Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:18]([CH3:20])[N:17]([CH3:21])[C:16]2=O)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([Li])[CH3:30]>C1(C)C=CC=CC=1.C(=O)=O>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:18]([CH3:20])[N:17]([CH3:21])[C:16]2=[CH:29][CH3:30])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1CC(c2ccccc2)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C(=O)N1C
Reactant: [Li]CC
Agent: O=C=O
Solvent: Cc1ccccc1
Product: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Product of Step 7 (2.5 g) was dissolved in toluene (150 mL). The solution was cooled by surrounding the flask with dry ice and the contents were stirred under argon purging for 30 min. To this was added a dispersion of ethyl lithium (25 mL, 1.7 M in butyl ether). The reaction mixture was stirred in dry ice under argon purging for 1 hr and allowed to warm to 25° C. The reaction mixture was stirred for 3 hr at 25° C. under argon purging. Then, the reaction mixture was poured in a beaker and cooled to 0° C. using an ice bath. The reaction was quenched by slow addition of water (5 mL) to the stirring toluene solution. After the evolution of gases ceased, the reaction mixture was extracted with water (three times at 50 mL each). The organic layer was diluted with ethyl acetate (500 mL) and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under vacuum to obtain Step 8 product as a red-brown viscous oil (3 mL). Mass spectrometry: m/z=408 (M+H). The product was carried forward without further purification.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[O:12][C:13]([CH:16]3[CH2:18][CH2:17]3)=[N:14][N:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>CO.[NH4+].[Cl-]>[C:1]1([S:7]([CH:10]([C:11]2[O:12][C:13]([CH:16]3[CH2:17][CH2:18]3)=[N:14][N:15]=2)[CH:22]2[CH2:23][CH2:24][CH2:25][C:20](=[O:26])[CH2:21]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CCCC1
Reactant: O=S(=O)(Cc1nnc(C2CC2)o1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: O=C1CCCC(C(c2nnc(C3CC3)o2)S(=O)(=O)c2ccccc2)C1
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
To 2.47 g (9.3 mmol) of 2-benzenesulfonylmethyl-5-cyclopropyl-[1,3,4]oxadiazole in 25 mL of MeOH at 0° C., 170 μL (0.93 mmol, 0.1 eq) of a solution of sodium methoxyde (5.4 M in MeOH) were added. After 15 min, 895 mg (9.3 mmol, 1 eq) of cyclohex-2-enone were added. The reaction mixture was stirred from 0° C. to RT over 4 hours, diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with EtOAc/heptane 2:1 gave 1.48 g (44%) of 3-[benzenesulfonyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-methyl]-cyclohexanone as a racemic mixture of diastereomers, white solid, MS: 361 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[CH:11](=O)[CH:12]([CH3:14])[CH3:13].CO>C(O)=O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[CH:11][CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(C)C=O
Solvent: O=CO
Solvent: CO
Product: Cc1cc(C)c(N=CC(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,4,6-Trimethylaniline (7.0 mL, 50 mmol, Aldrich) was mixed with isobutyraldehyde (4.5 mL, 50 mmol, Aldrich), methanol (20 mL), and formic acid (1 mL of a 88% aqueous solution, Fisher). The reaction mixture became reddish and was stirred at RT for 4 h. Assay by 1H-NMR showed a 2/1 mixture of product/starting materials. Additional isobutyric aldehyde (4 mL, 44 mmol) was added to the reaction mixture and it was stirred for 12 h. At this point assay by 1H-NMR showed a 5/1 mixture of product/amine. The solvent and excess aldehyde was evaporated, the residue was distilled at reduced pressure collecting three fractions: 1. 53–56° C./27 Pa, 1/1 mixture of product/amine; 2. 56–59° C., 7/1 product/amine; 3. 59–60° C., pure product (2.3 g, 24.3%). 1H NMR (CDCl3) 7.52 (d, 1H; J=4.8 Hz); 6.84 (br s, 2H); 2.70 (d of septets, 1H; J=4.8; 6.9 Hz); 2.26 (s, 3H); 2.05 (s, 6H); 1.22 (d, 6H; J=6.9 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.4 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,3-dichlorophenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure the residue purified by preparative HPLC to provide 9 mg (16%) of the desired product as a trifluoroacetic acid salt. 1H NMR (500 MHz, DMSO-d6) δ 2.62 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.68 (m, 2H), 7.88 (m, 2H), 8.12 (d, J=5 Hz, 1H), 10.12 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[CH:5]=O.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=1[NH2:30]>>[CH3:21][C:22]1[C:23]2[N:30]=[C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)=[C:2]([CH3:1])[CH:3]=3)[NH:29][C:24]=2[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1cc(C=O)ccc1OCCCN1CCN(C)CC1
Reactant: Cc1ccc(N)c(N)c1C
Product: Cc1cc(-c2nc3c(C)c(C)ccc3[nH]2)ccc1OCCCN1CCN(C)CC1
Yield: 75.3 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (180 mg, 0.65 mmol, 1.0 equiv), 3,4-dimethyl-benzene-1,2-diamine (89 mg, 0.65 mmol, 1.0 equiv), and Na2S2O5 (161 mg, 0.85 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 192 mg (75%) of the title compound. MS (electrospray): mass calculated for C24H32N4O, 392.26; m/z found, 393.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.95-7.85 (m, 2H), 7.35-7.23 (m, 1H), 7.08-7.00 (m, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.64-2.37 (m, 16H), 2.29 (s, 6H), 2.10-2.00 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[OH:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)c1cccc(C(=O)c2ccccc2)c1OCc1ccccc1
Reactant: COc1ccccc1-c1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(C(O)(c2ccccc2)c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of 3′-bromo-2-methoxybiphenyl (1 g, 3.8 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred at −78° C. and 2.5M n-butyllithium in hexanes (1.6 mL, 4 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 1 hr. A solution of (2-(benzyloxy)-3-tert-butylphenyl)(phenyl)methanone (1.3 g, 3.8 mmol) in tetrahydrofuran (5 mL) was added at such a rate that the temperature did not exceed −65° C. The reaction mixture was allowed to reach room temperature slowly and was poured onto saturated ammonium chloride (100 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in heptane (3.5 L). Pure 29 (1.2 g, 60%) was isolated.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1>ClCCl>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:13]([C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:18])[F:19])=[CH:17][CH:16]=2)=[N:1]1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (21.4 g) in dichloromethane (100 ml) at 0C was added dropwise a solution of 4-(trifluoromethyl)benzoyl chloride (25 g). The mixture was stirred at room temperature for 16 hours, washed with 2M HCl then sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was dissolved in dichloromethane (100 ml) and treated with thionyl chloride (14 ml) at 0C. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was partitioned between ethyl acetate and aqueous potassium hydroxide. The organic phase was dried (MgSO4) and evaporated. Yield 14.57 g.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A stirred suspension of 2-bromo-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (333 mg, 0.75 mmol) and cyclohexene (1.64 g, 20 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (5 mL, 5 mmol). After stirring for approximately four hours at room temperature, the reaction was quenched with methanol (20 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude orange residue (0.5 g). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 30% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min; and afforded, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of diethyl ether-hexane yielded the title compound (0.220 g, 0.51 mmol, 68%) as a homogeneous, off-white, crystalline solid, m.p. 201-203° C.;
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[O:12]1[C:6]2[C:5](=[CH:10][CH:9]=[C:8]([OH:11])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCCCc1ccc(O)cc1O
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)OCCC2
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.2 %

Procedure:
To a stirred solution of 4-(3-Hydroxy-propyl)-benzene-1,3-diol (3.05 g, 18.1 mmol, from Step 1) in anhydrous THF (50 mL ) were added Ph3P (7.13 g, 27.2 mmol, 1.5 eq) and ADDP (6.86 g, 27.2 mmol, 1.5 eq ) under argon. The mixture was stirred at rt for 17 h. The white solid was filtered off and the solvent was removed from the filtrate. The residue was purified on silica gel (flash column chromatography) eluting with 5% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide the desired product as white solid (1.80 g, 60.5%). 1H-NMR (CD3CN) δ 6.87 (d, 1H), 6.70 (broad, s, 1H, OH), 6.31 (dd, J=2.4, 8.2 Hz, 1H), 6.20 (d, 1H), 4.12 (t, 2H), 2.69 (t, 2H), 1.95 (m, 2H).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH2:15][CH:16]([C:18]3[CH:39]=[CH:38][C:21]([C:22]([NH:24][C@H:25]([C:33]([O:35]CC)=[O:34])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:23])=[CH:20][CH:19]=3)[CH3:17])[CH2:12][NH:11][C:9]=2[N:10]=1)(=O)C>[OH-].[Na+]>[NH2:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH2:15][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23])=[CH:38][CH:39]=3)[CH3:17])[CH2:12][NH:11][C:9]=2[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(C)CC2CNc3nc(NC(C)=O)nc(O)c3C2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(CC1CNc2nc(N)nc(O)c2C1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 72 h
Yield: 67.3 %

Procedure:
A homogeneous solution of 17.5 mg of diethyl N-(4-[1-(2-acetamido-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl]benzoyl)-L-glutamate in 2 mL of methanolic sodium hydroxide solution was allowed to stand at room temperature for 72 hours. Most of the solvent was then removed under reduced pressure and the mixture was diluted with water and acidified with acetic acid. The precipitate was collected by filtration, washed with water, and dried under reduced pressure (0.1 mm) for 48 hours to give 9.7 mg (67%) of the title compound, which may be alternatively named as 5,10-dideaza-10-methyl-5,6,7,8-tetrahydrofolic acid. mp >250° C., NMR delta 0.87-0.88 (brs, 1H each), 1-2.8 (m, 11H), 3.13 (m, 1H), 4.59 (m, 1H), 6.96 (d, 2H, J=9 Hz), 7.34 (d, 2H, J=9 Hz.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:27]=[C:26]([CH2:28][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[C:22]([CH3:23])[CH:21]=1
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cc(C)cc(C)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 66.5 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (850 mg, 3.5 mM), 3,5-dimethylbenzyl bromide (765 mg, 3.8 mM), and potassium carbonate (500 mg, 3.61 mM) in 25 mL DMF was stirred at room temperature for 19 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.84 g (67%) of the 9-[(3,5-dimethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.3-7.2 (m, 2H), 6.9 (s, 1H), 6.75 (s, 2H), 5.45 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), 2.2 (s, 6H), and 2.1 (m, 2H). IR (KBr, cm−1) 1726, 1653, 1602, 1465, 1442, 1282, 1172, and 1116. MS (ES) m/e 362.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6].CC(C)C(=O)[CH2:14][C:15]#[N:16]>>[CH3:1][O:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5](=[O:6])[CH2:14][C:15]#[N:16]
Reactant: CC(C)C(=O)CC#N
Reactant: COCC(C)(C)C(=O)OC
Product: COCC(C)(C)C(=O)CC#N
Yield: 29 %

Procedure:
Prepared from methyl 3-methoxy-2,2-dimethylpropanoate (8 g, 54.7 mmol) according to the method described in Example 122A Step 1 for 4-methyl-3-oxopentanenitrile. Purification via silica gel chromatography eluting with mixtures of petroleum ether and ethyl acetate afforded 5-methoxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (2.5 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.72 (s, 2H), 3.32-3.33 (m, 5H), 1.18 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]1=[O:21])[O:6][CH2:5]2.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:10][CH:9]=2)[CH2:5][O:6]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(Cl)cc2C1=C1OCc2cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Yield: 44.9 %

Procedure:
A solution of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (75 mg, 0.251 mmol), trityl chloride (84 mg, 0.301 mmol) and triethylamine (53 μμl, 0.377 mmol) in DMF (2.0 ml) was stirred at room temperature for 1.25 hours. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried with Na2SO4 and rotary evaporated. The yellow solid was precipitated from CHCl3 to give 5-chloro-3-[5-(trityl-amino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a bright yellow solid (61 mg, 45%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[Na].[CH3:16][SH:17].O>CO>[CH3:16][S:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CS
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: CSCC(=O)c1ccc(C(F)(F)F)cc1
Yield: 97.7 %

Procedure:
To 13.2 g of 2-bromo-4'-(trifluoromethyl)acetophenone dissolved in 40 ml of methanol was added under ice-cooling 34.6 g of a 15% aqueous solution of methyl mercaptan sodium salt. After the reaction at room temperature for 1 hour with stirring, the resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by evaporation of the solvent to obtain 11.3 g of oily product of 2-methylthio-4'-(trifluoromethyl)acetophenone (yield: 97.7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH:20]1([CH2:19][O:18][C@H:15]2[CH2:16][CH2:17][N:13]([C:11]([C:9]3[S:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[NH:33][C:29]4[CH:30]=[C:31]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:23])=[CH:32]5)[CH:8]=3)=[O:12])[CH2:14]2)[CH2:22][CH2:21]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@H](OCC2CC2)C1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC[C@H](OCC6CC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (3S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 447.2 (MH+); HPLC Rf: 5.341 min.; HPLC purity: 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:20])[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[O:14]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=[CH:19][C:15]2[O:14][C:13]([CH3:20])([CH3:12])[C:17](=[O:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=CC=Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=CC=Cc2ccc(Cl)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a solution of p-chlorocinnamaldehyde (2.7 g, 16.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.45 g, 19.4 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (32 mL, 3.2 mM). The reaction solution was stirred at room temperature for one day. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford yellow crystals (1.9 g, 36% yield), m.p. 95°-96° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:17][CH:18]([NH2:21])[CH2:19][CH3:20].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH:18]([NH:21][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1)([CH2:19][CH3:20])[CH3:17]
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CCC(C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCC(C)Nc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 38 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 22 mg of butan-2-amine and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-sec-Butyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18](Br)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccoc1
Reactant: Fc1ccc2c(c1Br)OCCN(Cc1ccccc1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc2c(c1-c1ccoc1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
A mixture of 4-benzyl-9-bromo-8-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine (500 mg, 1.49 mmol), 3-furanboronic acid (250 mg, 2.23 mmol), potassium carbonate (206 mg, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (172 mg, 0.149 mmol), 1,2-dimethoxyethane (5 ml) and water (0.5 ml) was stirred under an argon atmosphere at 100° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and preparative HPLC to give the desired product (104 mg, 21.7%) as an oil.