Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: N=CN
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 0 °C
Yield: 80.9 %

Procedure:
A solution of 2-amino-5-iodobenzoic acid (14.2 g, 50 mmol) and formamidine acetate (6.75 g, 65 mmol) in ethanol (200 mL) was refluxed for 20 hours. After cooling to 0° C. the solid product was collected by filtration. Further drying in a vacuum provided 6-Iodo-4-quinazolinone (11 g, 81%) as a gray solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[OH:11][CH2:12][C:13]1([CH2:17][CH2:18][CH3:19])[CH2:16]O[CH2:14]1>>[CH2:2]([C:1]12[O:11][CH2:12][C:13]([CH2:17][CH2:18][CH3:19])([CH2:16][O:10]1)[CH2:14][O:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8]
Reactant: C#CCCCCCC(=O)O
Reactant: CCCC1(CO)COC1
Product: C#CCCCCCC12OCC(CCC)(CO1)CO2

Procedure:
1-(Hept-6-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared from oct-7-ynoic acid and 3-hydroxymethyl-3-n-propyloxetane using methodology described in Example I.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[NH:8][C:7]2=O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]2[C:11](=[C:2]([I:1])[C:3]([CH3:14])=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[N:8]=1
Reactant: Cc1nc2c(I)c(C)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c2ccc(C)c(I)c2n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
8-Iodo-2,7-dimethylquinazolin-4(3H)-one (0.300 g, 1.00 mmol) was treated with phosphorus oxychloride (10 mL, 107 mmol) and the mixture stirred at 120° C. for 4 h. During this time, the reaction went from being a milky white suspension to a clear solution. The mixture was concentrated under vacuum and the residual phosphorous oxychloride was azeotroped with toluene. The residue was taken up in DCM and washed with cold water (2×) followed by washes (2×) with aqueous saturated sodium bicarbonate and brine. The organic solution was then dried with sodium sulfate and concentrated under vacuum to give 4-chloro-8-iodo-2,7-dimethylquinazoline (0.30 g, 94%) as an orange solid. MS (M+H)+ 319.
Reaction SMILES: CC(S(N)=O)(C)C.O1C2C=CC(C3(C(O)=O)CC3)=CC=2OC1.[C:23]([S@@:27]([NH:29][C@H:30]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[Cl:57])[C:31]1[S:35][C:34]([NH:36][C:37]([C:39]2([C:42]3[CH:50]=[CH:49][C:45]4[O:46][CH2:47][O:48][C:44]=4[CH:43]=3)[CH2:41][CH2:40]2)=[O:38])=[N:33][CH:32]=1)=[O:28])([CH3:26])([CH3:25])[CH3:24]>CC#N>[C:23]([S@:27]([NH:29][C@H:30]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[Cl:57])[C:31]1[S:35][C:34]([NH:36][C:37]([C:39]2([C:42]3[CH:50]=[CH:49][C:45]4[O:46][CH2:47][O:48][C:44]=4[CH:43]=3)[CH2:40][CH2:41]2)=[O:38])=[N:33][CH:32]=1)=[O:28])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Agent: CC(C)(C)S(N)=O
Agent: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CC#N
Product: CC(C)(C)[S@@](=O)N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl

Procedure:
(R)-N-(5-((R)-t-butylsulfinylamino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamide was prepared from (R)-N-(R)-1-(2-aminothiazol-5-yl)-1-(2-chlorophenyl)methyl)-1,1-dimethylethylsulfinamide and 1-(benzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxylic acid using the same protocol for (S)-N-(5-((R)-t-butylsulfinylamino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamide. 1H-NMR (400 MHz, CDC3) δ 8.55 (s, 1H), 7.62 (dd, J=7.7, 1.7 Hz, 1H), 7.37 (d, J=0.7 Hz, 1H), 7.34 (dd, J=7.8, 1.4 Hz, 1H), 7.31-7.20 (m, 2H), 6.87 (td, J=8.4, 1.7 Hz, 2H), 6.81 (d, J=7.9 Hz, 1H), 6.30 (d, J=2.8 Hz, 1H), 6.01 (s, 2H), 3.74 (d, J=2.8 Hz, 1H), 1.71-1.68 (m, 2H), 1.24 (s, 9H), 0.88 (t, J=69 Hz, 2H), HPLC ret. time 3.59 mm, 10-99% CH3CN, 5 min run; ESI-MS 532.1 m/z (MH+).
Reaction SMILES: C(O[C@H]1CN(C2N=CC=CN=2)C[C@H]1NC1C(CC)=NC([C:24]2[C:25](C)=[N:26][C:27](OC)=[CH:28][CH:29]=2)=C(CC)N=1)C.BrC1C=CC=CN=1.[CH3:42][N:43]([CH3:70])[C:44]1[N:49]=[CH:48][C:47]([C:50]2[N:51]=[C:52]([CH2:67][CH3:68])[C:53]([NH:58][C@H:59]3[C@@H:63]([O:64][CH2:65][CH3:66])[CH2:62][NH:61][CH2:60]3)=[N:54][C:55]=2[CH2:56][CH3:57])=[C:46]([CH3:69])[CH:45]=1>>[CH3:70][N:43]([CH3:42])[C:44]1[N:49]=[CH:48][C:47]([C:50]2[N:51]=[C:52]([CH2:67][CH3:68])[C:53]([NH:58][C@H:59]3[C@@H:63]([O:64][CH2:65][CH3:66])[CH2:62][N:61]([C:25]4[CH:24]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:60]3)=[N:54][C:55]=2[CH2:56][CH3:57])=[C:46]([CH3:69])[CH:45]=1
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Agent: Brc1ccccn1
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromo pyridine and 5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.19, 7.99, 7.47, 6.58, 6.46, 6.41, 5.25, 4.90, 4.25, 4.02, 3.80–3.72, 3.55, 3.40, 3.13, 2.70, 2.54, 2.12, 1.29, 1.16; IR (liq.) 2969, 2930, 2871, 2414 (w), 1941 (w), 1602 (s), 1558 (s), 1490 (s), 1474 (s), 1443 (s), 1395 (s), 1374, 1166, 1124, 770 cm−1 HRMS (ESI) calcd for C27H37N7O+H1 476.3138. found 476.3134.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.C(OCC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a cold (0° C.) stirred solution of 1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in anhydrous THF (50 mL) under argon was added dropwise 1.0 M 4-chlorophenylmagnesium bromide in diethyl ether (10 mL, 10 mmol). The reaction was warmed to RT for 2 hrs then quenched with sat'd aqueous NH4Cl (5 mL). The reaction mixture was extracted with EtOAc (2×50 mL), the organic layers combined and dried over Na2SO4. Pure 1-t-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopiperidine (2.1 g, 96%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 1H NMR CDCl3 δ 1.43 (9H,s), 1.61–2.22 (6H, m), 3.21–3031 (2H, m), 3.48–3.82 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:13])([F:12])[CH2:10][OH:11])=[C:4]([CH3:14])[CH:3]=1.N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([C:9]([F:12])([F:13])[CH2:10][O:11][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(Br)cc(C)c1C(F)(F)CO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C)c1C(F)(F)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of Intermediate 7B (2.68 g, 10.11 mmol) and imidazole (1.376 g, 20.22 mmol) in DMF (30 ml) was added tert-butyl dimethylchlorosilane (1.828 g, 12.13 mmol). The mixture was stirred at rt overnight, diluted with EtOAc and sat. NaHCO3. The organic layer was extracted by EtOAc (3×20 ml). The combined organic layer was washed with water and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography to give Intermediate 7C (2.56 g, 66.8% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm −0.01 (s, 6H) 0.84 (s, 9H) 2.42 (t, J=4.61 Hz, 6H) 4.00 (t, J=13.18 Hz, 2H) 7.20 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ ppm −95.94 (br. s., 2F).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1.[NH3:17]>>[NH2:17][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c([N+](=O)[O-])cc2c1
Reactant: N
Product: COc1ccc2nc(N)c([N+](=O)[O-])cc2c1
Temperature: 125 °C
Reaction time: 6 h

Procedure:
0.75 g of 2-chloro-6-methoxy-3-nitroquinoline (compound C3) are dissolved in 70 ml of ethanolic ammonia solution and stirred at 125° C. for 6 h in an autoclave. After cooling to room temperature, the reaction mixture is concentrated in vacuo and the residue redissolved in 30 ml of ethyl acetate and extracted two times each with 30 ml of halfsaturated aqueous potassium carbonate solution. The organic phase is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is filtered over silica gel (dichloromethane/methanol 8:2). 0.64 g of the title compound are obtained as violet sold.
Reaction SMILES: [C:1]([NH:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)(Cl)Cl>[C:27]([N:5]([C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])[NH:4][C:1](=[O:3])[CH3:2])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NN(C(C)=O)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 20 °C

Procedure:
Trans-4-(2-acetylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, 320 mg, was dissolved in 6 ml of chloroform and to this was added 0.5 ml of pyridine. While stirring under water cooling (20° C.), 0.23 ml of acetyl chloride was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under a reduced pressure, and to the residue was added ice water to scrape and crush it. After filtration and drying, it was recrystallized from ethyl acetate - hexane (1:1) to give 260 mg of trans-4-(1,2-diacetylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol as white crystals, m.p. 230°-233° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+:25].[K+]>CC(C)=O.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[K+:25]
Reactant: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Yield: 163.7 %

Procedure:
The (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylic acid (4.83 g) prepared in Example 6 or 7 was dissolved in acetone (23 mL), and potassium carbonate (1.11 g) dissolved in water (4.5 mL) was slowly added. The solution was stirred at room temperature until the deposited inorganic salt was dissolved. While the solution was heated at 50° C. in a bath, acetone (100 mL) was dropped and a seed crystal was placed in the solution, and then the solution was stirred for 30 minutes, Acetone (94 mL) was again dropped, and the solution was stirred for 1 hour while the temperature was kept. While gradually cooled to room temperature, the solution was stirred overnight. The precipitated crystalline product was collected by filtration, washed with a mixture of 2% water-acetone (20 mL), dried in air to obtain white solid potassium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (4.28 g, 81.7%). The NMR data of the solid product were the same as those in Example 11.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:18])[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=2[O:9]1.[C:19](Cl)([Cl:21])=[O:20]>C1C=CC=CC=1>[Cl:21][C:19]([O:17][C:16]1[C:10]2[O:9][C:8]([CH3:18])([CH3:7])[CH2:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)=[O:20]
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)Cc2cccc(OC(=O)Cl)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 7.9 g. (0.1 mol) sample of pyridine was added dropwise to a solution of 16.4 g. (0.1 mol) 2,3-dihydro-2,2-dimethyl-7-benzofuranol and 9.9 g. (0.1 mol) phosgene in 100 ml. benzene at about 25° C. The reaction mixture was stirred at 25° C for 2 hours, filtered and evaporated under reduced pressure. The solid residue was washed with hexane and dried to give the product, m.p. 85°-87.5° C. Elemental analysis for C11H11O3Cl showed:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:24])[C:5]1=[O:35].C(N(C(C)C)CC)(C)C.[CH3:45][N:46]([CH:48]=[O:49])[CH3:47]>>[CH3:45][N:46]([CH3:47])[C:48]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:24])[C:5]1=[O:35])=[O:49]
Reactant: NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[3-(4-morpholinyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0055 mL, 0.06 mmol)@40° C. After 2½ h the reaction was cooled, concentrated in vacuo, and the resulting residue treated with 1N NaHSO4. Extracted the mixture 3× with EtOAc and concentrated the organics. The residue was then dissolved in EtOAc and washed with saturated NaHCO3 (aqueous) then concentrated the organics. Triturated the residue with Et2O, filtered, and dried in vacuo to provide the title compound as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66-1.79 (m, 2 H), 1.76-1.93 (m, 1 H), 2.35 (t, J=6.18 Hz, 6 H), 2.70 (s, 6 H), 3.19-3.31 (m, 2 H), 3.40-3.48 (m, 2 H), 3.53-3.63 (m, 4 H), 4.11 (s, 2 H), 4.25 (s, 2 H), 6.54-6.59 (m, 1 H), 7.14 (t, J=8.84 Hz, 2 H), 7.37-7.44 (m, 2 H), 8.17-8.39 (m, 1 H), 8.52 (s, 1 H), 10.38 (s, 1 H); ES+ MS: 555 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]([CH3:33])=[C:29]([CH2:31]O)[N:30]=2)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:31][C:29]2[N:30]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[O:27][C:28]=2[CH3:33])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(Cl)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 21 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with [2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanol (R. C. Self, W. E. Barber, J. P. Machin, J. M. Osbond, C. E. Smithen, B. P. Tong, J. C. Wickens, D. P. Bloxham, D. Bradshaw, C. H. Cashin, B. B. Dodge, E. J. Lewis, D. Westmacott, J. Med. Chem. 1991, 34, 772-777) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11]C1C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>C(OC)(OC)OC>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNc1nc(Cl)ccc1N
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Product: Cn1cnc2ccc(Cl)nc21
Reaction time: 3 h
Yield: 2681.7 %

Procedure:
To a solution of 6-chloro-N2-methylpyridine-2,3-diamine (300 mg, 1.9 mmol) in HC(OMe)3 (10 mL) was added TsOH (10 mg) at 22° C. The mixture was stirred for 3 h under reflux until TLC (PE: EA=3:1) showed that the reaction was complete. The mixture was concentrated to get the crude material which was purified by using column chromatography on silica gel to give the desired product (261 mg, 81.6%) as an oil. LCMS (m/z): 168.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:33]1[CH2:32][CH:31]2[CH:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 8619 %

Procedure:
N,N'-Carbonyldiimidazole (0.37 g) is added to a solution of 2-(tert-butoxycarbonylaminomethyl)phenylacetic acid (0.6 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.75 g) and triethylamine (0.6 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). (3aRS,7aRS)-2-[(2-(tert-butoxycarbonylaminomethyl)phenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (105 g) is obtained in the form of a white meringue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:42]([C:39]1[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=1[O:46][C:47]([F:48])([F:49])[F:50])(=[O:44])=[O:43])[C:6](=[O:11])[C:5]2([N:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[C:29]([N:31]([CH3:32])[CH3:33])=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(N2Cc3ccccc3C2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3Cc4ccccc4C3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 1.00 g of 2-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl isoindoline-1-carboxamide (diastereoisomer mixture), which is the compound described in Preparation 3.5 of the brochure Publication No. WO01/64668, and 692 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 770 mg (Isomer mixture A, colorless amorphous) and 423 mg (Isomer mixture B, colorless amorphous) each of mixtures of diastereoisomers of the title compound were obtained by a similar method to Example 2.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:3]1.[H-].[Na+].[CH3:18]I.CO>CN(C=O)C>[CH3:1][C:2]1([CH3:15])[N:7]([CH3:18])[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:3]1
Reactant: CC1(C)CN(c2ccncc2N)CCN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(c2ccncc2N)CC1(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To 4-(3,3-dimethylpiperazin-1-yl)pyridin-3-amine (prepared according to methods similar to the one depicted in Preparation N-1) (120 mg, 0.5817 mmol) in DMF (2 mL) at 0° C. was added NaH (20.94 mg, 0.5235 mmol). The reaction mixture was stirred for 10 mins at 0° C. then MeI (276.3 uL, 0.5526 mmol, 2M in TBDME) was added. The reaction mixture was allowed to warm to RT and was stirred for 2 hours at RT. The crude was loaded onto a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure to yield 4-(3,3,4-trimethylpiperazin-1-yl)pyridin-3-amine (128 mg, 73%). MS (ES+) 221.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[ClH:12].[CH3:13][OH:14]>>[ClH:12].[CH:13]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1)=[O:14]
Reactant: CC(N)Cc1cccc(N)c1
Reactant: CO
Agent: Cl
Product: CC(N)Cc1cccc(NC=O)c1

Procedure:
255 gm of 1-(3'-amino-phenyl)-2-amino-propane were dissolved in methanol, and the solution was acidified with ethereal hydrochloric acid. The monohydrochloride thus obtained was refluxed for 2 hours in 225 ml of formic acid, and the reaction mixture was then evaporated in a water aspirator vacuum, leaving a yellow oil which solidified upon being digested with ether. The solidified product was recrystallized from ethanol by addition of ether, yielding the compound of the formula ##STR15## which had a melting point of 150°-153° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[H-].[Na+].CCCCCC.Cl[CH2:31][CH2:32][O:33][CH2:34][CH2:35]Cl>CN(C)C=O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:4]=[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]2[C:2]=1[N:1]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: ClCCOCCCl
Reactant: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
A solution of 5.5 g of 3-amino-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 3) in 50 ml of dry N,N-dimethylformamide was added dropwise to a solution of 1.8 g of sodium hydride in oil (prewashed with hexane) in 150 ml of dry N,N-dimethylformamide over 30 minutes under dry argon atmosphere at room temperature. After the mixture was stirred for further 1 hour, 3.2 g of bis(2-chloroethyl)ether was added dropwise. The mixture was stirred at room temperature for 2 hours, and then at 60° C. for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 2.0 g of 2-(2-methylphenyl)-3-morpholinoimidazo[2,1-a]isoquinoline (Compound 218) as a yellow oily material. To a solution of 2.0 g of the product in 80 ml of ether was added a saturated solution of hydrogen chloride in ether. Precipitated crystalline was collected by filtration, and washed with ethanol to give 1.1 g of the title compound as a yellowish white powder.