Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Yield: 103.2 %

Procedure:
34.3 g (0.15 mol) of 2-naphthalenesulfonyl chloride, dissolved in 250 ml of tetrahydrofuran, were added dropwise to 25 g (0.15 mol) of ethyl 3-aminobenzoate and 63 ml (0.45 mol) of triethylamine in 400 ml of tetrahydrofuran at 0° C. The mixture was then heated to reflux for 1 h. The organic solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was dried and concentrated in vacuo. 55 g (100%) of the product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2F)=[N:10][NH2:11])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: NN=C(Nc1ccc(Br)cc1)c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(Nc2n[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
To a solution of N1-(4-bromophenyl)-2-fluoro-1-benzenecarbohydrazonamide (1.2 g, 0.00391 mol) in N-methyl pyrrolidinone (25 mL), potassium tert-butoxide (0.50 g, 0.0041 mol) was added and the resulting solution was heated at 100° C. under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield N-(4-bromophenyl)-N-(1H-3-indazolyl)amine (0.29 g, 0.0010 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.06 (s, 1H), 9.03 (s, 1H), 7.93 (d, 1H), 7.65 (d, 2H), 7.35 (m, 4H), 7.03 (dd, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].O>CN(C)C=O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH:4]2[N:3]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[C:23]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:24]=1)#[N:27]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
A mixture of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10, 1.78 g, 3.74 mmol) and cesium carbonate (1.83 g, 5.62 mmol) in N,N-dimethylformamide (25.0 mL) is treated with ethyl bromoacetate (0.50 mL, 4.50 mml), and the mixture is stirred at room temperature over night. Water (30 ml) is added, and the precipitate is filtered and dried. Yield: 1.80 g; ESI mass spectrum: [M+H]+=562; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: N1(CCO[C:10]2[CH:30]=[CH:29][C:13]([N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)CCCCC1.OC1C=CC(N(C2C=CC=CC=2)C(=O)C2C=CC=CC=2)=CC=1.N1(CCCl)CCCCC1.C[O-].[Na+]>>[C:13]1([N:14]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][CH:10]=[CH:30][CH:29]=1
Reactant: O=C(c1ccccc1)N(c1ccccc1)c1ccc(OCCN2CCCCC2)cc1
Agent: C[O-]
Agent: ClCCN1CCCCC1
Agent: O=C(c1ccccc1)N(c1ccccc1)c1ccc(O)cc1
Product: O=C(c1ccccc1)N(c1ccccc1)c1ccccc1

Procedure:
4'-[2-(1-Piperidyl)ethoxy]-N-phenylbenzanilide [IA; R is C6H5, Ar is -C6H4 -(p), Y is CH2CH2, N=Z is N(CH2)5, n is O, Ar' is C6H5 ] was prepared from 11.5 g. of 4'-hydroxy-N-phenylbenzanilide and 2-(1-piperidyl)ethyl chloride in the presence of sodium methoxide according to the procedure of Example 1. The product was recrystallized from benzene-hexane to give 4'-]2-(1-piperidyl)ethoxy]-N-phenylbenzanilide, colorless solid, m.p. 78.5°-82.5°C.; cyclohexanesulfamic acid salt form, m.p. 151.5°-157.5°C.
Reaction SMILES: Cl.[CH:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH:13]([CH2:14][CH2:15][NH2:16])[C:7]=3[C:6]=12.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>O1CCCC1>[CH:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH:13]([CH2:14][CH2:15][NH:16][C:24](=[O:26])[CH3:25])[C:7]=3[C:6]=12
Reactant: CC(=O)OC(C)=O
Reactant: NCCC1CCc2ccn3nccc3c21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCCC1CCc2ccn3nccc3c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a mixture of 2-(8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine hydrochloride (45.5 mg, 0.191 mmol) and triethylamine (206 μL, 1.48 mmol) in tetrahydrofuran (1.5 mL) was added acetic anhydride (42.0 μL, 0.444 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (22.4 mg, yield 48%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]1[C:39]([OH:40])=[CH:38][CH:37]=[CH:36][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27].[CH3:41][N:42]1[CH:47]=[CH:46][C:45](=[O:48])[C:44]([C:49]2[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=2)=[CH:43]1>O.CN(C)C=O.C(N(CC)CC)C>[ClH:35].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26](=[O:27])[C:25]2[CH:36]=[CH:37][CH:38]=[C:39]([OH:40])[C:24]=2[NH:23][C:53](=[O:54])[C:52]2[CH:51]=[CH:50][C:49]([C:44]3[C:45](=[O:48])[CH:46]=[CH:47][N:42]([CH3:41])[CH:43]=3)=[CH:57][CH:56]=2)=[N:30][CH:31]=1
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Reactant: Cn1ccc(=O)c(-c2ccc(C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1ccc(=O)c(-c2ccc(C(=O)Nc3c(O)cccc3C(=O)Nc3ccc(Cl)cn3)cc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 104.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg), 1-hydroxybenzotriazole (62 mg), triethylamine (64 μl) and 2-amino-N-(5-chloro-2-pyridinyl)-3-hydroxybenzamide (121 mg) were added to an N,N-dimethylformamide solution (3 ml) of 4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoic acid (88 mg), followed by stirring at room temperature for 14 hours. After this, water (30 ml) was added to the reaction solution, and the precipitated insoluble solid was collected by filtration. The resulting solid was dried at 60° C. under reduced pressure, then tetrahydrofuran (5 ml), N,N-dimethylformamide (1 ml) and acetic acid (104 μl) were added to the solid, followed by stirring under heating at 60° C. for 2 days. After this, the reaction solution was concentrated under reduced pressure, an aqueous saturated sodium hydrogencarbonate solution (30 ml) was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (chloroform:methanol=97:3). The purified product was suspended in ethanol, 1 M hydrochloric acid (324 μl) was added, followed by concentration under reduced pressure. The residue was recrystallized from ethanol to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoyl]amino}benzamide hydrochloride (123 mg).
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:23])[C:18]([NH:21][CH3:22])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[N+](C1C=CC=CC=1)([O-])=O.Cl>O>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]2[N:21]([CH3:22])[C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:9][CH2:10]4)=[CH:16][C:17]=3[N:23]=2)=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cn1c(-c2ccc(Cl)cc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3.9 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -methyl-1,2-benzenediamine, 2.5 parts of 4-chlorobenzaldehyde and 18 parts of nitrobenzene is stirred in an oil-bath first for 1 hour at 50° C. and further for 1.50 hours at 120° C. The reaction mixture is cooled and allowed to stand overnight at room temperature. About 100 parts of water are added and the whole is acidified with a hydrochloric acid solution 10 N. The product is extracted with 2,2'-oxybispropane. The aqueous phase is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with a sodium hydroxide solution 50%. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 35 parts of 1,1'-oxybisethane. The product is filtered off, washed with 1,1'-oxybisethane and dried, yielding 1.3 parts of 2-(4-chlorophenyl)-5-[4-(diphenylmethyl)-1-piperazinylmethyl]- 1-methyl-1H-benzimidazole; mp. 198.3° C.
Reaction SMILES: [OH-].[Na+].COS(OC)(=O)=O.CS(CC1C=CC=C(C(F)(F)F)C=1[N+]([O-])=O)(=O)=O.[CH3:28][S:29]([CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=1[N+:44]([O-])=O)[CH3:33])(=[O:31])=[O:30]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(O)(=O)C.[Pd].[C].CCOC(C)=O.CCO.C(Cl)Cl>[CH3:28][S:29]([CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[C:35]=1[NH2:44])[CH3:33])(=[O:31])=[O:30]
Reactant: CC(c1cccc(C(F)(F)F)c1[N+](=O)[O-])S(C)(=O)=O
Agent: [Pd]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: CS(=O)(=O)Cc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(c1cccc(C(F)(F)F)c1N)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A mixture of 50% NaOH (50 mL), CH2Cl2 (50 mL), triethylbenzylammonium chloride (30 mg), Me2SO4 (2.50 mL, 26.41 mmol) and 2-methylsulfonylmethyl-6-trifluoromethyl nitrobenzene 3 (6.8 g, 24.01 mmol) was stirred rapidly for 30 min. The mixture was poured onto ice/water (400 mL) and the organic layer separated. The solvent was removed and excess Me2SO4 removed at 60° C. and 0.7 mm, to give a yellow solid which was identified as the same product as in Example 2, i.e., 2-(1-methylsulfonylethyl)-6-trifluoromethyl nitrobenzene. The solid was transferred to a Parr bomb with EtOAc/EtOH (2:1, 100 mL, not all soluble). Five drops of acetic acid and Pd/carbon was added. The mixture was hydrogenated at 60° C. and 60 psi H2 for 15 hrs. The mixture was filtered and the solvent removed to give a brown solid. Washing with ether gave 4.03 g (15.07 mmol, 62.8%) of 2-(1-methylsulfonylethyl)-6-trifluoromethyl aniline as a white solid, mp 153°-5° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O.[Cl:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=1.Cl[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[N:27][CH:28]=1>C(OCC)(=O)C.[Cl-].[NH4+]>[Cl:14][C:15]1[C:20]([O:21][C:23]2[CH:28]=[N:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:30])=[O:31])=[CH:25][CH:24]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CCS(=O)(=O)c1ccc(Cl)cn1
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1ccc(Oc2cccnc2Cl)cn1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Cesium carbonate (20 g) was added to an N-methyl-2-pyrrolidinone (160 ml) solution of 2-chloro-3-hydroxypyridine (6 g) and 5-chloro-2-(ethylsulfonyl)pyridine (4.8 g), and stirred at 100° C. for 24 hours. After this was diluted with ethyl acetate, aqueous saturated ammonium chloride solution was added with cooling with ice. The organic layer was washed with water and saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the entitled compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:17]([NH:16][CH2:14][CH3:15])=[O:18])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CCN=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 44.7 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and ethyl isocyanate (64 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (88 mg, 44%). LC-MS (m/z) 294.0 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]2[N+:16]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2].[H][H]>C(O)C.O1CCCC1.[Ni]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH2:16])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2]
Reactant: [H][H]
Reactant: CCOc1cc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])ccc1OC
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc([C@@H]2CCCC[C@@H]2N)ccc1OC

Procedure:
40.0 g of (+/-)-cis-2-ethoxy-1-methoxy-4-(2-nitrocyclohex-4-enyl)benzene are dissolved in 1000 ml of ethanol and 500 ml of tetrahydrofuran, treated with 10 g of Raney nickel and hydrogenated at RT in an autoclave for 4 days at a hydrogen pressure of 100 bar. After filtration and removal of the solvent in vacuo, 35.9 g (99.8% of theory) of the title compound are obtained as a solidifying oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:22])=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 97 %

Procedure:
As described for example 35b, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (80 mg, 0.24 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (94 mg, 97%) which was obtained as a white solid. MS: m/e=401.3 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:5]=1[F:32])=[N+]=[N-].CCOCC.CS(C)=O.S1(CCCC1)(=O)=O>[Pd].[Ni].O.C(O)CC.C(O)C.CO.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:5]=1[F:32]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: CN1CCCN(C)C1=O
Solvent: CCCO
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1F

Procedure:
Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be hydrogenated catalyzed by appropriate catalyst (such as Pd/C, Pt, Ni) in the solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ester (such as ethyl acetate, methyl acetate), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanol, ethanol, propan-1-ol and water) for some time (1-12 h, prefer 3-10 h). Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.3 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.075 g, 0.34 mmol) in N-methyl 2-pyrolidone (0.5 mL) was added powdered potassium hydroxide (0.095 g, 1.7 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.102 g, 0.85 mmol) was added and stirred for further at 80 deg C. 3 h. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC to get the desired compound as yellow oil (0.020 g, 13% yield). 8-Chloro-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.020 g, 0.06 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.008 g, 0.06 mmol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.008 g, 32% yield).
Reaction SMILES: C[O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Se](=O)=O.[O:15]1CCOC[CH2:16]1>O.C(OCC)(=O)C>[OH2:2].[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([CH:3]=[O:2])=[O:5]
Reactant: COCC(=O)c1ccccc1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1C(=O)C=O

Procedure:
5 g of 2-methoxyacetophenone are dissolved in 30 ml of dioxane, and a solution of 4.8 g of selenium dioxide in 3 ml of water is added thereto. The mixture is refluxed for 6 hours. After the reaction is completed, insoluble materials are removed by filtration and the filtrate is condensed. The residue thus obtained is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, an aqueous sodium bicarbonate solution and water, successively. Then, said solution is dried and evaporated to remove solvent. 4.9 g of 2-methoxyphenylglyoxal hydrate are thereby obtained as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.C(=O)(O)O.C(=O)(O)O.[NH2:20][C:21]([NH2:23])=[NH:22].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:8]2[C:5]([CH:6]=[N:20][C:21]([NH2:23])=[N:22]2)=[C:4]([F:11])[CH:3]=1
Reactant: N=C(N)N
Reactant: O=Cc1c(F)cc(Cl)cc1F
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ncc2c(F)cc(Cl)cc2n1
Temperature: 140 °C
Yield: 62.7 %

Procedure:
To a stirred suspension of 4-chloro-2,6-difluorobenzaldehyde (45 g, 255 mmol) in DMA (360 mL), at room temperature under nitrogen was added guanidine bis(carbonate) (70.0 g, 382 mmol). The mixture was heated to 140° C. for 3 hours. The reaction was then cooled to room temperature followed by addition of 400 mL water with stirring. The mixture was then filtered. The solids were then collected and triturated in 200 mL methanol for 10 minutes, then filtered. These solids were then dried in vacuo to obtain 31.6 g (63%) of 7-chloro-5-fluoroquinazolin-2-amine (82a) as a brown solid.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].O.[NH2:10][NH2:11]>CO>[NH2:2][C:1]1[NH:11][N:10]=[C:4]([NH:8][CH2:7][CH2:6][S:5][S:5][CH2:6][CH2:7][NH:8][C:4]2[N:3]=[C:1]([NH2:2])[NH:11][N:10]=2)[N:3]=1
Reactant: NN
Reactant: N#CN=C1NCCS1
Solvent: CO
Solvent: O
Product: Nc1nc(NCCSSCCNc2n[nH]c(N)n2)n[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 1.27 g of 2-cyanoiminothiazolidine well-known and 20 ml of methanol was added 0.3 ml of hydrazine monohydrate, and the mixture was stirred at room temperature for an hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was recrystallized from water to give 1.42 g of bis{2-[N-(5-amino-1,2,4-triazol-3-yl)amino]ethyl}disulfide (Compound 3).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@@H:13]2[CH2:18][O:17][C@@H:16]([C@@H:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[C:28]([C:30](=[O:42])[NH:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([F:39])=[C:35]([O:40][CH3:41])[CH:34]=5)[N:27]=[C:26]([CH3:43])[N:25]=4)[CH2:20]3)[CH2:15][O:14]2)(=O)=O)=CC=1.O.[OH-].[Na+]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:30]([C:28]2[CH:29]=[C:24]([C:21]3[CH2:20][C@H:19]([C@H:16]4[CH2:15][O:14][C@H:13]([CH2:12][OH:11])[CH2:18][O:17]4)[O:23][N:22]=3)[N:25]=[C:26]([CH3:43])[N:27]=2)=[O:42])=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: COc1cc(CNC(=O)c2cc(C3=NO[C@@H]([C@H]4CO[C@H](COS(=O)(=O)c5ccc(C)cc5)CO4)C3)nc(C)n2)ccc1F
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(CNC(=O)c2cc(C3=NO[C@@H]([C@H]4CO[C@H](CO)CO4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A solution of ((2S,5R)-5-((R)-3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (0.7 g, 1.13 mmol, Preparation #G.6) and tetra butyl ammonium acetate (0.72 g, 2.34 mmol, Aldrich) in DMF (5 mL) were stirred for 3 h at 70° C. The reaction mixture was cooled to RT, the reaction vessel was charged sequentially with water (10 mL) and 1.0N aqueous sodium hydroxide (5 mL). After string for 20 minu at RT it was diluted with EtOAc (200 mL) and washed with 50% aqueous sodiumchloride solution (2×150 mL). The organic layer was dried over sodiumsulphate and evaporated to dryness. The resulting crude material was purified by column chromatography on silica gel eluting with 60% EtOAc in hexane to afford N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide 0.32 g (61%); 1H NMR (400 MHz, DMSO): δ 9.48 (t, J=6.4 Hz, 1H), 8.11 (s, 1H), 7.15-7.09 (m, 2H), 6.86-6.81 (m, 1H), 4.80-4.70 (m, 2H), 4.69 (t, J=5.2 Hz, 1H), 4.46 (d, J=6.4 Hz, 2H), 3.88-3.82 (m, 2H), 3.79 (s, 3H), 3.56-3.34 (m, 6H), 2.75 (s, 3H); LC/MS (Table 1, Method d) Rt=0.74 min; MS m/z: 461.1 (m+H)+.