Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[F:17][C:18]([F:28])([F:27])[C:19]1[N:20]=[C:21]([C:24](O)=[O:25])[NH:22][CH:23]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[F:28][C:18]([F:17])([F:27])[C:19]1[N:20]=[C:21]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:22][CH:23]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)c1nc(C(F)(F)F)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.90 g, 3.91 mmol), 4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained in Example (33c) (0.40 g, 2.22 mmol), WSC hydrochloride (1.25 g, 6.52 mmol) and HOBT (0.30 g, 2.22 mmol), to obtain 0.67 g of the title compound as a white foamy substance (77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: O=Cc1cc(Cl)cc(C(=O)O)c1O
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(C=O)c1O

Procedure:
193 g of 5-chloro-3-formyl-2-hydroxybenzoic acid are dissoved in 2 liters of methanol and the solution is saturated with hydrogen chloride. 100 ml of thionyl chloride are added to the solution and the mixture is refluxed for 8 hours. After cooling, the resultant crystals are collected by filtration and dried to give 190 g of methyl 5-chloro-3-formyl-2-hydroxybenzoate.
Reaction SMILES: NC1C2=C(C3C=CC([N+]([O-])=O)=CC=3)C(C=O)=CN2N=CN=1.Cl.NO.C(OC(=O)C)(=O)C.[C:32]([C:34]1[C:35]([C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[C:36]2[N:41]([CH:42]=1)[N:40]=[CH:39][N:38]=[C:37]2[NH:43]C(=O)C)#[N:33]>CCOC(C)=O.O.N1C=CC=CC=1>[NH2:43][C:37]1[C:36]2=[C:35]([C:47]3[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=3)[C:34]([C:32]#[N:33])=[CH:42][N:41]2[N:40]=[CH:39][N:38]=1
Reactant: CC(=O)Nc1ncnn2cc(C#N)c(-c3ccc([N+](=O)[O-])cc3)c12
Agent: Cl
Agent: NO
Agent: Nc1ncnn2cc(C=O)c(-c3ccc([N+](=O)[O-])cc3)c12
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of pyridine (8.75 mL) was added 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (Intermediate H, Step 2) (500 mg, 1.77 mmol) followed by hydroxylamine hydrochloride (135 mg, 1.94 mmol). The solution was stirred at rt for 1 h, acetic anhydride (366 mL, 3.88 mmol) was added, and the solution was heated to 80° C. for 17 h. Upon cooling to rt the reaction mixture was partially rotavapped and then diluted with EtOAc (50 mL) and H2O (50 mL). The solution was transferred to a separatory funnel, and the organic layer was isolated while the aqueous layers were back extracted with EtOAc (2×25 mL). The combined organic layers were collected, dried (Na2SO4), filtered, and concentrated to dryness to afford a brown solid. This proved to be a 1:1 ratio of the title compound and N-[6-cyano-5-(4-nitro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-acetamide. 1H-NMR (DMSO-d6) δ 10.67 (s, 1H), 8.96 (s, 1H), 8.62 (s, 1H), 8.57(s, 1H), 8.40 to 8.30 (m, 4H), 8.05 (s, 1H), 7.79 to 7.68 (m, 4H), 1.74 (s, 3H); MS [M+H]+=281.2, 323.0; LCMS RT=2.48 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)C>[NH2:18][CH2:17][CH2:16][NH:19][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14]
Reactant: NCCN
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NCCN)[C@@H]1O
Temperature: 25 °C
Reaction time: 36 h
Yield: 111.5 %

Procedure:
To a suspension of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (1.2 g, 5.97 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194) in ethanol (7.0 mL), ethylenediamine (2.4 mL, 35.8 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 36 hours. The solvent was removed under reduced pressure and the residue was further dried by use of vacuum pump to yield the title A compound (1.74 g, >100%) as a colorless foam. This material was used for the next reaction without any purification.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:25])[C@H:11]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[OH:8][NH:9][C:10](=[O:25])[C@H:11]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NO
Reaction time: 3 h
Yield: 80 %

Procedure:
A suspension of N-benzyloxy-2(R)-[(benzenesulfonyl)amino]-3-methyl butanamide (100 mg, 0.280 mmol) and Pearlman's catalyst (25 mg) in MeOH (10 mL) is hydrogenated at 1 atmosphere for 3 hours. The mixture is filtered through celite, and the filtrate is concentrated. The desired material is crystallized from EtOAc/pentane to give 61 mg (80%) of the title compound as a crystalline solid. mp 154°-155° C.; IR (mineral oil) 3268, 2925, 2954, 2881, 2855, 1636, 1449, 1336, 1165, 694 cm-1; 1H NMR (300 MHz, DMSO-d6) δ10.53, 8.83, 7.98, 7.76, 7.50-7.65, 3.28, 1.65-1.85, 0.74, 0.70; MS (EI) m/z 272; Analysis: C, 48.37; H, 6.07; N, 10.14.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])[CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([N:15]([CH2:2][CH:3]([CH3:5])[CH3:4])[S:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:17])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC(C)CBr
Reactant: C[C@@H](NS(=O)(=O)Cc1ccccc1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CN([C@H](C)c1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
1-Bromo-2-methylpropane (10.1 g, 73 mmol) was added into a solution of (R)—N-(1-(4-bromophenyl)ethyl)(phenyl)methanesulfonamide (13 g, 36.7 mmol) and Cs2CO3 (23.8 g, 73 mmol) in DMF (150 mL) dropwise at 0° C. The mixture was then stirred at 80° C. for 20 h before it was cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo to remove the solvent. The residue was dissolved with DCM (100 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified on silica gel chromatography (petroleum ether: ethyl acetate=10:1) to provide (R)—N-(1-(4-bromophenyl)ethyl)-N-isobutyl(phenyl)methanesulfonamide (10.8 g, 72% yield) as colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71 (d, 3H), 0.77 (d, 3H), 1.48 (d, 3H), 1.60-1.66 (m, 1H), 2.77-2.83 (m, 2H), 4.11-4.22 (m, 2H), 4.94-4.96 (m, 2H), 7.24-7.48 (m, 9H); >99% ee value (Chiral-HPLC, 214 nm).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5](Br)=[C:6]([CH3:8])[N:7]=1.[SH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[S:4][C:5]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Sc1ccccn1
Reactant: Cc1nc(N)sc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)sc1Sc1ccccn1
Temperature: 90 °C
Yield: 48 %

Procedure:
A mixture of 2-amino-5-bromo-4-methylthiazole hydrochloride (4.5 g), 2-mercaptopyridine (2.3 g) and potassium carbonate (7.0 g) in N,N-dimethylformamide (100 ml) was heated at 90° C. for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate, washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 300 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give oil. Again the oil was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 200 g) and eluted with a mixture of dichloromethane and acetone (5:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-methyl-5-(2-pyridylthio)thiazole (2.1 g, yield: 47.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH3:31])[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].C>O1CCOCC1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCCCCCC>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:19][C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH3:31])[CH:21]=3)[CH:3]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A mixture of 1-[(3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine (0.675 g, 2.15 mmol), methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.794 g, 2.30 mmol), Cs2CO3 (3.50 g, 10.7 mmol), XANTPHOS (0.053 g, 0.088 mmol) and tris(benzylideneacetone)dipalladium(0) (0.039 g, 0.043 mmol) in dioxane (5.4 mL) was heated to 55° C. for 1.5 h, analysed by HPLC, then cooled to room temperature. Heptane (2.4 mL), charcoal (0.27 g) and celite (0.27 g) were added. The suspension was stirred for 30 min at room temperature, and then filtered over celite, rinsing with toluene (13.5 mL×3). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (DCM:MeOH:NEt3 9:1:0.1) to give the title compound (0.867 g, 70%) as a red amorphous solid.
Reaction SMILES: Cl[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:3]1[C:8]([Cl:9])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)=[CH:5][C:4]=1[Cl:18].[N:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[NH2:32]>C(Cl)Cl>[Cl:18][C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)[CH:7]=[C:8]([Cl:9])[C:3]=1[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[NH:32][C:27]1[N:28]=[CH:29][CH:30]=[CH:31][N:26]=1
Reactant: O=c1cnn(-c2cc(Cl)c(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: Nc1ncccn1
Solvent: ClCCl
Product: O=c1cnn(-c2cc(Cl)c(C(Nc3ncccn3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 150 °C
Yield: 6.1 %

Procedure:
A mixture of 2-[4-[chloro(4-chlorophenyl)methyl]-3,5-dichlorophenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.00719 mol) and 2-pyrimidinamine (0.00863 mol) was heated for 2 hours at 150° C. in an autoclave. The mixture was cooled to RT. This fraction was taken up into CH2Cl2, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by HPLC (eluent: (0.5% NH4OAc in H2O)/CH3OH/CH3CN gradient elution from 70/15/15 over 0/50/50 to 0/0/100). The desired fractions were collected and the solvent was evaporated. The residue was coevaporated with EtOAc. The residue was stirred in DIPE, filtered off, washed and dried, yielding 0.21 g of (±)-2-[3,5-dichloro-4-[(4-chlorophenyl)[(2-pyrimidinyl)amino]-methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (comp. 413).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C(N(CC)CC)C.Cl[S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27]>C(Cl)Cl>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:7]2[CH2:6][CH2:5][N:4]([S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:27])=[O:28])[C:3]3([CH2:1][CH2:2]3)[CH2:8]2)=[N:14][CH:13]=1
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
N-(oxomethylene)sulfamoyl chloride (13.4 mmol) was dissolved in dry benzene (5 mL) and dropwise added t-BuOH (13.4 mmol) while the temperature was kept below 25° C. The reaction mixture was stirred at 25° C. for 2 h, added hexane (5 mL) and cooled to 0° C. Precipitate was collected by filtration, washed with hexane affording tert-butyl N-chlorosulfonylcarbamate as white crystals. 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (4.6 mmol) (intermediate 21) was suspended in dry DCM (25 mL) and added triethylamine (6.9 mmol). To this suspension was slowly added tert-butyl N-chlorosulfonylcarbamate (4.6 mmol) at rt. After 15 min all starting material has been consumed. The obtained reaction mixture was concentrated in vacuo on celite. The product was purified by flash chromatography on silica using EtOAc:MeOH in heptane as eluent.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH3:15])=[CH:10][CH:9]=1)[CH3:2].[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)C(N)(CO)CO.CS(Cl)(=O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([N:16]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[S:31]([CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:33])=[O:32])[CH3:15])=[CH:12][CH:13]=1)[CH3:23]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCN(CC)CCCOc1ccc(C(C)NCCN(C)C)cc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(C(C)N(CCN(C)C)S(=O)(=O)Cc2ccccc2)cc1
Reaction time: 4 h

Procedure:
To a 4 ml vial was placed N-{1-[4-(3-Diethylamino-propoxy)-phenyl]-ethyl}-N′,N′-dimethyl-ethane-1,2-diamine (22 mg, 0.07 mmol), phenyl-methanesulfonyl chloride (27 mg, 0.14 mmol), PS-DMAP (93 mg, 1.48 mmol/g), and CH2Cl2 (1.5 ml). The vial was agitated by means of a lab quake shaker for 4 h. To the solution was added PS-Trisamine (100 mg, 3.3 mmol, 3.0 mmol/g) and the reaction was allowed to agitate overnight to scavenge excess methansulfonyl chloride. Filtration, washing with CH2Cl2 and concentrating afforded N-{1-[4-(3-Diethylamino-propoxy)-phenyl]-ethyl}-N-(2-dimethylamino-ethyl)-C-phenyl-methanesulfonamide. Mass spec hit M+1, 476: LCMS>93% @ 230 nm and ELSD.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[N:6][N:5]=1
Reactant: OCCC1CCNCC1
Reactant: Cc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nnc(N2CCC(CCO)CC2)s1
Temperature: 120 °C
Yield: 32.2 %

Procedure:
A suspension containing 2-bromo-5-methyl-1,3,4-thiadiazole (Modarai, B., et al. J. Heterocyclic Chem. (1974) 11, 343-5) (100 mg, 0.56 mmol), 4-piperidine ethanol (87 mg, 0.67 mmol) and potassium carbonate (77 mg, 0.56 mmol) was heated overnight at 120° C. The reaction was cooled and the mixture partitioned between water (10 ml) and ethyl acetate (30 ml), then the organic layer was washed with brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel (8 g; eluent 2.5% methanol/DCM) gave 1-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(2-hydroxyethyl)piperidine (41 mg, 32%), 1H nmr; 1.33 (m, 2H), 1.54 (q, 2H), 1.7 (m, 1H), 1.79 (m, 2H), 2.54 (s, 3H), 3.08 (m, 2H), 3.71 (t, 2H), 3.88 (m, 2).
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[CH:19][C:18]([CH:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][C:16]=2[CH3:34])C2C=CC=CC=2)C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C>[NH2:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:22]2)=[CH:17][C:16]=1[CH3:34]
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1N=C(c1ccccc1)c1ccccc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-(diphenylmethyleneamino)-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.0 g) in ethanol (100 ml) was added ammonium formate (14 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (2.56 mg) was then added and the reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was then filtered through celite and the filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the mixture was washed sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: heptane/dichloromethane/MeOH) to afford tert-butyl (RS)-2-(6-amino-5-methylpyridin-3-yl)morpholine-4-carboxylate (246 mg, 38%) as a colourless oil. MS (ISP): 294.2 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[C:9]([O:11][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19])=[O:10]
Reactant: O=C1CCC(=O)N1O
Reactant: COc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
O-anisic acid (1.0 g), N-hydroxysuccinimide (0.76 g) and water-soluble carbodiimide hydrochloride (1.39 g) were dissolved in methylene chloride (15 ml), and the solution was stirred overnight at room temperature. The precipitate was removed by filtration. The mother liquor was concentrated under reduced pressure, and the residue was crystallized from isopropanol to give 1.47 g of N-(2-methoxybenzoyloxy)succinimide (mp. 180°-182° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19](I)=[C:14]3[C:13]([C:21]([F:24])([F:23])[F:22])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[CH:40][NH:41][CH:42]=2)[CH:33]=1>CS(C)=O.C(OCC)(=O)C.[Cu]=O>[NH2:1][C:2]1[CH:10]=[C:9]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([N:41]4[CH:42]=[C:38]([C:34]5[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=5)[N:39]=[CH:40]4)=[C:14]3[C:13]([C:21]([F:24])([F:23])[F:22])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)cc1N
Agent: O=[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(-n4cnc(-c5cccnc5)c4)ccnc32)cc1N
Temperature: 120 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
Compound (157a) (0.080 g) was dissolved in DMSO (1.2 mL), and potassium carbonate (0.160 g), copper(II) oxide (nanopowder) (0.009 g), and 4-(pyridin-3-yl)-1H-imidazole hydrochloride (0.053 g) were added to the resulting solution, followed by stirring at 120° C. for 4 hr. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered by celite. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (176) (0.031 g, 30%).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].Br[C:54]1[CH:55]=[N:56][C:57]2[C:62]([CH:63]=1)=[N:61][CH:60]=[CH:59][C:58]=2[Cl:64].[C:65]1([C:71]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[NH:72])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:64][C:58]1[CH:59]=[CH:60][N:61]=[C:62]2[C:57]=1[N:56]=[CH:55][C:54]([N:72]=[C:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[CH:63]2
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Clc1ccnc2cc(Br)cnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1ccnc2cc(N=C(c3ccccc3)c3ccccc3)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A 25 ml round bottom flask set up under nitrogen was charged with Pd2(dba)3 (301 mg, 0.33 mmol), BINAP (614 mg, 0.99 mmol) and sodium tert-butoxide (237 mg, 2.46 mmol). System was purged with Argon and 3-bromo-8-chloro-1,5-naphthyridine (400 mg, 1.64 mmol), diphenylmethanimine (0.28 mL, 1.64 mmol), and toluene (1M, 1.64 mL) were added. This was placed in a preheated oil bath at 80° C. and stirred at this temperature for 16 hours. Reaction cooled to room temperature, diluted with dichloromethane, and passed over a celite cake. Filtrate collected was concentrated to afford brown oil. This was purified by ISCO silica gel chromatography (40 g, 1% MeOH/DCM over 50 mins) to afford clean 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (280 mg, 50% yield). MS[M+H]=344.0. Calc'd for C21H14ClN3=343.8.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.CC(C)=[O:24]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:24][CH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cccc(-c2ccc3nnc(CCl)n3n2)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: OCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A 1.0 g. sample of 3-(chloromethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine is heated (50°-60° C.) in a mixture of acetone and water in the presence of silver nitrate. The mixture is filtered and the filtrate concentrated to give the product of the Example.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[N:23]=[C:22]([NH:24][CH3:25])[C:21]([N+:26]([O-])=O)=[CH:20][C:6]=1[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]1)=[O:8].CO>[Ni].C1COCC1>[NH2:26][C:21]1[C:22]([NH:24][CH3:25])=[N:23][C:5]([O:4][CH2:3][CH2:2][F:1])=[C:6]([CH:20]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([F:18])([F:17])[F:19])[CH2:12][CH2:11]1)=[O:8]
Reactant: CNc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-(2-fluoro-ethoxy)-6-methylamino-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (105 mg, 0.26 mmol), Ra—Ni (25 mg), MeOH (5 mL) and THF (10 mL) is stirred at rt for 2.5 h under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the filtrate is concentrated.