Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[NH2-].[Na+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)([CH2:20][CH:19]([O:22][CH2:23][CH3:24])[O:18][CH2:16][CH3:17])[C:10]#[N:11])[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(CC(C#N)(CC(OCC)OCC)c1cccc(C(F)(F)F)c1)OCC
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A mixture of 30 g of 3-(trifluoromethyl)-phenylacetonitrile and 14.4 g of sodium amide in 400 ml of toluene is left with stirring at AT for 5 minutes, 66 ml of bromoacetaldehyde diethyl acetal are added and then the mixture is heated at 60° C. for 3 hours. It is concentrated under vacuum, the residue is taken up with water and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel H, eluting with a DCM/AcOEt (100/5; v/v) mixture. This gives 26 g of the expected product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:38])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[CH:54][N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[C:51](Cl)[N:50]=1>C(O)(C)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:38])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:51]2[N:50]=[C:49]([Cl:48])[N:57]=[C:56]3[C:52]=2[N:53]=[CH:54][N:55]3[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](N)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6nc(Cl)nc7c6ncn7C6CCCCO6)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Temperature: 25 °C

Procedure:
(2R,3R,4R,5R)-2-{6-[(trans-4-Aminocyclohexyl)amino]-2-chloro-9H-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydrofuran-3,4-diyl diacetate (Intermediate 4) (7.9 g) was dissolved in isopropanol (200 ml) and stirred at room temperature under nitrogen. N,N-diisopropylethylamine (10 ml) was added followed by 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.92 g). The mixture was stirred at 60° C. under nitrogen for 18 h. The reaction mixture was allowed to cool to room temperature and evaporated down in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous extracted twice with ethyl acetate. The organic phases were combined, dried (MgSO4), and evaporated down in vacuo to give the title compound (10.35 g). Used without purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])(=[O:20])=[O:21])[CH:18]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 4-fluoro-2-nitroaniline (1 mmol) in pyridine (3 mL), 5-bromo-2-methoxybenzenesulfonyl chloride (1.2 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (20 mL). The contents were washed with 10% aqueous HCl (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate to give 223 mg of 5-bromo-N-(4-fluoro-2-nitrophenyl)-2-methoxybenzenesulfonamide.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:33])[N:9]([C@:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)([CH2:22][CH:23]=[CH2:24])[CH2:12][N:13]([CH3:21])[C:14](=[O:20])[CH2:15][C:16]([F:19])([F:18])[F:17])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:34].[OH-].[Na+].OO>O1CCCC1>[C:1]1([O:7][C:8](=[O:33])[N:9]([C@:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)([CH2:22][CH2:23][CH2:24][OH:34])[CH2:12][N:13]([CH3:21])[C:14](=[O:20])[CH2:15][C:16]([F:19])([F:18])[F:17])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: C=CC[C@@](CN(C)C(=O)CC(F)(F)F)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)Oc1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C[C@](CCCO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)Oc1ccccc1)C(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 70 %

Procedure:
Under argon, phenyl[1-(3,3,3-trifluoro-N-methylpropanamido)-2-(S)-(3,4-dichlorophenyl)-4-penten-2-yl]methylcarbamate (410 mg) was dissolved in anhydrous tetrahydrofuran (4 mL). Under cooling with ice, a 1.06M solution (0.80 mL) of borane tetrahydrofuran complex in tetrahydrofuran was added thereto, and the mixture was stirred for 1 hour. Water (0.3 mL), 3N aqueous sodium hydroxide (0.9 mL), and 30% aqueous hydrogen peroxide (0.9 mL) were added to the reaction mixture, and the resultant mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate, sequentially washed with water and saturated brine, and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby give the title compound (311 mg, 70.0%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]=3[C:5]([CH2:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)([C:17]([F:20])([F:19])[F:18])[C:4]=2[CH:3]=1.[CH3:26][N:27]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].[Zn]>[C:26]([C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]=3[C:5]([CH2:21][CH2:22][CH:23]3[CH2:24][CH2:25]3)([C:17]([F:18])([F:20])[F:19])[C:4]=2[CH:3]=1)#[N:27]
Reactant: CN1CCCC1=O
Reactant: O=c1[nH]cnc2c1Nc1ccc(Cl)cc1C2(CCC1CC1)C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: N#Cc1ccc2c(c1)C(CCC1CC1)(C(F)(F)F)c1nc[nH]c(=O)c1N2
Temperature: 170 °C
Yield: 46 %

Procedure:
A mixture of 17 (110 mg, 0.297 mmol), Zn(CN)2 (71 mg, 0.594 mmol, 2 equiv), [(t-Bu)3P]2 Pd (0.78 g, 0.149 mmol, 0.5 equiv) and Zn powder (29 mg, 0.446 mmol, 1.5 eq) were suspended in anhydrous NMP and degassed. The reaction mixture was heated to 170° C. for 30 h. After cooling to 25° C., the reaction was quenched with 2 N NH4OH (20 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine, dried (MgSO4) and concentrated. Chromatography (SiO2, 50 to 60% EtOAc-hexane) afforded the desired product as an off-white solid (49 mg, 46%). mp>280° C. ESI HRMS m/z 361.1293 (M++H, C18H16F3N4O requires 361.1276).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[N:37][CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (430 mg, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:1][C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: Oc1ccc2c(c1)Nc1ccccc1S2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)Nc2ccccc2S3)cc1
Temperature: 70 °C
Yield: 83 %

Procedure:
1.1 g (5.11 mmol) of 2-hydroxy-10H-phenothiazine (J. Med. Chem. (1992) 35, 716), 1.34 g (9.71 mmol) of K2CO3 and 0.94 g (6.64 mmol) of 4-fluoro-1-nitrobenzene are mixed in 25 ml anhydrous DMF in a flask under argon atmosphere. The reaction mixture is heated at 70° C. for 18 hours. The solvent is then evaporated off under vacuum and the residue is taken up in 50 ml of AcOEt and 50 ml of water. After agitation and decantation, the organic phase is washed with 50 ml of salt water. The organic solution is dried over MgSO4, filtered and concentrated under vacuum. The residue is crystallized from diisopropyl ether. After drying, a yellow solid is obtained with a yield of 83%. Melting point: 210-211° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8]O)[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13].S(Cl)([Cl:17])=O.CN(C)C=O.C(=O)(O)[O-].[Na+]>O>[O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][Cl:17])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1c[nH]c(CO)cc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1c[nH]c(CCl)cc1=O
Reaction time: 0.5 h

Procedure:
To crystals (10 g) of 2 -(4-oxo-6-hydroxymethyl-1,4-dihydropyridin-3-yloxy)acetic acid was added thionyl chloride (25 ml), and the mixture was stirred for 30 minutes. After cooling, dimethylformamide (125 ml) was added to the reaction mixture, and the resultant mixture was stirred for an hour. The resultant mixture was poured into cold water (750 ml) and the aqueous solution was adjusted to pH 3 with an aqueous sodium bicarbonate solution and then cooled with ice for 2 hours. Precipitated crystals were collected by filtration and washed with water to give crystals (8.7 g) of 2-(4-oxo-6-chloromethyl-1,4-dihydropyridin-3-yloxy)acetic acid. (This product was converted to its hydrochloride monohydrate, m.p. 150° to 155° C. by recrystallizing from a mixture of 10% hydrochloric acid (5 ml) and water (5 ml).)
Reaction SMILES: [OH:1][C@@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH:14]=1)[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:5][CH2:4][CH2:3][C@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH:14]=1)[OH:1]
Reactant: CN1CCC[C@H]1COc1cccc([C@H](O)CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCC[C@H]1COc1cccc([C@H](O)CCN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ((R)-3-hydroxy-3-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propyl)carbamate (0.32 g, 0.87 mmol) in DCM (10 mL) was added HCl/dioxane (4 mL) at 0° C. and the reaction mixture was stirred at rt for 2 h. After completion of the reaction the solvent was removed in vacuo. The compound was purified by prep HPLC to obtain (R)-3-Amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propan-1-ol (Example 21) as a yellow semi solid. Yield (0.18 g, 68%); 1H NMR (400 MHz, CD3OD) δ 7.29 (t, J=8.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.89-6.87 (m, 1H), 4.82-4.80 (m, 1H), 4.10-4.04 (m, 2H), 3.10-3.02 (m, 3H), 2.68 (s, 3H), 2.65-2.58 (m, 1H), 2.18-2.15 (m, 1H), 2.03-2.01 (m, 2H), 1.99-1.94 (m, 3H), 1.84-1.77 (m, 1H). MS: m/z 265.22 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][CH2:8][C:9]1[N:10]([CH2:22][C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH3:6].C(N(CC)CC)C>ClCCl>[C:1]([N:26]1[CH2:27][CH2:28][C:23]([CH2:22][N:10]2[C:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=[C:9]2[CH2:8][O:7][CH2:5][CH3:6])([OH:29])[CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(C)=O)CC1
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Acetyl chloride (0.57 mL, 8.1 mmol) was added to a suspension of 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (2.50 g, 7.34 mmol) and triethylamine (1.50 mL, 11.0 mmol) in dichloromethane (37 mL) at rt. The resulting solution was stirred for 1 h. The solution was diluted with dichloromethane (100 mL) and washed with water (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The combined aqueous layers were back-extracted with dichloromethane (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to a brown foam. Purification by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane) provided 1-acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol as a white foam (1.8 g, 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]4[O:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[C:27]=4[C:34]=3[CH3:35])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CCCCCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2([OH:33])[C:27]3[C:34]([CH3:35])=[C:23]([N:20]4[CH2:21][CH2:22][N:17]([C:14]5[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=5)[CH2:18][CH2:19]4)[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]=3[O:30][C:29]2([CH3:31])[CH3:32])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(Cl)cc3)C(C)(C)O4)CC2)cc1
Yield: 71 %

Procedure:
Using 1-bromo-4-chlorobenzene and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 71%. mp. 153–155° C. (hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>CN(C=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH2:16][CH2:17]2)=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=O)c3)CC2)cc1OC
Yield: 53 %

Procedure:
2-Nitro-5-piperazinylbenzaldehyde (5 g) was suspended in 50 ml of DMF and 6 ml of triethylamine was added to the suspension. A solution of 4.4 g of 3,4-dimethoxybenzoyl chloride in 20 ml of DMF was added dropwise thereto with ice cooling externally while stirring and the mixture was stirred at room temperature for 2 hours and poured into saturated saline and extracted with methylene chloride. After washing with water, the methylene chloride layer was dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation and to the residue was added methyl alcohol and the mixture was heated and cooled and crystals which formed were recrystallized form DMF to give 4.5 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]benzaldehyde, m.p. 196°-198° C., yellow crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 86 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 86%. Melting point: 161-163° C. (Ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[C:20](=[O:22])[CH3:21])=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine (120 mg) in dichloromethane (2 ml) was added acetyl chloride (31.4 μL) and triethylamine (61.6 μL). The reaction mixture was stirred at room temperature for 3.5 hours, then diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvents removed in vacuo to give a crude residue. This was purified by flash chromatography to yield N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-acetamide (110 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14](C(C)(C)C)[C:13]([OH:20])=[C:12](C(C)(C)C)[CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a solution of 5.0 g (15 mmol) of 4-(4'nitrophenyl)- 2,6-di-tert-butylphenol in 50 mL of toluene was added a solution of 9.2 g (69 mmol) of aluminum chloride in 10 mL of nitromethane. This mixture was stirred at ambient temperature for 4 hours and poured into 100 mL of 1N HCl mixed with ice. The resulting aqueous mixture was extracted with two 100-mL portions of ethyl acetate. Combination, drying (MgSO4), and concentration of the organic layers resulted in crystallization of 2.3 g (69% yield) of yellow 4-(4'-nitrophenyl)phenol, which may also be named as 4'-nitro-(1,1'-biphenyl)-4-ol: 1H NMR (DMSO-d6) 6.93 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.82 (d, 2H, J=9 Hz), 8.25 (d, 2H, J=9 Hz), 9.98 (broad s, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]1[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][C:6]1([CH:14]=[CH2:15])[CH:12]=[O:13].[NH4+].[Cl-]>>[CH3:4][CH:5]1[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][C:6]1([CH:12]([OH:13])[CH3:1])[CH:14]=[CH2:15]
Reactant: C[Mg]Br
Reactant: C=CC1(C=O)CCC(C)=CC1C
Agent: [Cl-]
Agent: [NH4+]
Product: C=CC1(C(C)O)CCC(C)=CC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methylmagnesium bromide (40 mmol, 1 M in THF) was added a solution of 2,4-dimethyl-1-vinylcyclohex-3-enecarbaldehyde (34 mmol) dropwise at 10° C. The mixture was stirred at room temperature for 1 h and was then cooled to 5° C. A sat. solution of NH4Cl was added dropwise and the mixture was extracted with MTBE (3×50 ml). The combined org. phases were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography to give (2,4-dimethyl-1-vinylcyclohex-3-enyl)ethanol (53% yield).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].O[CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[NH2:18]>>[ClH:14].[CH2:1]([NH:13][CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Product: CCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C

Procedure:
46 g of dodecylamine are fused at 60°, and 31 g of glucosamine hydrochloride are added with stirring. After cooling to room temperature, the product precipitates out. The solid is stirred with ether three times, filtered off with suction and then dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17]>C(OCC)(=O)C>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C=NCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)NCCCl)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 51.9 g (0.34 mol) of 3,4-dimethoxyaniline in 500 ml of ethyl acetate was added dropwise a solution of 35.8 g (0.34 mol) of 2-chloroethylisocyanate in 100 ml of ethyl acetate. The reaction mixture was stirred for one hour at ambient temperature and the precipitate filtered off by suction (crop 1). The filtrate was evaporated to dryness and the resulting residue washed with ether (crop 2). The two crops were combined and dried in vacuo; yield: 83.7 g, melting point 117° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[H-].[Na+].Br[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH3:7][N:6]1[C:2]([NH2:1])=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:4]([O:8][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5]1
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(OCCOc3ccccc3)nn(C)c2N)cc1
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (50 mg) in dimethylformamide (2 ml) at room temperature was added sodium hydride (60% dispersion in oil, 10 mg) and β-bromophenetole (49.5 mg). The mixture was stirred for 2 hrs. The reaction was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ether to yield the title compound as a white solid (20 mg).