Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[C:14]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[N:29]4)=[CH:24][CH:23]=3)=[CH:13]2)[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(=O)C(C(C([O-])=O)O)O.[Na+].[K+]>C1COCC1>[NH2:21][C:20]1[C:15]2[C:14]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[N:29]4)=[CH:24][CH:23]=3)=[CH:13][N:12]([C@@H:9]3[CH2:8][CH2:7][C@H:6]([CH2:4][OH:3])[CH2:11][CH2:10]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2cc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)ncnc32)CC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1CC[C@@H](CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into the THF (1 mL) solution of cis-4-[4-amino-5-(2-phenylquinolin-7-yl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanecarboxylic acid ethyl ester (13.3 mg, 0.0271 mmol) was added dropwise LiAlH4 (1 M in THF, 203 μL, 0.75 eq.) at 0° C. under N2. After stirring at rt for 2 h, the reaction mixture was treated with saturated potassium sodium tartarate solution (5 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with H2O (10 mL) and brine (10 mL), and dried over MgSO4. The drying agent was filtered off, and the filtrate was concentrated in vacuo. The crude material thus obtained was purified by preparative TLC (silica gel, eluting with 7% MeOH/CH2Cl2) to yield the title compound as beige powder. 1H NMR (CDCl3, 400 MHz): δ=1.77-2.02 (m, 9H), 3.77-3.78 (d, 2H, J=7.2 Hz), 4.77-4.82 (m, 1H), 5.30 (brs, 2H), 7.24 (s, 1H), 7.46-7.57 (m, 3H), 7.67-7.70 (dd, 1H, J=1.6 & 8.4 Hz), 7.89-7.93 (m, 2H), 8.18-8.20 (m, 2H), 8.25-8.28 (m, 2H), 8.36 (s, 1 H). MS (ES+): 450.2 [MH+]. HPLC: tR=2.5 min (polar—5 min).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:31])[CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH3:32])C.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1.CCO>[CH3:32][C:8]1[CH:9]=[C:10]([N:13]([CH3:31])[CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of crude (2-methyl-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester (0.84 g containing 0.74 g, 1.54 mmol) in THF/EtOH (9.2 ml, 1:1) were treated at 0° C. with 1M LiOH (4.6 ml, 4.6 mmol) for 2 min. After 2 h at RT, the solution was acidified by adding aqueous 10% KHSO4, and the mixture was extracted with Et2O (3×). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Crystallization (CH2Cl2/Et2O) gave 0.57 g (82%) (2-methyl-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid as light yellow powder, MS: 449 (M-H)−, MP: 146-149° C., dec.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]2[CH:11]=[C:12]([C@@H:14]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH3:15])[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:4].[I:27]N1C(=O)CCC1=O>C(#N)C.O>[CH2:20]([O:19][C:17]([NH:16][C@H:14]([C:12]1[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:10]2[C:11]=1[I:27])[CH3:15])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)cn12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(I)n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl-2-(1-(((benzyloxy)carbonyl)amino)ethyl)imidazo[1,2-a]pyridine-5-carboxylate (5.5 g, 7.93 mmol) in acetonitrile (50 mL) was added N-iodosuccinimide (2.3 g, 10.3 mmol) at 25° C. The reaction mixture was stirred at 25° C. overnight. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-50% EtOAc in hexane to provide (S)-methyl 2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-iodoimidazo[1,2-a]pyridine-5-carboxylate: 1H NMR (CDCl3, 400 MHz) δ 1.547 (d, J=6.8 Hz, 3H), 4.048 (s, 3H), 5.067-5.200 (m, 3H), 5.805 (d, J=7.2 Hz, 1H), 7.229-7.260 (m, 2H), 7.292-7.350 (m, 5H), 7.675-7.708 (m, 1H); LC-MS (ESI) m/z 479.9 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:28][CH2:27]1
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: O=c1[nH]c2cc(CN3CCC(O)CC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 4-hydroxypiperidine. To give a yellow solid. MS m/z: 419.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:13])[C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[N:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH2:51])=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:13])[C:10]([NH:51][CH2:50][C:47]2[CH:48]=[CH:49][N:44]=[CH:45][CH:46]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:22])[CH3:23])[C@H:16]1[CH3:24]
Reactant: NCc1ccncc1
Reactant: CC(C(=O)O)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C(=O)NCc1ccncc1)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Yield: 51.7 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoic acid (40 mg, 0.099 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.199 mmol), 1-hydroxybenzotriazole anhydride (4 mg, 0.03 mmol) and triethylamine (28 μL, 0.199 mmol) in N,N-dimethylformamide (1 mL) were stirred with 4-picolylamine (20 μL, 0.199 mmol) at room temperature for 17.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=20/1) to give the desired product (25 mg, 52% yield).
Reaction SMILES: [N+:1]([CH:3]([CH3:8])[C:4](OC)=[O:5])#[C-:2].[NH2:9][CH2:10][CH:11]1[CH2:16][CH:15]2[CH2:17][CH:13]([C:14]2([CH3:19])[CH3:18])[CH:12]1[CH3:20]>>[CH:13]12[CH2:17][CH:15]([C:14]1([CH3:18])[CH3:19])[CH2:16][CH:11]([CH2:10][NH:9][C:4](=[O:5])[CH:3]([N+:1]#[C-:2])[CH3:8])[CH:12]2[CH3:20]
Reactant: CC1C(CN)CC2CC1C2(C)C
Reactant: [C-]#[N+]C(C)C(=O)OC
Product: [C-]#[N+]C(C)C(=O)NCC1CC2CC(C1C)C2(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 5.7 g (50 mmoles) of methyl α-isocyanopropionate and 8.3 g (50 mmoles) of (+)-3-aminomethylpinane is stirred for 15 hours at room temperature, initially with slight cooling. After distilling off the resulting methanol in a high vacuum at 80° C., 11.6 g of crystalline α-isocyanopropionic acid (+)-3-pinylmethylamide of melting point 58°-59° C. remain. IR spectrum (KBr): 3,230 (N--H), 2,130 (N≡C), 1,670 cm-1 (C=O).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5].[Cl:26][CH2:27]OC(Cl)=O.CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:27][Cl:26])[C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(NCc1ccc(-c2cc[nH]c(=O)c2)cc1)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)OCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(-c2ccn(CCl)c(=O)c2)cc1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,6-Dichloro-N-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide (1.62 g, 4.34 mmol) was suspended in 15 mL dichloromethone. Chloromethylchloroformate (0.672 g, 5.21 mmol) was added followed by 3 mL DMF. The mixture was stirred at room temperature for five hours. After diluting with 200 mL ethyl acetate, the organic phase was washed with saturated, aqueous sodium bicarbonate solution and brine, dried with magnesium sulfate and evaporated under vacuum. The crude 2,6-dichloro-N-[4-(1-chloromethyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide was used in the following step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([OH:10])[C:3]=1[N+:11]([O-])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([OH:10])[C:3]=1[NH:11][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(O)c([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(O)c(NC(C)=O)c(O)c1
Yield: 67.3 %

Procedure:
2,6-Dihydroxy-4-methoxynitrobenzene (0.60 g, 3.24 mmol) was hydrogenated in the presence of acetic anhydride (0.29 g, 4.86 mmol) and 10% Pd/C (0.2 g) in methanol (30 mL) under atmospheric pressure and room temperature. The catalyst was removed by filtration through a pad of celite and the the crude product was purified by flash chromatography (SiO2, Toluene-ethyl acetate, 3:3 then 1:2) to afford the subtitle compound (0.43 g, 67.9%).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[C:2]#[CH:3].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[CH3:38][O:39][C:40]([C:42]1[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[C:44]([N+:50]([O-:52])=[O:51])[CH:43]=1)=[O:41].C(O)(=O)C>O1CCCC1.O>[OH:47][CH:46]([C:45]1[C:44]([N+:50]([O-:52])=[O:51])=[CH:43][C:42]([C:40]([O:39][CH3:38])=[O:41])=[CH:49][CH:48]=1)[C:3]#[C:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C#CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)C#CC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 106.2 %

Procedure:
To a solution of tert-butyl propiolate (3.54 ml, 25.81 mmole) in tetrahydrofuran (60 ml) was added at -70° C. under the argon atmosphere a solution of 2.0M lithium diisopropylamide in a heptane-tetrahydrofuran-ethylbenzene mixture (13.0 ml, 26 mmole), and the mixture was stirred for 30 minutes. The reaction mixture was then added to a solution of 4-methoxycarbonyl-2-nitrobenzaldehyde (4.5 g, 21.5 mmole) in tetrahydrofuran (100 ml), and the mixture was further stirred at -75° C. for 5 minutes. After a solution of acetic acid (3.2 ml, 53.3 mmole) in tetrahydrofuran (10 ml) and water were added, the reaction mixture was extracted with ethyl acetate (400 ml). The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give the crude product of tert-butyl 4-hydroxy-4-(4-methoxycarbonyl-6-nitrophenyl)-2-butynoate as a brown oil (7.655 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:3]=1[C:20](=[O:22])[CH3:21].[C:23]([Mg]Cl)([CH3:26])([CH3:25])[CH3:24].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:3]=1[C:20]([OH:22])([C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:21]
Reactant: CC(=O)c1c(F)cccc1Oc1cnc2c(F)cccc2c1
Reactant: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(C)(O)c1c(F)cccc1Oc1cnc2c(F)cccc2c1
Temperature: -78 °C

Procedure:
After 0.15 g of 1-[2-fluoro-6-(8-fluoro-quinolin-3-yloxy)-phenyl]-ethanone was dissolved in 1.5 ml of tetrahydrofuran, and then the solution was cooled to −78° C., 0.3 ml of t-butylmagnesium chloride (2.0 M diethyl ether solution) was added dropwise. After the reaction temperature was increased to room temperature, the reaction solution was treated with dilute hydrochloric acid, and then the liquid was separated with ethyl acetate. The organic layer was concentrated and then purified by silica gel column chromatography to obtain 0.04 g of 2-[2-fluoro-6-(8-fluoro-quinolin-3-yloxy)-phenyl]-3,3-dimethylbutan-2-ol (Compound Number 30).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH2:7][OH:8].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCOc1ccc(Br)cc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1ccc(Br)cc1C=O

Procedure:
5-Bromo-2-ethoxybenzyl alcohol (2.78 g, 12.0 mmol) and pyridinium dichromate (4.51 g, 12.0 mmol) in 120 ml of CH2Cl2 was stirred at RT for 6 h. The mixture was filtered, washed with H2O, 0.5 N HCl and brine and dried over Na2SO4. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100) to give 5-bromo-2-ethoxybenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]2=[O:14])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]2=[O:14])=[CH:6][CH:7]=1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(-n2cccnc2=O)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc(-n2cccnc2=O)cc1

Procedure:
1-(4-Aminophenyl)pyrimidin-2(1H)-one (2.3, 250 mg, 1.3 mmol) was dissolved in 10 mL TFA and stirred in ice bath. To it was added sodium nitrite (95 mg, 1.3 mmol) in small portions. The mixture was stirred in ice bath for 30 min. Sodium azide (260 mg, 4.0 mmol) was dissolved in 2 mL water and chilled in ice bath and added to the reaction mixture. The mixture was stirred for 2 hrs and directly subjected to reverse phase prep HPLC to isolate 1-(4-azidophenyl)pyrimidin-2(1H)-one 2.4. MS found for C10H7N5O (M+H)+ 214.1.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:24]2[S:25][C:17]([CH2:16][N:12]3[CH2:13][CH:14]4[CH:10]([CH2:9][NH:8][CH2:15]4)[CH2:11]3)=[CH:18][C:19]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1nc(N2CCOCC2)c2sc(CN3CC4CNCC4C3)cc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a stirred solution of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (390 mg; 0.81 mmol) in CH2Cl2 (4 mL) was added TFA (6 mL). The reaction mixture was stirred at RT for 4 h upon which time volatiles were removed in vacuo. Purification by SCX-2 gave the title compound as an off-white solid (273 mg; 89%).
Reaction SMILES: [Se](=O)=O.[OH2:4].[CH3:5][N:6]([C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)[C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:12])[CH3:11])=[O:8]>O1CCOCC1>[CH3:5][N:6]([C:15]1[S:16][CH:17]=[C:18]([C:20](=[O:4])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)[C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:11])[CH3:12])=[O:8]
Reactant: O
Reactant: CCOC(=O)Cc1csc(N(C)C(=O)OC(C)(C)CC)n1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1csc(N(C)C(=O)OC(C)(C)CC)n1
Temperature: 110 °C
Reaction time: 4.5 h

Procedure:
A mixture of selenium dioxide (0.452 g.), dioxane (9 ml.) and water (0.36 ml.) was refluxed in bath at 110° C., and to the solution was added a solution of ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]acetate (1.07 g.) and dioxane (9 ml.), and the mixture was stirred for 4.5 hours at the same temperature. After the reaction, the reaction mixture was filtered, and dioxane was distilled off from the filtrate under reduced pressure. To the residue were added water and ethyl acetate with stirring, and then ethyl acetate layer was separated. The ethyl acetate layer, was dried over magnesium sulfate and then concentrated to give oil of ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylate (0.45 g.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]#[N:23])=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].CCOC(C)=O>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]#[N:23])=[CH:16][NH:17]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reaction time: 19 h

Procedure:
To a solution of 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (620 mg, 1.96 mmol) in EtOH (30 ml) and EtOAc (15 ml) was added Degoussa-type catalyst (10% Pd/C wet, 70 mg). The reaction mixture was hydrogenated in a Parr apparatus at 55 psi of H2 for 19 hours. The reaction mixture was filtered through celite with EtOH, MeOH and EtOAc. The filtrate was concentrated to afford 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester LIX as a white solid in quantitative yield (648 mg).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9]([NH:13][C:14]([NH2:16])=[O:15])([CH3:12])([CH3:11])[CH3:10].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:9]([NH:13][C:14]([NH:16][C:1]1[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(C)(C)NC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)NC1=CC(=O)CCC1
Yield: 66.7 %

Procedure:
To a solution of 11.2 g of 1,3-cyclohexanedione in 250 ml of benzene is added 11.6 g tert-butylurea and 100 mg of p-toluenesulfonic acid. The solution is heated at reflux under nitrogen with water removal for three hours. At the end of this period the solution is cooled and the precipitated product removed by filtration. The precipitate is recrystallized from acetonitrile to give 14 g of 1-tert-butyl-3-(3-oxo-1-cyclohexene-1-yl)urea, m.p. 223°-225° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[C@H:17]([CH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:23])[OH:22])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[C@H:17]([CH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](=[O:22])[OH:23])[NH:18][S:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:48])=[O:47])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](CC(Cc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Cc1ccccc1)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
γ-Benzyl-L-glutamyl-L-proline benzylester hydrochloride (2.30 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mole) was added thereto at -30 ° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise thereto. The solution was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 55 aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice), and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-benzenesulfonyl-γ-benzyl-L-glutamyl-L-proline benzylester (yield: 2.61 g, 92.4%)
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:6]=2[C:5]1=[O:17])[CH:2]=[CH2:3].C1(C2CCCCCCCC2)BCCCCCCC1.[OH-].[Na+].OO.S([O-])([O-])(=[O:42])=S.[Na+].[Na+]>O1CCCC1.CCO>[OH:42][CH2:3][CH2:2][CH2:1][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:6]=2[C:5]1=[O:17]
Reactant: O=S([O-])([O-])=S
Reactant: C=CCN1CCCc2ccc(OC)cc2C1=O
Agent: B1CCCCCCCC1C1CCCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N(CCCO)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (8.0 g, 0.043 mol) in dry tetrahydrofuran (40 mL) was treated with 9-borabicyclononane (1.0M in THF) and the resulting mixture was stirred for 18 hours at room temperature. The solution was then diluted with EtOH (50 mL), cooled to 0° C. (ice bath), and treated with 15% aqueous NaOH (15 mL) followed by 30% aqueous H2O2 (10 mL). The resulting mixture was stirred for 1 hour at 0° C., then treated cautiously with saturated aqueous sodium thiosulfate (50 mL). The mixture was partitioned between ethyl acetate and brine, and the combined organic layers were concentrated in vacuo, and the residue was purified by chromatography over silica gel eluting with ethyl acetate to yield 6.5 g (60%) of 2-(3-hydroxypropyl)-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil;
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3([OH:34])[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:25][CH2:24]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C3(O)CCCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)CCCC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 1-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)cyclopentanol were reacted to give 323. LCMS m/z: 531.3 (MH+)