Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@@:6]1(C)[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C)C=O>[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C@@H:6]2[CH2:10][C@H:9]([S:11][C:12]([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:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][N:7]2[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[CH2:48][CH2:47]1
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN([C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.37 g) in dimethylformamide (100 ml) was added N-methylpiperazine (5.45 ml) and the mixture was stirred at 80°-90° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fraction containing the desired compound were collected and evaporated in vacuo to give (2S ,4S) 2-(4-methylpiperazin-1-yl)-1-(4-nitrobenzyloxy carbonyl)-4-(triphenylmethylthio)pyrrolidine (6.87 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH:13]([CH3:15])[NH:12][CH:11]([CH3:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:45]=[CH:44][C:21]([CH2:22][NH:23][C:24]([C:26]2([CH2:39][CH2:40][CH2:41][CH2:42]Br)[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:24]([C:26]2([CH2:39][CH2:40][CH2:41][CH2:42][N:12]3[CH:11]([CH3:16])[CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)[CH2:14][CH:13]3[CH3:15])[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:25])=[CH:44][CH:45]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1cccc(N2CC(C)NC(C)C2)n1
Product: COc1cccc(N2CC(C)N(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)C(C)C2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-3,5-dimethyl-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluorobenzyl-amide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (213 mg, 0.659 mmol) in tetrahydrofuran (10 mL) were added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (136 mg, 0.856 mmol) in tetrahydrofuran (0.5 mL) and triethylamine (200 mg, 1.98 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated and washed with ethyl acetate/hexane to give the title compound (222 mg, 77%) as a white powder. melting point 223° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
A mixture of 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester (2.55 g, 0.009 mol), NaOH (20 ml), water (70 ml), and methanol (70 ml) is heated to reflux for 20 minutes when a clear solution is formed. The reaction mixture is filtered and the filtrate is carefully acidified with 4N HCl (6 ml) to pH 1.0 when a solid pptd. out. The crude 4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid is filtered, washed with hot CH3OH and dried to give analytical sample. Yield 1.67 g (73%); mp >295° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[BrH:14]>>[Br:14][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1
Reactant: Br
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Product: Cc1nc(C(F)(F)F)ccc1CBr
Temperature: 135 °C
Yield: 71 %

Procedure:
A mixture of (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (1.677 g, 8.77 mmol, 76% pure) in 48% aq. HBr (10 mL) was heated to reflux (oil bath temperature, 135° C.) for 24 h. The volatile components of the resulting biphasic mixture were distilled under vacuum to remove most of the hydrogen bromide (sodium hydroxide trap). The residue was partitioned between 2:1 EtOAc/THF and water (at pH 3) and the organic phase was dried (MgSO4), filtered and evaporated. The solid residue was re-evaporated after addition of dichloromethane/hexanes to obtain the title compound as a tan solid, 1.19 g, 71% yield (based on the purity of the starting material). HPLC/MS: retention time=2.15 min, [M+H]+=254.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:10]([CH3:27])[C:11]([C:25]#[N:26])=[C:12]3[C:16]=2[O:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:13]3)[CH2:4]1.Cl.C(O)C.[H][H]>C(O)C>[CH3:34][N:2]([CH3:1])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:10]([CH3:27])[C:11]([C:25]#[N:26])=[C:12]3[C:16]=2[O:15][C:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:13]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(/C=C/c3ccccc3)nc2c1C#N
Reactant: [H][H]
Agent: Cl
Solvent: CCO
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(CCc3ccccc3)nc2c1C#N
Yield: 16.1 %

Procedure:
7-[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-2-[(E)-2-phenylethenyl]-1,3-benzoxazole-4-carbonitrile (I-93) (100 mg, 0.22 mmol) and 1 N hydrochloric acid/ethanol solution (223 μl, 10.22 mmol) were dissolved in ethanol (2 ml), 10% carbon-held palladium catalyst was added, followed by stirring at room temperature under atmospheric pressure of hydrogen for 3 hours. After filtration through Celite, the solvent was concentrated under reduced pressure, ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution were added to make the aqueous layer basic, followed by fractionation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to preparative thin-layer silica gel column chromatography, eluted with a mixed solvent of chloroform/methanol (20:1, v/v), recrystallized and purified with n-hexane/ethyl acetate/diisopropyl ether to obtain the entitled compound (16 mg, 16%) as a white solid.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:6][CH2:7][C:8]2[NH:9][C:10](=[O:18])[C:11]3[CH2:17][O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH3:5])[CH2:3][CH2:2]1.[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[CH:1]1([C@@H:4]([N:6]([CH2:7][C:8]2[NH:9][C:10](=[O:18])[C:11]3[CH2:17][O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[C:33](=[O:34])[CH2:32][N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:37][CH:36]=3)[CH2:27][CH2:28]2)[CH3:5])[CH2:3][CH2:2]1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: C[C@H](NCc1nc2c(c(=O)[nH]1)COCC2)C1CC1
Product: C[C@@H](C1CC1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (29 mg) from (S)-2-((1-cyclopropylethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C27H33FN4O4 496.6. found 497.6 (ESI, M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-8.21 (m, 2H) 7.40 (t, J=8.84 Hz, 2H) 4.25-4.54 (m, 5H) 3.84 (ddd, J=17.31, 5.56, 5.43 Hz, 3H) 3.70 (d, J=6.06 Hz, 1H) 3.56 (br. s., 2H) 3.23 (br. s., 1H) 2.99-3.20 (m, 2H) 1.99 (br. s., 4H) 1.00-1.29 (m, 4H) 0.68-0.94 (m, 1H) 0.46-0.68 (m, 1H) 0.38 (d, J=5.05 Hz, 1H) 0.24-0.34 (m, 1H) 0.15-0.24 (m, 1H).
Reaction SMILES: Cl[CH2:2][S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH2:11]([O:13][P:14]([CH2:2][S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]
Reactant: ClCSCc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CSCc1ccccc1)OCC
Temperature: 155 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl chloromethyl sulfide (20 g., 0.116 mole), prepared according to the method of Bohme, Fischer and Frank [Ann., 563, 54 (1949)], and triethylphosphite (26.9 g., 0.162 mole) was heated with stirring at 155° C. (bath temperature) for 8 hours under a nitrogen atmosphere. The temperature of the oil bath was then raised to 170° C. and the volatile materials removed by distillation under reduced pressure. The residue was chromatographed on silica by eluting with ethyl acetate/benzene mixtures which gave 21.5 g. of the title compound as a liquid.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][OH:7].[H-].[Na+].Cl[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1>O1CCCC1>[Cl:33][C:27]1[N:26]=[C:25]2[C:30]([CH:31]=[CH:32][C:23]([N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]3[O:7][CH2:6][C:5]([NH:4][CH2:3][CH:2]([CH3:9])[CH3:1])=[O:8])=[N:24]2)=[CH:29][CH:28]=1
Reactant: CC(C)CNC(=O)CO
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 52.3 %

Procedure:
The procedure is as in Example 22, but starting with N-(2-methylpropyl)glycolamide (8.9 g) in tetrahydrofuran (357 cc), an oily suspension (50% by weight; 3.3 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (15 g). After recrystallization in ethanol, [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1isoindolinyloxy]-N-(2-methylpropyl)acetamide (10.1 g), m.p. 146° C., is obtained.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Prepared in the same manner as intermediate 18. To a solution of tert-butyl 1-piperazinecarboxylate (15.0 g. 80.5 mmol) and benzoic acid (8.94 g, 73.2 mmol) in CH2Cl2 (500 mL), was added DMAP (9.84 g, 80.5 mmol) and EDC (15.39 g, 80.5 mmol). The reaction mixture was stirred at rt for 17 h, and then washed with excess hydrochloric acid (5×250 mL, 1 N aq.) and water (350 mL). The organic layer was dried (MgSO4) and evaporated in vacuo to give N-Benzoyl-N′-Boc piperazine as an off white solid (21 g, 99%). 1H NMR (300 MHz, CD3OD) δ 7.46 (m, 5H), 3.80-3.30 (b m, 8H), 1.47 (s, 9H); LC/MS (ES+) m/z (M+H)+=291, (2M+H)+=581, HPLC Rt=1.430.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([CH:23]=O)=[C:16]3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2].[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([CH:23]=[C:31]4[NH:25][C:26](=[O:27])[NH:28][C:29]4=[O:30])=[C:16]3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CNC(=O)N1
Reactant: CCN(CC)Cc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)Cc1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-((diethylamino)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (10 mg, 0.031 mmol) in EtOH was added hydantoin (3 mg, 0.031 mmol) and piperidine (3 μL, 0.031 mmol). The mixture was heated at 70° C. overnight. The product was purified by HPLC to yield 5-((5-(3-((diethylamino)methyl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=406)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=2)[N:6]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:11][CH:12]=2)[N:6]=1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2csc(N)n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)cs1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
tert-Butyl {2-[4-(2-amino-1,3-thiazol-4-yl)phenyl]ethyl}carbamate (290 mg) was dissolved in dichloromethane (5 mL), then acetic anhydride (0.103 mL), 4-dimethylaminopyridine (10 mg) and pyridine (0.147 mL) were added. The mixture was stirred overnight. The mixture was extracted with chloroform, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The solid was washed with ethyl ether, and dried in vacuo to give tert-butyl (2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)carbamate as a white solid (280 mg, 85.3%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][N-:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[K+].[CH:32](O)([CH3:34])[CH3:33]>>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:22]([C:23]4[N:27]=[N:26][N:25]([C:32]([C:34]5[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=5)([C:12]5[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:33]5[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=5)[N:24]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1
Reactant: CC(C)O
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Agent: [K+]
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Yield: 82 %

Procedure:
Surprisingly it was found that if the suspension of Losartan potassium in isopropyl alcohol, obtained by deprotection of trityl Losartan, kept at a temperature of 25-30 degree for a period of 6-13 hours preferably 12 hours and is cooled slowly to a temperature of 0-5° C. in 2-12 hours, then the precipitated and dried crystals isolated in 82-92% yield are identical with the polymorphic Form I of Losartan potassium. The crystal form was found to be identical with the Polymorph Form I disclosed in the patent U.S. Pat. No. 5,608,075 by differential scanning calorimetry and X-Ray powder diffraction patterns studies.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1c(Cl)cccc1N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-fluorobenzaldehyde (8.00 g, 50.5 mmol, 1.00 equiv), morpholine (6.60 g, 75.8 mmol, 1.50 equiv), potassium carbonate (17.4 g, 126 mmol, 2.50 equiv), and dimethyl sulfoxide (50 mL). The resulting solution was stirred for 3 hour at 100° C. in an oil bath and then diluted with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, washed with H2O (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to yield 5.00 g (44%) of 2-chloro-6-(morpholin-4-yl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 226 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH:19]=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]I>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH:19]([OH:20])[CH3:22])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C=O
Reactant: C[Mg]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-formyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 1 mmol) in THF (10 mL) was added MeMgI (1 mL, 3 mmol) in Et2O at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with H2O and brine. After drying over Na2SO4, the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[C:12]5[CH2:19][NH:18][CH2:17][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:40])[CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CNC5)ccc32)no1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (127 mg, 0.360 mmol) is dissolved in THF (8 mL), flushed with nitrogen and cooled to 0° C. Sodium hydride (23 mg, 0.575 mmol, 60% in mineral oil) is added and the mixture is stirred for 10 minutes. Phenyl 5-tert-butylisoxazol-3-ylcarbamate (140 mg, 0.538 mmol) is added neat and the reaction is allowed to stir at room temperature overnight. The reaction is cooled in an ice bath and quenched with a saturated solution of ammonium chloride (100 mL). The mixture is then diluted with ethyl acetate and the product is extracted (2×100 mL EtOAc). The organic layers are combined, dried and concentrated to a brown oil that is dissolved in 10 mL of DCM and cooled in an ice bath and 10 mL of TFA is added. Following completion of the reaction the DCM and TFA are removed and ethyl acetate is added to the residue along with ammonium hydroxide to quench the remaining TFA. The mixture is diluted with water and extracted with ethyl acetate (2×50 mL). The organic layers are removed, dried, and concentrated. The residue is absorbed onto silica and separated via FCC (0-6% Methanol/DCM) to obtain N-(5-tert-butylisoxazol-3-yl)-5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-1H-indole-1-carboxamide. MS (ESI) m/z 419.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1 H) 8.29 (d, J=8.84 Hz, 1 H) 8.17 (d, J=3.79 Hz, 1 H) 7.47 (d, J=2.27 Hz, 1 H) 7.15 (dd, J=8.97, 2.40 Hz, 1 H) 6.76 (d, J=3.28 Hz, 1 H) 6.68 (s, 1 H) 4.07-4.14 (m, 4 H) 1.34 (s, 9 H).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14].[OH-].[K+].Cl>O>[CH3:1][S:2]([NH:10][C:11]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])(=[O:5])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Nc1cc(C(=O)O)ccc1C(=O)O
Temperature: 130 °C
Reaction time: 2 h

Procedure:
First, 2-methylsulfonamidoterephthalic acid was prepared as follows. 19.4 g methanesulfonic anhydride was placed in a flask and heated to produce a liquid. 10.3 g dimethyl 2-aminoterephthalate was added to the liquid over a period of 2-3 minutes. The mixture was initially heated at 130° C. for 15 minutes and then at 100° C. for 2 hours and 30 minutes. The mixture was then cooled, 50 ml of cold water added, the mixture stirred for 1 hour and then filtered. The precipitate was recrystallized from 100 ml of methanol which yielded 10 g precipitate having a melting point of 120° C. To a flask were added 1 g of the precipitate, 40 ml of water and 0.6 g potassium hydroxide and the mixture stirred at room temperature. After 15 minutes the slurry became a solution and stirring continued for a total of 12 hours. The solution was then acidified to a pH of about 2 with 6 molar hydrochloric acid to produce a thick precipitate. The precipitate was filtered and dried to yield 0.4 g of a material having a melting point of 296°-298° C. The material was identified by NMR through its potassium salt to be 2-(methylsulfonamido)terephthalic acid.
Reaction SMILES: [CH3:1][C:2]1([C:17]([O-:19])=[O:18])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1(C(=O)[O-])CCN(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To 1-benzyl 3-methylpyrrolidine-1,3-dicarboxylate (3.45 g, 13.1 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (16.4 mL, 16.4 mmol) in THF at −78° C., and the reaction was stirred at this temperature for 20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate 4:1) to give 1-benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.