Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1CC1C(Cl)=O)CCCCC.C1(C(Cl)=O)CCCCC1.[C:22]([NH:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([CH:39]2[CH2:41][CH:40]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38])=[C:32]([O:48][C:49]([CH:51]2[CH2:53][CH:52]2[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:50])[CH:31]=1)=[O:29])([CH3:25])([CH3:24])[CH3:23]>>[CH2:54]([CH:52]1[CH2:53][CH:51]1[C:49]([O:48][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][C:37]([CH:39]1[CH2:41][CH:40]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38])[CH:28]([OH:29])[CH2:27][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:50])[CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCC1CC1C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C1CC1CCCCCC
Agent: CCCCCCC1CC1C(=O)Cl
Agent: O=C(Cl)C1CCCCC1
Product: CCCCCCC1CC1C(=O)Oc1ccc(C(O)CNC(C)(C)C)cc1OC(=O)C1CC1CCCCCC

Procedure:
When 2-hexylcyclopropanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(2-hexylcyclopropanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(2-hexylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:31])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:39][CH:40]([CH3:45])[CH2:41][C:42](Cl)=[O:43]>ClCCl>[CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:31])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][N:28]([C:42](=[O:43])[CH2:41][CH:40]([CH3:45])[CH3:39])[CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)CC(=O)Cl
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCC(c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of (R/S) tert-butyl methyl(2-(methyl((3-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate (200 mg, 0.46 mmol, 1.00 equiv) and triethylamine (1.14 g, 11.26 mmol, 24.52 equiv) in dichloromethane (15 mL) was added 3-methylbutanoyl chloride (67 mg, 0.56 mmol, 1.21 equiv). The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 2 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 250 mg of crude (R/S) tert-butyl methyl(2-(methyl((3-(1-(3-methylbutanoyl)piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate as a yellow solid. LCMS (method D, ESI): RT=1.22 min, m/z=520.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:6]1.C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:41])[C:31]1[CH:36]=[C:35]([CH2:37]Br)[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH3:28]>ClCCl>[CH2:27]([O:29][C:30](=[O:41])[C:31]1[CH:36]=[C:35]([CH2:37][N:17]2[CH2:18][CH2:19][CH:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]=3)[CH2:15][CH2:16]2)[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH3:28]
Reactant: COCCn1cc(C2CCNCC2)c2ccccc21
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CN2CCC(c3cn(CCOC)c4ccccc34)CC2)ccc1OC
Yield: 87.9 %

Procedure:
Over a solution of 6.5 g (0.025 mol) of 1-(2-methoxyethyl)-3-piperidin-4-yl-1H-indole in 90 ml of dichloromethane and 3.9 ml (0.026 mol) of triethylamine, a solution of 7.2 g (0.026 mol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester in 15 ml of dichloromethane was added. The crude mixture was stirred at room temperature for 24 hours. After standard work-up and purification by chromatography over silica gel, 9.9 g (70% of yield) of 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidin-1-ylmethy}-benzoic acid ethyl ester were obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([S:33]([C:36]1[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:13][CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[C:36]1([S:33]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=3)[CH:15]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)(=[O:34])=[O:35])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: O=S(=O)(c1cccc2ccccc12)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=S(=O)(c1cccc2ccccc12)N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1

Procedure:
A mixture of 6-benzyloxy-2-(naphthalene-1-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydroisoquinoline (0.012 g, 0.019 mmol), ammonium formate (0.033 g, 0.52 mmol), and 20% Pd(OH)2/C (0.002 g) in MeOH (10 ml) was refluxed under N2 for 1.5 hr, then filtered to remove the catalyst. The filtrate was evaporated in vacuo to a residue that was suspended in a mixture of H2O (0.4 ml) and sat. NaHCO3 (0.4 ml). The aqueous mixture was extracted with CH2Cl2 (3×0.8 ml), and all of the combined organic solutions were evaporated to give the crude product. Purification by reverse-phase HPLC, eluting with gradient Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1), increasing to H2O CH3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV detector (300 nM +/−90 nM and 254 nM +/−25 nM), gave an eluent that was evaporated to dryness to give the named product. MS m/e 493 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.ClC1C=C(C=CC=1F)N>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([NH:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1)[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])=[O:5])[CH3:2]
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1C
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1C

Procedure:
The title compound was prepared in analogy to the procedure described for Step D2, but 2-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step A4) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 3-chloro-4-fluoroaniline respectively to afford the title compound as a dark blue-green foam. tR: 5.19 min (HPLC 1); ESI-MS: tR=1.27 min, [M+H]+ 476/478/480 (LC-MS 1); TLC: Rf=0.53 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10]1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(CC3CCCCC3)C2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1cnc(N[C@@H]2CCN(CC3CCCCC3)C2)c(Cl)c1
Yield: 99.9 %

Procedure:
A solution of ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (330 mg) and 1N NaOH solution (1.5 ml) in MeOH (30 ml) was stirred at 80-85° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture was AcOEt and H2O. The aqueous solution was adjusted to PH 5.4 with 5% HCl solution and resultant solution was evaporated in vacuo and the residue was dissolved in a MeOH and THF. The solvent was evaporated in vacuo and dried to give (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (306 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7](C(=O)C(F)(F)F)[CH2:6][CH2:5]2.BrC1C=CC=C2C=1CN(C(=O)C(F)(F)F)CC2.CCN(C(C)C)C(C)C.[CH3:44][C@@:45]1([CH2:52][S:53](Cl)(=[O:55])=[O:54])[C:49](=[O:50])[NH:48][C:47](=[O:51])[NH:46]1>C(O)C.[OH-].[NH4+].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([S:53]([CH2:52][C@@:45]1([CH3:44])[NH:46][C:47](=[O:51])[NH:48][C:49]1=[O:50])(=[O:54])=[O:55])[CH2:6][CH2:5]2
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: O=C(N1CCc2cc(Br)ccc2C1)C(F)(F)F
Agent: O=C(N1CCc2cccc(Br)c2C1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(Br)ccc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 113.9 %

Procedure:
A 3:1 mixture (0.44 g, 1.4 mmol) of 6-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline and 8-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (prepared according to Tetrahedron Lett. 1996, 37(31), 5453-5456) was stirred in ethanol (10 mL) containing a few drops of 25% ammonium hydroxide at RT. After 2.5 h, the solution was concentrated, dissolved in dry THF (1.0 mL) under argon and cooled on an ice-bath. DIPEA (0.41 mL, 2.4 mmol) was added followed by a solution of [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl-chloride (0.27 g, 1.2 mmol) and dry THF (1.0 mL). The mixture was stirred at RT for 1 h and then concentrated. The crude product was taken up in water and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated to give 0.55 g of a mixture of (5S)-5-({[6-bromo-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione and (5S)-5-({[8-bromo-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione. The regioisomers were separated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1.[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1
Reactant: CCOC(=O)c1cn(C)nc1-c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.8 %

Procedure:
A mixture of 0.72 g of ethyl 3-(2-chlorophenyl)-1-methyl-1H-pyrazole-4-carboxylate, 0.23 g of potassium hydroxide, 1 ml of water and 5 ml of ethanol was stirred at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, water was poured into the resulting residue and the mixture was washed with methyl tert-butyl ether. The aqueous layer was adjusted to around pH 3 by an addition of a 10% aqueous citric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.61 g of 3-(2-chlorophenyl)-1-methyl-1H-pyrazole-4-carboxylic acid of the formula:
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]1([OH:41])[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][NH:36][CH2:37]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:36]5[CH2:37][CH:38]6[C:33]([OH:41])([CH3:32])[CH:34]([CH2:40][CH2:39]6)[CH2:35]5)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27]([N:28]([CH3:29])[CH3:30])=[O:31])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Reactant: CC1(O)C2CCC1CNC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)C5(C)O)cn3)nc2n1C1CCCCCC1
Yield: 26 %

Procedure:
Following general amide formation method 3, 6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with 8-methyl-3-azabicyclo[3.2.1]octan-8-ol which gave 7-cycloheptyl-2-(5-(8-hydroxy-8-methyl-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (68 mg) in 26% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.65 (s, 1H) 8.93-8.86 (m, 1H) 8.68 (d, J=8.59 Hz, 1H) 8.55 (d, J=2.02 Hz, 1H) 7.82 (dd, J=8.84, 2.27 Hz, 1H) 6.52-6.39 (m, 1H) 4.45-4.60 (m, 1H) 4.39 (br. s., 1H) 3.96 (br. s., 1H) 3.63-3.39 (m, 2H) 3.15 (s, 6H) 2.76-2.51 (m, 3H) 2.14 (br. s., 1H) 2.07-1.93 (m, 2H) 1.85 (ddd, J=6.95, 3.41, 3.28 Hz, 3H) 1.80-1.61 (m, 7H) 1.61-1.48 (m, 2H) 1.48-1.36 (m, 1H) 1.30 (s, 3H); HR-MS (m/z MH+) 546.32 RT 3.99 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:30].C(O)(=O)C.O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:30][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To the solution of (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (compound 18a, 5.0 g, 12.2 mmol) in xylene (75 ml) were added ammonium acetate (23.4 g, 304 mmol) and acetic acid (5 ml) at room temperature. The reaction mixture was placed in an oil bath and heated to 160° C. with water being azeotroped into a Dean-Stark trap. After 3 hours, the resulting mixture was cooled to room temperature and then extracted with ethyl acetate and distillated water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified with column chromatography (100% ethyl acetate) to yield the pure product 19a (4.4 g).
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[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19]Cl)=[CH:7]2.Cl.[NH2:22][C:23]1[CH:28]=[C:27]([NH2:29])[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl: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[Cl:18])[C:8]([CH2:19][NH:22][C:23]1[CH:28]=[C:27]([NH2:29])[N:26]=[CH:25][N:24]=1)=[CH:7]2
Reactant: Nc1cc(N)ncn1
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1cc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)ncn1

Procedure:
Prepared according to Procedure H using 8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (0.035 g, 0.11 mmol), 4,6-diaminopyrimidine hydrochloride (0.032 g, 0.22 mmol, 2 eq) and DIEA (0.55 mL, 2.2 mmol, 20 eq) in ethanol (1 mL). N4-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)pyrimidine-4,6-diamine [PI3Kδ IC50=6868 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (1H, s), 8.05 (1H, dd, J=8.4, 1.0 Hz), 7.95 (1H, dd, J=7.4, 1.2 Hz), 7.84 (1H, s), 7.51-7.67 (5H, m), 7.24 (1H, s), 6.19 (2H, s), 5.32 (1H, s), 4.33 (1H, s) Mass Spectrum (ESI) m/e=396.1 and 398.0 (M+1)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 2.7 h

Procedure:
A suspension of 1-isopropyl-4-(4-nitro-phenyl)-piperazine (5.18 g, 20.80 mmol) and Palladium (5%) on carbon (0.5 g) in MeOH (100 mL) is stirred for 2.7 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a violet solid: ESI-MS: 220.1 [MH]+; tR=0.95 min (gradient J).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[OH:18])=[C:7]([CH:16]=1)[CH2:8][O:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].OO.Cl>C(OC(=O)C)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])=[C:7]([CH:16]=1)[CH2:8][O:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: CC(C)(C)C(=O)OCc1cc(C#N)ccc1C(O)c1ccc(F)cc1
Agent: Cl
Agent: OO
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCc1cc(C#N)ccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a stirred solution of 2,2-dimethyl-propionic acid 5-cyano-2-[1-(4fluoro-phenyl)-1-hydroxy-methyl]-benzyl ester (8.0 g, 0.025 mol) in ethylacetate (20 mL) was added hydrogen peroxide solution 30% wt (10 g, 0.079 mol), Na2WO4.2H2O (0.15 g, 0.0005 mol), and (n-Octyl)3NCH3.HSO4 (0.23 g, 0.0005 mol). The mixture was then heated at reflux for 4 hrs, allowed to cool to room temperature and pored into dilute HCl, extracted with diethyl ether (2×50 mL), dried (MgSO4) and concentrated under reduced pressure to give the title ketone compound (7.8 g, 97.5%).
Reaction SMILES: [N+](C1C=CC(C([O:10][C:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)=[CH:29][C:30]([Cl:34])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[Li+].[OH-].O>C1COCC1>[Cl:34][C:30]1[CH:29]=[C:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:27]2[C:32](=[CH:33][C:24]([CH2:23][N:21]3[CH:22]=[C:18]([C@@:11]([OH:10])([CH2:12][CH3:13])[C:14]([F:17])([F:15])[F:16])[N:19]=[N:20]3)=[CH:25][CH:26]=2)[N:31]=1
Reactant: CCC(OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 1-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (300 mg, 0.49 mmol) and LiOH 2M/H2O (1.25 mL, 2.5 mmol) in THF (5 mL) was stirred at rt 5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 1:9) gave the title compound. MS (+ESI): 465 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:61]=[CH:60][C:15]2[NH:16][C:17]([CH2:19][CH2:20][CH:21]3[CH2:24][CH:23]([N:25]([CH2:28][C@@H:29]4[C@H:33]5[O:34]C(C)(C)[O:36][C@H:32]5[C@H:31]([N:39]5[C:43]6[N:44]=[CH:45][N:46]=[C:47]([NH:48]CC7C=CC(OC)=CC=7OC)[C:42]=6[CH:41]=[CH:40]5)[CH2:30]4)[CH2:26][CH3:27])[CH2:22]3)=[N:18][C:14]=2[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:48][C:47]1[C:42]2[CH:41]=[CH:40][N:39]([C@@H:31]3[CH2:30][C@H:29]([CH2:28][N:25]([CH:23]4[CH2:22][CH:21]([CH2:20][CH2:19][C:17]5[NH:16][C:15]6[CH:60]=[CH:61][C:12]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:13][C:14]=6[N:18]=5)[CH2:24]4)[CH2:26][CH3:27])[C@@H:33]([OH:34])[C@H:32]3[OH:36])[C:43]=2[N:44]=[CH:45][N:46]=1
Reactant: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CCN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
Trifluoroacetic Acid (20 mL) was added to a mixture of Water (2 mL) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(ethyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.85 g, 1.2 mmol) at RT. The reaction was allowed to proceed for one hour at which time Triethylsilane (0.37 mL, 2.3 mmol) was added. The volatiles were removed in vacuo and resulting residue was taken up in MeOH (3 mls), 1 ml of K2CO3 (saturated) was added and reaction stirred at RT for 1 hour. The mixture was partitioned between H2O and DCM/MeOH (9:1). The aqueous layer was extracted (3×) and the combined organics dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to yield the desired product (0.150 g) as an off white foam. MS (ESI+) for C31H43N7O2 m/z 546.3 [M+H]+; MS (ESI−) for C31H43N7O2 m/z 544.3 [M−H]−; HPLC purity >91% (ret. time, 2.734 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.081 (s, 1H), 7.493 (s, 1H), 7.414-7.393 (m, 1H), 7.291-7.266 (m, 1H), 7.215-7.202 (m, 1H), 6.619-6.609 (d, J=4.0 Hz, 1H), 4.345-4.312 (m, 1H), 3.923-3.885 (m, 1H), 2.994-2.915 (m, 0.5 H (methine of trans isomer)), 2.860-2.793 (m, 214), 2.701-2.578 (m, 3H), 2.501-2.380 (m, 2H), 2.259-2.234 (m, 2H), 2.109-2.008 (m, 314), 1.920-1.880 (m, 3H), 1.658-1.499 (m, 231), 1.364 (s, 9H), 1.036-0.991 (m, 3H). Retention time: 2.734 minutes. HPLC Conditions:Agilent Zorbax Exlipse XDB-C18 column, 4.6×50 mm (1.8 um packing), Solvent A—Water (0.1% TFA), Solvent B—Acetonitrile (0.07% TFA). 6 min gradient from 5 to 95% B; 1 min hold; then recycle
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=O.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].C[O-].[Na+].[H-].[Na+]>CN(C)C=O.C(O)(=O)C.O.CO>[C:16]([C:18]1[C:19](=[O:20])[NH:21][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])=[CH:4][CH:3]=1)#[N:17]
Reactant: N#CCC(N)=O
Reactant: COc1ccccc1C(=O)C=CN(C)C
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A stirred mixture of 3-dimethylamino-1-(2-methoxyphenyl)-2-propene-1-one (5.74 g); cyanoacetamide (2.48 g) and sodium methoxide (from sodium hydride (50%, 4.32 g) and methanol (3.5 ml) in dry dimethylformamide was heated under reflux for 10 hours. The reaction mixture was poured into water, acidified to pH 4 with glacial acetic acid and extracted with ethyl acetate. The ethyl acetate extract was evaporated under reduced pressure to low volume and water was added to cause precipitation of a crude product (3.67 g) which was collected and recrystallized twice from dimethylformamide to yield the title compound, 1.68 g, m.p. 236°-238° C.