Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:17][C:18]([CH3:23])([CH2:21][OH:22])[CH2:19][OH:20].OCCCOCC1C=CC=C(C)C=1C(OC(C)(C)C)=O>>[OH:20][CH2:19][C:18]([CH3:23])([CH3:17])[CH2:21][O:22][CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: Cc1cccc(CBr)c1C(=O)OC(C)(C)C
Reactant: CC(C)(CO)CO
Agent: Cc1cccc(COCCCO)c1C(=O)OC(C)(C)C
Product: Cc1cccc(COCC(C)(C)CO)c1C(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(3-hydroxy-2,2-dimethylpropoxymethyl)-6-methylbenzoate is prepared from tert-butyl 2-bromomethyl-6-methylbenzoate and 2,2-dimethylpropane-1,3-diol in analogy to the synthesis of tert-butyl 2-(3-hydroxypropoxymethyl)-6-methylbenzoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH2:24]([N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:29]=2[CH2:28][CH2:27]1)[CH3:25].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:37][C:34]2[CH:35]=[CH:36][C:29]3[CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:32][CH2:31][C:30]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc2CC1
Temperature: 120 °C
Reaction time: 6 h
Yield: 17 %

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (104 mg, 0.293 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55.0 mg, 0.289 mmol) in 2-Methoxyethanol (3 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After 6 h, Macroporous carbonate resin (3.16 mmol/g loading; 150 mg, 0.474 mmol) was added and the reaction was cooled to room temperature, stirred overnight, then was concentrated in vacuo onto Celite, and chromatographed (2×24 g ISCO Amine column, 0-0.5% MeOH:DCM). Product is ca. 75% pure; rechromatograph, (2×4 g ISCO Amine column, DCM) to isolate 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as a beige powder (25 mg, 17%). m.p.=157-162° C.; LCMS (m/e) 509 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.25 (d, 1H, J=8.8 Hz), 8.00 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.18 (m, 1H), 7.02 (m, 1H), 6.83 (s, 1H), 6.54 (s, 1H), 6.49 (d, 1H, J=9.1 Hz), 3.92 (s, 3H), 3.89 (t, 4H, J=4.8 Hz), 3.15 (t, 4H, J=4.8 Hz), 2.91 (m, 4H), 2.64 (m, 4H), 2.57 (q, 2H, J=7 Hz), 1.10 (t, 1H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:40][CH2:8][C:6]1[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C)c12
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CBr)c12
Temperature: 70 °C

Procedure:
6-Chloro-3-methoxy-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.5 g, 3.41 mmol) was dissolved in CCl4 (10 mL), charged with NBS (637 mg, 3.58 mmol) and AlBN (56.0 mg, 0.341 mmol), and heated to 70° C. overnight. The reaction was diluted with DCM (10 mL) and purified by flash chromatography (5-25% EtOAc/hexanes) to give 4-(bromomethyl)-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C27H21BrClN3O [M+1]+519. found 519.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(4-chlorophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 9, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:35])[CH2:33][CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:42]5[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:35])[CH2:33][CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 82.1 %

Procedure:
Following general procedure II, (S)-tert-butyl(1-(5-((6-chloro-3-prop ionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (83 mg, 0.31 mmol) to afford the product (102 mg) which was carried forward without any purification: ESI MS m/z 621 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:4][CH2:3]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CN1CCC(c2nc3cccnc3[nH]2)CC1
Product: CN1CCC(c2nc3cccnc3n2Cc2ccccc2)CC1

Procedure:
Operation is carried out similarly to the above description with the difference that 2-(1-methylpiperidin-4-yl)-3H-imidazo-[4,5-b] pyridine is reacted with benzylchloride to obtain 3-benzyl-2-(1-methylpiperidin-4-yl)-3H- imidazo-[4,5-b] pyridine which is isolated as fumarate melting at 205°-207° C. (ethyl alcohol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].[C:23]([O:27][C:28]([N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:19]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:31]3[N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH:34]=[CH:33][CH:32]=3)[CH:3]=1)[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])=[O:20]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2cccn2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
To a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (23 g, 62.47 mmol) in DME (300 mL) and water (30 mL) were added 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (14.50 g, 68.72 mmol), Na2CO3 (19.87 g, 187.41 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.877 g, 1.25 mmol). The mixture was degassed with argon and heated to 80° C. for 7 h. Reaction was cooled down and concentrated, the residue was dissolved in 300 mL of DCM and 300 mL of water. The organic phase was decanted, washed with brine then dried over MgSO4, filtered and concentrated to afford a crude compound which was purified on silica, eluting with 80% AcOEt in DCM. The solvents were evaporated to afford tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate (20 g, 70%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[O:17]1[CH2:20][C:19](=[O:21])[CH2:18]1.CC(=O)OCC>C1COCC1>[Br:1][C:2]1[C:7]([C:19]2([OH:21])[CH2:20][O:17][CH2:18]2)=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1COC1
Reactant: Clc1ccnc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2c(Cl)ccnc2Br)COC1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 2-bromo-4-chloropyridine (14 g, 70 mmol) in dry THF (200 mL) was added LDA (42.0 mL, 84.0 mmol, 2.0 M) dropwise at −70° C. After stirring for 0.5 h at this temperature, a solution of oxetan-3-one (6.6 g, 90 mmol) in dry THF (40 mL) was added slowly and the reaction mixture was stirred at 0° C. for an additional 1 h. Saturated aqueous NH4CI (50 mL) and EA (200 mL) were added. The mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was purified by SGC eluting with DCM) to afford 148a as a yellow solid (8.8 g, 45%). MS: [M+H]+ 266.0.
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:10][CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:7]2[CH2:8][CH2:9][CH2:10][C:5]3([C:1](=[O:11])[NH:2][CH2:3][CH2:4]3)[CH2:6]2)=[N:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C1NCCC12CCCNC2
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCC12CCCN(c1ccc(C(F)(F)F)cn1)C2

Procedure:
A mixture of 2,7-diazaspiro[4.5]decan-1-one (50.0 mg, 0.000324 mol), 2-chloro-5-(trifluoromethyl)pyridine (71 mg, 0.00039 mol) and N,N-diisopropylethylamine (0.17 mL, 0.00097 mol) in N-methylpyrrolidinone (2 mL, 0.02 mol) was irradiated with microwaves at 180° C. for 20 min. The product was purified by prep-HPLC. LC-MS: 300.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>>[CH3:10][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: Cc1ccc(O)cc1C=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(OCOCC[Si](C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103.3 %

Procedure:
5-hydroxy-2-methylbenzaldehyde (3.4 g) is added portionwise to a stirred suspension of sodium hydride (1.2 g, 60% dispersion in mineral oil). The reaction mixture is stirred at room temperature for 45 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (5 g) is added slowly and stirring continued for a further 3 hours. The mixture is evaporated and the residue partitioned between ethyl acetate (50 mL) and water (150 mL). The organic phase is washed with brine (150 mL) dried over magnesium sulphate and evaporated to give 2-methyl-5-(2-(trimethylsilyl)ethoxymethoxy)benzaldehyde (6.87 g) as a red-brown oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[N+:35]([O-:37])=[O:36]>ClCCl>[OH:16][C:3]1([CH2:2][NH:1][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][C:26]=2[N+:35]([O-:37])=[O:36])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (78.4 mmol, prepared as described above) in dichloromethane (300 mL) was added triethylamine (11 mL, 79 mmol) and 4-chloro-3-nitroquinoline (12.7 g, 61.2 mmol). The mixture was stirred at rt for 1 h, then heated at reflux for 1 h. The solution was transferred to a separatory funnel and extracted with water (100 mL). The organic layer was isolated and upon standing a precipitate formed. The solid was isolated by filtration and washed with dichloromethane and water and dried. Additional solid precipitated from the mother liquor and was isolated. The two yellow solids were combined and dried to yield tert-butyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate (20.23 g, 82%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:7]4[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)s1
Temperature: 79 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A dry 25 mL flask was charged with 5-Acetyl-thiophene-2-carboxylic acid (0.880 g, 5.15 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.01 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 5-Acetyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.275 g, 3.05 mmol, 77%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[C:6]=2[N:19]=1.IC.[CH3:22]N(C)C(=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[C:6]=2[N:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC1CCCC1N1CCC(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CCCC1N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-57), 0.047 mL (0.00075 mole) of iodomethane and 1 mL of N,N-dimethylacetamide at 0 degrees, was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.130 g of (rac)-2-chloro-5-methyl-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-57) as a yellow solid.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Reactant: OCCCCCCI
Agent: [K]
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCCCCO)cc2)cc1

Procedure:
Employing the procedure of Example I(A), 14 g (0.05M) of the potassium salt of 4-hydroxy-4'-nitrostilbene and 14 g (0.06M) of 6-iodo-1-hexanol are reacted. The resultant product is recrystallized from toluene, m.p. 154°-157° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][NH:34][CH3:35]>O1CCCC1.C(#N)C>[CH3:33][N:34]([CH3:35])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CNC
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CCl)cc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CN(C)C)cc2)C1
Yield: 125.2 %

Procedure:
A solution of 2-chloro-N-((2S)-4-(((1R)-1-phenylethyl)morpholin-2-yl)phenyl)acetamide (0.9 g, 2.5 mmol), potassium carbonate (1.72 g, 12.5 mmol), and dimethylamine hydrochloride (1.00 g, 12.5 mmol) in tetrahydrofuran (40 ml) and acetonitrile (80 ml) was stirred at 95° C. for 10 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure give N2,N2-dimethyl-N1-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)glycinamide (1.15 g, quant.) as an yellow oil.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9]Br)[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([NH:25][C:26]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]([CH2:9][CH2:8][CH2:7][C:6]([O:5][CH2:3][CH3:4])=[O:11])[C:26]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1cc(C)cc(C)c1NC(=O)OC(C)(C)C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)OC(C)(C)C)c1c(C)cc(C)cc1C(=O)OC
Temperature: 55 °C
Reaction time: 48 h
Yield: 113.6 %

Procedure:
Charge a 22 L flask, equipped with overhead agitation, heating mantle, condenser and a N2 purge, with DMF (10 L), ethyl-4-bromobutyrate (1.07 kg, 787.8 mL, 5.32 moles), cesium carbonate (2.92 kg, 22.5 moles), and methyl 2-(tert-butoxycarbonylamino)-3,5-dimethylbenzoate (1,000.0 g, 3.54 moles). Heat the resulting mixture to about 55° C. and stir for about 48 hours. Cool; filter off the solid; and wash the solid with MTBE (2×4 L). Combine the filtrate and the MTBE washings into a 50 L flask and cool to less than about 5° C. Add water (6 L) to quench the reaction. Separate the layers. Wash the aqueous layer with MTBE (3 L); combine the organic layers; and wash the resulting organic solution with brine (2×3 L). Dry the organic solution over Na2SO4; filter; and wash the collected solids with MTBE to yield 1.582 kg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)Cl)=[CH:5][CH:4]=1.[C:21]([NH:24][CH2:25][C:26](=[S:28])[NH2:27])(=[O:23])[CH3:22]>C(O)C>[C:21]([NH:24][CH2:25][C:26]1[S:28][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:27]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reactant: CC(=O)NCC(N)=S
Solvent: CCO
Product: COc1ccc(-c2nc(CNC(C)=O)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
A mixture of 1,2-bis(4-methoxyphenyl)-2-chloroethanone (5.99 g) and 2-(acetylamino)ethanethioamide (3.00 g) in ethanol (30 ml) was refluxed for 2 hours. After allowing to cool to room temperature, the solvent was evaporated in vacuo, and the residue was dissolved in chloroform (200 ml) and aqueous solution of sodium hydrogencarbonate (200 ml). The separated organic layer was washed with water and brine, dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The resulting residue was dissolved in diethyl ether, added ethanol solution of hydrogen chloride, and the resulting precipitate was collected by filtration. The resulting crude compound was recrystallized with ethanol (10 ml). And the resulting crystal was collected by filtration, washed with ethanol and diethyl ether, and dried to give 2-acetylaminomethyl-4,5-bis(4-methoxyphenyl)thiazole (2.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[C:35]([CH3:42])=[C:36]([CH:40]=O)[NH:37][C:38]=3[CH3:39])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>C(O)C.N1CCCCC1>[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[C:35]([CH3:42])=[C:36](/[CH:40]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=5)[NH:37][C:38]=3[CH3:39])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCN(CC2CC2)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCN(CC2CC2)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-(4-cyclopropylmethyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound. MS m/z 613 [M−1].