Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.[C:30]([C@:32]([CH3:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:33](O)=[O:34])#[N:31]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:30]([C:32]([CH3:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:33]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)=[O:34])#[N:31]
Reactant: CCCC[C@@](C)(C#N)C(=O)O
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC(C)(C#N)C(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
a solution of 22.7 g of DCCI in 20 ml of CH2Cl2 is added at 0° to a mixture of 18.6 g of 4,4'-dihydroxy-1,1'-biphenyl, 15.5 g of (S)-2-cyano-2-methylhexanoic acid, 1.2 g of 4-dimethylaminopyridine and 100 ml of CH2Cl2, and the mixture is stirred at room temperature for 2 hours. The precipitate is filtered off with suction, the filtrate is concentrated and chromatography over silica gel gives 4'-(2-cyano-2-methylhexanoyloxy)-4-hydroxy-1,1'-biphenyl (optically active).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:46][S:43]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6])(=[O:45])=[O:44]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide (0.01 g, 0.017 mmol) in chloroform (1 ml) is treated with mesyl chloride (1 ml of a 3 mg/ml solution in chloroform) and TEA (0.003 ml). After stirring at 5° C. for 1 hour, the reaction mixture is diluted with DCM and extracted with 1 M HCl. The organic portion is isolated and concentrated in vacuo to yield the title product. (MH+ 651.5)
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)(=[O:17])=[O:16])=[O:13])[N:5]=1.[H][H]>[Pd].C(O)(=O)C>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:15]([NH:14][C:12]([NH:11][C:6]1[N:5]=[C:4]([O:3][CH3:2])[CH:9]=[C:8]([CH3:10])[N:7]=1)=[O:13])(=[O:17])=[O:16]
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na]
Solvent: CC(=O)O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1

Procedure:
A suspension containing 2 g of the sodium salt of N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-nitrobenzenesulfonamide, 25 ml of glacial acetic acid and 0.2 g of 10% palladium on carbon was shaken in a Paar apparatus at 40 p.s.i.g. hydrogen at ambient temperature. After twenty-four hours, no further pressure drop was observed. The reaction mixture was filtered and the filtrate stripped to yield a small amount of the desired product. The solids which contained most of the product and catalyst, were stirred with 20 ml of 5% aqueous sodium hydroxide, filtered and the filtrate combined with the residue from the acetic acid filtrate. After refiltering the resultant alkaline solution, it was acidified to pH 3 with dilute hydrochloric acid to precipitate the desired compound. After filtration and drying, the compound, when heated to 160°, underwent a transformation in physical appearance and subsequently melted at 210°-215°. The infrared absorption spectrum for the compound showed absorption peaks at 3300 and 3400 cm-1, consistent for an amino substituent, and absorption bands at 1700, 1690, 1600 and 1550 cm-1 which are consistent for the amino-carbonyl sulfonamide function. The product thus obtained was sufficiently pure for the purposes of this invention.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Cl:15][C:16]1[C:17]([F:26])=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])C(O)=O.CN(C=O)C>C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:15][C:16]1[C:24]([F:25])=[C:23]([CH:22]=[CH:18][C:17]=1[F:26])[C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(F)c(Cl)c1F
Temperature: 80 °C

Procedure:
A 125 mL, single-neck, round-bottomed flask was charged with di-tert-butoxy-N,N-dimethylmethanamine (48.2 ml, 201 mmol), 3-chloro-2,4-difluorobenzoic acid (9.67 g, 50.2 mmol), and DMF (50 ml). The reaction was heated to 80° C. for 48 hours. After cooling to ambient temperature, the reaction was diluted with saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaHCO3 and brine, dried, filtered and concentrated to provide the desired product as a gold oil.
Reaction SMILES: [C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:5])[C@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.C(Cl)Cl.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].Cl>>[C:23]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])(=[O:26])[CH:24]=[CH2:25]
Reactant: C[C@H](O)C(=O)OC1CCCCC1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)O[C@@H](C)C(=O)OC1CCCCC1
Temperature: -20 °C
Reaction time: 5.5 h
Yield: 102 %

Procedure:
To a mixture of 10.1 g (58.5 mmol) of cyclohexyl (s)-(-)-lactate, 8.1 g (80.4 mmol) of triethylamine and ml of methylene chloride, 5.7 ml (70.2 mmol) of acryloyl chloride was added dropwise at a temperature of -20° C., and the mixture was stirred at -20° C. for 5.5 hours. On ice cooling, 1N hydrochloric acid was added to the reaction mixture to separate an organic layer, and an aqueous layer was extracted with methylene chloride. Organic layers were combined and washed with successive, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and filtered, the solvent was distilled off, and 13.5 g of crude (S)-cyclohexyl 2-propenoyloxypropionate was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=O)[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=[O:26])=[N:10]2)=[CH:5][CH:4]=1.COC1N=C2C(C=CC(N3CC4C(=CC=CC=4)C3OCC(OC(C)(C)C)=O)=N2)=CC=1>FC(F)(F)C(O)=O.C(OC(C)C)(C)C>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=[O:26])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Agent: COc1ccc2ccc(N3Cc4ccccc4C3OCC(=O)OC(C)(C)C)nc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: COc1ccc2ccc(N3Cc4ccccc4C3OCC(=O)O)nc2n1

Procedure:
[2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid may be prepared in the following manner: a solution of tert-butyl [2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinyloxy]acetate (29.4 g) in trifluoroacetic acid is stirred for 2 hours at a temperature in the region of 25° C. The reaction mixture is then concentrated to dryness and the residue obtained is stirred in isopropyl ether (200 cc). The crystallized solid obtained is separated by filtration and then taken up with water (400 cc). The mixture is brought to pH 10 with 4N aqueous sodium hydroxide solution. An insoluble product is separated by filtration; the filtrate is washed with ethyl acetate (3×200 cc) and then acidified to pH 2 with 4N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with water and dried in the air. [2-(7-Methoxy-1,8-naph-thyridin-2-yl)-1-isoindolinyloxy]acetic acid (14.6 g), m.p. 190° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:12][C:13]([C:14]([O:16]C)=[O:15])=[C:8]2[N:7]=[C:6]1[CH3:24]>[Li+].[OH-].C1COCC1>[Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[C:8]2[N:7]=[C:6]1[CH3:24]
Reactant: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(Cl)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
A mixture of methyl 3-(2,3-dichlorobenzyl)-2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (239 mg, 0.55 mmol) in 2N LiOH (15 mL) and THF (15 mL) was stirred at 60° C. for 5 h. It was cooled to room temperature and the precipitate was collected by filtration. It was then poured into water (50 mL) and the suspension was acidified with formic acid to pH=1. It was filtered and the solid was washed with water to afford the desired product as a gray solid (146 mg, 63%); LC/MS: MS (ES+) m/e 421 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (s, 3H), 3.39 (t, J=4.8 Hz, 4H), 3.67 (t, J=4.8 Hz, 4H), 5.50 (s, 2H), 6.67 (d, J=4.5 Hz, 1H), 7.04 (s, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.60 (d, J=4.5 Hz, 1H), 8.14 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][CH:8]([O:10]CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:7][CH:8]([OH:10])[CH2:9]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(O)C1
Temperature: 25 °C

Procedure:
The 1-(N-(t-butoxycarbonyl)amino)-3-benzyloxy-cyclobutane-1-carboxylic acid ethyl ester synthesized as above is dissolved in an alcohol solvent such as ethanol or an acetate ester solvent such as ethyl acetate ester, and palladium-on-activated carbon (amount: 10 w/w % or more relative to the substrate) is added to the solution in an atmosphere of hydrogen to allow them to react under stirring at room temperature. The reaction solution is then filtered through Celite, and the filtrate is concentrated and purified to yield 1-(N-(t-butoxycarbonyl)amino)-3-hydroxy-cyclobutane-1-carboxylic acid ethyl ester (Step 4).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].O[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CCCC1CC(=O)N(CO)C1
Solvent: Cc1ccccc1
Product: CCCC1CC(=O)N(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of 5-nitro-1H-indole x3 (100 mg, 1 eq, 0.62 mmol), 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (108.27 mg, 1 eq, 0.62 mmol), paratoluenesulfonic acid (11 mg, 0.1 eq, 0.062 mmol) in 5 ml of toluene is refluxed for 4 hours. After cooling to room temperature, the solvent is removed under reduced pressure and the crude product is purified by preparative chromatography on reverse phase (gradient: H2O/CH3CN/TFA: 95/5/0.1 (v/v/v) to 5/95/0.1 (v/v/v)) affording 1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 148 as a colorless oil.
Reaction SMILES: [K].C([O:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:29][C:28](=[O:30])[NH:27][S:26]1(=[O:32])=[O:31])[CH2:13][CH:14]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:29][C:28](=[O:30])[NH:27][S:26]1(=[O:32])=[O:31])[CH2:13][CH:14]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC(Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)N1
Agent: [Pd]
Agent: [K]
Solvent: CCO
Solvent: O
Product: O=C1CCCCC(Cc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)N1

Procedure:
A solution of 7-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-azepan-2-one potassium salt in 6 mL of EtOH/water (1:1) is hydrogenated over 10% Pd/C at 1 atm for 2 h. The catalyst is filtered and the solvent is removed under reduced pressure. The residue is purified by reverse phase HPLC followed by lyophilization to give the title compound as a solid: 1H NMR (DMSO-d6): δ 7.85-7.83 (d, J=8.09 Hz, 1H), 7.42-7.41 (d, J=2.02 Hz, 1H), 7.34-7.32 (dd, J=1.77 Hz, 8.09 Hz, 1 H), 6.49-6.50 (d, J=3.53 Hz, 1H), 4.94 (s, 2H), 4.21-4.13 (m, 2H), 3.33-3.20 (m, 3H), 2.98-2.91 (m, 1H), 2.72-2.67 (m, 1H), 2.40-2.21 (m, 3H), 2.08-1.75 (m, 3H). (M−1)−=352.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CSC.[CH3:10][C:11]1[S:12][C:13]([CH2:17][OH:18])=[C:14]([CH3:16])[N:15]=1.C(N(CC)CC)C>C(Cl)Cl.CCOCC.CCOC(C)=O.CCCCCC>[CH3:10][C:11]1[S:12][C:13]([CH:17]=[O:18])=[C:14]([CH3:16])[N:15]=1
Reactant: Cc1nc(C)c(CO)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CSC
Product: Cc1nc(C)c(C=O)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 3-neck 100 mL round-bottom flask was charged with anhydrous CH2Cl2 (20 mL) and oxalyl chloride (1.0 mL, 11.25 mmol) under N2 atmosphere. The mixture was cooled to −78° C. Anhydrous DMS O (1.1 mL, 15 mmol) was slowly added. The reaction was allowed to stir for 30 min. 2,4-dimethylthiazole-5-methanol (1.181 g, 7.5 mmol) in CH2Cl2 (5 mL) was slowly added. The reaction was allowed to stir for about 3 h, until TLC (1:1 EtOAc/Hexane) showed no starting material. The reaction was quenched with triethylamine (4.3 mL, 30 mmol) and stirred for 10 min. before warming to room temperature. The reaction was poured into Et2O (100 mL) and then extracted with water (2×25 mL). The organic phase was washed with NaHCO3(aq) (25 mL) and brine (25 mL). Dry over MgSO4 and concentrated under vacuum. The product was stored in the freezer. Yield: 1.04 g (89%) orange crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C([N:36]1C=CC(=O)[C:38]([OH:43])=[C:37]1C)(=O)C.OCCN.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:36]([CH2:37][CH2:38][OH:43])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)n1ccc(=O)c(O)c1C
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCO
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCO
Temperature: 25 °C
Reaction time: 144 h

Procedure:
3-Benzyloxy-2-methyl-4-pyrone (4.8 g), prepared as described under (J), and 2-hydroxyethylamine (1.22 g) are dissolved in water (220 ml) and ethanol (100 ml) containing sodium hydroxide (2 g) is added. The mixture is stirred at room temperature for 6 days and is then acidified with concentrated hydrochloric acid to pH 2, and evaporated to dryness. The resulting colourless solid is washed with water and extracted into chloroform (2×50 ml). The chloroform extracts are combined, dried over magnesium sulphate, and evaporated to yield 3-benzyloxy-1-(2'-hydroxyethyl)-2-methylpyrid-4-one, as a white solid (3.4 g), m.p. 198°-199° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1>Br>[CH3:14][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[O:10][C:11]=1[CH3:15]
Reactant: COc1ccc(-c2nc(C)c(C)o2)cc1
Agent: Br
Product: Cc1nc(-c2ccc(O)cc2)oc1C
Yield: 81.6 %

Procedure:
A mixture of 32.0 g of 2-(4-methoxyphenyl)-4,5-dimethyloxazole and 250 ml of 48% hydrogen bromide solution was stirred and heated at reflux for 2.5 hours. The reaction mixture was concentrated in vacuo, the residue dissolved in 2N sodium hydroxide and the solution acidified with acetic acid. The solid product was collected and recrystallized from methanol to give 24.3 g of 4-(4,5-dimethyl-2-oxazolyl)phenol, m.p. 202°-203° C.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH:21]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:22][CH2:23][CH3:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH:21]([O:25][C:26]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:27])[CH2:22][CH2:23][CH3:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl benzoate (700 mg, 2.1 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 39 (150 mg, 19% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.84-0.99 (m, 5H), 1.20-1.38 (br. m, 3H), 1.41-1.51 (m, 2H), 1.70-1.73 (m, 2H), 1.84-1.89 (m, 4H), 2.11 (tt, J 12, 3.2 Hz, 1H), 2.82-2.91 (m, 2H), 6.61 (t, J=5.6 Hz, 1H), 7.52-7.58 (m, 3H), 7.47 (t, J=6.0 Hz, 1H), 7.95-7.97 (m, 2H), 12.04 (s, 1H). MS (ESI) m/z 400.15 (M+Na)+; 376.16 (M−H)−.
Reaction SMILES: C1(P([C:14]2[CH:19]=[CH:18]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(O)(C)C.[Cl:36][C:37]1[C:45]2[C:40](=[N:41][C:42]([S:46][CH3:47])=[N:43][CH:44]=2)[NH:39][N:38]=1>C1COCC1>[Cl:36][C:37]1[C:45]2[C:40](=[N:41][C:42]([S:46][CH3:47])=[N:43][CH:44]=2)[N:39]([CH:19]([CH3:18])[CH3:14])[N:38]=1
Reactant: CSc1ncc2c(Cl)n[nH]c2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CSc1ncc2c(Cl)nn(C(C)C)c2n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Triphenylphosphine (387 mg, 1.5 mmol) was dissolved in THF (15 mL) and the solution was cooled to −78° C. Diethyl azodicarboxylate (225 uL, 1.5 mmol) was added slowly to the reaction mixture. The reaction was stirred for 5 min and then isopropanol was added (115 uL, 1.5 mmol) dropwise. After stirring an additional 5 min. the 3-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (305 mg, 1.6 mmol) was added as a solid. The resulting suspension was kept at −78° C. for 5 min then the cooling bath was removed. The reaction was stirred for 3 hours at room temperature. After concentration the desired 3-Chloro-1-isopropyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine was obtained by column chromotography (0–5% MeOH/methylene chloride); 1H-NMR (CDCl3): • 1.46 (d, 1H), 2.66 (s, 3H), 4.53 (q, 6H), 8.87 (s, 1H); LC/MS (m/e)=243.0 (MH+), Rt=2.25 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:11]=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].Cl.[NH2:14][OH:15].C(O)C.C([O-])(=O)C.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:11]=[N:14][OH:15])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C=O)[nH]1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(C=NO)[nH]1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester (as prepared in the previous step, 300 mg, 1.80 mmol), hydroxylamine hydrochloride (560 mg, 8.10 mmol), ethanol (10 mL), sodium acetate (1.10 g, 13.4 mmol) and water (10 mL) was stirred at 90° C. for 30 min. The solvents were removed in vacuo and the solid was collected on a Buchner funnel and washed with water (10 mL) to yield 226 mg (69%) of the title compound as a white solid: LC-MS (ESI, m/z): Calcd. for C8H11N2O3, 183.1 (M+H); found: 183.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:49]2[CH2:51][CH2:50]2)=[N:4][N:5]([CH3:48])[C:6]=1[N:7]1[CH2:47][CH2:46][C:10]2[N:11]=[C:12]([C:25]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:26]=3[C:27]([CH3:45])=[N:28][N:29]4S(C3C=CC(C)=CC=3)(=O)=O)[N:13]=[C:14]([N:15]3[CH2:20][CH2:19][C@@H:18]([O:21][CH3:22])[C:17]([CH3:24])([CH3:23])[CH2:16]3)[C:9]=2[CH2:8]1.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH:49]2[CH2:50][CH2:51]2)=[N:4][N:5]([CH3:48])[C:6]=1[N:7]1[CH2:47][CH2:46][C:10]2[N:11]=[C:12]([C:25]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:26]=3[C:27]([CH3:45])=[N:28][NH:29]4)[N:13]=[C:14]([N:15]3[CH2:20][CH2:19][C@@H:18]([O:21][CH3:22])[C:17]([CH3:24])([CH3:23])[CH2:16]3)[C:9]=2[CH2:8]1
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2c(Cl)c(C4CC4)nn2C)CC3)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4[nH]nc(C)c34)nc3c2CN(c2c(Cl)c(C4CC4)nn2C)CC3)CC1(C)C
Reaction time: 2 h

Procedure:
To a solution of (R)-6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.050 g, 0.068 mmol) in MeOH (3 mL) was added K2CO3 (0.057 g, 0.410 mmol). The mixture was heated at 55C. under a nitrogen atmosphere for 2 h. At that point the mixture was diluted with EtOAc and washed with sat aq NH4Cl and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by FCC (0-10% MeOH/DCM) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.59 (s, 1 H), 7.39 (d, J=8.3 Hz, 1 H), 7.21 (d, J=8.8 Hz, 1 H), 4.39 (d, J=14.9 Hz, 1 H), 4.25 (d, J=14.7 Hz, 1 H), 3.62-3.78 (m, 1 H), 3.56 (s, 3 H), 3.46-3.55 (m, 2 H), 3.30 (d, J=3.5 Hz, 1 H), 3.26 (s, 3 H), 2.99-3.08 (m, 1 H), 2.97 (dd, J=9.1, 4.0 Hz, 1 H), 2.92 (app. t, J=5.9 Hz, 2 H), 2.85 (d, J=12.9 Hz, 1 H), 2.18 (s, 3 H), 1.85-1.96 (m, 4 H), 1.74-1.82 (m, 1 H), 1.49-1.60 (m, 1 H), 0.92 (s, 3 H), (overlapped m, 2 H), 0.81 (s, 3H), 0.72-0.77 (m, 2 H); MS (ESI+) m/z 575.5 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH3:29])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([OH:28])=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[N:20]([CH3:29])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(O)ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc2c(c1)cc(C(=O)N1CCN(c3ccccc3C(C)(C)C)CC1)n2C
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A mixture of 2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-indol-5-ol obtained in Example 28 (510 mg), methyl bromoacetate (239 mg), potassium carbonate (276 mg), and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 3 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford crystals. Crystals were washed with diethyl ether and dried under reduced pressure to provide the title compound (509 mg, 84%) as crystals.