Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.C(N(CC)CC)C.[CH3:29][C:30](=[CH2:34])[C:31](Cl)=[O:32].O>O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:31](=[O:32])[C:30]([CH3:34])=[CH2:29])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Yield: 53.1 %

Procedure:
To a solution of 0.5 g (1.48 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile and 0.194 g (1.92 mmol) of triethylamine in 6 ml tetrahydrofuran was added at 0° C., under nitrogen, with stirring, 0.21 g (1.92 mmol) of 2-methyl acryloyl chloride over a 10 minute period. The solution was stirred at room temperature overnight. The mixture was poured into water. The solid was collected and air dried. The solid was washed with bioling ethyl acetate and air dried giving 0.32 g of N-[4-[(3-bromophenyl)amino]-3-cyano -6-quinolinyl]-2-methyl-2-propenamide : mass spectrum (electrospray, m/e): M+H 407, 409.
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.Cl[C:14]1[C:15]([C:23]([OH:25])=[O:24])=[N:16][C:17]([Cl:22])=[C:18]([Cl:21])[C:19]=1[Cl:20]>[Ni](Cl)Cl.[Zn].O>[Cl:20][C:19]1[C:18]([Cl:21])=[C:17]([Cl:22])[N:16]=[C:15]([C:23]([OH:25])=[O:24])[CH:14]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 3 h
Yield: 35.9 %

Procedure:
Anhydrous nickel chloride (NiCl2; 77 milligrams (mg), 0.596 millimoles (mmol)) and 2,2′-bipyridine (186 mg, 1.19 mmol) were stirred in 9:1 dimethylformamide (DMF)-water (10 milliliters (mL)) for 24 hours (h). Solid 3,4,5,6-tetrachloropicolinic acid (1.556 grams (g), 5.96 mmol) was added, followed by zinc powder (3.32 g, 50.7 mmol). After 3 h, water was added. The solids were removed by filtration and washed with water (100 mL). The aqueous filtrate was made acidic (pH 1) with concentrated hydrochloric acid (HCl). A white solid appeared upon standing. The solid was isolated, washed with water and dried under vacuum to give the title compound (484 mg, 35.8%) which was 94% pure by high-performance liquid chromatography (HPLC): 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H); 13C NMR (101 MHz, DMSO-d6) δ 163.4, 148.9, 146.5, 144.4, 131.6, 125.7.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([Li])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:11][Si:12](Cl)([Cl:14])[Cl:13]>C1COCC1>[CH3:1][C:2]1[CH:3]([Si:12]([Cl:14])([Cl:13])[CH3:11])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: [Li]C1C(C)=C(C)C(C)=C1C
Reactant: C[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(Cl)Cl)C(C)=C1C
Temperature: -78 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
(2,3,4,5-Tetramethylcyclopentadienyl)lithium (1.33 g, 10.37 mmol) was dissolved in 80 mL THF and cooled to −78° C., and MeSiCl3 (1.70 g, 11.4 mmol) was added via a syringe. After addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. Volatiles were removed under vacuum at room temperature, and the residue was extracted twice with hexanes (2×20 mL). The hexane fractions were combined and the solvent was removed under vacuum to give a pale yellow oil (tetramethylcyclopentadienyl methyl silicon dichloride); 2.0 g, 82% yield. 1H-NMR (C6D6): δ (ppm): 2.95 (broad s, 1 H; Me4CpH), 1.92 (s, 6H;), 1.63 (s, 6H; Me4Cp), 0.19 (s, 3 H; MeSi).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]3[CH2:13][CH2:14][O:15][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.C[O-].[Na+].[CH3:27][O:28][CH2:29]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:27][O:28][CH3:29])[C:10](=[O:12])[CH2:9][N:8]3[CH2:13][CH2:14][O:15][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: COCCl
Reactant: O=C1CN2CCOC2(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)CN2CCOC2(c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.08 h

Procedure:
A solution of 2.8 g. of 10-chloro-11b-(2-chlorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one in 50 ml. of dimethylformamide was cooled to -10° and treated with 0.65 g. of sodium methoxide. After stirring for 5 minutes, the mixture was cooled to -40° and 1 ml. of chlorodimethyl ether was added. The cooling bath was removed and when the temperature had reached 0° the reaction mixture was poured into 300 ml. of ice-water. The precipitated material was collected by suction and dissolved in methylene chloride. The solution was dried over sodium sulfate, filtered and evaporated. The residue was crystallized from a mixture of ether and hexane to give, after recrystallization from ethanol, 10-chloro-11b-(2-chlorophenyl)-7-methoxymethyl-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4] benzodiazepin-6(7H)-one as white prisms, m.p. 144°-147°.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][C:9]([NH2:11])=[NH:10].[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:14]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[O:29][C:30](S(C)=O)=[N:31][N:32]=1>C(O)(C)(C)C>[ClH:12].[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:14]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[O:29][C:30]([NH:10][C:9]([NH2:11])=[NH:8])=[N:31][N:32]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2-c2nnc(S(C)=O)o2)c1Cl
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nnc(NC(=N)N)o2)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 141.9 %

Procedure:
To a solution of potassium tert-butoxide (111.3 mg, 0.99 mmoles) in 15 ml of tert-butyl alcohol is added guanidine hydrochloride (108.2 mg, 1.13 mmoles). The reaction mixture is stirred at room temperature for 10 minutes, then 2,6-dichloro-3-methyl-N-[2-[5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl]phenyl]benzenamine (201.0 mg, 0.526 mmoles) is added, and the reaction mixture is heated at reflux for five minutes. The mixture is concentrated in vacuo. 20 ml of methanol is added to the residue followed by 100 ml of water. The resultant solid is collected by filtration and dissolved in 10% methanol in ethyl acetate. 50 ml of ether is added, followed by a few drops of saturated etheral hydrochloric acid. The white solid is collected and washed with ether to provide 154.4 mg (71%) of 5-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-1,3,4-oxadiazol-2-yl-guanidine monohydrochloride, mp 245°-248° C.
Reaction SMILES: O.[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.N1CCOCC1.[N+:20]([C:23]1[CH:36]=[CH:35][C:26]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1)([O-])=O>O1CCOCC1.[Pd]>[NH2:20][C:23]1[CH:36]=[CH:35][C:26]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCOCC1
Agent: [Pd]
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1COCCO1
Solvent: C1COCCN1
Product: Nc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
The above dyes can be prepared by a conventional method. For example, the dye (1) given in Table 1, which is a red water-soluble dye, can be prepared as follows: One mole of 4-nitrobenzoyl chloride is allowed to react with 2 moles of morpholine in dioxane at a temperature below room temperature, so that 4-nitrobenzoylmorpholine (m.p. 108° 109° C.) is obtained. The thus obtained nitro compound is reduced in the presence of a 5%Pd-C catalyst to produce 4-aminobenzoylmorpholine. This is subjected to diazotization by a conventional method to produce a diazonium compound, which is then coupled with H-acid in an alkaline solution, followed by subjecting it to acidic precipitation, so that the dye (I) in Table 1 is obtained.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:5]2[CH2:6][C:7]3([O:12][C:4]=2[C:3]=1[O:23][CH3:24])[CH2:11][CH2:10][CH2:9][CH2:8]3.C([Li])CCC.Cl.O>C1COCC1.CCCCCC>[CH3:24][O:23][C:3]1[C:4]2[O:12][C:7]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:6][C:5]=2[C:13]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:14][CH:2]=1
Reactant: COc1c(Br)cc(C#Cc2ccncc2)c2c1OC1(CCCC1)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccncc2)c2c1OC1(CCCC1)C2
Reaction time: 1 h
Yield: 17.6 %

Procedure:
Under an argon atmosphere, a solution (2.6 ml) of Compound 142b (0.1 g) obtained in Step B in THF was cooled to −78° C., and then a 1.7M solution (0.2 ml) of n-butyl lithium in hexane was dropwise added thereto, followed by stirring at the same temperature for one hour. The reaction solution was adjusted to pH 7 by adding dropwise 1N hydrochloric acid, followed by stirring at room temperature for one hour. A small amount of water was added to the reaction solution and the mixture was extracted with ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to give Compound 142 (0.014 g, 17.4%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)=[O:4].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH3:43][O:44][CH2:45][C@@H:46]1[CH2:50][N:49](C(OC(C)(C)C)=O)[C@H:48]([C:58]2[NH:59][C:60]([C:63]3[CH:68]=[C:67]4[CH2:69][O:70][C:71]5[CH:88]=[C:87]6[C:74]([CH:75]=[CH:76][C:77]7[N:81]=[C:80]([C@@H:82]8[CH2:86][CH2:85][CH2:84][NH:83]8)[NH:79][C:78]=76)=[CH:73][C:72]=5[C:66]4=[CH:65][CH:64]=3)=[CH:61][N:62]=2)[CH2:47]1>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:43][O:44][CH2:45][C@@H:46]1[CH2:50][NH:49][C@H:48]([C:58]2[NH:59][C:60]([C:63]3[CH:68]=[C:67]4[CH2:69][O:70][C:71]5[CH:88]=[C:87]6[C:74]([CH:75]=[CH:76][C:77]7[N:81]=[C:80]([C@@H:82]8[CH2:86][CH2:85][CH2:84][N:83]8[C:7](=[O:9])[C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]8[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=8)[NH:79][C:78]=76)=[CH:73][C:72]=5[C:66]4=[CH:65][CH:64]=3)=[CH:61][N:62]=2)[CH2:47]1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Reaction time: 1.5 h

Procedure:
A mixture of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (22 mg, 0.105 mmol), COMU (45 mg, 0.069 mmol), and tert-butyl (2S,4S)-4-(methoxymethyl)-2-(5-{2-[(2S)-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (65 mg, 0.105 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1.5 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude intermediate was treated with 8 mL 1.25N HCl in ethanol at 50° C. for 4 h. Added saturated sodium bicarbonate and extracted the free base into dichloromethane. (106 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:22][CH2:23]OS(C)(=O)=O)([CH2:15][CH2:16]OS(C)(=O)=O)[C:12](=[O:14])[N:13]=1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1.CO>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]2([CH2:22][CH2:23][N:34]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:16][CH2:15]2)[C:12](=[O:14])[N:13]=1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)SC(NC2CC3CCC2C3)=NC1=O
Solvent: CO
Solvent: ClCCl
Product: O=C1N=C(NC2CC3CCC2C3)SC12CCN(C1CCCC1)CC2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of methanesulfonic acid 2-[2-(bicyclo[2.2.1]hept-2-ylamino)-5-(2-methanesulfonyloxy-ethyl)-4-oxo-4,5-dihydro-thiazol-5-yl]-ethyl ester (half of the crude product from above) and cyclopentylamine (799 mg, 9.38 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature for 4 d. Flash column chromatography (silica gel, 0-10% MeOH in CH2Cl2) afforded the title compound as an off-white solid (52 mg). MS (ESI, pos. ion) m/z: 348 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH2:12]=O.[C:14]([O:19][CH3:20])(=[O:18])[C:15]([CH3:17])=[CH2:16]>>[OH:1][C:2]1[C:7]([CH3:12])=[C:6]2[C:5](=[C:4]([CH3:10])[C:3]=1[CH3:11])[O:9][C:15]([CH3:17])([C:14]([O:19][CH3:20])=[O:18])[CH2:16][CH2:8]2
Reactant: C=O
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=C(C)C(=O)OC
Product: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 40 °C
Yield: 72.6 %

Procedure:
In a 1 L stainless-steel autoclave, 100 g (0.657 mol) of 1,4-dihydroxy-2,3,5-trimethylbenzene, 110 g of an aqueous formalin solution (formaldehyde 37 wt %, water 56 wt %, and methanol 7 wt %), and 330 g (3.296 mol) of methyl methacrylate were placed. The mixture was allowed to react at 180° C. for 3 hours under stirring. After the mixture was cooled to 40° C., precipitated crystals were filtered, and rinsed twice with 200 g of methanol. The collected crystals were dried to obtain the aimed methyl 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylate (hereinafter, referred to as CCM) in an amount of 135 g (0.478 mol as CCM, yield: 72.6%, chemical purity: 93.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].Br[N:20]1[C:24](=O)[CH2:23][CH2:22][C:21]1=O.C(OOC(=O)C1C=CC=CC=1)(=[O:34])C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:20]2[CH2:24][CH2:23][O:34][CH2:22][CH2:21]2)=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: COCCCCOc1cc(C)ccc1C(=O)OC
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COCCCCOc1cc(CN2CCOCC2)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 2-(4-methoxybutoxy)-4-(morpholin-4-ylmethyl)-benzoic acid methyl ester that is used is prepared as follows: A mixture of 2-(4-methoxybutoxy)-4-methyl-benzoic acid methyl ester (1.0 g), N-bromosuccinimide (0.70 g), 2',2"-azoisobutyronitrile (23 mg) and dibenzoyl peroxide (34 mg) in carbon tetrachloride (10 ml) is stirred under reflux for 5 hours. After cooling to room temperature, the precipitate is filtered off, morpholine (1.03 ml) is added to the filtrate, and stirring is carried out for a further 2 hours at room temperature. The crude product obtained after filtration and concentration is purified by FC on silica gel (40 g, eluant gradient from C to F). The title compound, Rf (F)=0.14, is obtained in the form of a yellowish oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[CH:38]=[N:39][C:40]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:42]=2)=[CH:29][CH:28]=1.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[CH:38]=[N:39][C:40]([CH2:43][N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[CH:41][CH:42]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:22])([CH3:21])[CH3:23]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-c3ccc(CN4CCOCC4)nc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), duisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[CH:20]1([N:23]2[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:44]CCCl>>[ClH:44].[CH:20]1([N:23]2[CH:27]=[C:26]([CH2:28][N:17]3[CH2:16][CH2:15][N:14]([C:9]4[C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[N:13][CH:12]=[CH:11][N:10]=4)[CH2:19][CH2:18]3)[CH:25]=[N:24]2)[CH2:22][CH2:21]1
Reactant: ClCCCl
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: O=Cc1cnn(C2CC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cl
Product: Fc1ccc(-c2nccnc2N2CCN(Cc3cnn(C4CC4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7 %

Procedure:
Dissolve 3′-(4-Fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.157 g, 0.608 mmol) in DCE (5 mL). Add 1-cyclopropyl-1H-pyrazole-4-carbaldehyde (0.354 g, 2.60 mmol) followed by sodium triacetoxyborohydride (0.193 g, 0.912 mmol) and stir at room temperature for 18 hr. Purify via SCX chromatography, followed by silica gel chromatography (eluting with 100:0 to 0:100 hexanes:ethyl acetate then 10:90 methanol:ethyl acetate), to give the free base of the title compound (16 mg, 7%). Dissolve this free base (0.014 g, 0.038 mmol) in methanol and add a solution of ammonium chloride (0.002 g, 0.038 mmol) in a minimal volume of methanol. Shake for 18 hr. at ambient temperature and concentrate to give the title compound (15 mg, 100%). MS (ES): m/z=379 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:14][C:5]2=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]2[C:3]=1[CH3:15].Cl[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[CH3:1][C:2]1[N:14]=[C:5]2[N:6]([CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=[C:4]2[C:3]=1[CH3:15]
Reactant: Cc1[nH]c2ncc(C(F)(F)F)cc2c1C
Reactant: O=C(CCl)c1ccccc1
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(C(F)(F)F)cc-2c1C

Procedure:
A solution of 0,1 g (0,47 mmol) 2,3-dimethyl-5-trifluoromethyl-pyrrolo[2,3-b]pyridine and 0,13g (0,84 mmol) 2-chloroacetophenone in 5 ml acetronitrile was refluxed for 48 h. The solvent was evaporated. Chromatography on silica gel eluting with methylene chloride and methanol (100:5) gave the desired product. (0,023 g 15%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:20]#[N:21])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1>>[C:20]([C:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][CH2:2][N:23]([CH3:22])[CH2:24][CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1)#[N:21]
Reactant: COC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C#N)(C(=O)OC)c2ccc(OC)c(OC)c2)cc1

Procedure:
Reaction of 1b with 2c produced 3n. MS found M+H=483. The oxalate salt of 3n was recrystallized from ethyl acetate; mp 88-89° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[Na+].[Na+].O>CO>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: N#Cc1ccc(CN)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
13.2 g of p-cyanobenzylamine, 28.6 g of sodium persulfate, 10 ml of water, and 100 ml of methanol were mixed and allowed to react at 50° C. for 40 minutes while stirring. After cooling the reaction mixture to room temperature, methanol was distilled off to precipitate solids. To the resulting suspension was added dichloromethane for extraction. The organic layer was washed twice with saturated aqueous sodium bicarbonate solution and then twice with water, and then magnesium sulfate was added thereto. The residue after distilling off dichloromethane was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=5/1), and hexane and ethyl acetate were distilled off. The resultant crude product concentrated to dryness was recrystallized from cyclohexane, the crystals were filtered, and dried to obtain 7.7 g (yield: 58%) of p-cyanobenzaldehyde. The obtained p-cyanobenzaldehyde had a purity of 99% by the analysis of high performance liquid chromatography.
Reaction SMILES: C([O:5][C:6](=[O:59])[CH2:7][N:8]([CH2:51][C:52](=[O:58])[O:53]C(C)(C)C)[CH:9]([CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:10][N:11]([CH2:20][CH2:21][N:22]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:23][C:24](=[O:30])[O:25]C(C)(C)C)[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:6]([CH2:7][N:8]([CH2:51][C:52]([OH:58])=[O:53])[CH:9]([CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:10][N:11]([CH2:20][CH2:21][N:22]([CH2:31][C:32]([OH:34])=[O:33])[CH2:23][C:24]([OH:30])=[O:25])[CH2:12][C:13]([OH:15])=[O:14])([OH:59])=[O:5]
Reactant: CC(C)(C)OC(=O)CN(CCN(CC(=O)OC(C)(C)C)CC(CCCc1ccc([N+](=O)[O-])cc1)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)CN(CCN(CC(=O)O)CC(CCCc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 120.5 %

Procedure:
To a flask containing compound 4b (30 mg, 0.0358 mmol) at 0-5° C. was added dropwise 4M HCl (g) in 1,4-dioxane (2 mL) over 10 min. The resulting mixture was gradually warmed to room temperature and continuously stirred for 40 h. Ether (20 mL) was added to the reaction mixture which was then stirred for 10 min. The resulting precipitate was filtered and washed with ether. The solid product was quickly dissolved deionized water. The aqueous solution was concentrated in vacuo to provide 5b (24 mg, 100%) as an off-white solid. 1H NMR (D2O, 300 MHz) δ1.03-1.89 (m, 4H), 2.21-4.32 (m, 20H), 7.27 (s, 2H), 7.97 (s, 2H); 13C NMR (D2O, 300 MHz) δ25.0 (t), 26.3 (t), 34.6 (t), 46.9 (t), 48.7 (t), 52.3 (t), 52.7 (t), 53.6 (t), 54.6 (t), 55.3 (t), 62.4 (d), 123.7 (d), 129.4 (d), 145.9 (s), 150.0 (s), 168.5 (s), 170.5 (s), 172.7 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.O.CS[C:26](=[NH:28])[NH2:27]>C(O)(=O)C>[CH2:17]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([NH2:28])=[NH:27])[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])[NH:13][C:12](=[O:14])[C:11]=1[CH2:15][CH3:16])[CH3:18]
Reactant: CSC(=N)N
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Solvent: CC(=O)O
Solvent: O
Product: CCCOc1ccc(NC(=N)N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reaction time: 10 h
Yield: 24.9 %

Procedure:
The compound (140 mg, 0.41 mmol) of example 42 was suspended in a mixed solution of water (2.5 ml) and acetic acid (2.5 ml), added with S-methylisothiourea (64 mg, 0.45 mmol), and heated to reflux under stirring for 10 h. The reaction mixture was concentrated to dryness, dissolved in dichloromethane (20 ml), and washed orderly with 1N NaOH (5 ml), water (10 ml) and saturated saline. The organic phase was dried with anhydrous Na2SO4 and concentrated under reduced pressure to give an oil, which was passed through a silica gel column using ethyl acetate-petroleum ether as an eluant to obtain the title compound (35 mg, yield: 25%). 1H NMR (CDCl3) δ: 8.26 (1H, d), 8.00 (1H, dd), 7.50 (1H, br), 6.99 (1H, d), 4.14 (2H, t), 2.67 (2H, q), 2.59 (2H, q), 1.97 (2H, m), 1.29 (3H, t), 1.15 (3H, t), 1.13 (3H, t).