Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C1(CN)CCCCC1.[O:19]=[C:20]1[C:28]2([CH2:32][O:31][C:30]3[CH:33]=[C:34]4[C:38](=[CH:39][C:29]2=3)[CH2:37][CH2:36][O:35]4)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[CH2:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:43](O)=[O:44].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][CH:48]=[CH:49][C:41]=2[CH2:40][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3([CH2:32][O:31][C:30]4[CH:33]=[C:34]5[C:38](=[CH:39][C:29]3=4)[CH2:37][CH2:36][O:35]5)[C:20]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: NCCc1ccc(Cl)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-(4-chlorophenyl)ethylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]benzoic acid, N-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]benzamide was obtained (78%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.59 (br, 1H), 7.44-7.23 (m, 7H), 7.23-6.11 (m, 2H), 7.10-6.94 (m, 2H), 6.73 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 4.94-4.65 (m, 4H), 4.47 (t, J=8.6 Hz, 2H), 3.57-3.42 (m, 2H), 2.95 (t, J=8.3 Hz, 2H), 2.84 (t, J=6.7 Hz, 2H); MS (ES+) m/z 573.1 (M+23).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[N:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:16]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[N:11]=[C:10]([CH2:12][Br:16])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: BrP(Br)Br
Reactant: Nc1nc(N)c2nc(CO)ccc2n1
Solvent: C1CCOC1
Product: Nc1nc(N)c2nc(CBr)ccc2n1

Procedure:
A suspension of 0.72 g (3.77 mmol) of 6 in 12 mL dry THF was stirred for 8 hours with 1 mL of phosphorus tribromide. The precipitated solid was filtered, washed with cold 50% THF-Ether, and dried to give 7. Because of the instability, this compound was not purified further. The 1HNMR showed that the majority of the solid was the desired compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@H:28]2[CH2:33]N[CH2:31][CH2:30][NH:29]2)=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[F:18][C:19]([F:34])([F:35])[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C@@H:28]2[NH:29][CH2:30][CH2:31][N:17]([C:6]3[C:5]4[CH:4]=[C:3]([CH3:2])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:33]2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1ccc(CC[C@H]2CNCCN2)cc1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(C(F)(F)F)cc2)C1
Temperature: 105 °C
Reaction time: 48 h
Yield: 41.7 %

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (514.5 mg, 1.94 mmol), (S)-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87 mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 380.3 mg (42%) of the title compound as a brown foam: mp 78°, dec; mass spectrum (ion spray): m/z=471.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[H-].[Na+].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br.Cl>CN(C)C=O>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][CH2:2][C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:3]
Reactant: Clc1ccccc1CBr
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.6 %

Procedure:
A solution of 1.706 g of ethyl 3-acetylamino-4-nitrobenzoate in 12 ml of N,N-dimethylformamide were added 0.406 g of 60% sodium hydride while being cooled with ice, and the mixture was stirred at room temperature for 40 minutes. A solution of 1.806 g of 2-chlorobenzyl bromide in 10 ml of N,N-dimethylformamide was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into cold 1-N hydrochloric acid, and the mixed solution was extracted twice with ethyl acetate. The organic layer was washed with 1-N hydrochloric acid and then with water, and was dried. The solvent was distilled off under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and hexane at a ratio of from 1:10 to 1:4) to give 2.08 g of oily ethyl 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][C:7]([F:10])([F:9])[F:8])[CH3:2].O.[F:32][C:33]([F:37])([F:36])[CH:34]=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[C:5]([CH2:6][C:7]([F:8])([F:9])[F:10])=[CH:34][C:33]([F:37])([F:36])[F:32])[CH3:2]
Reactant: O=CC(F)(F)F
Reactant: CCOC(=O)C(CC(F)(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=CC(F)(F)F)CC(F)(F)F
Temperature: 100 °C
Yield: 86 %

Procedure:
To a solution of 4,4,4-trifluoro-2-(triphenyl-λ5-phosphanylidene)-butyric acid ethyl ester (2.0 g, 4.65 mmol) in THF (5 mL) was added 1 mL of trifluoroacetaldehyde hydrate (tech.). The mixture was sealed in a pressure tube and heated at 100° C. for 3.5 h. After cooling to 23° C., the reaction mixture was eluted through a pad of silica gel (100 g) and Na2SO4 with Et2O (100 mL) to remove the by-products triphenylphosphine oxide and water. The eluent was distilled to remove Et2O and to afford the product as a colorless liquid (1.0 g, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:13][C:14]([OH:20])([CH3:19])[C:15]#[C:16][CH2:17]O>>[OH:20][C:14]([CH3:19])([CH3:13])[C:15]#[C:16][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(O)cc1C
Reactant: CC(C)(O)C#CCO
Product: COC(=O)c1ncc(OCC#CC(C)(C)O)cc1C

Procedure:
The title compound was synthesized analogously according to Method S starting from methyl 5-hydroxy-3-methylpicolinate and 4-methylpent-2-yne-1,4-diol. MS m/z=264 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccsc1
Product: O=C(O)CCC(=O)c1cccs1

Procedure:
Thiophene (a) is reacted with succinic anhydride (c) under Friedel-Crafts reaction conditions to afford 4-(2-thienyl)-4-oxobutyric acid (XII). Substitution of benzene (b) in the above reaction affords 4-phenyl-4-oxobutyric acid (XVII). ##STR18## The oxobutyric acids of formulas (XII) and (XVII) obtained in Step 1 above, are reacted with a suitable 1,2-dithiol (d), R3 and R4 are each either hydrogen or methyl, in an aromatic solvent such as benzene, toluene or xylene, in the presence of catalytic amounts of p-toluenesulfonic acid at a temperature range of 25° to 120° C and, preferably, from 75° to 110° C while azeotroping the water formed in the reaction. Alternatively, the reaction is conducted in a C2 -C5 alkanoic acid, preferably, acetic acid in the presence of an acid catalyst such as boron trifluoride/methanol, boron trifluoride/ether, ZnCl 2 /Na 2 SO4 , HCl/ether and the like, at the temperature range specified above, to afford 2-(2-thienyl)-1,3-dithiolane-propionic acid (XIII) and 2-phenyl-1,3-dithiolane-2-propionic acid (XVIII), respectively. R3 and R4 are as hereinabove defined. ##STR19## The dithiolane propionic acids of formulae (IIIa) and (IIIb) are converted to the corresponding acid chlorides of formulae (XIV) and (XIX) with oxalyl chloride or thionyl chloride (with a small amount of DMF added if desired) in an inert anhydrous solvent selected from the group consisting of benzene, toluene, xylene, chlorobenzene, at a temperature range of about 0° to 30° C and preferably 15° to 30° C. ##STR20##
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2cccc(Cl)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-chlorophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed that the resulting solid was determined to be the named product (m.p. 56° C.-57° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH:28]=O)=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O>C(O)(=O)C.C(O)C.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[CH:28][CH:27]=[CH:26]4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=CC=O)c3O2)cc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4ncccc4c3O2)cc1

Procedure:
To a solution of {(2R)-7-nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (3.50 g, 8.35 mmole) in 200 mL of acetic acid/ethanol (1:1) was added 2.35 g (42.1 mmole) of iron powder and the mixture was heated at reflux under nitrogen for 8 hours. After the reaction was complete, 150 mL of water was added and the mixture filtered through a pad of celite. The filtrate was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and evaporated in vacuum. The residue was column chromatographed on silica gel using a gradient elution commencing with 20% ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 1.85 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 8.8 δ (1 H); doublet 8.2 δ (1 H); doublet 7.8 δ (2 H); doublet 7.6 δ (1 H); multiplet 7.35 δ (1 H); multiplet 7.25 δ (3 H); multiplet 4.6 δ (1 H); multiplet 4.3-4.4 δ (3 H); multiplet 4.2 δ (1 H); singlet 2.4 δ (3 H).
Reaction SMILES: S1C=CC=C1.C(O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=3)[CH2:29][CH2:28]2)=[CH:12][CH:11]=1.[H][H]>[Pt].CO>[NH2:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][N:30]2[CH2:29][CH2:28][CH:27]([NH:26][C:18]3[N:17]([CH2:16][C:13]4[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=3)[CH2:32][CH2:31]2)=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Yield: 42 %

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol are added 3.3 parts of 1-(4-fluorophenylmethyl)-N-{1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of methylbenzene and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 1.3 parts (42%) of N-{1-[2-(4-aminophenyl)ethyl]-4-piperidinyl}-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine; mp. 195.4° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([C:31]2[CH:32]=[C:33](/[C:43](=[CH:47]\[C@H:48]3[CH2:68][CH2:67][C:50]4([O:54][C@H:53]([C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)[C@@H:52]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[O:51]4)[CH2:49]3)/[C:44](O)=[O:45])[CH:34]=[CH:35][C:36]=2[S:37]([CH:40]2[CH2:42][CH2:41]2)(=[O:39])=[O:38])[CH2:30][CH2:29]1.[NH2:69][C:70]1[CH:79]=[CH:78][C:73]([C:74]([O:76]C)=[O:75])=[CH:72][N:71]=1>ClCCl.N1C=CC=CC=1.O>[CH:28]1([C:31]2[CH:32]=[C:33](/[C:43](=[CH:47]\[C@H:48]3[CH2:68][CH2:67][C:50]4([O:54][C@H:53]([C:55]5[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=5)[C@@H:52]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)[O:51]4)[CH2:49]3)/[C:44]([NH:69][C:70]3[CH:79]=[CH:78][C:73]([C:74]([OH:76])=[O:75])=[CH:72][N:71]=3)=[O:45])[CH:34]=[CH:35][C:36]=2[S:37]([CH:40]2[CH2:41][CH2:42]2)(=[O:39])=[O:38])[CH2:29][CH2:30]1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)/C(=C/[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)O)cn1)/C(=C/[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
To a solution of triphenylphosphine (607 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (412 mg) under ice-cooling, followed by stirring for 15 minutes under ice-cooling. A solution of (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]acrylic acid (600 mg) in dichloromethane (10 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 0.5 hour. A solution of methyl 6-aminonicotinate (160 mg) in dichloromethane (10 mL) and pyridine (0.17 mL) were added thereto at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:1). To the solution of the obtained pale yellow amorphous dioxane (4 mL) was added a 1 M aqueous sodium hydroxide solution (1.2 mL), followed by stirring at 50° C. for 1 hour. 1 M Hydrochloric acid was added thereto to adjust the pH to 2, and then saturated brine was added thereto. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-3:1) to obtain 6-({(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]prop-2-enoyl}amino)nicotinic acid (194 mg) as a white amorphous substance.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[C-:21]#[N:22].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]([C:21]#[N:22])=[N:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:5]1
Reactant: [C-]#N
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(-c2ccccn2)nn1Cc1ccccc1F
Temperature: 100 °C

Procedure:
To a solution of 2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16, e.g., about 0.95 g, 2.9 mmol) in N,N-dimethylformamide (e.g., 9.5 mL) is added potassium cyanide (e.g., about 0.928 g, 14.3 mmol). After heating the solution at about 100° C. for about 22 h, the solution is diluted with ethyl acetate (e.g., about 125 mL) and water (e.g., about 100 mL). The layers are separated, and the aqueous layer is extracted with ethyl acetate (e.g., about 2×50 mL). The organics are combined, washed with water (e.g., about 50 mL) and brine (e.g., about 50 mL), dried, e.g., over sodium sulfate or magnesium sulfate, filtered, and the solvent is removed in vacuo to give the crude product, I-33. Purification by silica gel chromatography (0-15% ethyl acetate in dichloromethane) yields 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile I-33 (I-33) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[CH:13](=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>C(O)C.[Pd]>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]1[NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10]([N:12]=1)=[CH:9][CH:8]=[CH:7]3
Reactant: Nc1cccc2cccc(N)c12
Reactant: O=Cc1ccccc1O
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1C1=Nc2cccc3cccc(c23)N1
Reaction time: 18 h

Procedure:
To 1,8-diaminonaphthalene (31.6 g, 0.2 mole) suspended in 200 ml absolute ethanol is added salicylaldehyde (24.4 g, 0.2 mole) and 7 g 10% palladium-on-carbon. The mixture is stirred and heated under reflux for 45 min., after which it is allowed to stand for 18 hours at ambient temperature. The mixture is then filtered and the filtrate is washed with ethanol and ether. The green solid is treated with heated dimethylformamide (charcoal) and filtered hot. The catalyst is removed from the product by filtration along with the charcoal. The yellow-orange filtrate is cooled, and upon addition of water, yields the desired product, 2-(o-hydroxyphenyl)perimidine, orange crystals, m.p. 258°-260° dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:9]1.[Cl:32]N1C(=O)CCC1=O>CC#N>[Cl:32][C:11]1[C:10]([C:28]([OH:31])([CH3:29])[CH3:30])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:12]=1[C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2F)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(O)c1nn(-c2ccccc2F)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 2-{1-(2-Fluoro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazol-3-yl}-propan-2-ol (115 mg, 0.25 mmol) in dry MeCN was added N-chlorosuccinimide (35 mg, 026 mmol) at 20° C. and the reaction mixture was stirred in a sealed vial at 75° C. overnight. Evaporation of solvent gave a residue, which was purified by flash chromatography on silica gel eluting with EtOAC-hexane (0-60%) to afford the title compound as a white solid (123 mg, 100%). 1H-NMR (CDCl3): δ 8.08 (m, 1H), 7.84 (m, 1H), 7.78 (m, 1H), 7.59-7.49 (m, 3H), 7.30-7.28 (m, 2H), 7.17 (t, 1H), 7.03 (d, 1H), 3.08 (s, 4H), 1.74 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[N:12][C:11]([CH2:14]Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C-:17]#[N:18].[Na+]>CN(C)C=O.[Cl-].[Na+]>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[N:12][C:11]([CH2:14][C:17]#[N:18])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cnc(CC#N)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of (5-bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (prepared according to WO 02/070494, 1.00 g, 3.470 mmol) in N,N-dimethylformamide (6.9 mL) was treated with sodium cyanide (350.7 mg, 6.940 mmol). The reaction mixture was stirred at 40° C. for 1 h. The reaction was diluted with a saturated aqueous sodium chloride solution (100 mL) and then extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/7 ethyl acetate/hexanes) afforded (5-cyanomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (807.6 mg, 99%) as a light yellow solid: mp 162–164° C.; EI-HRMS m/e calcd for C11H14N4O2 (M+) 234.1117, found 234.1120.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reaction time: 8 h
Yield: 88.8 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.55 g, 1.6 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.31 g, 0.08 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step C (0.445 g, 1.42 mmol, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 6.62 (d, J=8.24 Hz, 1H), 6.47 (d, J=2.56 Hz, 1H), 6.37 (dd, J=8.42, 2.56 Hz, 1H), 3.81 (s, 3H), 3.15 (t, J=6.32 Hz, 2H), 2.98-3.08 (m, 7H), 2.91 (t, J=6.41 Hz, 2H), 2.62-2.70 (m, 4H).
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][C@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]1>O1CCOCC1>[ClH:1].[NH2:10][C@H:7]1[CH2:8][CH2:9][N:5]([CH2:4][CH2:3][OH:2])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CCO)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(CCO)C1
Reaction time: 2 h

Procedure:
4M HCl solution (in dioxane) (1.5 mL) was added to a stirred solution of (S)-tert-butyl (1-(2-hydroxyethyl)pyrrolidin-3-yl)carbamate (400 mg, 1.73 mmol) in Dioxane (1 mL) and stirring was continued at 20-35° C. for 2 h. After which the reaction mixture was concentrated under reduced pressure to afford the crude. The crude obtained was purified by washing with diethyl ether and dried to afford 300 mg (crude) of the title compound.