Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH2:18](C(CC)(CC)C([O-])([O-])[O-])[CH3:19].C(O)(=O)C>ClC(Cl)C>[OH:17][CH2:16][C:2]1([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=2)[CH2:14][O:15][C:18]([CH3:19])=[N:1]1
Reactant: CC(=O)c1ccc(CCC(N)(CO)CO)cc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc(CCC2(CO)COC(C)=N2)cc1
Temperature: 80 °C

Procedure:
To a suspension of 1-[4-(3-amino-4-hydroxy-3-hydroxymethyl-butyl)-phenyl]-ethanone (1 mmol) in anhydrous dichloroethane (2 mL) is added triethylorthoacetate (1.1 mmol) and acetic acid (0.05 mmol). The resulting mixture is heated at 80° C. for 12 hours. After concentration, the residue is purified by flash column chromatography (EtOAc) to give 1-{4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-ethanone as an oil; MS: (ES+): 262.1 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[C:8]([O:10][C:11]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([OH:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:36]([O:54][C:15](=[O:16])[C:14]1[CH:18]=[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]([O:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:30]([OH:31])=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=2)=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:13]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
10.0 grams of 4-(3,5-di-t-butyl-4-hydroxybenzoyloxy)-3,5-di-t-butylbenzoyl chloride (0.02 moles) 5.4 grams of n-octadecanol (0.02 moles) and 2.0 grams of triethylamine were stirred together in 100 ml. of benzene at room temperature for 2 hours and then heated for 1 hour at 60° to 70° C. The reaction mixture was cooled to room temperature and the precipitate filtered. The benzene solution was washed with water and dried over sodium sulfate. The benzene solution was then concentrated at reduced pressure yielding about 15 grams of the product. The product was crystallized twice from isopropanol yielding white crystals melting at 75° to 76° C.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([N+:17]([O-])=O)=[C:15]([C:20]#[C:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:14]([F:26])=[CH:13][C:12]=2[C:27](=[O:29])[CH3:28])[CH:8]=[CH:9][CH:10]=1>CO>[NH2:17][C:16]1[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)=[C:12]([C:27](=[O:29])[CH3:28])[CH:13]=[C:14]([F:26])[C:15]=1[C:20]#[C:21][Si:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: CC(=O)c1cc(F)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cccc(F)c1
Solvent: CCO
Solvent: CO
Product: CC(=O)c1cc(F)c(C#C[Si](C)(C)C)c(N)c1-c1cccc(F)c1
Yield: 90 %

Procedure:
The desired compound was prepared according to the procedure of Example 16, step F, using ethanol (instead of methanol) and 1-{3′,4-difluoro-6-nitro-5-[(trimethylsilyl)ethynyl]biphenyl-2-yl}ethanone as the starting material in 90% yield. LCMS for C19H20F2NOSi (M+H)+: m/z=344.1; Found: 343.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[N:27]=[C:28]([NH:31][CH:32]([CH3:34])[CH3:33])[S:29][CH:30]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35]([OH:37])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41]([C:43]1([NH2:48])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:42])[CH3:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[N:27]=[C:28]([NH:31][CH:32]([CH3:33])[CH3:34])[S:29][CH:30]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](=[O:37])[NH:48][C:43]1([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1CC1(N)C(=O)OCC
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3csc(NC(C)C)n3)nc2c1
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 81 %

Procedure:
Compound 133 (300 mg, 0.56 mmol) was reacted with 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (130 mg, 0.84 mmol) as described in Example 11 which gave the title compound (302 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]2C(=C(CBr)[C:7]([Cl:17])=[CH:8][CH:9]=2)[N:4]=1.S(=O)(=O)(O)O.[N+]([O-])(O)=O.[C:31]([OH:35])(=[O:34])[CH2:32][CH3:33]>O>[F:1][C:2]([F:20])([F:21])[C:3]1[C:12]([C:13]([F:15])([F:16])[F:14])=[CH:11][C:10]2[C:33](=[C:32]([C:31]([OH:35])=[O:34])[C:7]([Cl:17])=[CH:8][CH:9]=2)[N:4]=1
Reactant: FC(F)(F)c1cc2ccc(Cl)c(CBr)c2nc1C(F)(F)F
Reactant: CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C(O)c1c(Cl)ccc2cc(C(F)(F)F)c(C(F)(F)F)nc12
Reaction time: 2 h
Yield: 80.9 %

Procedure:
2.4 g of 2,3-bis-(trifluoromethyl)-8-bromomethyl-7-chloroquinoline are suspended in 6.8 g of propionic acid and 6.8 g of 70% strength sulfuric acid, and 5.5 g of 65% strength nitric acid are added dropwise at 120° C. After 2 hours at 120° C., the mixture is diluted with water and the precipitate is filtered off under suction, washed and dried; 1.7 g (84%) of 2,3-bis-(trifluoromethyl)-7-chloroquinoline-8-carboxylic acid of melting point 108°-111° C. are isolated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.Cl.CN.[CH2:22]([N:24](CC)CC)C>C(O)(C)C>[CH3:22][NH:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1NC
Yield: 81.7 %

Procedure:
A mixture of ethyl 4-chloro-2-phenylpyrimidine-5-carboxylate (10 g), methylamine hydrochloride (2.8 g), triethylamine (8.5 g) and isopropanol (100 ml) is refluxed for six hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added chloroform and water. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give ethyl 4-methylamino-2-phenylpyrimidine-5-carboxylate (8 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7](B(O)O)[CH:8]=1)=[O:2].I[C:15]1[CH:16]=[C:17]([C:21]2[O:22][CH:23]=[N:24][N:25]=2)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)(=O)C.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>[CH3:13][O:12][C:6]1[C:7]([C:19]2[CH:20]=[CH:15][CH:16]=[C:17]([C:21]3[O:22][CH:23]=[N:24][N:25]=3)[CH:18]=2)=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: Ic1cccc(-c2nnco2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)cc1-c1cccc(-c2nnco2)c1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A mixture of 5-formyl-2-methoxyphenyl boronic acid (414 mg, 2.29 mmol), the above product, 2-(3-iodo-phenyl)-[1,3,4]oxadiazole, (626 mg, 2.29 mmol), aqueous 2N K2CO3 (3.4 mL, 3 equivalents), Pd(PPh3)2Cl2 (50 mg, 0.068 mmol) in DME (15 mL) was stirred at room 80° C. for 7 hours. Reaction mixture was cooled to r.t., then it was diluted with ethyl acetate (45 mL) and washed with water, brine and dried over Na2SO4. After removal of solvent, 700 mg of crude was obtained. Purification by column chromatography gave 350 mg of the product (Yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:28](S(Cl)(=O)=O)[CH2:29]C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH2:28][CH3:29])(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 36 %

Procedure:
According to the procedure for compound 398 using propylsulfonyl chloride (20 mg, 0.14 mmol) afforded 15.5 mg (36% yield) of 410, as a solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16](Cl)(=[O:18])=[O:17])[C:7]=1[OH:20])(=[O:3])[CH3:2].[CH3:21][NH2:22]>CC(C)=O>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16](=[O:18])(=[O:17])[NH:22][CH3:21])[C:7]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1cc(C(C)(C)C)cc(CNC(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9 g (0.028 mole) of 2-acetamidomethyl-6-chlorosulfonyl-4-(1,1-dimethylethyl)-phenol are dissolved in 100 ml of acetone, and 4.9 ml (0.056 mole) of 40% strength aqueous methylamine solution are added dropwise, while cooling with ice. The mixture is stirred for 30 minutes at room temperature and poured into ice water. Recrystallization from n-propanol gives white crystals of melting point 173°-174° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH:11][NH2:12])[CH:8]=[CH:7][C:6]=1[Cl:13].O=[CH:16][C:17]([OH:19])=[O:18]>Cl>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH:11][N:12]=[CH:16][C:17]([OH:19])=[O:18])[CH:8]=[CH:7][C:6]=1[Cl:13]
Reactant: COC(=O)c1cc(NN)ccc1Cl
Reactant: O=CC(=O)O
Agent: Cl
Product: COC(=O)c1cc(NN=CC(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Chloro-5-hydrazino-benzoic acid methyl ester hydrochloride salt (2.0 g, 8.5 mmol) and oxoacetic acid (1.0 g, 10 mmol) were taken up in 10% HCl and stirred at ambient temperature for 1.5 hours. The resulting orange precipitate was collected by filtration. The filter cake was taken up in EtOAc, washed with brine, and dried over sodium sulfate. Concentration in vacuo yielded the above named compound (1.2 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:11][CH:12]=[CH2:13])=[CH:5][CH:4]=1.[NH:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N:23]=[CH:22]1>>[CH:14]1([CH:10]([CH2:11][CH:12]=[CH2:13])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:26]3[CH:27]=[CH:28][C:29]4=[N:21][CH:22]=[N:23][C:24]4=[CH:25]3)=[CH:4][CH:5]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C=CCC(C(=O)c1ccc(CCl)cc1)C1CCCCC1
Reactant: c1cc2[nH]cnc2cn1
Product: C=CCC(C(=O)c1ccc(Cn2ccc3ncnc-3c2)cc1)C1CCCCC1
Yield: 60 %

Procedure:
Following the procedure of Example 1, 85mg (0.00029 moles) of the product of Example Q was reacted with 35mgs of 1H-imidazo[4,5-c]pyridine. The crude product was chromatographed on silica gel using MeOH/CH2Cl2/ NH4OH (5/94/1) as eluent to give 65 mg (60% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[N:23]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Solvent: c1ccncc1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)N3CCOCC3)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.7 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.5 g, 4.5 mmol) in pyridine (15 mL) was added morpholine-4-sulfonyl chloride (1.26 g, 6.8 mmol). The reaction was stirred at rt for 12 h. Then the reaction was washed with water (50 mL), and extracted with DCM (2×50 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:EtOAc 60:1) to afford the title compound of Step A (297 mg, 13.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.27-7.36 (m, 2H), 7.21-7.26 (m, 2H), 6.98 (d, J=5.3 Hz, 1H), 3.58-3.64 (m, 4H), 3.22-3.33 (m, 1H), 3.14-3.21 (m, 4H), 1.40 (d, J=7.0 Hz, 6H). MS (ES+): 480 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]3[N:8]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1cccn2nc(N)nc12
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: Cc1cccn2nc(Nc3ccc(S(C)(=O)=O)cc3)nc12

Procedure:
(4-Methanesulfonyl-phenyl)-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 8-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500 mg, 3.37 mmol) and 1-bromo-4-methanesulfonyl-benzene (973 mg, 1.23 mmol) in a manner analogous to Example 2d. Product was isolated as an off-white solid (0.369 g, 36%). MP=227-230° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.35 (s, 1H), 8.67 (d, J=6.9 Hz, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 7.42 (d, J=7.1 Hz, 1HO, 6.99 (dd, J=7.1 Hz, 7.1 Hz, 1H), 3.14 (s, 3H). MS=303 (MH)+.
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: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)ncn1

Procedure:
Prepared according to Procedure H using 8-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)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. 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: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][S:20][C:12]=3[N:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=2)[CH2:6][CH2:5]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]3[C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][S:20][C:12]=3[N:13]=[C:14]([CH2:16][C:17]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:18])[N:15]=2)[CH2:6][CH2:5]1
Reactant: COCC1CCN(c2nc(CC(=O)O)nc3scc(-c4ccccc4)c23)CC1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCC1CCN(c2nc(CC(=O)N3CCCC3)nc3scc(-c4ccccc4)c23)CC1
Yield: 11.1 %

Procedure:
2-[4-[4-(Methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]acetic acid (24 mg, 0.06 mmol), pyrrolidine (5 mg, 0.067 mmol), HATU (26 mg) and triethylamine (0.025 mL) were stirred in acetonitrile (2 mL) at 50° C. for 20 hrs. The reaction was partitioned between water and DCM. The organics were separated and concentrated in vacuo. The residue was purified by preparative TLC, eluting 10% methanol in DCM. The isolated band was repurified by preparative TLC, eluting ethyl acetate to give 2-[4-[4-(methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]-1-pyrrolidin-1-yl-ethanone (3 mg). LCMS RT=4.61 min. M+1=451.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH3:18])[CH3:17])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([CH:44]=1)[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:18][N:16]([CH3:17])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:41]([C:40]4[CH:44]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=4[N:45]4[N:49]=[CH:48][CH:47]=[N:46]4)=[O:42])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(N(C)C)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)nc(N(C)C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-methyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate 8) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H25FN8O, 436.49; m/z found 437.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.14-6.61 (m, 5H), 5.82-5.45 (m, 1H), 4.75-3.27 (m, 6H), 3.22-2.55 (m, 8H), 2.37-1.78 m (m, 5H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[O:18]([CH2:25][CH2:26][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: BrCCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc2[nH]cc(C3CCN(CCCOc4ccccc4)CC3)c2c1
Yield: 44.3 %

Procedure:
A stirred solution of 3-(4-piperidinyl)-5-cyanoindole (0.71 g, 2.2 mmol), 3-phenoxypropyl bromide (0.52 g, 2.4 mmol), and triethylamine (0.6 ml, 4.4 mmol) in methanol (10 mL) was heated at reflux for 18 hours. The solution was concentrated in vacuo. Purification by flash chromatography yielded the product (0.35 g, 44%). 1H-NMR δ(CD3OD) 8.11 (s, 1 H), 7.49 (d, 1 H), 7.40 (d, 1 H), 7.28 (m, 3 H), 6.94 (m, 3 H), 4.12 (t, 2 H), 3.59 (br d, 2 H), 3.26-3.18 (m, 3 H), 3.04 (br t, 2 H), 2.25 (m, 4 H), 2.02 (br q, 2 H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.C(N(CC)CC)C.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22]Cl>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][N:3]1[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=[C:2]1[Br:1]
Reactant: Clc1nc(Br)[nH]c1Cl
Reactant: ClCCCCOCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCCCCOCn1c(Br)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a mixture of 1.08 g of 2-bromo-4,5-dichloroimidazole, 0.51 g of triethylamine and about 30 ml of toluene was added dropwise 0.79 g of 4-chlorobutoxymethyl chloride at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The deposited crystal was filtered off and washed with about 10 ml of toluene. The filtrate thus obtained was concentrated under reduced pressure, and the residual oily product was purified by column chromatography on silica gel to obtain 0.60 g of 1-(4-chlorobutoxymethyl)-2-bromo-4,5-dichloroimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([C:10]3[CH:24]=[CH:23][C:13]([CH2:14]P(=O)(OCC)OCC)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.C[O-].[Na+].[F:30][CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>CO>[F:30][CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:26]=[CH:25][C:6]=4[N:7]=3)=[CH:24][CH:23]=2)=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(OCCF)cc1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(-c3ccc(C=Cc4ccc(OCCF)cc4)cc3)sc2c1
Yield: 77.4 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methoxybenzothiazol-2-yl)benzylphosphonate (0.06 g, 0.153 mmol), sodium methoxide (0.5 M solution in MeOH, 0.46 ml, 0.23 mmol) and 4-(2-fluoroethoxy)-benzaldehyde (0.028 g, 0.168 mmol) in dry MeOH (5 ml) to give the title compound (0.048 g, 77%) as a pale yellow solid after work-up.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.Cl.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12)(=[O:20])=[O:21]
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(CNc2ccnc3cc(-c4ccccc4)oc23)c1

Procedure:
The title compound was prepared by procedure D using 7-chloro-2-phenyl-furo[3,2-b]pyridine (50.00 mg; 0.22 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and using 3-(methylsulfonyl)-benzylamine hydrochloride (57.92 mg; 0.26 mmol; 1.20 eq.) instead of N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide and was obtained as a waxy yellow solid (73 mg, 88%). (HPLC (method F): 98%, RT: 3.37 min); MS (m/z) 379 [M+H]+, RT: 2.2 min.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[C:13]([Cl:28])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>C(OCC)(=O)C>[C:38]1([O:37][C:35](=[O:36])[NH:10][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si:18]([CH:19]([CH3:20])[CH3:21])([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26])=[C:13]([Cl:28])[CH:12]=3)[N:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:9]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2N)cc1Cl)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1Cl)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of aminopyrazole of Example 2 (325 g, 0.707 moles) in ethyl acetate (1625 ml) under nitrogen, was added sodium bicarbonate aqueous solution (8% w/v, 1625 ml, 1.54 moles). Phenyl chloroformate (145 ml, 1.155 moles) was added over 15 minutes and stirred at 20° C. for 16 hours. The organic phase was separated and washed with water (1625 ml). Solvent was distilled under reduced pressure and replaced by n-heptane (1625 ml). The solution was cooled to 5° C. and granulated for 3 hours. The solid was collected by filtration to give the title compound as a white solid (368 g, 88%).