Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]3[CH2:28][O:27]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)#[N:30]>CCO.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]([OH:27])[CH2:28][N:40]3[CH2:39][CH2:38][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:29]#[N:30])[CH2:42][CH2:41]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2nn(CC3CO3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Temperature: 80 °C
Yield: 83.4 %

Procedure:
3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (5.33 g, 13.2 mmol) and 1-(2-cyanophenyl)-piperazine (2.97 g, 15.86 mmol) were partially dissolved in EtOH (50 mL) and triethylamine (2 mL). The reaction mixture was heated to 80° C. for 18 h. The mixture was concentrated and purified by column chromatography (silica, 20% acetone/CH2Cl2) to give 3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (6.51 g, 83%) as a yellow solid. TLC (silica, 20% acetone/CH2Cl2): Rf=0.35. MS (electrospray): m/z 591.3 (591.3, calculated for C32H39ClN6O3, [M+H]+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[C:20]([C:23]1[C:24]([OH:36])=[C:25]([O:34][CH3:35])[C:26]2[O:30][CH:29]=[CH:28][C:27]=2[C:31]=1[O:32][CH3:33])(=[O:22])[CH3:21]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:36][C:24]1[C:23]([C:20](=[O:22])[CH3:21])=[C:31]([O:32][CH3:33])[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]=1[O:34][CH3:35])(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Product: COc1c(C(C)=O)c(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c(OC)c2occc12

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 5-acetyl-4,7-dimethoxy-6-hydroxybenzofuran, the desired product is obtained and is directly used in the following deprotection step without prior purification.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[H][H]>CO.ClCCl.[Pd]>[NH2:9][C:3]1[C:2]([OH:1])=[N:7][C:6]([CH3:8])=[CH:5][CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])c(O)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(N)c(O)n1

Procedure:
6-hydroxy-5-nitro-2-picoline (500 mg, 3.247 mmol) was dissolved in methanol:dichloromethane (5:1, 60 ml) and 10% palladium on active carbon was added thereto slowly, and then stirred for 2 hours with adding hydrogen gas at room temperature. The reaction mixture was filtered by using celite and evaporated under reduced pressure to quantitatively obtain white solid (400 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:9]1([C:15](O)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:38])=O.CN(C)C=O>ClCCl>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][N:8]([C:9]1([C:15]([Cl:38])=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCN(C1(C(=O)O)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCN(C1(C(=O)Cl)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of (15.1 mmol) of the product from Step E in 73 mL of dichloromethane is treated with 1.4 mL (17 mmol, 1.1 equivalents) of oxalyl chloride and 0.02 mL (0.3 mmol, 0.02 equivalents) of dimethylformamide at ambient temperature, causing some bubbling, and is stirred overnight. The resulting solution of the title compound is used in step G without isolation.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:27][CH3:28])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Temperature: 100 °C

Procedure:
A suspension of 0.237 part of 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid and 0.83 part of pulverized potassium carbonate in 6 parts by volume of dry dimethylformmide is stirred under heating at 100°C for 1 hour. To the mixture is then added 0.3 part by volume of diethyl sulfate. The mixture is stirred under heating at 100°C for 1 hour and filtered to remove insoluble material. The filtrate is concentrated to dryness under reduced pressure and the residue is extracted with chloroform. Evaporation of the solvent from the extract gives ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate as crystals. Recrystallization from ethyl acetate yields colorless plates melting at 140°-142°C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[C:12]3[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][C:16]([O:28][CH3:25])=[CH:15][CH:14]=4)=[CH:16][CH:17]=3)[C:12]3[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(Br)cc2c2cc(Cl)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(/C=C/c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To a solution of 9-benzenesulfonyl-6-bromo-3-chloro-9H-pyrido[2,3-b]indole (250 mg, 0.59 mmol, 1 equiv.) in anhydrous dioxane (25 ml) under Argon, Pd(PPh3)4 (102 mg, 0.09 mmol, 0.15 equiv.), K2CO3 (244 mg, 1.77 mmol, 3 equiv.), (E)-2′-(4-methoxyphenyl)ethenylboronic acid (110 mg, 0.77 mmol, 1.3 equiv.) and H2O (5 ml) are added respectively. The mixture is stirred at 100° C. overnight and then filtered over celite which is washed with AcOEt (20 ml) and THF (10 ml). The filtrate is concentrated under reduced pressure and the crude residue is purified over silica gel column (eluant CH2Cl2/PE 7:3). The product is obtained as a white solid (212 mg, 0.40 mmol) in 68% yield.
Reaction SMILES: [F-].[Cs+].CC1C=CC(S([O:13][CH2:14][C@@H:15]2[O:17][CH2:16]2)(=O)=O)=CC=1.[Cl:18][C:19]1[C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](F)=[CH:33][C:34]=3[O:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:29]=[CH:28][N:27]=2)=[C:23]2[O:44][CH2:45][O:46][C:22]2=[CH:21][CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:13][CH2:14][C@@H:15]4[O:17][CH2:16]4)=[CH:33][C:34]=3[O:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:29]=[CH:28][N:27]=2)=[C:23]2[O:44][CH2:45][O:46][C:22]2=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Fc1cc(OC2CCOCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1Nc1ncnc3cc(OC[C@H]4CO4)cc(OC4CCOCC4)c13)OCO2
Temperature: 70 °C
Yield: 76.6 %

Procedure:
Caesium fluoride (0.46 g) and (2R)-(−)-glycidyl tosylate (0.275 g) were added in turn to a solution of 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (0.416 g) in DMF (5 ml) and the reaction mixture was stirred and heated to 60° C. for 2 hours and to 70° C. for a further 1.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 49:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.36 g); NMR Spectrum: (CDCl3) 1.9–2.1 (m, 2H), 2.2–2.3 (m, 2H), 2.8 (m, 1H), 2.98 (m, 1H), 3.42 (m, 1H), 3.6–3.7 (m, 2H), 3.95–4.1 (m, 3H), 4.45 (m, 1H), 4.8 (m, 1H), 6.02 (s, 2H), 6.59 (m, 12H), 6.72 (d, 1H), 6.81 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.27 (s, 1H); Mass Spectrum: M+H+ 472 and 474.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][S:7]([N:10]([C:18]2[C:19]([F:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])S(CC2CC2)(=O)=O)(=[O:9])=[O:8])[CH2:5][CH2:4]1>C1COCC1.CO>[CH:3]1([CH2:6][S:7]([NH:10][C:18]2[C:19]([F:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])(=[O:8])=[O:9])[CH2:5][CH2:4]1
Reactant: O=C(O)c1c(F)ccc(N(S(=O)(=O)CC2CC2)S(=O)(=O)CC2CC2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(F)ccc(NS(=O)(=O)CC2CC2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
A solution of 1N NaOH (2.78 mL, 2.78 mmol) was added to a solution of crude 3-(1-cyclopropyl-N-(cyclopropylmethylsulfonyl)methylsulfonamido)-2,6-difluorobenzoic acid (380 mg, 0.928 mmol) in 4:1 THF/MeOH (5 mL, 0.2M). The reaction mixture was stirred at room temperature for 1 hour, after which most of the organic solvents were removed. 1N HCl (3 mL) was slowly added to the mixture to acidify to a pH of 1. The acidified aqueous layer was extracted with ethyl acetate (75 mL). The ethyl acetate extract was washed with water (2×20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated. Trituration of the residue with Et2O afforded 3-(cyclopropylmethylsulfonamido)-2,6-difluorobenzoic acid as a solid (139 mg, 51%). 1H NMR (400 MHz, d6-DMSO) δ 9.76 (s, 1H), 7.60-7.54 (m, 1H), 7.22-7.16 (m, 1H), 3.10 (d, J=7.0 Hz, 2H), 1.10-0.99 (m, 1H), 0.58-0.53 (m, 2H), 0.36-0.31 (m, 2H); m/z (APCI-neg) M−1=289.9.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH3:25]
Reactant: CCNCC
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Product: CCN(CC)c1cccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12

Procedure:
7-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine and excess of diethylamine in alcohol (1 mL) in sealed tube was heated at 120° C. for overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give N,N-diethyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine. 1H NMR (CDCl3): δ 8.61 (d, 2H, J=6.0 Hz), 7.61–7.66 (m, 2H), 7.22–7.34 (m, 4H), 7.09 (t, 2H, J=8.7 Hz), 6.32 (d, 1H, J=6.1 Hz), 3.64 (q, 4H, J=7.0 Hz), 1.26 (t, 6H, J=7 Hz). MS (ES+ve): 362 (25, M+2), 361 (100, M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](=[O:43])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:36]([NH:35][C:34]([C@H:10]1[C@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12][NH:8][CH2:9]1)=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)NCc2ccccc2)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2C(=O)NCc2ccccc2)C(C)C)ccc1OC
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of (3S*,4R*)-3-benzylcarbamoyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (61 mg, 0.098 mmol) in 2 mL CH2Cl2, TFA (113 μL, 1.46 mmol) is added. The mixture is stirred at 30° C. for 2 h, then overnight at RT, and poured into a saturated solution of NaHCO3. The layers are separated, and the aqueous one is back-extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on an NH2 Isolute SPE Flash column (eluent: CH2Cl2:MeOH 100:0 to 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 9:1)=0.2. MS (LC-MS): 498 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.38 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13].[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:13][CH3:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 47.4 %

Procedure:
788 mg (4 mmol) of 2-hydroxy-4-nitro-benzoic acid methyl ester is mixed in 20 ml of absolute dimethylformamide with 177 mg of sodium hydride (60%; 4.4 mmol), and it is heated for 1 hour to 50° C. After cooling to room temperature, it is mixed with 625 mg (4.4 mmol) of methyl iodide and heated for 4 hours to a bath temperature of 80° C. After concentration by evaporation, it is taken up in 50 ml of water and extracted three times with 25 ml each of ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on 5 g of Isolute SI. (50 μm) with a gradient from cyclohexane to cyclohexane:ethyl acetate=80:20 as an eluant, and 400 mg (47% of theory) of 2-methoxy-4-nitro-benzoic acid methyl ester is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C@H:21]([C:23]([O:25]C(C)(C)C)=[O:24])[CH3:22])=[O:19])=[C:5]2[OH:30]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22])=[O:19])=[C:5]2[OH:30]
Reactant: C[C@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)O
Yield: 84 %

Procedure:
1,1-Dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)-L-alaninate (525 mg, 1204 μmol) was dissolved in TFA for 30 minutes before it was concentrated, precipitated with hexanes, washed with hexanes, and dried in a vacuum oven to give the title compound (384 mg) as a white solid. MS (m/z)=380 (M+H)+. Calculated for C18H18ClNO6 379.08.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][N:29]5[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]5)=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][N:29]5[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]5)=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)C1CCN(Cc2c[nH]c3cc(-c4noc(-c5cnc(OC(C)C)c(Cl)c5)n4)ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CN5CCC(C(=O)O)CC5)c[nH]c4c3)no2)cc1Cl
Temperature: 70 °C
Yield: 93 %

Procedure:
Sodium hydroxide (19 mg) was added to a solution of ethyl 1-{[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D103) (134 mg) in iPrOH (4 mL) and water (4 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 1-{[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylic acid (E78) (118 mg) as a pale red-white solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 1.55 (2H, m), 1.77 (2H, m), 2.01 (2H, m), 2.18 (1H, m), 2.85 (2H, m), 3.67 (2H, m), 5.46 (1H, m), 7.46 (1H, s), 7.73 (1H, dd), 7.81 (1H, d), 8.14 (1H, s), 8.56 (1H, d), 8.94 (1H, d), 11.37 (1H, s), 12.02 (1H, br s). MS (ES): C26H26ClN6O4 requires 495; found 496.2 (M+H+).
Reaction SMILES: [CH3:1][SH:2].C([O:6][C@H:7]1[CH2:24][C@@:22]2([CH3:23])[C@@H:18]([CH2:19][CH2:20][C@@H:21]2OS(C)(=O)=O)[C@H:17]2[C@@:8]1([F:32])[C@:9]1([CH3:31])[C:14]([CH2:15][CH2:16]2)=[CH:13][C:12](=[O:30])[CH:11]=[CH:10]1)(=O)C.O>CN(C)C=O>[F:32][C@:8]12[C@@H:7]([OH:6])[CH2:24][C@@:22]3([CH3:23])[C@@H:18]([CH2:19][CH2:20][C@H:21]3[S:2][CH3:1])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:31])[CH:10]=[CH:11][C:12](=[O:30])[CH:13]=1
Reactant: CS
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Solvent: O
Solvent: CN(C)C=O
Product: CS[C@@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C

Procedure:
To a suspension of 50% sodium hydride/paraffin (100 mg) in dry dimethylformamide (10 ml), cooled and stirred in an ice bath, a stream of methanethiol was passed until a homogeneous solution resulted. (11β,17β)-11-(Acetyloxy)-9-fluoro-17-(methanesulfonyloxy)androsta-1,4-dien-3-one (280 mg, 0.64 mmole) was added and the solution was heated in an atmosphere of nitrogen in a bath at 100°-120° C. for 5.0 hours. The mixture was then cooled to room temperature and water (1.0 ml) was added. After stirring for 20 minutes, the mixture was poured into water and was extracted with chloroform. The chloroform solution was washed with water, dried (anhydrous magnesium sulfate) and evaporated in vacuo. The residue was dissolved in chloroform-hexane (7:3; 15 ml) and absorbed on a column of silica gel (5.0 g). The column was first eluted with chloroform to remove the paraffin. Further elution of the column with chloroform: hexane (9:1) gave the title compound (179 mg) which had a small amount of a slightly less polar impurity (tlc). One crystallization of this from ethyl acetate followed by drying (110° C., 0.3 mm of Hg, 20 hours) gave the analytical specimen (157 mg), melting point 235°-236° C. with consistent spectral data.
Reaction SMILES: [NH2:1][C:2]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:30][CH2:31][C:32](Br)=[O:33].CCN(CC)CC>C(Cl)Cl>[Br:30][CH2:31][C:32]([NH:1][C:2]([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])([CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:33]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)CCC(N)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of di-tert-butyl 4-amino-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (5.00 g, 12.0 mmol) and 2-bromoacetyl bromide (1.46 mL, 3.40 g, 16.80 mmol) in DCM (60 mL) was added Et3N (2.5 mL) at room temperature. The reaction mixtures were stirred at room temperature for overnight. The reaction mixtures were diluted with DCM (300 mL), washed with 1N HCl solution, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 10% EtOC in hexanes to 100% EtOAc to afford di-tert-butyl 4-(2-bromoacetamido)-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (2.58 g, 40%). 1H NMR (400 MHz, CDCl3) 6.43 (s, 1H), 3.76 (s, 2H), 2.20 (t, J=8.0 Hz, 2H), 1.98 (t, J=8.0 Hz, 6H), 1.43 (s, 27H); MS (ESI), 558, 560 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[C:8]([C@@H:17]([NH2:19])[CH3:18])=[CH:7]2.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[C:8]([C@@H:17]([NH:19][C:21]1[N:29]=[CH:28][N:27]=[C:26]3[C:22]=1[N:23]=[CH:24][NH:25]3)[CH3:18])=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1cscn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cscn1

Procedure:
Prepared according to Procedure H using (1S)-1-(8-chloro-2-(thiazol-4-yl)-quinolin-3-yl)ethanamine (0.045 g, 0.155 mmol), 6-chloropurine (0.029 g, 0.19 mmol, 1.2 eq) and DIEA (0.33 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(8-chloro-2-(thiazol-4-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=16 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 9.22 (s, 1 H), 8.63 (s, 1 H), 8.44-8.46 (m, 1 H), 8.42 (s, 1 H), 8.34 (s, 1 H), 7.88-7.93 (m, 2 H), 7.56 (t, 1 H), 1.77 (d, 3H), Mass Spectrum (ESI) m/e=408 (M+1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1(=O)CCN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8 -benzylthio-2-chloro-4-(1,1-dioxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 238°-239° C.) and piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([CH3:15])[N:11]=1)[NH2:6].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:6]([C:5]1[CH:7]=[CH:8][C:9]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: COc1cc(N)ccc1-c1nc(C)no1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1nc(C)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
Step I (1): Dichloromethane (50 mL) was added to a flask charged with 3-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)aniline (1.2 g, 5.85 mmol, N. Smith et. al PCT Publication WO 2003/077918) and 1,1′-thiocarbonyldipyridin-2(1H)-one (1.36 g, 5.85 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography (20-50% EtOAc/hexane) linear gradient to afford 5-(4-isothiocyanato-2-methoxyphenyl)-3-methyl-1,2,4-oxadiazole (1.28 g, 5.18 mmol, 89% yield). LC-MS (M+H)+ 248.2.