Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[S:32]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:37]([C:34]1[CH:35]=[CH:36][S:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccsc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. thiophene-3-sulfonyl chloride (13 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)thiophene-3-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH3:19].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:20][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH3:19])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCC#CCCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC#CCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (4.3 ml) was added to a solution of 9-dodecyn-1-ol (5.1 g, 28 mmol) in 50 ml CH2Cl2, and the mixture was then added dropwise at 0° C. to a solution of methanesulfonyl chloride (2,2 ml, 28 mmol) in 10 ml CH2Cl2. The mixture was stirred another 4 hours at room temperature, then cooled to 0°-5° C. The solution was washed with cold 5% aqueous sodium bicarbonate, cold 1N HCl, cold water, then saturated brine. The extract was dried over Na2SO4 and filtered and evaporated. The solvent was evaporated to leave crude 1-(9-dodecynyl) methanesulfonate.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[N:6][NH:5][C:4]1=S)[CH3:2].[OH:13]O>[OH-].[Na+]>[CH2:1]([N:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[N:6][NH:5][C:4]1=[O:13])[CH3:2]
Reactant: OO
Reactant: CCn1c(C(F)(F)F)n[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C(F)(F)F)n[nH]c1=O
Reaction time: 6 h
Yield: 58 %

Procedure:
9.9 g (0.05 mol) of 4-ethyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazole-3-thione and 50 ml of 2.5-molar sodium hydroxide solution are introduced. 17 ml (0.165 mol) of 30% strength hydrogen peroxide solution are added dropwise in the course of 20 minutes at a maximum temperature of 40° C. to 50° C. (cooling), stirring is continued for 6 hours at 40° C., the excess of hydrogen peroxide is removed by adding sodium hydrogen sulphite, and the mixture is acidified using concentrated hydrochloric acid and refluxed for 10 hours. When cold, the mixture is poured into ice-water, this is extracted repeatedly using dichloromethane, the combined organic phases are dried over sodium sulphate, and the solvent is evaporated on a rotary evaporator. 5.2 g (58% of theory) of 4-ethyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 53° C. are obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>O1CCCC1.ClCCl>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11]([C:10]2[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([S:14][CH3:15])=[N:8][CH:9]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: CSc1ncc(C(=O)Cl)c(NC(C)C)n1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2cnc(SC)nc2NC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a 0° C. suspension of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid chloride (as prepared in the above example, Preparation 16) in 30 mL of tetrahydrofuran is added 6.0 mL (46.3 mmol) of 4-methoxybenzylamine and 30 mL of tetrahydrofuran. The reaction suspension is allowed to warm briefly to room temperature, then stored at 0° C. overnight. The reaction mixture is diluted with dichloromethane, washed with 1N HCl and water. The combined aqueous phase is washed with dichloromethane. The combined organic phase is washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue is crystallized from ethyl acetate/hexane to give 3.27 g (61%) of the title compound: mp 176-177° C.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@H:11]([CH:16](C)C)[O:10]C1(C)C)=O)(C)(C)C.[NH2:21][C:22]1[CH:23]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH:25]=[CH:26][C:27]=1[NH2:28]>>[NH2:8][C@H:12]([C:13]1[NH:28][C:27]2[CH:26]=[CH:25][C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[CH:23][C:22]=2[N:21]=1)[C@@H:11]([OH:10])[CH3:16]
Reactant: CC(C)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1
Product: C[C@H](O)[C@H](N)c1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using (4S,5S)-3-(tert-butoxycarbonyl)-5-isopropyl-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 59B) and 3′,4′-diaminobiphenyl-4-carbonitrile (Preparation 82). The reaction mixture was concentrated in vacuo and purified by SCX-2 cartridge (16 mg, 72%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:17]#[N:18].[K+].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][C:17]#[N:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: COc1ccc(CCl)cc1OC1CCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC#N)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.2 %

Procedure:
A mixture of 3-cyclopentyloxy-4-methoxybenzyl chloride (119 grams, 0.49 mol), 120 milliliters of methylene chloride, KCN (70.7 grams, 1.09 mol), benzyltriethylammonium chloride (35 grams, 0.015 mol) and water (120 milliliters) was stirred vigorously at room temperature for 48 hours. The reaction mixture was diluted with methylene chloride and the layers were separated. The methylene chloride solution was extracted several times with water and evaporated to yield 3-cyclopentyloxy-4-methoxyphenylacetonitrile (109 grams, 95%) for the subsequent transformation.
Reaction SMILES: [CH2:1]=[O:2].[C:3](=[O:6])([O-])[O-].[K+].[K+].[CH3:9][NH:10][C:11]1[N:16]=[C:15]([NH:17][CH3:18])[N:14]=[C:13]([NH:19][CH3:20])[N:12]=1>>[OH:2][CH2:1][N:19]([CH3:20])[C:13]1[N:12]=[C:11]([N:10]([CH2:3][OH:6])[CH3:9])[N:16]=[C:15]([NH:17][CH3:18])[N:14]=1
Reactant: C=O
Reactant: CNc1nc(NC)nc(NC)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CNc1nc(N(C)CO)nc(N(C)CO)n1
Reaction time: 8 h

Procedure:
To a 3% w/v aqueous solution of formaldehyde (15 ml) was added potassium carbonate (691 mg, 5 mmol) then trimethylmelamine (841 mg, 5 mmol). The reaction mixture was stirred at room temperature until the initially clear solution (pH 11.5) became cloudy (2-3 h) then set aside overnight (16 h). The white granular solid which separated was recovered by filtration, washed with water (4×5 ml) and the product dried in vacuo over anhydrous CaCl2. Yield 593 mg (52%); 1H-NMR spectrum δH (Me2SO-d6) 2.75 (app d, 3, HNCH3), 4.99 (br s, 4, HOCH2), 5.36 (br s, 2, OH) 6.61 (br s, 1, NH); mass spectrum (FAB; glycerol/thioglycerol matrix) m/z 229 ([M+H]+, 70%), 211 (229-H2O, 100%), 199 (229-CH2O, 35 %), 181 (199-H2O, 50%), 169 (199-CH2O, 30%). Anal. C8H16N6O2 requires C. 42.10; H, 7.07; N, 36.82: found C, 41.87; H, 7.01; N, 36.55%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]#[C:21][CH2:22][CH2:23][CH3:24].C[Si](C#C)(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:20]#[C:21][CH2:22][CH2:23][CH3:24])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: C#CCCC
Agent: C#C[Si](C)(C)C
Product: CCCC#Cc1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
The reaction was conducted in the same manner as in the step (i) of the Example 31, except for using 2-(benzyloxy)-6-bromonaphthalene synthesized in the step (i) and 1-n-pentyne instead of 1-bromo-4-n-propylbenzene and trimethylsilylacetylene, respectively. The resultant was recrystallized from ethanol to give 2-(benzyloxy)-6-(2-n-propylethynyl)naphthalene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:13]([Mg]Br)=[CH2:14].Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]([OH:8])[CH:13]=[CH2:14])[CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: -78 °C
Yield: 73 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (6.0 g) is dissolved in dry tetrahyrofuran (90 ml) and thereto is added dropwise vinylmagnesium bromide (2.3 equivalents) with stirring at −78° C. The temperature of the reaction mixture is raised gradually. After completion of the reaction, 1N HCl is added to the reaction mixture, and the mixture is extracted with ethyl acetate, and the organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate, and then distilled off the solvent. The residue is purified with a silica column chromatography to give 1-(5′-hydroxy-2′-nitrophenyl)-2-propen-1-ol (5.09 g) as yellowish brown powders.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:41][NH:42][CH2:43][C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH3:54])=[CH:46][CH:45]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:42]([CH3:41])[CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]([CH3:54])=[CH:46][CH:45]=2)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CNCc1ccc(C)c2ccccc12
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCN(C)CC3)c2)c2ccccc12
Yield: 20 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(4-methyl-naphthalen-1-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (143 mg, 20%) was prepared as a pale, yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.35-8.29 (m, 2H), 8.18-8.05 (m, 4H), 7.65-7.52 (m, 3H), 7.41-7.03 (m, 3H), 5.30-5.07 (m, 2H), 3.63-3.33 (m, 6H), 3.04-2.95 (m, 7H), 2.72-2.65 (m, 6H); MS (ESI) m/e 444 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][C:13]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([BH3-])#N.[Na+].[C:47](O)(=O)[CH3:48]>CO.C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:9]2[CH:12]=[CH:13][C:47]([CH2:48][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:6][CH:10]=2)=[C:9]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][C:13]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Reactant: CC(=O)O
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in methanol and powdered 3A sieves were added. Morpholine (2 eq) was added, followed by sodium cyanoborohydride (2 eq). Acetic acid (5 eq) was added drop wise and the suspension was stirred under nitrogen at ambient temperature for 16 hours. The reaction mixture was diluted with DCM and washed with sat. NaHCO3 (aq). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting gum was purified by flash chromatography, eluting with 1% MeOH in DCM to give 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH:12]2[C:17](=O)[CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]2)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:26][C:27]1[N:28]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH2:41])=[NH:40])=[CH:34][CH:33]=2)[CH:29]=[CH:30][N:31]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][C:10]1[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:16][C:17]=2[N:41]=[C:39]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH3:26])=[CH:33][CH:34]=2)[N:40]=1
Reactant: COc1cccc(CC(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)c1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Product: COc1cccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CN(C(=O)OC(C)(C)C)CC3)c1
Yield: 62 %

Procedure:
tert-Butyl 4-(3-methoxybenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (373 mg, 62%) was synthesised from tert-butyl 3-(2-(3-methoxyphenyl)acetyl)-4-oxopiperidine-1-carboxylate and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for synthesis of pyrimidines. MS (ES+) m/z 527.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22]CCC[O:18]2)[C:3]1=[O:23].[F:24][C:25]([F:36])([F:35])[O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O.C([O-])(=O)C.[Na+]>CC(O)=O.CC(=O)OCC.O>[C:17]([O:16][CH2:15][CH2:14][CH2:13][N:4]1[C:5](=[O:12])[C:6]([N+:9]([O-:11])=[O:10])=[C:7](/[CH:8]=[CH:30]/[C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([O:26][C:25]([F:24])([F:35])[F:36])[CH:28]=2)[N:2]([CH3:1])[C:3]1=[O:23])(=[O:18])[CH3:22]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(/C=C/c2cccc(OC(F)(F)F)c2)n(C)c1=O
Temperature: 140 °C
Yield: 14.3 %

Procedure:
To a solution of 1,6-dimethyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrimidine-2,4(1H,3H)-dione (1 g, 3.05 mmol) in HOAc (4 mL) was added 3-(trifluoromethoxy)benzaldehyde (0.755 g, 3.97 mmol) and sodium acetate (0.752 g, 9.16 mmol). The reaction was heated at 140° C. for 6 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (5:1 to 2:1) to give (E)-3-(3-methyl-5-nitro-2,6-dioxo-4-(3-(trifluoromethoxy)styryl)-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (200 mg, 14.3% yield) as a brown oil. LCMS: MH+ 458 and TR=1.689 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>>[C:14]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([Cl:9])=[C:5]([F:8])[CH:6]=1)(=[O:16])[CH3:15]
Reactant: Fc1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of 229.6 g of 1,3-dichloro-4-fluorobenzene and 205.34 g of aluminum chloride was heated at 80° C. A 56 g portion of acetic anhydride was added dropwise over 2 hours, then the reaction ws heated at 100° C. for 8 hours, poured onto a mixture of concentrated hydrochloric acid and ice and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvents evaporated. The solid was purified by vacuum distillation, giving 156.63 g of 6-acetyl-1,3-dichloro-4-fluorobenzene.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:20]([O-])=[O:21].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCN(C(=O)N(CCCl)N=O)C1OC[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 37.5 %

Procedure:
9.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-xylopyranosylurea are dissolved in 25 ml of formic acid, and 6.0 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is stirred at the same temperature for 30 minutes. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 3.7 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-xylopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([NH2:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>>[CH:9]([C@@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][C@@H:6]1[NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=1)([CH3:11])[CH3:10].[CH:9]([C@H:5]1[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][C@H:6]1[NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=1)([CH3:11])[CH3:10]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC1CCC(C(C)C)C(N)C1
Product: COc1ccc(C(=O)N[C@@H]2C[C@@H](C)CC[C@@H]2C(C)C)cc1OC
Product: COc1ccc(C(=O)N[C@H]2C[C@H](C)CC[C@H]2C(C)C)cc1OC

Procedure:
The aforementioned product is obtained as a colorless solid containing in total 97.8% of the desired neomenthylamine derivatives from racemic neomenthylamine, as in the GP, by reaction with 3,4-dimethoxybenzoylchloride. Furthermore, two further isomeric menthylamine derivatives are present at 1.3% and 0.9%, corresponding to a purity over all stereoisomers of 100.0%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[F:45][C:46]([F:52])([F:51])[S:47](Cl)(=[O:49])=[O:48]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([S:47]([C:46]([F:52])([F:51])[F:45])(=[O:49])=[O:48])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(S(=O)(=O)C(F)(F)F)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0473 g, 0.115 mmol) in dry N,N-Dimethylformamide (0.60 mL, 7.7 mmol) was added N,N-Diisopropylethylamine (0.0636 mL, 0.365 mmol) followed by Trifluoromethanesulfonyl chloride (0.01940 mL, 0.1822 mmol). The reaction mixture was stirred for overnight. The reaction mixture was concentrated and was chromatographed through silica gel (4 g, 0-100% EtOAc in heptane followed by 10% MeOH in dichloromethane). The trifluoromethanesulfonamide was isolated and purified by HPLC. (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-7-(trifluoromethylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (xi): 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.16 (d, J=8.7, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.68-4.52 (m, 2H), 4.01 (s, 1H), 3.82 (dd, J=26.3, 11.2, 3H), 3.69 (t, J=12.6, 3H), 3.54 (t, J=11.1, 1H), 3.49-3.38 (m, 1H), 3.18-3.06 (m, 2H), 2.87 (s, 1H), 2.75 (d, J=16.4, 1H), 1.80 (dd, J=11.3, 6.9, 2H), 1.06 (t, J=7.2, 3H), 0.83 (t, J=7.4, 3H). LC/MS-m/z+543.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:10]=1[CH:11]=O.[OH:19]S(O)(=O)=O.CC(OC(C)=O)=O>CC(O)=O.CCOC(C)=O>[CH3:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH3:7])[C:10]=1[CH:11]1[NH:4][C:3](=[O:19])[C:2]([CH3:6])([CH3:1])[O:5]1
Reactant: COc1cccc(OC)c1C=O
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)C#N
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1C1NC(=O)C(C)(C)O1
Temperature: 10 °C
Reaction time: 0.67 h
Yield: 52 %

Procedure:
To a mixture of acetone cyanhydrin (851 mg), 2,6-dimethoxybenzaldehyde (1.58 g) in AcOH (10 mL) is added at 10° C. dropwise H2SO4 (1 mL) and Ac2O (0.5 mL). The reaction mixture is stirred at 10° C. for 40 min and then 10 min at RT. The reaction mixture is poured into cracked ice and extracted three times with ether. The combined organic extracts are washed with 10% aq. NaHCO3, dried (Na2SO4), filtered and concentrated to yield a crude oil. FC (EtOAc) gives the title compound as a brown oil (1.3 g, 52%). LC-MS: tR=0.47 min; [M+H]+=252.25.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].O>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:19]3[C:18](=[O:20])[C:17]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]4[C:15]3=[O:25])=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: ClCc1ncc(-c2ccc(Cl)cc2)o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A suspension of 2.3 g of 2-chloromethyl-5-(4-chlorophenyl) oxazole and 1.94 g of potassium phthalimide in 15 ml of dimethylformamide was stirred at room temperature for one hour. The reaction mixture was poured into 300 ml of water, and the resultant precipitate was filtered and recrystallized from ethanol to give 2.4 g (71 percent) of N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide.