)cc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
To a mixture of 6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde (80 mg, 0.24 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (420 mg, 4.80 mmol) and sodium phosphate monobasic hydrate (650 mg, 4.80 mmol) in water (3 mL) dropwise via additional funnel. The ice bath was removed, and the reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo to give a residue, which was purified by prep-HPLC (Kromasil Eternity-5-C18 150*30 mm*5 μm Mobile phase: from 35% MeCN in water (0.1% TFA) to 50% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylic acid (25 mg, 32% yield) as a white solid. MS (ES+) 377.9 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.97 (s, 1H), 7.57 (s, 1 H), 7.39 (d, 2 H), 7.23 (d, 2 H), 3.70 (s, 2H), 2.39-2.30 (m, 4 H), 2.11-2.09 (m, 1 H), 1.92-1.91 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]([C:33]([O:35]C)=[O:34])[CH2:21]3)[CH:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[OH-].[Li+].Cl>O1CCOCC1.O.C(Cl)Cl>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:19]=2)[CH2:21][CH:22]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)C1CN(c2ccnc(Nc3cc(OC)c(OC)c(OC)c3)n2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nccc(N3CCN(C(=O)OC(C)(C)C)C(C(=O)O)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2.2 (0.05 g, 0.099 mmol) in dioxane (0.331 mL) was added lithium hydroxide monohydrate (6.25 mg, 0.149 mmol) in water (0.331 mL). The reaction was stirred at room temperature for 1 hour. The reaction was then acidified with 1N HCl and diluted with DCM. The organic layer was extracted, dried over Na2SO4, filtered and concentrated to provide 2.3 as a light yellow solid. ESI-MS M+H 490.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25]([C:27]1[S:28][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:30][CH:31]=1)=[NH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:21][N:26]=[C:25]([C:27]5[S:28][C:29]([S:32]([NH2:33])(=[O:35])=[O:34])=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) (162 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a light yellow solid (96 mg, 38%). MS (EI) 508.0 [(M)+]; mp 259° C.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:64]=[C:63]3[C:59]([CH2:60][N:61]([C@@H:66]([CH:71]([CH3:73])[CH3:72])[C:67]([O:69]C)=[O:68])[C:62]3=[O:65])=[CH:58][CH:57]=2)=[C:52]([C:74]([F:77])([F:76])[F:75])[CH:51]=1)=[O:48]>>[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:64]=[C:63]3[C:59]([CH2:60][N:61]([C@@H:66]([CH:71]([CH3:72])[CH3:73])[C:67]([OH:69])=[O:68])[C:62]3=[O:65])=[CH:58][CH:57]=2)=[C:52]([C:74]([F:75])([F:76])[F:77])[CH:51]=1)=[O:48]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc5ccccc5c4)cc3C(F)(F)F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc5ccccc5c4)cc3C(F)(F)F)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 428 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 427.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Cl.Cl[CH2:12][CH2:13][NH2:14].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cccc(SCCN)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
A mixture of 3-methoxybenzenethiol (5 g), 2-chloroethylamine hydrochloride (1.1 eq.) and Cs2CO3 (2.2 eq.) in CH3CN (60 mL) was stirred at 60° C. for 20 h. To the reaction mixture, EtOAc (100 mL) was added, and washed with H2O (2×30 mL). The organic phase was concentrated under reduced pressure to give product 20 (Yield: 6.2 g, 95%), which appeared to be pure by TLC and NMR and was used for the next step reaction without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21]Cl)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>CCOCC>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21][NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH2:8])=[CH:17][CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(CN[C@@H]1CCCC[C@H]1N)Cc1ccc(C(C)(C)C)cc1
Temperature: 140 °C
Reaction time: 10 h
Yield: 83.5 %

Procedure:
274 g of trans-1,2-diaminocyclohexane and 134.4 g of 3-(4-tert.-butylphenyl)-2-methylpropyl chloride (German Laid-Open Application DOS No. 2,752,096) were stirred for 10 hours at 140° C. and then cooled to +10° C. in an ice bath, and 200 ml of a 50% strength by weight sodium hydroxide solution were added slowly, followed by the addition of 200 ml of ether. The organic phase was separated off, dried over potassium hydroxide and distilled to give 151 g of N-(3-(4-tert.-butylphenyl)-2-methylpropyl)-trans-1,2-diaminocyclohexane of boiling point 175°-180° C./0.3 mbar. Yield: 83.3% of theory.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.Cl.Cl.[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH2:40])[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH:40][C:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][C:5]=1[O:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1])=[O:15])[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Reactant: COC(=O)[C@@H](N)CCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CCN1CCCCC1)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (0.050 g, 0.14 mmol), (S)-2-amino-4-piperidin-1-yl-butyric acid methyl ester dihydrochloride (0.043 g, 0.16 mmol), EDCI (0.033 g, 0.17 mmol) and HOBt (0.023 g, 0.17 mmol) in dichloromethane was added dropwise DIEA (0.093 g, 0.72 mmol). The reaction mixture was stirred at room temperature until HPLC analysis showed consumption of the starting material and then was diluted with dichloromethane and washed with saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed to afford 0.051 g of product (67% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].C1N2[CH2:20][CH2:21]N(CC2)C1>C(OCC)C>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([CH:12]([OH:13])[C:6]([C:8]([O:10][CH2:20][CH3:21])=[O:9])=[CH2:5])=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: C1CN2CCN1CC2
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Solvent: CCOCC
Product: C=C(C(=O)OCC)C(O)c1ccc(C(=O)OC)nc1Cl

Procedure:
To a mixture of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and DABCO (10 mmol. 1.12 g) was added an methyl/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜5 min.) was diluted with diethyl ether (300 ml) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.98 g.).