Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[C-:13]#[N:14].[Na+].C(OC(=O)C)C>CS(C)=O.CCCCCC>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: N#CCc1ccccc1C(F)(F)F
Temperature: 90 °C
Yield: 88.5 %

Procedure:
A solution of 1-bromomethyl-2-trifluoromethyl-benzene (3.5 g, 14.641 mmol) in DMSO (18 mL) and sodium cyanide (1.076 g, 21.962 mmol) were taken in a flask and the flask was heated to 90° C. for 3 hours. The reaction was monitored by TLC (2% ethylacetate in hexane). The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 2.4 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].C(N1CCOCC1)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:14][N:15]([O:16][CH3:17])[C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A solution containing 18.8 g of N-tert.-butoxycarbonylglycine in 180 ml of anhydrous dichloromethane was stirred under nitrogen and cooled at 0-5° C. while 11.5 g of N,O-dimethylhydroxylamine hydrochloride, 27.1 g of N-ethylmorpholine and 22.5 g of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. The mixture was allowed to warm slowly to room temperature and stirred for 16 h. The mixture was washed twice with 150 ml of 1M hydrochloric acid, and 150 ml of saturated sodium hydrogen carbonate then dried over anhydrous sodium sulphate, filtered and evaporated to give 22.5 g of N-tert.-butoxycarbonylglycine N-methyl-N-methoxyamide as a white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([NH2:17])=[CH:14][C:13]([CH3:18])=[N:12][C:11]=3[S:10][C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[Cl:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([NH:17][C:15]2[CH:14]=[C:13]([CH3:18])[N:12]=[C:11]3[S:10][C:9]([CH3:19])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:16]=23)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1cc(N)c2c(-c3cccc(Cl)c3)c(C)sc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(Cl)c3)c(C)sc2n1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of 3-(3-chlorophenyl)-2,6-dimethylthieno[2,3-b]pyridin-4-amine (100 mg, 0.346 mmol) (Description 9) in THF (3 mL) was added potassium tert-butoxide (155 mg, 1.385 mmol) and the mixture stirred for 5 min before the addition of 3-chlorobenzenesulfonyl chloride (0.049 mL, 0.346 mmol). The mixture was then stirred for 1 h and the solvent then removed in vacuo. Ethyl acetate (10 mL) was then added and the mixture washed with water (3×10 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, was followed by trituration with MeOH, to afford the title compound (67.8 mg). LCMS (A) m/z: 463 [M+1]+, Rt 1.09 min (basic), Rt 1.44 min (acidic).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([O:17][CH3:18])[C:6]([O:15][CH3:16])=[N:7]2.[CH2:19](C([SnH3])=C(CCCC)CCCC)[CH2:20]CC.[Cl-].[Li+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:15][C:6]1[C:5]([O:17][CH3:18])=[N:4][C:3]2[C:8](=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:2]=2[CH:19]=[CH2:20])[N:7]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(Br)c2nc1OC
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12
Temperature: 100 °C

Procedure:
A mixture of 3.14 g (1 mmol) of 5-bromo-2,3-dimethoxy-7-nitro-quinoxaline, 6.34 g (2 mmol) of tributylvinylstannane, 1.26 g (3 mmol) of lithium chloride and 1.4 g (0.2 mmol) of bis(triphenylphosphine)-palladium(II) chloride in 20 ml of dimethylformamide is heated for 2 hours at 100° C. The mixture is cooled to room temperature and concentrated to dryness by evaporation under reduced pressure. Purification by flash chromatography using toluene as eluant yields the title compound in the form of a slightly yellowish solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:15][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[N:20][C:21]=1Cl.O>O1CCOCC1>[Br:15][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[N:20][C:21]=1[O:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:4]([F:13])([F:14])[F:3])=[CH:6][CH:7]=1
Reactant: Cn1cnc(Cl)c(Br)c1=O
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc(OCc2ccc(C(F)(F)F)cc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Sodium hydride (55% in mineral oil) (0.22 g) was suspended in 10 ml of dioxane, and then 0.88 g of 4-trifluoromethylbenzyl alcohol was added thereto. The resulting mixture was stirred for one hour at room temperature, then incorporated with 1.12 g of 5-bromo-6-chloro-3-methyl-4(3H)-pyrimidinone and stirred for 15 hours. The resulting solution was poured into water, and the resulting crystals were filtered off and then recrystallized from a benzene-hexane mixture to give 1.60 g of the intended product.
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]2[N:11]=[C:10]([C:12]3[N:13]=[CH:14][N:15]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[N:18]5[CH2:27][CH2:28][C@H:17]5[C:16]=34)[O:9][N:8]=2)C(=O)C2=CC=CC=C12>C(O)C.CN>[NH2:5][CH2:6][C:7]1[N:11]=[C:10]([C:12]2[N:13]=[CH:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19](=[O:26])[N:18]4[CH2:27][CH2:28][C@H:17]4[C:16]=23)[O:9][N:8]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1
Agent: CN
Solvent: CCO
Product: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1

Procedure:
9 g (19.9 mmol) of (S)-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 20 ml of ethanol and 65 ml of methylamine (33%) in ethanol were stirred at 70° for 2 hours. The solution was concentrated and the residue was triturated with 70 ml of methylene chloride. The suspension obtained was filtered. After drying the filter residue there was obtained (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was used without further crystallization as the starting material for the Example described hereinafter.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([OH:8])=[O:7].C(Cl)(=O)C(C)=C.[C:16]([N:21]=[C:22]=[O:23])(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(N(CC)CC)C>[C:16]([NH:21][C:22]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([OH:8])=[O:7])=[O:23])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)N=C=O
Reactant: O=C(O)C(=O)NCCO
Agent: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NC(=O)OCCNC(=O)C(=O)O

Procedure:
In example 1, when the reaction of a triethylamine salt of 2-hydroxyethyloxamic acid with methacrylic acid chloride was performed, 5.5 g (0.05 moles) of methacryloylisocyanate were used instead of methacrylic acid chloride with no use of TEA and the reaction was carried out at room temperature. Except the forementioned, the same procedure as for example 1 was carried out to get methacryloylcarbamoyloxyethyloxamic acid of the following structure. ##STR18##
Reaction SMILES: [Si](O[C@H]1[C:18]2[C:17]3[O:19][C:20](=[O:26])[CH:21]=[C:22](CCC)[C:16]=3[C:15]3OC(C)(C)C=C[C:14]=3[C:13]=2O[C@H](C)[C@H]1C)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CCN(CC)CC.CC(O)=O>C1COCC1.CCOC(C)=O.CC(O)=O.CCN(CC)CC>[O:19]1[C:17]2[C:16](=[CH:15][CH:14]=[CH:13][CH:18]=2)[CH:22]=[CH:21][C:20]1=[O:26]
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@H](C)[C@@H](C)[C@H]3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1ccc2ccccc2o1
Reaction time: 0.33 h
Yield: 208.5 %

Procedure:
To a solution of 11 (622 mg, 1.28 mmol) in THF (25 mL) was added Bu4NF (12.5 mL, 1 M solution in THF), and the reaction mixture was stirred for 20 min. A mixture of Et3N (65 mg, 0.064 mmol) and HOAc (44 mg, 0.73 mmol) in THF (1.5 mL) was then added, and stirring was continued. The HOAc-Et3N addition was repeated after 2 h, and the reaction was stirred an additional 5 h, after which time the solvent was evaporated. The syrup obtained was then dissolved in EtOAc (30 mL) and washed with water (30 mL). The aqueous layer was separated and extracted with EtOAc (2×30 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue obtained was purified by silica gel chromatography to give 2 (390 mg, 82%) as a white solid: mp 175°-176° C.; [α]D20 +44.0° (c 1.0, acetone); 1H NMR (CDCl3): δ 1.00 (t, 3H, J=7.30 Hz, --CH2CH3), 1.10 (d, 3H, J=6.9 Hz, --CH3), 1.40 (d, 3H, J=6.3 Hz, --CH3), 1.45, 1.47 (2s, 6H, --C(CH3)2), 1.62 (m, 2H, --CH2CH3), 1.71 (m, 1H, H-11), 2.86 (m, 2H, H-13), 2.91 (d, 1H, J=3.9 Hz, --OH), 4.24 (m, 1H, H-10), 4.94 (t, 1H, J=3.4 Hz, H-12), 5.50 (d, 1H, J=9.9 Hz, H-7), 5.90 (s, 1H, H-3), 6.61 (d, 1H, J=9.89 Hz, H-8); 13C NMR (CDCl3): δ 12.46, 13.94, 18.81, 23.20, 27.63, 27.81, 38.26, 38.51, 61.74, 72.94, 77.60, 103.47, 106.08, 106.39, 110.26, 116.55, 126.70, 151.33, 153.12, 153.90, 158.67, 160.95. Anal. Calcd for C22H26O5 : C, 71.33; H, 7.07. Found C, 71.18; H, 7.12.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH2:25])[N:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([NH:40][C@H:41]([C:43](O)=[O:44])[CH3:42])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O=P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH:25][C:43](=[O:44])[CH:41]([NH:40][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:42])[N:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)(c2cc(N)n(C(C)(C)C)n2)CC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)nn1C(C)(C)C
Reaction time: 0.42 h

Procedure:
A solution of 0.68 g (1.7 mmol) of 4-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)-4-phenylpiperidine-1-carboxylic acid tert-butyl ester and 0.39 g (1.7 mmol) of carbobenzyloxy-L-alanine in 9.0 mL of dry pyridine was stirred at −10° C. as 0.18 mL (1.9 mmol) of POCl3 was added. After 25 min, the reaction mixture was poured into 1M HCl and extracted with EtOAc. The organic layer washed with sat. aq. NaHCO3, dried over MgSO4 and concentrated. Purification on silica gel using 50:50 EtOAc-hexanes as eluant afforded 4-[5-(2-benzyloxycarbonylamino-propionylamino)-1-tert-butyl-1H-pyrazol-3-yl]-4-phenylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])(=[O:6])=[O:5].C(N(CC)CC)C>ClCCl>[CH:3]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:15])([F:14])[F:16])(=[O:5])=[O:6])=[CH2:2]
Reactant: O=S(=O)(CCBr)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 50 °C
Yield: 84.2 %

Procedure:
To a stirred solution of 1-(2-bromo-ethylsulfonyl)-2-trifluoromethyl-benzene (5.4 g, 19 mmol) in dichloromethane (50 ml) was added triethylamine (4.66 ml, 34 mmol). The reaction mixture was heated under reflux conditions to 50° C. for 12 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/heptane) to yield the title compound (3.68 g, 16 mmol; 69%) as off-white semi-solid. MS (ESI): m/z=254.1 [M+NH4]+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>COCCOCCO.O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:20]1[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[N:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ncc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOCCO
Solvent: O
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3)ncc2c1
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A mixture of 2-chloro-6-methoxyquinazoline (Intermediate 8, 200 mg, 1.03 mmol), 4-carboxyphenylboronic acid (205 mg, 1.23 mmol) and K2CO3 (370 mg, 2.68 mmol) in DEGME/H2O (7.0 mL/2.0 mL) was degassed three times under N2 atmosphere. Then PdCl2(dppf) (75 mg, 0.103 mmol) was added and the mixture was heated to 100° C. for 3 hours under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL). The aqueous layer extracted with EtOAc/MeOH (v/v=10:1, 30 mL×2). Then the aqueous layer was acidified with 2M HCl to pH 6. The precipitate was collected by filtration and washed with MeOH (10 mL), dried under high vacuum to give the desired product (220 mg, yield 76%). 1H NMR (DMSO 400 MHz): δ 13.10 (brs, 1H), 9.63 (s, 1H), 8.62 (d, J=8.0 Hz, 2H), 8.10 (d, J=8.0 Hz, 2H), 8.05 (d, J=9.2 Hz, 1H), 7.70 (dd, J=9.2, 2.8 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 3.98 (s, 3H).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[K+].[C:15]([C@@H:17]1[C@:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]([CH2:25][CH:26]=[CH2:27])[C@H:19]([CH:20]=[CH:21][C:22]2=[O:34])[CH2:18]1)#[N:16]>C1COCC1>[C:15]([C@@H:17]1[C@:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]([CH2:25][CH:26]=[CH2:27])[C@@H:19]([CH2:20][CH2:21][C@H:22]2[OH:34])[CH2:18]1)#[N:16]
Reactant: C=CCN1[C@@H]2C=CC(=O)[C@]1(c1ccccc1)[C@@H](C#N)C2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN1[C@H]2CC[C@@H](O)[C@]1(c1ccccc1)[C@@H](C#N)C2
Reaction time: 0.33 h
Yield: 16.8 %

Procedure:
A solution of K-Selectride® in THF (1M, 6.5 ml, 6.5 mmol) was added dropwise to a stirred solution of (1R*,5S*,7S*)-7-cyano-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]oct-3-en-2-one (Description 23c; 295 mg, 1.11 mmol) in THF (7 ml) at −78° C. The reaction mixture was slowly warm up to +15° C. over 6 hours and carefully quenched with a mixture of 2M NaOH (8 ml) and H2O2 (35%, 2 ml). The mixture was stirred for 20 minutes. The mixture was treated with saturated aqueous Na2SO3 and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (50 mg, 17%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34].[OH-].[Na+].Cl>C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:34]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2.00 g (9.01 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 mL of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.55 mmol) of triethylamine and a solution of 1.35 g (7.70 mmol) of 3-chlorobenzoyl chloride dissolved in 5 mL of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl and extract several times with ethyl acetate. Dry the organic phase with MgSO4 anhydrous and eliminate at low pressure. Wash the crude product several times with ether and finally, purify by recrystallization (EtOH/H2O). This yields 0.83 g (30%) of 4-[2-(3-chlorobenzoylamino)benzoylamino]butanoic acid as a cream-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:23]1([S:29]([C:32]2[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([S:29]([C:32]2[CH:33]=[C:34]([NH:38][C:20]([C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]([F:16])[F:15])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[O:22])[CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 548.3 [(M+H)+]; mp 253° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22][NH2:23])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:34]1[N:42]=[CH:41][N:40]=[C:39]2[C:35]=1[NH:36][CH:37]=[N:38]2>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:19])[F:20])[C:8]([CH2:22][NH:23][C:34]1[N:42]=[CH:41][N:40]=[C:39]3[C:35]=1[N:36]=[CH:37][NH:38]3)=[CH:7]2
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3C(F)(F)F)nc12
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure H using (8-methyl-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methanamine (0.1 g, 0.316 mmol, 1 eq) in EtOH (2 mL) was treated with iPr2NEt (0.07 mL, 0.4 mmol, 1.2 eq) followed by 6-chloropurine (0.049 g, 0.317 mmol, 1 eq). After purification, N-((8-methyl-2-(2-(trifluoro-methyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine as yellow syrup. The yellow syrup was triturated with CH2Cl2 and filtered to provide N-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=91 nM] as yellow syrup. 1H NMR (DMSO-d6) δ ppm 12.93 (1H, s), 7.98-8.31 (4H, m), 7.90 (1H, d, J=7.8 Hz), 7.74-7.82 (2H, m), 7.69 (2H, t, J=6.5 Hz), 7.59 (1H, d, J=7.0 Hz), 7.42-7.52 (1H, m), 4.42-4.77 (2H, m), 2.62 (3H, s). Mass Spectrum (ESI) m/e=435.1 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+]>C1COCC1>[CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCCl)NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCCN1C1CCCCC1
Temperature: 70 °C
Yield: 63 %

Procedure:
Take up the 5-chloro-pentanoic acid cyclohexylamide in THF (700 mL), add sodium hydride (31 g, 60% dispersion on mineral oil, 775 mmol) and heat at 70° C. 19 h. Cool the mixture, filter through a fritted funnel, wash the filtrate with brine, dry the organic layer over sodium sulfate and evaporate. Purify the residue by column chromatography on silica gel (eluting 50% to 100% ethyl acetate) to obtain 1-cyclohexyl-piperidin-2-one as a beige solid (8.8 g, 63%). MS (EI) m/z=181 (M+).
Reaction SMILES: [O:1]=[S:2]1(=[O:50])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[CH:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([O:33][C:34](=[O:42])[CH2:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=[O:38])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1>[Pd].CO>[O:50]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:46][CH2:45][C@@H:44]([CH:47]([CH3:48])[CH3:49])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[CH:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C@@H:20]([O:33][C:34](=[O:42])[CH2:35][C:36]([CH3:40])([CH3:41])[C:37]([OH:39])=[O:38])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
A mixture of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (10 mg, 0.014 mmol) and 10% palladium on carbon (14.84 mg, 0.014 mmol) in methanol (5 mL) was stirred at 20° C. for 18 h under hydrogen at 40 psi. The reaction mixture was filtered to remove the catalyst and the solution was purified by reverse phase prep HPLC to provide the title compound as a white solid (4.1 mg, 39%). LCMS: m/e 719.53 (M+H)+, 2.41 min (method 1). 1H NMR (500 MHz, Acetic) δ 4.58 (dd, J=10.5, 5.6 Hz, 1H), 3.43-3.36 (m, 1H), 3.34-3.19 (m, 6H), 3.18-3.01 (m, 5H), 2.80-2.61 (m, 2H), 2.27-0.89 (m, 26H), 1.33 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H), 1.09 (s, 3H), 0.98 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.90 (s, 6H), 0.84 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[OH-].[Na+].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][Cl:20]>C(O)C>[ClH:20].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: ClCc1ccccn1
Reactant: COc1ccccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1SCc1ccccn1
Yield: 43 %

Procedure:
2-Methoxybenzenethiol (5 g) was added to a solution of sodium hydroxide (2.85 g) in ethanol (50 ml) and the resulting mixture was treated with 2-picolyl chloride, hydrochloride (5.7 g) in ethanol (25 ml) at 0° C. After 16 hours at ambient temperature the mixture was filtered through kieselghur and evaporated. The residue was converted into the hydrochloride in ether with ethereal HCl solution and this was recrystallised from propan-2-ol/acetone to give 2-(((2-methoxyphenyl)thio)methyl)pyridine, hydrochloride (4.0 g) mp 141°-3° C. (Found: C,58.5; H,5.4; N,4.9 C13H13NOS.HCl requires C,58.3; H,5.3; N,5.2%).