Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.[C:51](Cl)(=[O:58])[C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>ClCCl.C(N(CC)CC)C>[C:51]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1)(=[O:58])[C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: O=C(Cl)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCN(C(=O)c4ccncc4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (100 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with isonicotinoyl chloride (100 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 593.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[C:15]([C:20](O)=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:20](=[O:21])[C:15]3[C:14]([CH3:13])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccnc1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2Cl2 (10 mL) was treated with 3-methylpicolinic acid (143 mg, 1.04 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was filtered to remove the product, and the filtrate was concentrated in vacuo. The residue was stirred in anhydrous THF (10 mL), treated with 2M LiOH solution (3 mL) and stirred at room temperature for 1 hour. The organic solvent was removed in vacuo, and then water (10 mL) was added. The reaction stirred for 1 hour. The solid, which separated, was filtered and washed with water and CH2Cl2 (10 mL). The combined filtered cakes were dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpicolinamide (197 mg, 65% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.13 (br s, 1H), 10.42 (s, 1H), 8.56 (d, 1H), 8.39 (d, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.55 (dd, 1H) 2.67 (s, 3H); LCMS (APCI+) m/z 349.1, 351 (M+H)+, Retention time=3.42 minutes (Method 3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14])[CH3:2].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:20][CH:19]=1)=[C:16]=[O:17].COC1C=C(C(F)(F)F)C=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=1[NH:14][C:16]([NH:15][C:18]1[CH:19]=[CH:20][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:22][CH:23]=1)=[O:17])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: CCOc1ccc(C(F)(F)F)cc1N
Agent: COc1cc(C(F)(F)F)ccc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
2-Ethoxy-5-trifluoromethylphenylamine is reacted with 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane according to the preparation of 1-(2-methoxy-4-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea described in Example 5. After purification, a beige-coloured powder of 1-(2-ethoxy-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])([CH2:8][OH:9])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3].[CH3:14]I>>[CH2:1]([C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])([CH2:6][O:7][CH3:14])[CH2:8][OH:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CI
Reactant: CC(C)CC(CO)(CO)CC(C)C
Product: COCC(CO)(CC(C)C)CC(C)C

Procedure:
2,2-Di-iso-butyl-3-methoxy-1-propanol was prepared from 2,2-di-iso-butyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: Br[CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3]1.C(O)C.[Na].[CH3:17][SH:18]>O>[CH3:17][S:18][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3]1
Reactant: CS
Reactant: O=C1c2ccccc2OCC1Br
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CSC1COc2ccccc2C1=O
Reaction time: 2 h
Yield: 17 %

Procedure:
After 10.4 g of 3-bromo-4-chromanone [synthesized in accordance with procedures described in W. S. Johnson, et al., J. Am. Chem. Soc., vol.66, p.218 to 220 (1944)] was dissolved into 42 ml of ethanol, 21.3 ml of a 15% aqueous solution of a sodium salt of methylmercaptan was added dropwise thereto. After the stirring for 2 hours at room temperature, the reaction mixture was poured into 300 ml of cold water. An organic layer was extracted with 200 ml of ether, and the ether layer was sequentially washed with a sodium chloride aqueous solution and water. After the ether layer was dried with magnesium sulfate, the solvent was removed by evaporated under vacuum. The residue was isolated and purified through a silica gel column (elute: hexane/ethyl acetate=3/1) to provide 1.52 g of 3-methylthio-4-chromanone (yield: 17%).
Reaction SMILES: Cl.Cl.Cl.[C:4]([C:6]1[CH:25]=[CH:24][C:9]([CH2:10][N:11]2[C:15]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][N:13]=[CH:12]2)=[CH:8][C:7]=1[F:26])#[N:5].[CH:27]([Si:30]([CH:48]([CH3:50])[CH3:49])([CH:45]([CH3:47])[CH3:46])[O:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][CH:38]=[C:39]2[C:42](O)=[O:43])=[CH:34][CH:33]=1)([CH3:29])[CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[C:4]([C:6]1[CH:25]=[CH:24][C:9]([CH2:10][N:11]2[C:15]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:42]([C:39]4[C:40]5[C:35](=[CH:34][CH:33]=[C:32]([O:31][Si:30]([CH:45]([CH3:47])[CH3:46])([CH:48]([CH3:50])[CH3:49])[CH:27]([CH3:28])[CH3:29])[CH:41]=5)[CH:36]=[CH:37][CH:38]=4)=[O:43])[CH2:20][CH2:19]3)=[CH:14][N:13]=[CH:12]2)=[CH:8][C:7]=1[F:26])#[N:5]
Reactant: N#Cc1ccc(Cn2cncc2CCN2CCNCC2)cc1F
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc2cccc(C(=O)N3CCN(CCc4cncn4Cc4ccc(C#N)c(F)c4)CC3)c2c1)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
The product from Step D (66.1 mg, 0.156 mmol), 7-triisopropylsilyloxy-1-naphthoic acid from Step F (53.8 mg, 0.156 mmol), EDC hydrochloride (33.0 mg, 0.172 mmol), HOBT (23.2 mg, 0.172 mmol), and N,N-diisopropylethylamine (0.136 mL, 0.781 mmol) were stirred in dry, degassed DMF (0.5 mL) at 20° C. overnight. The reaction was stirred overnight and then injected onto a C18 preparative HPLC column and purified with a mixed gradient of 5%-95% acetonitrile/0.1% TFA; 95%-5%/0.1% aqueous TFA over 15 min. The title compound was isolated after conversion to the free base.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH2:28][CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:27][CH2:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 38.2 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (20 mg, 0.077 mmol), potassium carbonate (107 mg, 0.77 mmol) and propyl iodide (0.023 mL, 0.23 mmol) in N,N-dimethylformamide (1 mL) were heated in a sealed vial at 150° C. for 5 minutes. After cooling the reaction was diluted with dichloromethane, washed with water (3 times) and saturated brine, filtered and concentrated. Silica gel chromatography using a mixture of hexanes, ethyl acetate, and dichloromethane (3.5:0.5:4) followed by trituration with diethyl ether and hexanes afforded 9 mg (40%) of 3-(2-pyridyl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ-8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H) 7.39 (s, 1H), 4.06 (t, 2H), 1.88 (m, 2H), 1.08 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([OH:19])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:34][NH:35][O:36][CH3:37].CCN(C(C)C)C(C)C>C1COCC1.O.Cl>[Br:1][C:2]1[C:3]([F:20])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:35]([O:36][CH3:37])[CH3:34])=[O:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: COc1cn(-c2cccc(Br)c2F)nc(C(=O)O)c1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2cccc(Br)c2F)nc(C(=O)N(C)OC)c1=O
Temperature: 40 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.76 g, 11.0 mmol) and CDI (1.95 g, 12.1 mmol) in THF (38 mL) was heated to 40° C. for 2 h. To the solution were added N,O-dimethylhydroxylamine hydrochloride (1.60 g, 16.4 mmol) and i-Pr2NEt (2.86 mL, 16.4 mmol) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water and 1 M HCl aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (EtOAc/MeOH=100/0 to 80/20) to yield the title compound (4.22 g, >99% yield) as a white solid: NMR (DMSO-d6, 300 MHz): δ ppm 3.25 (3H, s), 3.58 (3H, s), 3.80 (3H, s), 7.39 (1H, td, J=8.1, 1.5 Hz), 7.78 (1H, ddd, J=8.2, 6.9, 1.5 Hz), 7.92 (1H, ddd, J=8.0, 6.3, 1.5 Hz), 8.58 (1H, s).
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]2[C:16]([O:18][CH3:19])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20]OS([O-])=O.[K+].[K+].S(=O)(=O)([O-])[O-].[K+].S([O-])(OO)(=O)=O.[K+].[OH2:40]>CO.ClC(Cl)C>[C:1]1([S:7]([CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]2[C:16]([O:18][CH3:19])=[O:17])(=[O:20])=[O:40])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: O=S([O-])OO
Reactant: COC(=O)C1CC(Sc2ccccc2)C1C(=O)OC
Agent: O=S(=O)([O-])OO
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: COC(=O)C1CC(S(=O)(=O)c2ccccc2)C1C(=O)OC
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a vigorously stirred solution of 1.05 g (3.75 mmol) of dimethyl 3-(phenylthio)cyclobutane-1,2-dicarboxylate from Step A in 20 mL of methanol, was added slowly a suspension of 3.46 g (11.25 mmol) of OXONE (a commercially available mixture of sulfuric acid potassium salt and potassium hydrogen peroxymonosulfate) in 20 mL of water. The resultant cloudy suspension was stirred for 0.5 h then diluted with 50 mL of water and 100 mL of 1,2=dichloroethane. The phases were allowed to separate and the aqueous phase was extracted with 20 mL of 1,2-dichloroethane. The combined organic layers were washed with 2×50 mL of dilute aqueous sodium bicarbonate solution, 2×50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate and concentrated to give 1.10 g (94% yield) of the title compound as a viscous oil; EI-MS, m/e (relative intensity): 281 (M+ --OCH3, 9), 171 (100), 139 (24), 111 (47); 1H NMR (CDCl3) δ2.48 (m, 1H), 2.76 (m, 1H), 3.23 (q, 1H), 3.52 (s, 3H), 3.74 (s, 3H), 3.80 (m, 1H), 3.92 (q, 1H), 7.58 (m, 2H), 7.68 (m, 1H), 7.89 (m, 2H).
Reaction SMILES: ClC(OCC)=O.[F:7][C:8]1[CH:45]=[CH:44][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]=4[O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:23]3[C:41]([OH:43])=O)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.CN1CCOCC1.C[Si](C)(C)[O:55][NH2:56]>CN(C=O)C>[OH:55][NH:56][C:41]([CH:23]1[C:24]2[C:29](=[C:28]([O:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:44]=[CH:45][C:8]([F:7])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1)(=[O:20])=[O:21])=[O:43]
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C1c2cccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NO)C1c2cccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
8.16 μl (85.6 μmol) of ethyl chloroformate are added to a solution of 38 mg (68.5 μmol) of 2-[4-(4-fluorophenoxy)benzenesulfonyl]-5-(2-piperidin-1-ylethoxy)-1,2,3,4-tetra-hydroisoquinoline-1-carboxylic acid and 16.6 μl (151 μmol) of N-methylmorpholine in 2 ml of DMF at −20° C., and the mixture is stirred at −20° C. for 30 minutes. Then 37.2 μl (274 μmol) of O-trimethylsilylhydroxylamine are added, and the solution is warmed slowly to room temperature. After standing overnight, it is concentrated in vacuo and the residue is purified by chromatography on silica gel, allowing the title compound to be isolated as a colorless solid. Yield 46%.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[CH:9][C:8]=1[O:16][CH3:17])(=[O:5])[CH3:4].[CH3:18]I>CN(C)C=O>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[N:6]([CH3:18])[C:3](=[O:5])[CH3:4]
Reactant: CI
Reactant: COc1cc(C)cc(OC)c1NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)cc(OC)c1N(C)C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 12.0 g. of sodium hydride (50% dispersion in oil) in 50 ml. of absolute dimethylformamide was treated with a solution of 46.0 g. of 4-acetamido-3,5-dimethoxy-toluene in 200 ml. of absolute dimethylformamide over a period of 30 minutes with stirring and exclusion of moisture. After stirring at room temperature for 4 hours, 31.2 ml. of methyl iodide were added dropwise over a period of 20 minutes with stirring and ice-cooling. The mixture was stirred at room temperature for 70 hours and subsequently evaporated to dryness under vacuum. The residue was treated with 300 ml. of water and the resulting suspension was extracted with two 500 ml. portions of ethyl acetate. The combined ethyl acetate extracts were washed with 300 ml. of water, dried over magnesium sulfate, filtered and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 3,5-dimethoxy-4-(N-methyl-acetamido)-toluene having a melting point of 160°-161° C.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[CH2:21]([N:23]([CH2:33][CH3:34])[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[CH3:22].P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C=O)C>[CH2:33]([N:23]([CH2:21][CH3:22])[C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[O:29])=[CH:26][CH:25]=1)[CH3:34]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reactant: CCN(CC)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Yield: 27.7 %

Procedure:
To a solution of 1-(2-naphthalenesulfonyl)piperazine hydrochloride (625 mg) and 4-diethylamino benzoic acid (386 mg) in DMF (12 ml) was added diethyl phosphorocyanidate (489 mg) and then triethylamine (606 mg), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was purified with silica gel column chromatography (dichloromethane:10% ammonia containing methanol=20:1) to give colorless amorphous of the title compound (250 mg).
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:12]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:12][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#N
Reactant: [N-]=[N+]=NCc1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nnnn1Cc1ccccc1
Yield: 93.9 %

Procedure:
A mixture of freshly prepared benzyl azide (1.3 g) and ethyl cyanoformate (1.0 g) in xylene (10 ml) was heated at reflux for 48 hours. The mixture was evaporated under reduced pressure and below 40° C. to give a residue of ethyl 1-benzyl-1H-tetrazole-5-carboxylate (2.13 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[CH3:2].[ClH:13].Cl.Cl.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:33].[ClH:13].[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[O:12])[CH2:25][CH2:24]2)=[CH:28][CH:29]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCOc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 135.7 %

Procedure:
The procedure described in Example 29 was followed, using 4-ethoxyphenyl isocyanate (1.63 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (16 ml), and triethylamine (4.3 ml; 31 mmole). Recrystallization from ethanol provided the title compound (3.42 g; 68% yield) as colorless crystals, m.p. 225°-227° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
A mixture of 3,4-dihydroxybenzonitrile (540 mg, 4 mmol), K2CO3 (552 mg, 4 mmol) and benzyl bromide (476 mg, 4 mmol) in acetone (20 mL) was stirred at room temperature for 3 days. The mixture was evaporated under vacuum and subjected to flash column chromatography (2% MeOH in toluene-hexane, 2:1) to give the desired product (224 mg, 25%): MP 101° C.; 1H NMR (Acetone-d6, 500 MHz) δ8.55 (s, 1H), 7.50 (d, 2H, J=7.3 Hz), 7.39 (dd, 2H, J=7.0 and 7.3), 7.34 (dd, 1H, J=7.0 and 7.3), 7.2 (m, complex, 3H), 5.25 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[CH:5][CH:4]=1)(=[O:43])=[O:42]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(CN)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(CNS(C)(=O)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 1 h
Yield: 36515.5 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)—N-(4-(aminomethyl)phenyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide (21.0 mg, 0.0367 mmol, example XJ-2) in CH2Cl2 (4 ml) was treated with METHANESULFONYL CHLORIDE (8.5 mg, 5.78 μl, 0.0742 μmol) and the reaction was stirred at 0 C for 1 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 1% to 10% MeOH/CH2Cl2) to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(methanesulfonylamino-methyl)-phenyl]-amide as off-white solid (17.6 mg, 73%). MS (ES+) m/z Calcd: [(M+H)+]: 649. found: 649.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[C:3]=1[C:13]#[N:14].[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.O>C1COCC1>[CH2:15]([NH:21][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[C:3]=1[C:13]#[N:14])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccco1
Reactant: CSc1nc2ccnn2c(Cl)c1C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc2ccnn2c(NCc2ccco2)c1C#N
Yield: 70.9 %

Procedure:
200 mg of 7-chloro-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 62) and 100 mg of furfurylamine were reacted in 5 ml of THF in the presence of 110 mg of triethylamine for about 30 minutes, then about 30 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were washed with ether to obtain 180 mg of 7-furfurylamino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 78) having a melting point of 110° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.[NH3:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Na+]>C(O)C.O>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])=[NH:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: N
Reactant: N#CCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: N=C(N)Cc1ccc(F)cc1
Reaction time: 72 h

Procedure:
A mixture of 4-fluorophenylacetonitrile (71 g.) and dry ethanol (27.6 g.) was cooled in an ice-bath and dry hydrogen chloride was passed in until a weight increase of 25.5 g. was obtained. The mixture was allowed to stand at room temperature for 3 days and then treated portionwise, with vigorous shaking and occasional cooling, with a saturated solution of ammonia in dry ethanol. Addition was continued until a smell of ammonia persisted. The mixture was allowed to stand at room temperature for 2 days and then filtered. The filtrate was treated with a saturated aqueous solution of 1.1 equivalents of sodium p-toluenesulphonate and diluted with water. The crystalline precipitate was removed and recrystallised from ethanol to give pure 4-fluorophenylacetamidine p-toluenesulphonate, m.p. 215°-218°. The following amidines were also prepared by Method E; crystallisation solvents are given in brackets: