Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:14]([C:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)(Cc1ccccc1)C(=O)OCC
Yield: 95 %

Procedure:
Diethyl malonate (4.53 mL, 30.0 mmol) was added gradually at 0° C. to a mixed liquid containing sodium hydride (55 wt % in oil, 2.95 g, 67.5 mmol) and anhydrous N,N-dimethylformamide (60 mL). Following stirring of the resulting mixed liquid at this temperature for 30 minutes, benzyl chloride (7.25 mL, 63.0 mmol) was added. The resulting mixed liquid was stirred at room temperature for one hour, and a saturated aqueous solution of ammonium chloride was then added to halt the reaction. The organic layer was separated from the mixed liquid, and the water layer was extracted with ethyl acetate. The thus obtained organic layer was washed with a saturated saline solution and then dried using anhydrous magnesium sulfate, yielding the title compound (1a-1) in a yield of 95%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:12]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(OCC)C>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(C2CCCN(C(=O)CCc3ccccc3)C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(C2CCCN(CCCc3ccccc3)C2)c1
Reaction time: 0.75 h

Procedure:
The 1-(3-phenylpropionyl)-3-(3-methoxyphenyl)piperidine was dissolved in 150 ml of dry tetrahydrofuran, and the solution was added to a suspension of 8.59 g (226 mmole) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran, at room temperature. The resulting mixture was heated under reflux for 1 hour and then it was cooled in an ice-bath. To the cooled mixture was added, dropwise, with stirring, 43 ml of 3% aqueous sodium hydroxide, followed by 400 ml of diethyl ether. Stirring was continued for 45 minutes, and then the mixture was filtered. The filtrate was evaporated in vacuo to give 18.4 g of material.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([F:19])=[CH:13][CH:14]=2)[C:9]1=[O:20])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([F:19])=[CH:13][CH:14]=2)[C:9]1=[O:20]
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(F)ccc2C1(C)C
Solvent: CO
Solvent: ClCCl
Product: CC1(C)c2ccc(F)cc2C(=O)C1CC=O
Reaction time: 0.5 h
Yield: 95 %

Procedure:
An ozone stream (1.5 g ozone/hour) was conducted for 30 minutes while stirring through a solution, cooled to -70°, of 3.38 g of (RS)-2-(2-buten-1-yl)-6-fluoro-3,3-dimethyl-1-indanone in 75 ml of anhydrous dichloromethane and 15 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 1.6 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 40 ml of dichoromethane and, after the addition of 5 ml of water and 5 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 90 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 3.04 g (95%) of (RS)-2-(2-oxoethyl)-6-fluoro-3,3-dimethyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][NH2:35])=[CH:25]1.CCN(C(C)C)C(C)C>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:35][CH2:34][CH2:33][C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]([CH3:23])[CH:25]=3)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21]
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: Cn1cc(CCN)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(CCNc2ncc(C#N)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)c2ccccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, crude), 2-(1-methyl-1H-indol-3-yl)ethanamine (60 mg, 0.34 mmol), and DIEA (72 mg, 0.56 mmol) in THF (3 mL) was stirred at 100° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to afford the title compound (21.5 mg, 0.051 mmol, 15% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.00 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.94 (s, 1H), 4.28-4.23 (m, 1H), 3.75 (s, 3H), 3.75-3.62 (m, 2H), 3.02 (t, J=7.6 Hz, 1H), 1.82-1.26 (m, 6H), 1.02-0.87 (m, 6H). MS (ESI) m/z 419.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4].C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:21](=[O:22])[C:20]2[C:19]([Cl:18])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:28])=[CH:8][NH:7][N:6]=1)=[O:4]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)c1n[nH]cc1N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
A solution of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (0.634 Kg, 4.49 mol, 1 wt) in 1,4-dioxane (8.90 L, 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6-dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25° C. Residual 2,6-dichlorobenzoyl chloride was washed in with a line rinse of 1,4-dioxane (0.990 L, 1 vol) and the reaction mixture stirred at 18 to 25° C. until complete (16 hours) by TLC analysis (eluent: ethyl acetate:heptanes 3:1; Rf amine 0.25, Rf product 0.65). The reaction mixture was filtered, the filter-cake washed with 1,4-dioxane (2×0.990 L, 2×1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:46][C:47]1[O:51][N:50]=[C:49]([CH3:52])[N:48]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:46][C:47]3[O:51][N:50]=[C:49]([CH3:52])[N:48]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Reactant: Cc1noc(CCl)n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cc1noc(Cn2nc3nc(C(C)(C)C)nc(N4CC(F)(F)C(F)(F)C4)c3n2)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as light yellow gum. MS (m/e): 415.3 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:7]1[CH:49]=[CH:48][C:10]([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@@H:24]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:25]([OH:40])[C:26]([N:28]2[CH2:39][CH2:38][CH2:37][C@H:29]2[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])=[O:22])[CH2:17][C:18](=[O:20])[NH2:19])=[O:14])=[CH:9][CH:8]=1)[CH3:6])=[O:4].[CH3:50][NH:51][CH3:52]>>[CH3:50][N:51]([CH2:2][C:3]([N:5]([C:7]1[CH:49]=[CH:48][C:10]([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:21]([NH:23][C@@H:24]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:25]([OH:40])[C:26]([N:28]2[CH2:39][CH2:38][CH2:37][C@H:29]2[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])=[O:22])[CH2:17][C:18](=[O:20])[NH2:19])=[O:14])=[CH:9][CH:8]=1)[CH3:6])=[O:4])[CH3:52]
Reactant: CN(C(=O)CBr)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reactant: CNC
Product: CN(C)CC(=O)N(C)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Yield: 97.5 %

Procedure:
Following a procedure similar to that described in Example 38, but using 100 mg (0.13 mmol) of 1-[(2S,3S)-3-{N2 -[4-(N-bromoacetyl-N-methylamino)phenoxy]acetyl-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide (prepared as described in Example 30) and 0.12 ml (1.3 mmol) of dimethylamine, 90 mg of the title compound were obtained as a colorless powder, melting at 129°-135° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH:4]=1.C(Br)(Br)(Br)[Br:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:17][CH2:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH:4]=1
Reactant: O=c1cc(CO)ccn1-c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1cc(CBr)ccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Hydroxymethyl-1-phenyl-1H-pyridin-2-one from Step 4 (1.0 g, 5 mmol) was dissolved in CH2Cl2. CBr4 (6 mmol, 2 g) was added and the reaction mixture was cooled to 0°. PPh3 (6 mmol, 2.0 g) was added dropwise in CH2Cl2. The reaction mixture was stirred at 0° for 15 minutes and then warmed to room temperature. The reaction mixture was concentrated and purified on a column of silica eluting with (30% EtOAc/hexane to 50% EtOAc/hexane) to give 4-bromomethyl-1-phenyl-1H-pyridin-2-one (8, x=H) as a white solid.
Reaction SMILES: [N:1]1([C:12]([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[CH2:17][N:18](C)[C:19](=O)OC(C)(C)C)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[CH2:2]1>Cl.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:19][NH:18][CH2:17][C:16]1[CH:15]=[C:14]([CH:29]=[CH:28][CH:27]=1)[C:12]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[CH2:2]1)=[O:13]
Reactant: CN(Cc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CNCc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1
Yield: 46.7 %

Procedure:
A solution of tert-butyl N-(3-(1,2,3,4-tetrahydroquinoxalin-3-on-1-carbonyl)benzyl)-N-methylcarbamate (280 mg, 0.71 mmol) in 4N hydrogen chloride/dioxan (30 ml) was stirred at room temperature for 1 h. The mixture was reduced in vacuo, taken up in chloroform, washed with saturated sodium hydrogen carbonate solution and brine, dried and reduced. Chromatography (10% methanol/90% chloroform) afforded 1-(3-(methylaminomethyl)benzoyl-1,2,3,4-tetrahydroquinoxalin-3-one (98 mg, 49%) as an orange solid.
Reaction SMILES: Cl.C(OC([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([NH2:27])[CH:20]=2)[C:14](=[O:28])[CH2:13]1)=O)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[NH2:27][C:21]1[CH:20]=[C:19]([CH2:18][N:15]2[CH2:16][CH2:17][NH:12][CH2:13][C:14]2=[O:28])[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(CN2CCNCC2=O)cc1N
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 4-(3-Amino-4-cyano-benzyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester hydrochloride (4.0 g, 10.0 mmol) in CH3OH (45 ml) and CH2Cl2 (10 ml) is added 10% Pd on carbon (0.6 g). The mixture is stirred under an atmosphere of H2 for 2 hours then is filtered through a pad of celite. The filtrate is concentrated and the residue purified by column chromatography eluting with 10% 7M NH3 in CH3OH/CH2Cl2 to yield the title compound (1.62 g, 7.0 mmol). 1H NMR (DMSO, 300 MHz) δ7.34 (d, 1H), 6.64 (s, 1H), 6.46 (d, 1H), 6.04 (bs, 2H), 4.40 (s, 2H), 3.28 (s, 2H), 3.14 (m, 2H), 2.87 (m, 2H), 2.77 (bs, 1H). MS (ion spray): m/z 231 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1ccc([N+](=O)[O-])cc1
Yield: 93.3 %

Procedure:
Following General Procedure A, the title compound (624 mg, 92%) was prepared from 2-amino-4-chlorobenzenethiol (555 mg, 3.10 mmol), 1-(bromomethyl)-4-nitrobenzene (490 mg, 2.268 mmol) and K2CO3 (1.3 g, 9.50 mmol) in DMF (20 ml).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17]C)=[N:15][CH:16]=3)[C:3]=12.CC(O)=O>Br.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([OH:17])=[N:15][CH:16]=3)[C:3]=12
Reactant: COc1ncc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccccc3)c3ncnc(N)c23)cn1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(O)nc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
3-(1-(4-amino-3-(2-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (Example 55, 23.3 mg, 0.047 mmol) was dissolved in HBr 33% in CH3COOH (1 ml, 0.047 mmol) and stirred at rt for 1 h. The reaction was then diluted with water (3 mL) and the resulting mixture purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (20 mg, 88%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:26])[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[C:17]=2[N+:23]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:26])[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[C:17]=2[NH2:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc(N)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc(N)c1N
Yield: 98.3 %

Procedure:
To a solution of N4-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N4-methyl-3-nitro-2,4-pyridinediamine (230 mg) in ethanol (3.45 mL) and water (1.15 mL) were added iron powder (108 mg) and ammonium chloride (17 mg). The mixture was refluxed for 4 hours, then filtrated and extracted with 4:1 solution of chloroform and methanol. The extract was washed with saturated aqueous sodium hydrogencarbonate, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:0:90:10) to give N4-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N4-methyl-2,3,4-pyridinetriamine (207 mg) as a pale brown powder.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:2].[Br:28]Br>ClCCl>[Br:28][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=1
Reactant: BrBr
Reactant: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Product: CCC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A stirred solution of 6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (6.0 g, 15.8 mmol) in dichloromethane (800 mL) was treated drop-wise with excess bromine (2.1 mL, 41 mmol). The reaction mixture was heated to reflux and additional bromine (1.0 mL, 10 mmol) was added. The reaction was cooled and stirred at room temperature overnight. The reaction mixture was washed sequentially with a saturated, aqueous sodium thiosulfate solution, water, and a saturated, aqueous, sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered through a short column of silica gel, and the solvent was removed in vacuo to afford a crude yellow solid. The crude solid was crystallized from a mixture of ethyl acetate-hexane (1:1), and yielded the title compound (6.3 g, 13.8 mmol, 87%) as a colorless, crystalline solid;
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]1[C:12](=[O:13])[NH:11][C:10]([NH:14][C:15](=[O:17])[CH3:16])=[N:9][C:8]=1[N:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20])C>O>[C:15]([NH:14][C:10]1[NH:11][C:12](=[O:13])[C:7]([CH2:6][CH2:5][CH:4]=[O:3])=[C:8]([N:18]([C:22](=[O:24])[CH3:23])[C:19](=[O:21])[CH3:20])[N:9]=1)(=[O:17])[CH3:16]
Reactant: CCOC(CCc1c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c1=O)OCC
Solvent: O
Product: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1

Procedure:
A solution of 3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde diethyl acetal (1.00 g, 2.6 mmol) in distilled water (30 ml) was stirred at room temperature for 18 hours. This solution was extracted with ethyl ether (3×50 ml), and chloroform (5×50 ml). The chloroform extracts were combined, washed with water (25 ml), brine (25 ml), dried (MgSO4) and spin evaporated in vacuo. The residue was recrystallized from chloroform/cyclohexane to yield 0.200 g (25% of theory) of analytically pure 3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde quarter hydrate, mp 164°-168° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[Na+].Cl.[C:9]([NH2:13])(=[NH:12])[CH2:10][CH3:11].C(Cl)Cl>O>[CH3:5][O:4][C:2]([NH:13][C:9](=[NH:12])[CH2:10][CH3:11])=[O:3]
Reactant: CCC(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC(=N)NC(=O)OC
Yield: 91 %

Procedure:
298.6 parts of methyl chloroformate and 472.8 parts of 50% strength sodium hydroxide solution are added via two inlets to a mixture of 298 parts of propionamidine hydrochloride in 1,300 parts of methylene chloride and 200 parts of water, at from 20° to 25° C., in the course of 25 minutes, while stirring. The reaction mixture is stirred at 25° C. for three hours and diluted with 300 parts of water, and the phases are separated. The aqueous phase is extracted once with 200 parts of methyl chloride and the solvent is stripped off from the organic extract to give 325 parts (=91% of theory) of N-methoxycarbonylpropionamidine of melting point 87°-93° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22].O>C(O)C>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 85.6 %

Procedure:
To a solution of acetophenone (7.4 g) and 4N-sodium hydroxide solution (16 ml) in ethanol {60 ml) was added 4-methyl-3-nitrobenzaldehyde (7.4 g) at ambient temperature under stirring and the resultant mixture was stirred at same condition for 1.5 hours. To the reaction mixture was added water and resulting precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and tetrahydrofuran. The solution was washed with brine and dried over magnesium sulfate. The solvent was concentrated in vacuo and the crystalline residue was collected by filtration to give 3-(4-methyl-3-nitrophenyl)-1-phenyl-2-propen-1-one (10.25 g).
Reaction SMILES: CC(C)(S([NH:6][C:7]1([CH3:19])[CH2:10][CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8]1)=O)C.[ClH:21]>CO.O1CCOCC1>[ClH:21].[NH2:6][C:7]1([CH3:19])[CH2:10][CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:8]1
Reactant: CC1(NS(=O)C(C)(C)C)CC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(N)CC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of tert-butyl 3-(1,1-dimethylethylsulfinamido)-3-methylcyclobutylcarbamate (0.45 g, 1.48 mmol) in 150 mL of MeOH was added 2N HCl in dioxane (1.8 mL). The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was triturated with EtOAc, then decanted and dried to give tert-butyl 3-amino-3-methylcyclobutylcarbamate hydrochloride (0.22 g, 63%) as a white solid. MS: (M+H)+=201.2; 1H NMR (300 MHz, DMSO): δ 2.24-2.22 (m, 1H), 1.43-1.383 (m, 13H), 1.10 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:16][NH2:17])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([C:28](=O)[CH3:29])[CH:27]=1>CO.C(O)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](/[C:28](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([S:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:10])=[O:9])[CH:12]=2)/[CH3:29])[CH:27]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CC1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCC(C)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 13.6 %

Procedure:
3-((4-methylpiperidin-1-yl)sulfonyl)benzohydrazide (70 mg, 0.235 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (40.2 mg, 0.235 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperidin-1-yl)sulfonyl)benzohydrazide (15 mg, 0.032 mmol, 13.60% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.11 (m, 2H), 7.81 (m, 1H), 7.59 (m, 1H), 7.39 (m, 1H), 7.19 (m, 1H), 6.89 (m, 1H), 3.69 (m, 2H), 2.41 (m, 2H), 2.24 (m, 2H), 1.63 (m, 2H), 1.24 (m, 4H), 0.87 (d, 3H, J=4.4 Hz). Mass [M+H]+: 450.2