Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[CH2:14]([O:16][C:17]([C@@:19]1([CH3:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1)=[O:18])[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:14]([O:16][C:17]([C@@:19]1([CH3:25])[CH2:24][CH2:23][CH2:22][N:21]([C:11]([C@@H:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)=[O:12])[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)[C@@]1(C)CCCNC1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@]1(C)CCCN(C(=O)[C@H]2COc3ccccc3O2)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (6.05 g, 30.5 mmol) in DCM (20 ml) was added to a stirred mixture of (S)-3-methyl-piperidine-3-carboxylic acid ethyl ester (5.0 g, 29.2 mmol), DIPEA (5.5 ml, 31.7 mmol) and DCM (30 ml), previously cooled down to 5° C. The cooling bath was removed and stirring continued at RT for 1 h. The reaction mixture was washed twice with 1 M HCl, twice with sat. aq NaHCO3 and twice with water and dried with Na2SO4. Solvent was evaporated to give 9.66 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Cl.[NH2:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH2:19][C:20]2([OH:26])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=1)(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1(O)CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(NCC2(O)CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(isopropylsulfonyl)-2-nitrobenzene (Step C of Example 1), 4-(aminomethyl)tetrahydro-2H-pyran-4-ol hydrochloride (Step A of Example 19) and triethylamine.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: CC1CCCNC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCC(C)C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
A mixture of 2-(1, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), 3-methyl piperidine (19 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 34.2 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3-methylpiperidin-1-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% Bin 30 min, injection vol. 5 mL).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.N[CH2:13][C:14]1C=C(C=CC=1)CN(CC1NC2C=CC=CC=2N=1)C1C2N=CC=CC=2CCC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:13]([O:9][C:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=1[CH3:11])=[O:10])[CH3:14]
Reactant: NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Reactant: Cc1ncnc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1c(C)ncnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F: A solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid from above (prepared as described in patent application PCT/US00/11632) (42 mg, 0.28 mmol), (3-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (100 mg, 0.25 mmol), HOBT (38 mg, 0.28 mmol) and 4-methylmorpholine (40 μL, 0.38 mmol) in DMF (0.8 mL) was flushed with N2. EDCI (54 mg, 0.28 mmol) was added and the mixture was stirred at room temperature overnight. Purification of the colorless syrup (150 mg) by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) afforded AMD11084 (80 mg, 60%) as a white foam. 1H NMR (CDCl3) δ 1.64-1.77 (m, 1H), 1.91-2.08 (m, 2H), 2.18-2.34 (m, 1H), 2.37 (s, 6H), 2.69-2.91 (m, 2H), 3.73 (s, 2H), 3.80 (d, 1H, J=16.5 Hz), 4.00 (d, 1H, J=16.5 Hz), 4.07-4.13 (m, 1H), 4.69 (d, 2H, J=5.7 Hz), 6.53 (t, 1H, J=5.7 Hz), 6.96-7.10 (m, 3H), 7.16-7.22 (m, 2H), 7.29-7.31 (m, 2H), 7.40-7.45 (m, 3H), 8.64 (d, 1H, J=3.6 Hz), 8.81 (s, 1H); 13C NMR (CDCl3) δ 21.71, 22.28, 24.38, 29.55, 44.29, 49.22, 55.11, 61.90, 111.12, 118.82, 121.68, 122.78, 127.32, 128.67, 129.09, 129.24, 130.48, 135.22, 137.66, 137.83, 140.30, 147.22, 156.42, 157.60,157.91, 163.43, 166.96. ES-MS m/z 532.4 (M+H). Anal. Calcd. for C32H33N7O.0.4CH2Cl2: C, 68.80; H, 6.02; N, 17.33. Found: C, 68.56; H, 6.09; N, 17.34.
Reaction SMILES: [NH2:1][C@:2]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([F:17])[CH:8]=1)[CH2:3][C:4](O)=[O:5].CC[N:27]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>ClCCCl.C(Cl)Cl>[NH2:1][C@:2]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)([C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[C:9]([F:17])[CH:8]=1)[CH2:3][C:4]([NH2:27])=[O:5]
Reactant: N[C@@](CC(=O)O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)C[C@](N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
(S)-3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoic acid (0.047 g, 0.13 mmol, prepared as described in Procedure 29) was dissolved in DCE (5 mL) at room temperature. To the solution was added EDCI (0.035 g, 0.14 mmol), HOBt (0.025 mg, 0.14 mmol), NH4Cl (0.075 g, 1.3 mmol) and TEA (ca.0.070 g). The resulting solution was stirred for 18 h then heated to 50° C. for 8 h. On cooling the reaction mixture was diluted with DCM (ca. 10 mL) and washed with saturated NaCl solution (ca.2×10 mL). (S)-3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl) propanamide was isolated as a colorless oil (0.03 lg, 65% yield) and was used without further purification. LCMS: 1.25 min [M+1] 362.2 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)(=O)=O)=CC=1>CC(C)=O>[CH:37]1([CH2:36][CH2:35][N:15]2[C:16](=[O:17])[N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[CH:13]=[N:14]2)[CH2:39][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(-n2cnn(CCC3CC3)c2=O)nc1C
Temperature: 25 °C
Yield: 63 %

Procedure:
To a suspension of ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (0.25 g, 0.98 mmol) and potassium carbonate (0.20 g, 1.47 mmol) in acetone (20 mL) was added 2-cyclopropylethyl 4-methylbenzenesulfonate (0.28 g, 1.18 mmol). The reaction mixture was heated to reflux for 24 hours, cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo to afford ethyl 2-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate in 63% yield (0.20 g): MS (ES+) m/z 323.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([CH2:34][C:35](O)=[O:36])[CH:31]=[CH:32][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:23]=[CH:24][CH:25]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:38])([F:26])[F:39])[CH:29]=2)[CH:3]=1)#[N:22]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cccc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 85 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.285 mmol) produced in Example 3(vi), [3-(trifluoromethyl)phenyl]acetic acid (138 mg, 0.684 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (260 mg, 0.684 mmol) and pyridine (2 mL) was stirred at 85° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), washed successively with saturated aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/2) to give the title compound (87 mg, 57%) as a white powder.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:19])[CH:9]=2)[N:4]=1)[NH2:2].[CH:20]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[C:13]1([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:19])[CH:9]=3)[N:4]3[CH:20]=[N:2][N:1]=[C:3]3[N:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Reactant: CCOC([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc2c(c1)c(-c1ccccc1)nc1nncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2.0 g of 2-hydrazino-4-phenyl-6-chloroquinazoline in 50 ml of ethanol were added 5.5 g of ethyl orthoformate and 1 ml of concentrated sulfuric acid. The resulting mixture was stirred at room temperature for 1 hour and then 30 ml of dilute sodium bicarbonate solution was added thereto. The resulting crystals were collected by filtration and recrystallized from ethanol to give 5-phenyl-7-chloro-s-triazolo[4,3-a]quinazoline as colorless needles, m.p. 295° - 297° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[C:14]#[N:15].[OH-].[Na+]>CC(C)=O.O>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:12][C:13]([C:14]#[N:15])([CH3:17])[CH3:16])[N:3]=1
Reactant: CC(C)(N)C#N
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A stirred solution of 6.3 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 25 ml of acetone was cooled to -10°, and 2.5 grams of 2-amino-2-methylpropionitrile was added. With the reaction mixture at -10°, a solution of 1.3 grams of sodium hydroxide in 3.5 ml of water was added dropwise. Upon complete addition, the reaction mixture was stirred at -10° for 30 minutes. The acetone was removed under reduced pressure; the residue was extracted with diethyl ether, and the extract was separated and dried over magnesium sulfate. The extract was filtered, and the filtrate was evaporated under reduced pressure, yielding a residue. The residue was recrystallized from methylcyclohexane to give 3.1 grams of 4,6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile; mp, 154-158°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:15].[Cl:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:16][C:10]1[C:5]2[NH:4][C:3](=[O:15])[N:2]([CH3:1])[C:6]=2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc2[nH]c(=O)n(C)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c2[nH]c(=O)n(C)c12
Yield: 2.9 %

Procedure:
A solution of methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (500 mg, 2.42 mmol), N-chlorosuccinimide (355 mg, 2.66 mmol) and 2,2′-azobis(isobutyronitrile) (20 mg, 0.12 mmol) in carbon tetrachloride (40 mL) was refluxed for 2 days. After cooling, the reaction mixture was concentrated in vacuo. The resultant was extracted with ethyl acetate and water. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel to give 167 mg (0.07 mmol, 29%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:46]=[CH:47][CH:48]=1)[C:8]([NH:10][C:11]1[C:12]([CH3:45])=[C:13]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[C:26]([CH:37]=2)[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:9].C(OC([NH:56][CH2:57][C:58](O)=[O:59])=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:56][CH2:57][C:58]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:46]=[CH:47][CH:48]=1)[C:8]([NH:10][C:11]1[C:12]([CH3:45])=[C:13]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([NH:38][C:39](=[O:44])[C:40]([F:41])([F:42])[F:43])=[C:26]([CH:37]=2)[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:9])=[O:59]
Reactant: Cc1c(NC(=O)c2cccc(OCCN)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC(=O)c2cccc(OCCNC(=O)CN)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1

Procedure:
By following the process described in stage G of Example 42, the coupling of benzyl 5-[(1-{[3-(2-aminoethoxy)benzoyl]amino}-2-methylindolizin-3-yl)carbonyl]-2-[(trifluoroacetyl)amino]benzoate (described in stage F, Example 42) with N-tert-butoxycarbonylglycine is carried out. The compound obtained is then deprotected with trifluoroacetic acid to give the amine according to the process described in stage F of Example 42.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.CCOC(C)=O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: Oc1cccc(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Oc3cccc(Cl)c3)c2cc1OC
Temperature: 25 °C

Procedure:
THF (5 ml) and NaH (60% disp in oil, approx. 28 mg) is added to a dry flask maintained under inert atmosphere at room temperature. 3-Chlorophenol (0.09 g) is added as a soln. in THF (1 mL) and stirring is continued until the solution became clear. 4-Chloro-6,7-dimethoxyquinazoline is added all at once (as the solid) and stirring was maintained overnight at RT. The solution is partitioned between CH2Cl2 and 5% NaOH. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (40% EtOAc/Hex) provided the pure compound. An analytical sample is obtained by recrystallization from EtOAc/Hex to provide 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline (0.05 g), white needles, m.p. 152-153° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH2:14][NH:15][CH2:16][C:17]([O:19]CC)=O)C.[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=[C:30]=[O:31])=[CH:26][CH:25]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:22])=[C:8]([CH2:14][N:15]2[CH2:16][C:17](=[O:19])[N:29]([CH2:28][C:27]3[CH:32]=[CH:33][C:24]([Cl:23])=[CH:25][CH:26]=3)[C:30]2=[O:31])[CH:9]=1
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: CCOC(=O)CNCc1cc(Br)ccc1OCC(=O)OCC
Product: O=C(O)COc1ccc(Br)cc1CN1CC(=O)N(Cc2ccc(Cl)cc2)C1=O

Procedure:
Prepared from 4-bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic acid ethyl ester (235 mg, 0.63 mmol) and 4-chlorobenzylisocyanate (166 μL, 1.26 mmol) according to GP12 (yield: 183.4 mg, 62%): LC/MS (an10p8): Rt 2.3 min, m/z 465 [M−H]−; 1H NMR (DMSO-d6): δ 4.05 (s, 2H), 4.48 (s, 2H), 4.55 (s, 2H), 4.73 (s, 2H), 6.92 (d, J=8.3 Hz, 1H), 7.25-7.45 (m, 6H), 13.11 (br. s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH3:16][O-:17].[Na+].CO.O.Cl>CO>[CH3:16][O:17][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(CCl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1ccc(C(=O)O)c([N+](=O)[O-])c1

Procedure:
A mixture of methyl 4-chloromethyl-2-nitrobenzoate (1.6 g), 28% sodium methoxide-methanol solution (2.5 ml) in methanol [16 ml) was stirred under reflux for 24 hours. To this mixture, water (5 ml) was added and the mixture was stirred for 2 hours, acidified with 1N hydrochloric acid, extracted with ethyl acetate. The combined organic extract was washed with water, dried over magnesium sulfate and evaporated to give 4-methoxymethyl-2-nitrobenzoic acid (0.84 g).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14]>>[Cl:1][C:2]1[N:3]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]=[O:14])[CH:20]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Yield: 99 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-formylphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(3-formylphenyl)-1H-indole-3-carboxaldehyde (99% yield) as a white solid. ESI/MS 284 (M+H); RT=3.37 min; NMR 10.15 (1H, s); 10.12 (1H, s); 8.23 (3H, m); 7.98 (2H, m); 7.41 (2H, m); 7.18 (1H, d, J=9 Hz).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15].Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:15][CH:14]([CH3:16])[C:13]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17]
Reactant: CC(C)(C)O
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 48370 %

Procedure:
With ice-cooling, a solution of 73.0 g (0.985 mol) of tert-butanol, 190 g (1.877 mol) of triethylamine and 0.573 g (0.0047 mol) of DMAP in 750 ml of dichloromethane is treated with a solution of 100 g (0.939 mmol) of isobutyryl chloride in 150 ml of dichloromethane, and the mixture is then stirred overnight. 500 ml of 2 M hydrochloric acid are then added, the aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water, sat. NaHCO3 solution and sat. NaCl solution, dried over sodium sulphate and concentrated. Distillative purification of the crude product gives 65.5 g (48%) of tert-butyl 2-methylpropionate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.ClC(OCC)=O.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=[C:27]2[C:33]3[CH:34]=[C:35]([CH2:38][NH2:39])[CH:36]=[CH:37][C:32]=3[CH:31]=[CH:30][C:29]3[CH:40]=[CH:41][CH:42]=[CH:43][C:28]2=3)[CH2:23][CH2:22]1>C(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]3[CH:31]=[CH:30][C:29]4[CH:40]=[CH:41][CH:42]=[CH:43][C:28]=4[C:27](=[C:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)[C:33]=3[CH:34]=2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(CN)cc32)CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCc1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1C=C2
Reaction time: 0.5 h

Procedure:
To a solution of 0.6 g (3.2 mmole) of 4-amino-5-chloro-2-methoxybenzoic acid in 15 ml of methylene chloride cooled to -15° C. was added 0.347 g (3.7 mmol) of ethyl chloroformate. The solution was stirred for 30 minutes and 1.0 g (3.2 mmole) of 1-methyl-4-(3-aminomethyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine in 10 ml of methylene chloride was added. The solution was allowed to stir at room temperature for 2 hours. The solution was washed with 1N sodium hydroxide solution, water, and brine, and then was dried (MgSO4). After filtration, the solvent was removed under reduced pressure to give 4-amino-5-chloro-2-methoxy-N-((5-(l-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cyclohepten-3-yl)methyl)benzamide as an amorphous foam.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6]C[CH2:4][CH2:3][CH2:2]1.[CH:9](OC)([O:12][CH3:13])[O:10][CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:11][O:10][C:9]1([O:12][CH3:13])[CH2:4][CH2:3][CH2:2][CH2:1][CH2:7][CH2:6]1
Reactant: O=C1CCCCCC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)CCCCCC1
Temperature: 27.5 °C
Reaction time: 1.5 h

Procedure:
To a flask with reflux condenser (5 g) cycloheptanone, and 10 ml methanol was taken. (10 ml) (2.0 eq.) trimethyl orthoformate and several crystals of p-toluenesulfonic acid were added in to the reaction mixture and the mixture was stirred at 25-30° C. to about 1.5 hrs. Color of the reaction mixture became pale yellow. Reaction was monitored by TLC. Then remove the methanol on rotavapour. Water was added in to the reaction mixture and extract with ethyl acetate. Organic layer was washed with 5% sodium bicarbonate solution then water and brine solution. Concentrate it on rotavapor yellow colored oily product obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[N:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[S@@](=O)N=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
To a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (5 g, 20.7 mmol) and (R)-2-methylpropane-2-sulfinamide (3.3 g, 26.9 mmol) in DCM (50 ml) at 0° C., was drop wise added Ti(O-iPr)4 (5.9 g, 24.8 mmol) under N2 atmosphere. After stirring for 20 h at room temperature, the reaction mixture was poured into water (100 mL) with vigorous stirring. The precipitate was filtered off and the filtrate was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (5.5 g, yield: 78%); m/z (ES+): 346 [M+H]+.