Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[F:37][C:33]1[CH:32]=[C:31]([C:8]2([CH2:11][CH2:12][N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][CH:16]([N:21]3[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]3[CH3:30])[CH2:17]4)[CH2:9][CH2:10][N:5]([C:3]([CH:2]([NH:1][C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:38][CH3:39])=[O:4])[CH2:6][CH2:7]2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC(N)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)C(C)(C)C)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Yield: 54 %

Procedure:
N-[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-2,2-dimethyl-propionamide was obtained from treating[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester (0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.488 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.049 g, 0.09 mmol, 2,2-Dimethyl-propionyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, N-[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-2,2-dimethyl-propionamide (0.030 g, 54%) as an oil. ES-LCMS m/z 616 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28](I)[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:28][CH3:29])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(O)cc(Cl)c2OC1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OCC)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 8-chloro-6-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Step 3 (0.500 g, 1.55 mmole) in anhydrous DMF (5.0 mL) under a dry N2 atmosphere was added KI (26 mg, 0.155 mmole), K2CO3 (0.643 g, 4.65 mmole) and ethyl iodide (272 uL, 4.65 mmole). After stirring overnight at room temperature, the mixture was poured into H2O (150 mL), saturated with solid NaCI and extracted with EtOAc (200 mL). The extract was then washed with brine (2×200 mL), dried over MgSO4, filtered and concentrated in vacuo to give a quantitative yield of the product as a tan solid: EIHRMS m/z 350.0564 (M+, C15H14ClF3O4, Calc'd 350.0533). 1H NMR (dmso-d6/300 MHz) 7.93 (s, 1H), 7.18 (d, 1H, J=3.0 Hz), 7.13 (d, 1H, J=2.8 Hz), 6.06 (q, 1H, J=7.3 Hz), 4.23-4.31 (m, 2H), 4.01 (q, 2H, 7.0 Hz), 1.29 (q, 6H, J=7.0 Hz).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:13]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:18]([O-])=O)([CH3:3])[CH3:2].N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:18][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:14](=[O:17])(=[O:16])[NH2:15])[C:5]=1[NH:4][CH:1]([CH3:2])[CH3:3])[C:9]([OH:11])=[O:10]
Reactant: CC(C)Nc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: CC(C)Nc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
By substituting 4-isopropylamino-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 226°C (decomp.).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:13]1=[O:30].[OH-].[Na+]>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:14]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])[C:13]2=[O:30])=[CH:24][CH:25]=1
Reactant: COC(=O)CCCCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is produced as described in example 18 from 4.4 g of 9-[3-(4-chlorophenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] pelargonic acid methyl ester and 0.4 g of NaOH in 20 cc. of methanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:12]([O:14]C)=O.C(O)(=O)C.[CH:20](=[NH:22])[NH2:21].[H-].[Na+]>O1CCOCC1>[OH:14][C:12]1[C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]=2[N:21]=[CH:20][N:22]=1
Reactant: COC(=O)c1cncc(C(=O)OC)c1Cl
Reactant: N=CN
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cncc2c(O)ncnc12
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To the mixture of dimethyl 4-chloropyridine-3,5-dicarboxylate (0.6 g, 2.6 mmol) and formimidamide acetate (0.82 g, 7.8 mmol) in dioxane (20 mL) was added NaH (0.31 g, 7.8 mmol). The resulting mixture was refluxed for 48 hours, cooled to RT. The precipitate was filtered, and washed with EA to afford the title compound as grey solid (yield 56.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]2[CH3:15])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:9]2[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1nc(CO)cn1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C=O)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-yl]-methanol is dissolved in methylene chloride. Manganese (IV) oxide is added and the reaction mixture is stirred at room temperature for 3 days. The suspension is filtered through a dicalite speed plus pad and the desired compound (4-fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:26][CH2:25][C:15]3([CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])C.C1COCC1.CO.O.[OH-].[Li+]>O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:26][CH2:25][C:15]3([CH:17]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16]3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(C2CCC3(CC2)CC3C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC12CCC(c1ccc(C(=O)O)cc1)CC2
Reaction time: 16 h
Yield: 83.9 %

Procedure:
0.159 g of tert-butyl 6-(4-ethoxycarbonylphenyl)spiro[2.5]octane-1-carboxylate (0.44 mmol, 1 eq.) is placed in 4 mL of a 3/1 mixture of THF/methanol in a 50 mL round-bottomed flask. 0.075 g of lithium hydroxide monohydrate (1.78 mmol; 4 eq.) dissolved in 1 mL of water is added with stirring. After 16 hours at room temperature, the reaction medium is evaporated and aqueous 6% sulfur dioxide solution is added. The precipitate is filtered off to give 0.122 g of tert-butyl 6-(4-carboxyphenyl)-spiro[2.5]octane-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN1CCCC1=O>[F:12][C:8]1[CH:7]=[C:3]2[C:2](=[C:10]([CH3:11])[CH:9]=1)[N:1]=[C:24]([C:23]1[CH:22]=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)=[CH:27][CH:26]=1)[NH:6][C:4]2=[O:5]
Reactant: Cc1cc(F)cc(C(N)=O)c1N
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(F)cc2c(=O)[nH]c(-c3ccc(N4CCN(C)CC4)cc3)nc12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 2-amino-5-fluoro-3-methyl-benzamide (84.1 mg, 0.50 mmol), 4-(4-methyl-piperazin-1-yl)-benzaldehyde (123 mg, 0.60 mmol) and sodium disulfite (97 mg, 0.51 mmol) in N-methyl-pyrrolidone (1 ml) is heated to 150° C. and stirred at this temperature for 16 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 6-fluoro-8-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-3H-quinazolin-4-one as brown powder; HPLC/MS 1.47 min (A), [M+H] 353; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 12.34 (s, 1H), 8.69-7.90 (m, 2H), 7.86-7.26 (m, 2H), 7.28-6.73 (m, 2H), 3.33-3.27 (m, 4H), 2.61 (s, 3H), 2.45 (t, J=5.1 Hz, 4H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([O:20]CC)=[O:19])[N:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Na+]>CO>[C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([OH:20])=[O:19])[N:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)Cn1nc(C(=O)C(C)C)c2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(C(=O)C(C)C)nn(CC(=O)O)c2c1

Procedure:
Dissolve 1.68 g ethyl (3-isobutyryl-6-methoxy-1H-indazol-1-yl)acetate in 50 mL MeOH at 45° C. Add 10 mL water and 1.5 mL 5 N NaOH solution. The resulting mixture was heated overnight and evaporated to dry. The residue was taken up in water, acidified with 0.8 mL concentrated HCl, and extracted with 3×50 mL EtOAc. The combined organic extract was washed with water and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the title compound as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, 8.9 Hz, 1H), 7.01 (dd, 2.1 & 8.9 Hz, 1H), 6.69 (d, 2.1 Hz, 1H), 5.23 (s, 2H), 3.91 (s, 3H), 3.85 (heptet, 6.9 Hz, 1H), 1.28 (d, 7.1 Hz, 6H). In NOE difference spectrum, irradiation of the 5.23 ppm singlet showed positive NOE at the 6.69 ppm doublet. LC-MS: 2.94 min. (m/Z=277.0, 299.0).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=O)=[CH:5]2.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:13])=[CH:5]2
Reactant: Cc1ccc2[nH]c(C(N)=O)cc2c1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc2[nH]c(C#N)cc2c1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A mixture of 340 mg of 5-methylindole-2-carboxamide (1.95 mmol), 1.5 g of phosphorus oxychloride (9.75) and 8 mL of chloroform was refluxed for 2 hs. Then cooled solution was poured into 20 mL of water and stirred for 1 hr. After separation the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 5:1 to afford 245 mg of 5-methyl-1H-indole-2-carbonitrile. 1H NMR (600 MHz, CDCl3): δ 8.61 (br, 1H), 7.44 (s, 1H), 7.30 (d, 1H, J=8.4 Hz), 7.21 (d, 1H, J=8.4 Hz), 7.11 (s, 1H), 2.44 (s, 3H). 13C NMR (150 MHz, CDCl3): δC 135.34, 131.25, 128.28, 126.53, 121.33, 114.41, 113.95, 111.39, 106.11, 21.36.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH:16]1([C:19]2[O:23][N:22]=[C:21]([NH:24][CH2:25][CH2:26][NH2:27])[N:20]=2)[CH2:18][CH2:17]1.ClCCl>ClCCl.C(OCC)(=O)C.CN(C=O)C>[CH:16]1([C:19]2[O:23][N:22]=[C:21]([NH:24][CH2:25][CH2:26][NH:27][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[N:20]=2)[CH2:18][CH2:17]1
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: NCCNc1noc(C2CC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(/C=C/C(F)(F)F)NCCNc1noc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (17 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (11 μl, 0.12 mmol) and the solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethane-1,2-diamine (17 mg, 0.1 mmol) and TEA (42 μl, 0.3 mmol) in a mixture of anhydrous dichloromethane (1 ml) and anhydrous DMF (1 ml) and the resulting mixture was stirred at room temperature. After one hour, additional acid chloride (0.12 mmol as prepared above) was added and stirring was continued for one hour. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 5% to 100% acetonitrile) to yield 8 mg of a solid (0.019 mmol, 19%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH:8]1[CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24]>Cl>[F:25][C:23]([F:24])([F:26])[C:22]([NH:21][CH2:20][CH:8]1[CH2:9][NH:10][CH2:11][CH2:12][N:7]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(CCOCCO)C(CNC(=O)C(F)(F)F)C1
Agent: Cl
Product: O=C(NCC1CNCCN1CCOCCO)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(2-(2-hydroxyethoxy)ethyl)-3-((2,2,2-trifluoroacetamido)methyl)piperazine-1-carboxylate, prepared as described in the previous step, (8.6 g, crude) in methanolic hydrogen chloride (20 mL) was stirred at room temperature for 1 hour, followed by concentration to provide the title compound which was used without further purification. ESI-MS (M+1): 300 calc. for C11H20F3N3O3 299.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1.C(N(C(C)C)C(C)C)C.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>C(Cl)Cl>[C:23]([NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc(CN)nc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)C(C)C)nc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To an ice-cold suspension of methyl 6-(aminomethyl)nicotinate hydrochloride (1.00 g, 4.18 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.89 g, 2.55 mL, 14.6 mmol) in DCM (10 mL) was added dropwise a solution of isobutyryl chloride (535 mg, 526 μL, 5.02 mmol) in DCM (3 mL). The reaction mixture was allowed to warm to room temperature, washed with water (5 mL), 10% aqueous citric acid solution (5 mL), saturated aqueous sodium bicarbonate solution (5 mL), brine (5 mL), dried over magnesium sulfate, filtered and evaporated to yield the title compound as a pale orange solid (0.988 g, 100%):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:24](=[S:25])[NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(C(N)=S)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.37 g (6.85 mmol) of 1,4-diazepane-1-carboxylic acid tert-butyl ester and 1.12 g (6.85 mmol) of benzoyl isothiocyanate were dissolved in 13 ml of THF and stirred at 50° C. for 2 h. The solvent was subsequently distilled off, and the residue was taken up in 34 ml of methanol and 3.4 ml of water, and 1.89 g of potassium carbonate were added. The mixture was boiled under reflux overnight and then filtered off. The filtrate was evaporated, slurried in 80 ml of water and extracted 3 times with 20 ml of EA each time. The organic phase was dried over sodium sulfate, filtered, evaporated, digested using a little PE and EA and filtered off with suction.
Reaction SMILES: [F:1][CH:2]([F:44])[O:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:5]=1>C(O)(C(F)(F)F)=O.CS(C)=O>[F:44][CH:2]([F:1])[O:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(OC(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(OC(F)F)c2cn1)c1ccccc1

Procedure:
A solution of (R)-1-(3-(difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (58.5 mg, 0.099 mmol) in TFA (2 mL) was stirred at room temperature for 2.5 h. The reaction mixture was diluted with DMSO (2 mL) and purified by mass-triggered reverse-phase HPLC. The fractions containing pure product were freebased with a PL-HCO3 cartridge and concentrated in vacuo to give (R)-1-(3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C16H15F2N5O2 [M+1]+ 348. found 348. 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.66 (s, 1H), 7.64 (m, 2H), 7.52 (t, J=7.3 Hz, 1H), 7.32 (m, 4H), 7.23 (m, 1H), 4.85 (m, 1H), 1.39 (d, J=7.0 Hz, 3H). Example 53 was prepared according to Scheme 3 method A following similar procedures described for Example 52, which can be achieved by those of ordinary skill in the art of organic synthesis.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([Cl:22])[N:3]=1>[OH-].[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:5]=[C:4]([Cl:22])[N:3]=[C:2]([NH2:1])[N:7]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Yield: 97.5 %

Procedure:
0.885 g (0.0026 mol) of N-[4-(2-amino-6-chloropyrimidin-4-ylsulfamoyl)phenyl]-acetamide was dissolved in 31 ml of 0.5N NaOH and boiled at reflux for 3 hours. The mixture was extracted with ethyl acetate, the aqueous phase was saturated with sodium chloride and the remaining ethyl acetate was distilled off on a rotary evaporator. Then, the aqueous phase was made acid with 3N HCl and the precipitate which separated was filtered off under suction. After drying there was obtained 0.76 g (86%) of 4-amino-N-(2-amino-6-chloro-pyrimidine-4-yl)-benzenesulfonamide as beige crystals; m.p.: >265° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]#[C:16][C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH2:43][CH2:42]1>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:41]1[CH2:42][CH2:43][CH:44]([N:47]3[CH2:51][CH2:50][CH2:49][C:48]3=[O:52])[CH2:45][CH2:46]1)=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CCCN1C1CCNCC1
Reactant: O=C(O)C#CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.5 %

Procedure:
After 3-((6-chloronaphthalen-2-yl)sulfonyl)propinoic acid (0.30 g), HOBt (0.23 g) and WSC (0.29 g) were dissolved in DMF (10 mL), 1-(piperidin-4-yl)-2-pyrrolidinone (0.17 g) and triethylamine (0.10 g) were added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol 10/1) to obtain the title compound (0.17 g, 39%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:3]=1.[CH3:15][NH2:16].CCO>CO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:3]=[C:2]([NH:16][CH3:15])[N:7]=1
Reactant: Cc1ccc(-c2cc(Cl)nc(Cl)n2)o1
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNc1nc(Cl)cc(-c2ccc(C)o2)n1
Temperature: 80 °C
Yield: 22 %

Procedure:
A solution of 2,4-dichloro-6-(5-methylfuran-2-yl)pyrimidine (0.70 g, 3.07 mmol) in MeOH (5 mL) was treated with 2-M methylamine in EtOH (2 mL, 4 mmol), heated at 80° C. for 30 min, cooled, concentrated in vacuo and purified by chromatography [SiO2; hexane:EtOAc (100:0-90:10)] to give the title compound (0.17 g, 22%) as a white solid; NMR δH (400 MHz, CD3OD) 2.38 (3H, s), 2.93 (3H, s), 6.22-6.23 (1H, m), 6.83 (1H, s) and 7.12-7.13 (1H, m); M/Z 224, 226 (M+H)+
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[CH3:7][C:8]([CH3:19])([C:13](=O)[C:14]([O:16][CH3:17])=[O:15])[C:9]([O:11][CH3:12])=[O:10].C([O-])(=O)C.[Na+]>O>[C:4]([NH:3][N:2]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:8]([CH3:19])([CH3:7])[C:9]([O:11][CH3:12])=[O:10])(=[O:5])[NH2:6]
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)C(=NNC(N)=O)C(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
10 g (90 mmol) of semicarbazide hydrochloride, 15.5 g (82 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate and 8.1 g (82 mmol) of sodium acetate were stirred in 135 ml of water at RT overnight and left to stand for two days. The mixture was cooled with ice-water, and the colourless precipitate was filtered off, washed with a little water and dried.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:6]=[CH:7][CH:8]([CH3:10])[CH3:9])C>CO.[OH-].[Na+]>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([C:5]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[C:4]([OH:29])=[O:3])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C=CC(C)C)(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(CC=C(C)C)(Cc2cccnc2)C(=O)O)cc1

Procedure:
2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexenoic acid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 3.2 g, 87%; ivory solid; mp 117-119° C.; MS: 390 (M+)+.