Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH2:19][N:20]([S:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[CH:27][C:26]=3[CH3:34])(=[O:24])=[O:23])[CH3:21])[O:16][CH:15]=2)=[O:13])[CH3:10])=[CH:5][CH:4]=1)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.CC(O)=O.ClCCCl>C(Cl)Cl>[CH3:33][O:32][C:28]1[CH:29]=[C:30]([CH3:31])[C:25]([S:22]([N:20]([CH2:19][C:17]2[O:16][CH:15]=[C:14]([C:12]([NH:11][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:4][CH:5]=3)[CH3:10])=[O:13])[CH:18]=2)[CH3:21])(=[O:24])=[O:23])=[C:26]([CH3:34])[CH:27]=1
Reactant: C1CCNC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NC(C)c3ccc(C=O)cc3)co2)c(C)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NC(C)c3ccc(CN4CCCC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BF using N-[1-(4-formylphenyl)ethyl]-5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxamide (39 mg, 0.08 mmol), pyrrolidine (6.8 mg, 0.1 mmol), AcOH (7 mg, 0.12 mmol), STAB (34 mg, 0.16 mmol) and DCE (1 mL). The reaction was diluted with DCM (1 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic phase was dried over Na2SO4 and the solvent removed in vacuo. The crude product was purified by FCC eluting with 2-10% MeOH in DCM to afford the title compound.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1>>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[NH:9][C:8]([N:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:24]2[CH:23]=[CH:22][C:21]3[O:17][CH2:18][O:19][C:20]=3[CH:25]=2)[CH2:28][CH2:29]1)=[O:16]
Reactant: O=C(Nc1ncccn1)Oc1ccccc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: O=C(Nc1ncccn1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from pyrimidin-2-yl-carbamic acid phenyl ester and 1-benzo[1,3]dioxol-5-ylmethyl-piperazine. 1H NMR (400 MHz, CDCl3): 8.46 (d, J=5.3 Hz, 2H), 7.31 (br s, 1H), 6.85-6.83 (m, 2H), 6.72-6.68 (m, 2H), 5.89 (s, 2H), 3.56 (br s, 4H), 3.45 (bs, 2H), 2.48 (br s, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5](/[CH:16]=[CH:17]/[C:18](OCC)=[O:19])=[C:4]([CH3:23])[N:3]=1.CC(C)([O-])C.[K+]>CC(N(C)C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:23])[C:5]2[CH:16]=[CH:17][C:18](=[O:19])[N:8]([C@H:9]3[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@H](O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(N)nc2c1ccc(=O)n2[C@H]1CC[C@H](O)CC1
Temperature: 150 °C

Procedure:
To a solution of (E)-ethyl 3-(2-amino-4-(trans-4-hydroxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate (233 mg, 0.727 mmol) in dimethylacetamide was added 1,5-diazbicyclo[5,4,0]undec-5-ene (544 uL, 3.64 mmol) followed by potassium tert-butoxide (1 M in THF, 364 uL, 364 mmol). The resulting solution was heated at 150° C. overnight then concentrated. The residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-5%). The product was then triturated with 1:1 chloroform:hexane to afford the title compound (119 mg, 60%).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15](C(=O)C(F)(F)F)=[CH:14][CH:13]=2)[N:7]=1)=[O:4].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][CH:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH3:2])[CH2:10]1
Reactant: CC1CC(NC(=O)C(F)(F)F)=NN1c1ccc(C(=O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC1=NN(c2ccccc2)C(C)C1
Reaction time: 3 h

Procedure:
A mixture of 2.0 g. of 3-amino-5-methyl-1-phenyl-2-pyrazoline (prepared in Example 5), 5.0 ml. of acetic anhydride and 100 mg. of 4-dimethylaminopyridine is allowed to stand at room temperature for 3 hours. The mixture is filtered to give a white solid. The solid is dissolved in dichloromethane and is columnized and recrystallized as for Example 14 (B) to give 0.90 g. of the desired product as colorless plates, m.p. 144.5°-146.5° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]([CH2:19][N:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:21]([CH3:23])[CH3:22])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)[CH3:6].C(OC(=O)COC1C=CC(CCC2CC3C=CC(OC)=CC=3O2)=CC=1)C>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:20]([CH2:19][C:16]2[S:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:5]([CH3:6])[CH2:4][CH2:3][OH:2])=[CH:9][CH:10]=3)=[CH:18][CH:17]=2)[CH:21]([CH3:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: COC(=O)CN(C)Cc1ccc(-c2ccc(CN(c3ccc(F)cc3)C(C)C)s2)cc1
Agent: CCOC(=O)COc1ccc(CCC2Cc3ccc(OC)cc3O2)cc1
Product: CC(C)N(Cc1ccc(-c2ccc(CN(C)CCO)cc2)s1)c1ccc(F)cc1
Yield: 28 %

Procedure:
When the product of Step C was substituted for ethyl-2-(4-(2-(6-methoxy-2,3-dihydrobenzofuran-2-yl)ethyl)phenoxy)acetate in Example 21, Step D, the similar process afforded the title compound in 28% yield, as light yellow paste. 1H NMR (CDCl3) 7.47 (d, 2H, J=8.05 Hz); 7.24 (d, 2H, J=8.04 Hz); 7.10 (d, 1H, J=3.60 Hz); 6.91-6.85 (m, 3H); 6.81-6.76 (m, 2H); 4.44 (s, 2H); 4.07-3.98 (m, 1H); 3.61 (t, 2H, J=5.31 Hz); 3.53 (s, 3H); 2.58 (t, 2H, J=5.31 Hz); 2.21 (s, 3H); 1.21 (d, 6H, J=6.56 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[NH:17][NH2:18]>C(O)CCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:18][NH:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccc(C#N)cc2)nn1
Temperature: 25 °C

Procedure:
A mixture of 0.40 g. of 6-(p-cyanophenyl)-3-chloropyridazine and 0.70 g. of 97% ethyl carbazate in 25 ml. of n-butanol is prepared. The solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and the product precipitated from solution. The product is filtered, washed with n-butanol, water, dried and recrystallized from ethanol giving a crystalline material, m.p. 235° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>C(O)(C)C.C(Cl)(Cl)Cl>[F:20][C:18]([F:19])([F:21])[C:15]1[CH:14]=[CH:13][C:12]([S:9]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)(=[O:10])=[O:11])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
To a solution of 2.99 g (9.29 mmol) of 1-(4-trifluoromethyl -benzenesulfonyl)-cyclopropanecarboxylic acid ethyl ester in THF/water (1/1, 50 mL) were added 0.82 g (19.5 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The organic solvent was removed under reduced pressure and the aqueous layer washed with diethyl ether (2×50 mL). The basic aqueous layer was cooled in an ice bath and acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 2.19 g of 1-(4-trifluoromethyl-benzenesulfonyl)-cyclopropanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br-:8].[Br:9][CH2:10][CH2:11][CH2:12][N+:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15]>CN(C=O)C>[Br-:9].[Br-:8].[CH2:14]([N+:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:12][CH2:11][CH2:10][N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: CC[N+](CC)(CC)CCCBr
Reactant: Cc1ccncc1
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC[N+](CC)(CC)CCC[n+]1ccc(C)cc1
Yield: 57.4 %

Procedure:
4-Methylpyridine (307 mg, 3.3 mmol), (3-bromopropyl)triethylammonium bromide (1.0 g, 3.3 mmol), and 4 mL DMF were stirred at 100° C. in a pressure vessel for 41 h. Precipitates formed during the reaction. After cooling down, the precipitates were filtered out and washed with CH2Cl2 to give 1-(3-triethylammoniopropyl)-4-methylpyridinium dibromide as a light pink solid (750 mg, 57%), which was used in the next aldol condensation without further purification. 1H NMR (400 MHz, CD3OD): δ 1.34 (t, J=7.0 Hz, 9 H), 2.50 (m, 2 H), 2.70 (s, 3 H), 3.35-3.47 (m, 8 H), 4.73 (t, J=7.8 Hz, 2 H), 7.99 (d, J=6.4 Hz, 2 H), 8.98 (d, J=6.4 Hz, 2 H); 13C NMR (100 MHz, CD3OD): δ 8.0, 22.1, 25.2, 54.4, 54.5, 58.3, 130.1, 145.2, 161.9; HRMS (FAB+): m/z=315.1428 [M-Br]+ (calcd for C15H28BrN2: 315.1430).
Reaction SMILES: [O:1]=[C:2]1[CH:16]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:15]2[N:14]=[CH:13][N:6]3[CH2:7][C:8](=[O:12])[CH2:9][CH2:10][NH:11][C:4]([C:5]=23)=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15]2[N:14]=[CH:13][N:6]3[CH2:7][C:8](=[O:12])[CH2:9][CH2:10][NH:11][C:4]([C:5]=23)=[CH:3]1
Reactant: CC(C)(C)OC(=O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate from Step D (15 mg, 0.045 mmol) in CH2Cl2 (3 mL) was added TFA (1 mL). After 2 h, the mixture was concentrated under reduced pressure to give the title compound. MS: m/z 276 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])=[O:15])[CH2:7]2)([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])=[O:15])[CH2:7]2
Reactant: O=C(CC1Cc2ccc([N+](=O)[O-])cc2C1)C1SCN[C@@H]1C(=O)N1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2c(c1)CC(CC(=O)C1SCN[C@@H]1C(=O)N1CCCC1)C2
Reaction time: 1 h
Yield: 58.5 %

Procedure:
0.63 g of 1-[3-(5-nitroindan-2-ylacetyl)-L-thioprolyl]pyrrolidine prepared in Example 29 was dissolved in a mixed solution of 9 ml of acetic acid and 6 ml of water. 1.00 g of iron powder was gradually added with stirring. After 1 hour, the iron powder was filtered. The filtrate was alkalinized using 10% sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue obtained was purified by silica gel chromatography to produce 0.34 g of 1-[3-(5-aminoindan-2-ylacetyl)-L-thioprolyl]pyrrolidine as a brownish and oily substance (yield: 59%).
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: Clc1cc(Br)ccc1OCc1ccccc1
Agent: COc1ccc(Br)cc1C
Product: Clc1cc(N2CCNCC2)ccc1OCc1ccccc1
Yield: 65.2 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenethyl)piperazine were replaced with 1-benzyloxy-4-bromo-2-chlorobenzene (7.138 g) and piperazine (12.404 g), respectively. Thus obtained crude product was purified on silica gel column chromatography (eluent, chloroform: methanol=5:2) to provide 1-(4-benzyloxy-3-chlorophenyl)piperazine (4.739 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Yield: 62.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (1.12 g, 1.544 mmol) was deprotected in TFA/DCM (10/5 ml). This afforded 600 mg (64.8% yield) of the titled compound. MS: m/z=625.8 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:7][C:6]3[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=3)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2ccc(Cl)cc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(Cl)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-chloro-2-oxindole to give 0.3 g of 6-chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1I.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>COCCOC.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[Cl:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1
Reactant: Nc1ncnc2c1c(I)c(Cl)n2-c1cccc([N+](=O)[O-])c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Cl)cc1)c(Cl)n2-c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 95.5 %

Procedure:
A mixture of 6-chloro-5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (18) (1.4 g, 3.4 mmol), 4-chlorophenylboronic acid (696 mg, 4.5 mmol), Pd(dppf)Cl2.DCM (140 mg, 0.17 mmol) and Na2CO3 (1.1 g, 10.3 mmol) in DME (30 mL) and H2O (15 mL) was purged with N2 before heated to 90° C. overnight. After cooled down to r.t., the reaction was quenched with H2O (50 mL). The resulting mixture was extracted with DCM contained 25% i-PrOH(50 mL×3). The combined organic phase were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatographic (silica gel, 0 to 50% EA in a mixture of PE & DCM (1:1) and then 0 to 5% MeOH in DCM) to afford 6-chloro-5-(4-chlorophenyl)-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (19) (1.3 g, 91% yield) as a yellow solid. LC-MS (ESI): m/z (M/M+2) 399.9/401.9.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][CH:16]1[NH:20][C:19](=O)[CH2:18][CH2:17]1>>[CH3:15][CH:16]1[N:20]=[C:19]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1CCC(=O)N1
Product: CC1CCC(N2c3ccccc3Oc3ccccc32)=N1

Procedure:
Reaction of phenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Example 1 affords the free base 10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 135°-137° C., from n-heptane. Conversion of the free base to the hydrochloride salt provides 10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 229.5°-236.0° C. (dec.) (corr.), in a 57% overall yield.
Reaction SMILES: C[O:2][C:3](=[O:5])[O-:4].[CH3:6][N+:7]([CH3:11])([CH3:10])[CH2:8][CH3:9]>O>[C:3](=[O:2])([O-:5])[OH:4].[CH3:6][N+:7]([CH3:11])([CH3:10])[CH2:8][CH3:9]
Reactant: COC(=O)[O-]
Agent: CC[N+](C)(C)C
Solvent: O
Product: O=C([O-])O
Reaction time: 3 h

Procedure:
114.1 g of trimethylethylammonium monomethylcarbonate and 75.6 g of water were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature in the reactor reached 120° C., the reaction was continued for 3 hours at 120° C. Trimethylethylammonium hydrogencarbonate was obtained in a yield of 96.3 mol %.
Reaction SMILES: C([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([OH:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.C1(C(C)C)C=CC(C)=CC=1>[Pd]>[OH:24][C:23]1[C:14]2[C:12]3[C:11]([C:17]([CH3:18])([CH3:19])[O:16][C:15]=2[CH:20]=[C:21]([CH3:25])[CH:22]=1)=[CH:10][CH:9]=[N:8][CH:13]=3
Reactant: Cc1cc(O)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: Cc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
Reaction of 2-benzyl-10-hydroxy-5,5,8-trimethyl-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine (100 mg., U.S. Pat. No. 3,535,327) with Pd/C in boiling cymene gives 10-hydroxy-5,5,8-trimethyl-5H[1]benzopyrano[3,4-d]pyridine.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:12](O)=[O:13])=[CH:6][CH:5]=1.[CH3:37][NH2:38]>>[CH3:37][NH:38][C:12](=[O:13])[CH:11]([NH:15][C:16](=[O:34])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:35])([F:36])[F:1])=[CH:5][CH:6]=1
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CN
Product: CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 3-[4-(trifluoromethoxy)phenyl]-2-({4-[4-(trifluoromethyl)phenoxy]benzoyl}amino)propanoic acid (720 mg) prepared in Example 88 (88a) and methylamine (798 μL, 2 M methanol solution) to give 330 mg of the title compound (white powder).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[F:13][CH:14]([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:20]([OH:21])[C:19]1[CH:22]=[CH:23][C:16]([O:15][CH:14]([F:13])[F:24])=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: OC(c1ccc(OC(F)F)cc1)c1ccccc1C(F)(F)F
Yield: 63.9 %

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and 4-(difluoromethoxy)benzaldehyde (2.09 mL, 15 mmol) using the procedure described for compound (96). The product was obtained as an amber gum (3.05 g, 64%).
Reaction SMILES: [H-].[Na+].Br.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:18]3[C:14]([S:15][CH2:16][CH2:17]3)=[N:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:7][CH:6]=1.FC(F)(F)S(O[CH2:32][C:33]([F:36])([F:35])[F:34])(=O)=O>O1CCCC1>[F:34][C:33]([F:36])([F:35])[CH2:32][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:18]3[C:14]([S:15][CH2:16][CH2:17]3)=[N:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:32][C:33]([F:34])([F:35])[F:36])=[CH:21][CH:20]=2)=[CH:9][CH:10]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(-c2nc3n(c2-c2ccc(O)cc2)CCS3)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COc1ccc(-c2nc3n(c2-c2ccc(OCC(F)(F)F)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 6.14 g. of sodium hydride [50% dispersion in oil, (0.128 mole)] in 150 ml. of tetrahydrofuran (distilled from lithium aluminum hydride) at 0° C. under nitrogen was added 10.0 g. (0.0256 mole) of 5,6-bis(p-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole hydrobromide. After 30 minutes, 17.82 g. (0.0768 mole) of 2,2,2-trifluoroethyl trifluoromethanesulfonate was added dropwise, maintaining the temperature below 0° C. After stirring overnight at room temperature, the suspension was added portionwise to 500 ml. of ice water under nitrogen and extracted three times with methylene chloride. The organic layer was washed with water, dried over potassium carbonate and concentrated in vacuo. The residue was recrystallized from methylene chloride-hexane to give 5,6-bis[p-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 163°-164° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:9]([CH3:20])=[N:10][C:11]([CH:17]2[CH2:19][CH2:18]2)=[C:12]([CH:16]=1)[C:13](O)=[O:14])#[N:2].[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:9]([CH3:20])=[N:10][C:11]([CH:17]2[CH2:19][CH2:18]2)=[C:12]([CH:16]=1)[C:13]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)=[O:14])#[N:2]
Reactant: Cc1nc(C2CC2)c(C(=O)O)cc1OCc1cccc(C#N)c1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1nc(C2CC2)c(C(=O)Nc2ccc(C#N)cc2)cc1OCc1cccc(C#N)c1
Yield: 33.2 %

Procedure:
The amide coupling of 5-(3-cyano-benzyloxy)-2-cyclopropyl-6-methyl-nicotinic acid (185) (230 mg, 0.7 mmol) and 4-amino-benzonitrile (106 mg, 0.9 mmol), as described in Example 67, gave 5-(3-cyano-benzyloxy)-N-(4-cyano-phenyl)-2-cyclopropyl-6-methyl-nicotinamide (186) (95 mg, 27% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][C@H:5]1[O:7][C@@H:6]1[CH2:8][OH:9].[H-].C([Al+]CC(C)C)C(C)C>>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][CH:6]([OH:7])[CH2:8][OH:9]
Reactant: COC(C[C@H]1O[C@@H]1CO)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COC(CCC(O)CO)OC

Procedure:
reacting (2R,3R) 3-(2,2-dimethoxyethyl)oxiranemethanol with diisobutylaluminum hydride to form 5,5-dimethoxypentane-1,2-diol;
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH2:11][C:12]#[N:13])=[C:6]([CH3:10])[S:7][C:8]=1[CH3:9])#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>CCO>[CH3:9][C:8]1[S:7][C:6]([CH3:10])=[C:5]([CH2:11][C:12]2[S:25][C:17]3[C:18]([F:24])=[CH:19][C:20]([F:23])=[C:21]([F:22])[C:16]=3[N:13]=2)[C:4]=1[CH2:3][C:1]#[N:2]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: Cc1sc(C)c(CC#N)c1CC#N
Agent: Cl
Solvent: CCO
Product: Cc1sc(C)c(Cc2nc3c(F)c(F)cc(F)c3s2)c1CC#N
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A solution of (4-cyanomethyl-2,5-dimethyl-thiophen-3-yl)-acetonitrile (1.90 g, 10.0 mmol) and 2-amino-3,4,6-trifluoro-benzenethiol hydrochloride (2.16 g, 10.0 mmol) in EtOH (22 mL) is heated to reflux for 44 h. After cooling to room temperature, the mixture is concentrated in vacuo and purified by flash chromatography (silica gel, 10-30% ethyl acetate in heptane). Further purification by recrystallization with ethyl acetate and heptane gave [2,5-dimethyl-4-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetonitrile (1.1 g, 31.2%) as a white powder: mp 145-146° C.; Rf 0.54 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 6.95-7.08 (m, 1 H), 4.36 (s, 2 H), 3.59 (s, 2 H), 2.43 (s, 3 H), 2.41 (s, 3 H).