Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH2:24][CH2:25][N:26]([CH:34]([CH3:36])[CH3:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:14]#[N:15].C1(C)C=CC=CC=1>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH2:24][CH2:25][N:26]([CH:34]([CH3:36])[CH3:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:14]([NH2:15])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccc1Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(CCN1CCCCC1)(C(N)=O)c1ccccc1Cl)Cc1ccccc1
Temperature: 70 °C
Yield: 70 %

Procedure:
A nitrogen atmosphere was applied to a reaction vessel containing 109.3 L of sulfuric acid (96% w/w) which was warmed to 70° C. with stirring. Heating was discontinued, and 89.2 kg of α-(2-chlorophenyl)-α-[2-[(1-methylethyl)(phenylmethyl)amino]ethyl]-1-piperidinebutanenitrile (product of Example 4) was added at a rate such that the temperature was maintained at 80°-85° C. The reaction mixture was stirred at 80°-85° C. for 2.5 h and cooled to 75° C. The reaction mixture was added to a cooled and stirred mixture of 322 L of water and 219 L of toluene at 5° C. at a rate such that the temperature did not exceed 30° C. An additional 127 L of water was added to rinse the reactor. The mixture was cooled to 5° C. and basified to pH>12 with 219 L of sodium hydroxide solution (50% w/w) while maintaining the temperature below 35° C. Near the end of the base addition, the mixture was allowed to warm to 45° C. and stirred for 15 min. After separation of the layers, the aqueous phase was maintained at 45° C. and extracted with two 126-L portions of toluene. The organic phases were combined using 126 L of toluene. The combined organic phase was washed with 126 L of water at 45° C. The solution was cooled to 25° C. and stirred with 64.3 kg of neutral alumina for 1 h. The slurry was filtered through a layer of diatomaceous earth, and the filter cake was washed with 126 L of toluene. Alternatively, the solution may be passed through a bed of neutral alumina followed by a toluene wash of the bed. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 322 L of heptane by heating to reflux. The solution was allowed to cool to 25° C. with stirring, and the resulting slurry was cooled to less than 10° C. The solid was collected by filtration and washed twice with 200 L of heptane. The solid was dried under vacuum at 35 to 40° C. to give 65.0 kg (70.0%) of the title product α-(2-chlorophenyl)-α-[ 2-[(1-methylethyl)(phenylmethyl) amino]ethyl]-1-piperidinebutanamide. Analysis calcd for C27H38ClN3O: C,71.11; H,8.40; Cl,7.77; N,9.21. Found C,71.09; H,8.50; Cl,7.94; N,9.17. mp 104°-111° C. The purity of the title compound was estimated to be >95% based on TLC Method A.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1.Cl>C1COCC1.O>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[O:2])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOc1cccc(OCCCCC(OC)OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOc1cccc(OCCCCC=O)c1
Temperature: 50 °C
Yield: 107.8 %

Procedure:
A solution of 1-(5,5-dimethoxypentyloxy)-3-(hexyloxy)benzene (127 mg, 0.39 mmol) and 2 M aq HCl (0.47 mL, 0.94 mmol) in THF (4.5 mL), H2O (0.28 mL) was stirred at rt overnight. Later, the reaction was heated at 50° C. for 5 h. After cooling to rt the reaction mixture was diluted with H2O, extracted with Et2O (3×), washed (aq NaHCO3, brine), dried (Na2SO4) and concentrated under reduced pressure to yield 5-(3-(hexyloxy)phenoxy)pentanal as a colorless oil (117 mg). The material was used in the following step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 9.80 (s, 1 H), 7.16 (t, J=8.08 Hz, 1 H), 6.43-6.53 (m, 3 H), 3.89-4.01 (m, 4 H), 2.50-2.57 (m, 2 H), 1.14-1.92 (m, 12 H), 0.92 (t, J=6.69 Hz, 3 H). MS ESI [M+H]+, calcd for [C17H26O3+H]+: 279.2 found m/z 279.2 (95) and 301.1 ([M+Na]+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[C:16]([C:23]2[N:24]=[C:25]([NH2:28])[S:26][CH:27]=2)=[CH:15]1.C(N(CC)CC)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:28][C:25]2[S:26][CH:27]=[C:23]([C:16]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:14][CH:15]=3)[N:24]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1nc(-c2c[nH]c3ncccc23)cs1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Yield: 66 %

Procedure:
Prepared from 3-nitrophenyl acetic acid (1 g, 5.52 mmol), N-(1-methanesulfonyl)-benzotriazole (1.5 eq, 1.6 g), 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine and triethylamine (3eq, 2.3 ml) in THF (20 mL) by microwave irradiation at 170° C. for 10 mins as described above. The reaction mixture was concentrated to dryness and CH3CN added. The desired final product was filtered and washed with ether to give clean 2-(3-nitrophenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (1.4 g, 66% yield.)
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH2:25][CH3:26])[C:5]1=[O:33])[CH:2]=[CH2:3].[CH3:35][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])([CH3:35])[CH3:31])[CH2:25][CH3:26])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)=O)C1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-7-oxooctan-3-yl)piperidin-2-one prepared above in Step C (122 mg, 0.244 mmol) in THF (2.4 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (522 μL, 0.731 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure and purification of the residue by chromatography on silica gel (12 g SiO2, 30% and 40% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[N:22]([C:36]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH3:44])[CH2:40][CH2:39]1)=[O:37])[C@H:23]1[CH2:28][CH2:27][C@H:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25][CH2:24]1)=[O:16].[C:45]1(=[O:51])[CH2:50][CH2:49][CH2:48][CH:47]=[CH:46]1.[NH4+].[Cl-]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:45]2([OH:51])[CH2:50][CH2:49][CH2:48][CH:47]=[CH:46]2)=[CH:20][C:21]=1[N:22]([C:36]([C@H:38]1[CH2:39][CH2:40][C@H:41]([CH3:44])[CH2:42][CH2:43]1)=[O:37])[C@H:23]1[CH2:24][CH2:25][C@H:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:27][CH2:28]1)=[O:16]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: O=C1C=CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(C2(O)C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of THF (0.5 mL) and diisopropylamine (31 μl, 0.22 mmol) cooled to −40° C. n-BuLi (1.3 M, 165 μl, 0.21 mmol) was added dropwise. After stirring at this temperature for 30 min it was cooled to −78° C. and 3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (82 mg, 0.18 mmol) in THF (0.5 mL) was added dropwise. The mixture was stirred at this temperature for 30 min. Cyclohex-2-enone (20 μl, 0.21 mmol) was added quickly and it was stirred for 20 min at −78° C. Saturated NH4Cl solution was added and the mixture was allowed to come to room temperature. It was extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and evaporated. Pure 5-(1-hydroxy-cyclohex-2-enyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester was obtained after chromatography over silica gel (hexane:EtOAc—80:20 as eluent) (48 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH2:19][CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:16][C:17]1([CH2:18][CH2:19][CH3:20])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-pentanone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 2 h at 70° C. then for 3 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 150 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was triturated with dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.0632 g, 44%) as a yellow solid:
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].B(F)(F)F.CCOCC.[CH3:16][C:17]([CH3:31])=[CH:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1](=[O:6])[NH:2][C:17]([CH3:31])([CH3:16])[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[CH3:5]
Reactant: CCOC(N)=O
Reactant: CC(C)=CCN1C(=O)c2ccccc2C1=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)NC(C)(C)CCN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
34.2 g of ethyl carbamate are put in the solution in the toluene, 22 mL of BF3.Et2O are added and heating is performed for 1 h 30 mins at 70° C. 11 g of 2-(3-methylbut-2-en-1-yl)-1H-isoindole-1,3-dione are added and heating with reflux is performed for 12 h. After returning to RT, the mixture is dry evaporated and then taken up in an H2O/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried on magnesium sulfate. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1). 5.12 g (yield=31%) of ethyl[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,1-dimethylpropyl]-carbamate are obtained as a brown powder used as such.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[O:12]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C>[O:6]=[C:5]1[C:7](=[CH:23][C:22]2[CH:25]=[CH:26][C:19]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:20][CH:21]=2)[S:1][C:2](=[S:3])[N:4]1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)CN1C(=O)C(=Cc2ccc(Oc3ccccc3)cc2)SC1=S

Procedure:
To a solution of rhodanine-3-acetic acid (1.00 g) in acetonitrile (20 ml) were added 4-phenoxybenzaldehyde (1.14) and triethylamine (1.06 g), and the mixture was heated with reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (50 ml). The solution was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to give [4-oxo-5-(4-phenoxybenzylidene)-2-thioxo-thiazolidin-3-yl]acetic acid (1.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then the reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The ethyl acetate layer was concentrated and then purified by trituration with diethyl ether.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.Cl[CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([O:17][CH2:16][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1)=[O:23]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Sodium hydride (218 mg) was added to a solution of 1H-indole-3-carboxylic acid (400 mg) in N,N-dimethylformamide (4 ml) with ice cooling, and the mixture was stirred for 30 minutes. Chloromethyl2,2-dimethylpropionate (373 mg) was added thereto, and the mixture was warmed to room temperature and stirred for 2 hours. Water was added thereto, and the aqueous phase was washed with ether. The aqueous phase was acidified by 2 N hydrochloric acid and extracted with ether. The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give the title compound (540 mg, Y.:79%) as orange crystals.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1ccc(B(O)O)c(C)c1
Product: Cc1ccc(-n2cnc3ccc(O)nc32)c(C)c1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,4-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([O:10][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][C:8]=1[O:11][CH3:12])[CH:4]=[O:5])[CH:16]=[CH2:15]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1c(OC)ccc(C=O)c1Br
Reaction time: 0.5 h

Procedure:
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (1.68 g) was dissolved in DMF (17 ml), and sodium hydride (0.209 g) was added thereto under ice-cooling, followed by stirring for 30 minutes. Allyl bromide (0.944 ml) was added to the mixture, followed by stirring at 60° C. for one hour. After being allowed to stand for cooling, water was added to the mixture and the precipitated solid was collected by filtration. The obtained crude crystals were recrystallized from isopropanol to give Compound IIe-a (1.30 g, 66%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:26])([CH3:25])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)C>[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
157 g of N-carbobenzoxy-L-phenylalanine in 500 ml methylene chloride and 300 ml absolute diethyl ether is treated at 15°-18° C. with 85.5 g L-proline tert.-butyl ester in 100 ml diethyl ether over 5 minutes, and then with 114 g of dicyclohexylcarbodiimide in 150 ml of diethyl ether over 15 minutes, both additions being at such a rate that the reaction mixture temperature does not rise above 18° C. The resultant mixture is stirred for a further hour at room temperature, and filtered, the solid residue being washed with ether. The filtrate is washed with, in turn, 2N hydrochloric acid, water, potassium bicarbonate, and then water, each washing being extracted with diethyl ether. All the organic phases are combined, dried over sodium sulphate and concentrated to yield an oily residue. The oily residue is taken up in methylene chloride, filtered, concentrated and dried in a high vacuum to yield the heading compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([F:31])[CH:25]=1>>[F:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[CH3:30])[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1ccc(CBr)cc1F
Product: Cc1ccc(CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1F

Procedure:
Compound 146 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-(bromomethyl)-2-fluoro-1-methylbenzene and conditions outlined in procedure V. LCMS: 424 [M+H]; Rt=1.03 min.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]3[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].Br[CH2:32][CH:33]1[O:37][CH2:36][CH2:35][O:34]1.[I-].[Na+]>>[O:34]1[CH2:35][CH2:36][O:37][CH:33]1[CH2:32][N:21]1[CH2:22][CH2:23][C:17]2[C:16]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[N:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=3)=[N:19][C:18]=2[CH:20]1[CH3:24]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3C)cc1
Reactant: BrCC1OCCO1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(CC2OCCO2)C3C)cc1

Procedure:
The compound sj was prepared following the general procedure in Example 296, substituting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt for 1-ethyl-3-(4-(8-methyl-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt and substituting 1-bromo-2-methoxyethane for 2-(bromomethyl)-1,3-dioxolane. For this reaction, a catalytic amount Sodium iodide was also added: LC-MS m/z=483 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccncc4)cc3)cc21
Yield: 72.3 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), isonicotinoylchloride (142 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (306 mg).
Reaction SMILES: C([O-])C.[Na+].[CH3:5][C:6]([CH3:12])([CH3:11])[CH2:7][C:8](=[O:10])[CH3:9].[CH2:13]([O:15][C:16](=[O:22])[C:17](OCC)=[O:18])[CH3:14].Cl>CCO.O>[CH2:13]([O:15][C:16](=[O:22])/[C:17](/[OH:18])=[CH:9]/[C:8](=[O:10])[CH2:7][C:6]([CH3:12])([CH3:11])[CH3:5])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CC(C)(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C(O)=C/C(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice-cooled solution of sodium ethanolate (128.5 g, 1.79 mol) in EtOH (2500 ml) under nitrogen atmosphere is added 4,4-dimethyl-pentan-2-one (195.0 g, 1.71 mol). Half an hour later, oxalic acid diethyl ester (231.5 g, 1.71 mol) is added. After being stirred at rt for 24 h, the reaction mixture is diluted with water, and acidified to pH 2.0 by 6N aq hydrochloric acid. The mixture is contracted to about 1 L and extracted with DCM. The combined extracts are washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the product as a brown liquid.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[CH:24](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:24]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH3:23]
Reactant: CCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: NC=O
Agent: O=S(=O)(O)O
Product: CCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
In a similar manner to Example 1 reaction of 4,5-diamino-2-(2-ethoxyphenyl)pyrimidin-6-one sulphate (1.5 g) with formamide (15 ml) afforded the title compound, 0.36 g, m.p. 276°-277° C., (recrystallised from ethanol).