Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7](Cl)[C:8]([Cl:16])=[N:9]2)([O-:3])=[O:2].[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+].C1(C)C=CC=CC=1.O>C(O)(C)(C)C>[C:19]([O:21][C:7]1[C:8]([Cl:16])=[N:9][C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=2)[N:6]=1)([CH3:22])([CH3:20])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)cc2nc(Cl)c(Cl)nc12
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1nc2c([N+](=O)[O-])c(Cl)c(Cl)cc2nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To 5-nitro-2,3,6,7-tetrachloroquinoxaline 1608 mg obtained in Example 7(1), was added dropwise a solution of potassium tert-butoxide 644 mg in tert-butanol (15 mL) at −5 to 0° C. The reaction mixture was stirred at 0° C. for 30 min, and toluene 50 mL, 0.1 M sodium dihydrogen phosphate 5 mL, and water were added thereto with shaking. The organic layer was separated, washed with water and saturated saline, and dried over MgSO4. After evaporation, the residue was subjected to column chromato (silica gel/toluene) and crystallized from acetone, to give the title compound (colorless crystal) 1092 mg.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([NH:12][CH:6]1[CH2:5][CH2:1][NH:2][CH2:8][CH2:7]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccc1
Reactant: [BH3-]C#N
Agent: [Na+]
Product: c1ccc(CNC2CCNCC2)cc1

Procedure:
The compounds of formula A and G are prepared as is described in Reaction Sequences 1 and 2. Compound G is then treated with sodium cyanoborohydride, optionally in the presence of benzylamine, to produce the 4-(benzyl)amino piperidine which is subsequently coupled with the compound of formula A to produce the benzyl derivative (formula G"). The compound of formula G" is then hydrogenated using, for instance, palladium-on-carbon catalyst to produce the compound of formula I.
Reaction SMILES: [F:1][CH:2]([F:24])[S:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:56]([SH:64])(=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>O1CCCC1>[C:56]([S:64][C@@H:8]1[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:5]([CH2:4][S:3][CH:2]([F:24])[F:1])[CH2:9]1)(=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1CSC(F)F
Reactant: O=C(S)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(S[C@H]1C[C@@H](CSC(F)F)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1

Procedure:
To a solution of (2S,4R)-2-(difluoromethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.01 g) and triphenylphosphine (1.1 g) in tetrahydrofuran (20 ml) was added dropwise a solution of diethyl azodicarboxylate (0.66 ml) in tetrahydrofuran (3 ml) at -10° C. to -5° C. with stirring. The mixture was stirred at the same temperature for 30 minutes. To the solution was added thiobenzoic S-acid (0.49 ml) at the same temperature and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (60 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of n-hexane and ethyl acetate (3.1 , V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-benzoylthio-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.01 g).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)=O>>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: COc1cccc(-c2csc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)c1

Procedure:
100 mg (0.152 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 42 mg (0.182 mmol) of 2-bromo-1-(3-methoxyphenyl)ethanone were reacted according to the General Method 3. Yield: 29 mg (35% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C@@H:10]([C:11]#[CH:12])[CH2:9][CH2:8][C:7]1=[O:13].Cl.N[C@@H](C(OC)=O)CCC(OC)=O.Br[C:34]1[N:39]=[C:38]([O:40][CH3:41])[C:37]([Cl:42])=[CH:36][CH:35]=1.O>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:42][C:37]1[CH:36]=[CH:35][C:34]([C:12]#[C:11][C@@H:10]2[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:7](=[O:13])[CH2:8][CH2:9]2)=[N:39][C:38]=1[O:40][CH3:41]
Reactant: COc1nc(Br)ccc1Cl
Reactant: C#C[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: COC(=O)CC[C@@H](N)C(=O)OC
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)CC[C@@H]2C#Cc2ccc(Cl)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
(5R)-1-(2,4-Dimethoxybenzyl)-5-ethynylpyrrolidin-2-one (600 mg, synthesized according to Tetrahedron Asymmetry, 1995, 239 using dimethyl (R)-glutamate hydrochloride as a raw material) in acetonitrile (6 mL) was added to a solution of 6-bromo-3-chloro-2-methoxypyridine (667 mg), bis(triphenylphosphine)palladium(II) dichloride (81 mg) and copper iodide (22 mg) in triethylamine (12 mL) in a nitrogen gas stream at 40° C. over 30 minutes. The mixture was stirred at room temperature for four hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give the title compound as a colorless oil (452 mg, 52%).
Reaction SMILES: [CH3:1][C:2]([C:10]1[N:11]=[CH:12][O:13][CH:14]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[CH3:3][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:6][CH:5]=1)([C:10]1[N:11]=[CH:12][O:13][CH:14]=1)[CH3:1]
Reactant: CC(C)(c1ccccc1)c1cocn1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1cocn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 261 mg (1.4 mmol) of 4-(1-Methyl-1-phenyl-ethyl)-oxazole in 15 ml of chloroform at 0° C. was added 0.49 gm (4.2 mmol) of chlorosulfonic acid. After 30 minutes, the solution was allowed to warm to ambient temperature and an additional 0.49 gm (4.2 mmol) of chlorosulfonic acid was added. After one hour, the mixture was cooled in an ice/water bath, and crushed ice was added to the reaction. The mixture was partitioned between 1M pH=7 phosphate buffer and ether, and the phases were separated. The ether phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude title product as an oil.
Reaction SMILES: [BrH:1].[CH3:2][CH:3]1[CH2:9][NH:8][CH2:7][CH2:6][C:5](=[O:10])[CH2:4]1.BrBr>C(O)(=O)C>[BrH:1].[Br:1][CH:4]1[CH:3]([CH3:2])[CH2:9][NH:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: CC1CNCCC(=O)C1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CC1CNCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6-methylazepan-4-one hydrobromic acid was dissolved in 100 mL acetic acid. A solution of 3.2 mL bromine in 10 mL acetic acid was added. The mixture was stirred for 1.5 h at RT. The volatiles were removed in vacuo and the residue was crystallized with acetonitrile to yield 18.5 g of the desired product. (M+H)+: 228
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.Br[CH2:12][CH2:13][C:14](OCC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(OC(C)C)(C)C>CC(C)=O>[S:1]1[CH:5]=[C:4]([O:6][CH2:12][CH2:13][CH2:14][OH:15])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)CCBr
Reactant: O=C1CSc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Product: OCCCOc1csc2ccccc12
Yield: 1.3 %

Procedure:
A mixture of benzo[b]thiophen-3-one (30 g), ethyl 3-bromopropionate (73 g), potassium carbonate (55 g), potassium iodide (1.3 g) and acetone (600 ml) was refluxed for 18 h. Filtration and removal of solvent in vacuo a red oil which was dissolved in ether (200 ml) and dried over magnesium sulfate. The ether solution was added dropwise to a suspension of lithium aluminium hydride (5 g) in ether (100ml) followed by reflux for 1 h. Usual work-up gave a viscous oil which was applied to a silica gel column (eluent: isopropyl ether) giving 3-(benzo(b]thiophen-3-yloxy)-1-propanol (0.54 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[N:4]=[CH:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[CH:57]=[C:56]([O:58][CH:59]([F:61])[F:60])[N:55]=[C:54]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:53]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:61][CH:59]([F:60])[O:58][C:56]1[N:55]=[C:54]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:53]=[C:52]([NH:10][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[CH:57]=1
Reactant: Cn1cnc(S(N)(=O)=O)c1
Reactant: Fc1cccc(CSc2nc(Cl)cc(OC(F)F)n2)c1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cnc(S(=O)(=O)Nc2cc(OC(F)F)nc(SCc3cccc(F)c3F)n2)c1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 1-methyl-1H-imidazole-4-sulfonamide (0.25 g), tris(dibenzylideneacetone)dipalladium (0) (0.10 g), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (60 mg), cesium carbonate (0.26 g), 4-chloro-6-(difluoromethoxy)-2-[[(2,3-difluorophenyl)methyl]thio]-pyrimidine (product of example 12, step ii) (0.18 g) and anhydrous dioxane (5 ml). Purification was by tituration with methanol/DCM. The resulting white solid was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O (×2) then brine and dried (MgSO4), filtered and evaporated. The resulting oil was triturated with methanol/DCM to give the title compound as a white solid. Yield: 15 mg
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.C([OH:15])C#C.BrC1C=CC=CN=1.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C.C(N(CC)CC)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10][OH:15]
Reactant: BrCC#Cc1ccccn1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: Brc1ccccn1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: OCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
3-(2-Pyridyl)prop-2-yn-1-yl bromide hydrobromide used as a starting material was obtained as follows: 2-Propynyl alcohol (35 ml) was added dropwise to a stirred mixture of 2-bromopyridine (13.7 g), bis(triphenylphosphine)palladium chloride (1.54 g), triethylamine (21 ml),cuprous iodide (1.5 g) and acetonitrile (150 ml) and the mixture was stirred at ambient temperature for 30 minutes and then heated to 60° C. for 2 hours. The mixture was cooled to ambient temperature, poured into water (200 ml) and neutralised by adding dilute aqueous hydrochloric acid. The mixture was extracted with methylene chloride (2×500 ml) and the combined extracts were washed with water (500 ml), dried (MgSO4) and evaporated. The residue was purified by columnchromatography eluting with a 1:1 v/v mixture of methylene chloride and ethyl acetate to give 3-(2-pyridyl)prop-2-yn-1-yl alcohol (14 g, 70%), m.p. 78°-80° C. (recrystallised from a mixture of hexane andethyl acetate).
Reaction SMILES: [C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Br-:19].[Li+]>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6]([Br:19])=[O:7])(=[O:3])[CH3:2]
Reactant: [Br-]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
2,3,4-Triacetoxybutanoyl chloride (39.9 g, 0.142 mol), prepared according to the literature procedure Glattfeld, J. and Kribben, B., J.Am. Chem. Soc. 61 (1939) 1720) was mixed with lithium bromide (30.9 g, 0.356 mol) in methylene chloride (400 ml) and stirred at ambient temperature for 24 h. The mixture was filtered, the solid was washed with additional methylene chloride (50 ml) and the filtrate was evaporated at ambient temperature to give 45 g (97%) of the crude product as an oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34](S(C)(=O)=O)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>Cl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34]([NH:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(S(C)(=O)=O)nc2N(c2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C1=O
Reactant: Nc1ccccc1
Agent: Cl
Product: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C1=O
Temperature: 180 °C
Yield: 100 %

Procedure:
A mixture of 1.1 g (1.5 mmol) of 1-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]-3-(2-chloro-6-methylphenyl)-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 3 ml of aniline was heated at 180° C. for 20 minutes. The mixture was cooled and added to 50 ml of 2M aqueous hydrochloric acid. The resulting suspension was filtered and the solid washed with water and dried to give 1.2 g (100%) of 1-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]-7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a tan solid. [Mass spectrum (ESI) MH+ =724].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:16][CH2:15]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCO)CC1
Yield: 89.6 %

Procedure:
A mixture of 3-bromopropanol (10.5 mL, 116 mmol), 1-(2-methoxyphenyl)piperazine (21 g, 109.23 mmol), sodium iodide (16.4 g, 109 mmol), potassium carbonate (38 g, 275 mmol) in 300 mL of acetonitrile was heated at reflux for 3 hours. The mixture was cooled and filtered. The filtrate was washed with saturated sodium chloride, dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with 5% methanol/methylene chloride. Product fractions were combined and concentrated to give 3-[4-(2-methoxyphenyl)piperazin-1-yl]-1-propanol (24.5 g, 97.86 mmol), m.p. 88°-89° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4′-hydroxy-2′-methylacetophenone (24.88 g; 165.7 mmol)), KI (5.50 g; 33.1 mmol), K2CO3 (34.3 g; 248.5 mmol) and benzyl bromide (21.7 mL; 182.2 mmol) in acetone (200 mL) was stirred overnight at RT. Subsequently the resulting mixture was filtered and partitioned between EtOAc and 5% aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford 1-(4-benzyloxy-2-methylphenyl)-ethanone, which was used as such.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:25][CH2:24][N:23]([CH2:3][C:4]3[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=3)[CH2:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CC=C(c3ccc(F)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
A suspension of 27.2 g (0.14 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride, 29.8 g (0.14 mol) of 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 42 g (0.30 mol) of dry potassium carbonate in 200 ml of dimethyl-formamide was stirred at room temperature for 18 hours. The mixture was suction filtered, the filter cake was washed with dichloromethane, the filtrate was completely freed from the solvents and the residue was crystallized twice from ethyl acetate/cyclohexane. 11.6 g (28%) of 5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as yellowish crystals; m.p. 176°-178°.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1.[NH2:16][NH2:17]>C(O)(C)C>[NH:16]([C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1)[NH2:17]
Reactant: NN
Reactant: CSc1nnc(-c2ccccc2)c(=O)[nH]1
Solvent: CC(C)O
Product: NNc1nnc(-c2ccccc2)c(=O)[nH]1

Procedure:
To 3-(methylthio)-6-phenyl-1,2,4-triazin-5(4H)-one (4.3 g) in isopropyl alcohol (40 mL) was added hydrazine (6.41 g, 0.200 mol). The reaction mixture was refluxed for 10 h. After cooling, the crystalline solid formed was filtered and washed with isopropyl alcohol. The crystalline solid was collected and dried in vacuo to afford the desired product. Analytical LCMS: (M+H)+=204.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH3:17][N:18]([CH3:26])[CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>Cl>[CH3:17][N:18]([CH3:26])[CH:19]1[CH2:24][CH2:23][C:22]2([NH:1][C:2]3[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][C:3]=3[S:13](=[O:15])(=[O:14])[NH:16]2)[CH2:21][CH2:20]1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: CN(C)C1CCC(=O)CC1
Agent: Cl
Product: CN(C)C1CCC2(CC1)Nc1cc(Cl)c(S(N)(=O)=O)cc1S(=O)(=O)N2

Procedure:
A mixture of 4-amino-6-chloro-1,3-benzenedisulfonamide (5.72 g., 0.02 mole) and 4-dimethylaminocyclohexanone (3.38 g., 0.022 mole) in 2 N ethanolic HCl (100 ml) is refluxed for one hour and cooled. 4'-Dimethylamino-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-7-sulfonamide-1,1-dioxide hydrochloride is filtered, dissolved in warm water (200 ml.) and treated with aqueous ammonia (1.0 ml.) to give 4'-dimethylamino-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-7-sulfonamide-1,1-dioxide which melts at 255° C. after recrystallization from dimethylsulfoxide--H2O.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([NH:8][C:9]1([CH2:12][CH:13]=[O:14])[CH2:11][CH2:10]1)=[O:7])C.[Na]>C1(C)C=CC=CC=1.CO>[CH3:1][O:3][C:4]([CH:5]1[C:13](=[O:14])[CH2:12][C:9]2([CH2:11][CH2:10]2)[NH:8][C:6]1=[O:7])=[O:15]
Reactant: CCOC(=O)CC(=O)NC1(CC=O)CC1
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)CC2(CC2)NC1=O

Procedure:
N-[1-(2-Oxo-ethyl)-cyclopropyl]-malonamic acid ethyl ester (200 mg; 0.823 mmol) in toluene (3 ml) is added to a solution of sodium (18.9 mg; 0.823 mmol) in MeOH (1 ml). The reaction mixture is refluxed for 45 minutes, poured on water and washed with TBME. The aqueous phase is acidified with 2N HCl (0.2 ml) and evaporated to dryness to yield the title compound as yellow resin (162 mg; 100%). 1H-NMR (400 MHz; DMSO-d6): 8.39 (s, 1H); 3.73 (s, 3H); 3.18 (s, 1H); 2.48 (s, 2H); 0.76 (m, 2H); 0.64 (m, 2H). MS (m/z) ES+: 198 (MH+).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:12]=[CH:13][C:14]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]>C(OCC)C.ClCCl>[ClH:1].[CH3:38][O:37][C:35]1[CH:34]=[C:6]([CH:5]=[C:4]([O:3][CH3:2])[CH:36]=1)[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:12]=[CH:13][C:14]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: COc1cc(CNc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)cc(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(CNc2cc(N3CCNCC3)ccc2C(=O)C(F)(F)F)cc(OC)c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A saturated solution of HCl gas in anhydrous diethyl ether was added portion wise to a solution of tert-butyl 4-(3-(3,5-dimethoxybenzylamino)-4-(2,2,2-trifluoroacetyl)-phenyl)piperazine-1-carboxylate (230 mg, 0.44 mmol) in anhydrous dichloromethane (1.5 mL). The resulting mixture was allowed to stand at room temperature for 30 min, and conversion was monitored by LCMS. The supernatant was pipetted out and the residue was concentrated down in vacuo and co-evaporated with diethyl ether to yield 150 mg (81%) of the title compound: 1H NMR (400 MHz, CD3OD): δ 7.65 (dd, 1H), 6.54 (d, 2H), 6.42-6.39 (m, 2H), 6.07 (d, 1H), 4.48 (br s, 2H), 3.76 (s, 6H), 3.63-3.60 (m, 4H), 3.30-3.25 (m, 4H). MS (ESI) m/z: Calculated: 423.18; Observed: 847.4 (2M++1)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][Br:9])=[CH:4][C:3]=1[N+:12]([O-])=O>CCO>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH2:1])[O:6][CH2:7][CH2:8][Br:9]
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1ccc(OCCBr)cc1N
Yield: 83 %

Procedure:
From a mixture of 2-(4-amino-3-nitrophenoxy)ethyl bromide (1.30 g, 5.0 mmol) and stannouschloride dihydrate (5.65 g, 25 mmol) in 95% EtOH (35 mL) was obtained 960 mg (83%) of 2-(3,4-diaminophenoxy)ethyl bromide as a pale powder. 1H NMR (CDCl3): 3.597 (t, 2H, J=6), 4.210 (t, 2H, J=6), 6.273 (dd, 1H, J=8; 3), 6.359 (d, 1H, J=3), 6.637 (d, 1H, J=8).