Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[C:9]1([OH:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[C:9]1([O:19][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)N1CC(O)C1
Reactant: Oc1cccc2ccccc12
Product: CC(C)NCC(O)COc1cccc2ccccc12

Procedure:
1-(isopropyl)-3-azetidinol and α-naphthol were reacted in the same manner as in Example 6 to form 1-(α-naphthoxy)-3-(iso-propylamino)-2-propanol. Then the propanol was dissolved in anhydrous ether and was converted to a hydrochloride by blowing a hydrochloric acid gas into the resulting solution. As a result 1-(α-naphthoxy)-3-(isopropylamino)-2-propanol hydrochloride melting at 162°-164° C was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:4][CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=2)[C:26]([Sn](CCCC)(CCCC)CCCC)=[N:25]1.O>CN(C=O)C.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.[Cu]I>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:34])([F:35])[F:36])[CH:31]=2)[C:26]([C:2]2[N:7]=[C:6]3[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]3=[N:4][CH:3]=2)=[N:25]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(F)(F)F)ccc12
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(C(F)(F)F)ccc34)nc12
Temperature: 90 °C
Yield: 50.4 %

Procedure:
A mixture of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (0.3 g, 0.81 mmol), 1-methyl-3-(tributylstannyl)-6-(trifluoromethyl)-1H-indazole (0.98 g, 1.51 mmol), Pd(PPh3)4 (174 mg, 0.151 mmol) and CuI (58 mg, 0.302 mmol) in dry DMF (10 mL) was heated to 90° C. for 3 hours. Water (10 mL) was added. The formed precipitate was separated by filtration, washed with petroleum ether (3 mL) to afford methyl 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (200 mg, 50%) as a white solid. LCMS: (M+H)+=490.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1.[CH3:24][Si:25]([CH3:28])([CH3:27])Cl>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11]([O:14][Si:25]([CH3:28])([CH3:27])[CH3:24])=[CH:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(C(F)(F)F)ccc21
Reactant: C[Si](C)(C)Cl
Product: CN1C(O[Si](C)(C)C)=CN=C(c2ccccc2)c2cc(C(F)(F)F)ccc21

Procedure:
Following the general procedure of Part A, 2.4 g of 7-trifluoromethyl-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one was reacted with trimethylchlorosilane. The filtrate was evaporated, the residue was dissolved in CFCl3 and the CFCl3 was removed by evaporation to give 7-trifluoromethyl-1-methyl-5-phenyl-2-trimethylsiloxy-1H-1,4-benzodiazepin which was again dissolved in CFCl3 and reacted with trifluoromethyl hypofluorite to give 7-trifluoromethyl-3-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one whose measured mass spectrum was m/c 336.0859; Calculated for C17H12ON2F4 : 336.0885.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=1.CC[N:35](C(C)C)C(C)C>C(O)CCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:24]2[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][N:27]=[C:22]([NH2:35])[N:23]=2)=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:27]=[C:26]([NH2:35])[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=2)=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3Cl)nc12
Solvent: CCCCCO
Product: Cc1cccc2cc(CNc3nc(N)ncc3C(F)(F)F)c(-c3ccccc3Cl)nc12
Product: Cc1cccc2cc(CNc3ncc(C(F)(F)F)c(N)n3)c(-c3ccccc3Cl)nc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanamine (81.1 mg, 0.261 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (51.6 mg, 0.261 mmol), and DIEA (0.09 mL, 0.52 mmol, 2 eq) in 1-pentanol (1.3 mL) was stirred at 80° C. for 30 min. The mixture was transferred to a pressure vessel and ammonia gas was bubbled through the mixture at rt for 15 min. The mixture was stirred at 100° C. 14 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min as eluent to provide N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine [PI3Kδ IC50=127 nM] as light yellow solid (Example 3) and N2-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine [PI3Kδ IC50=2825 nM] (Example 4) as light yellow solid. For Example 3: 1H NMR (DMSO-d6) δ ppm 8.12 (1H, s), 8.01 (1H, d, J=0.8 Hz), 7.82 (1H, d, J=8. Hz), 7.43-7.65 (6H, m), 7.17 (1H, t, J=5. Hz), 6.57 (2H, br. s.), 4.51 (2H, t, J=5.9 Hz), 2.65 (3H, s); Mass Spectrum (ESI) m/e=444.1 (M+1). For Example 4: 1H NMR (DMSO-d6) 8 ppm 8.17-8.28 (1H, m), 8.00 (1H, s), 7.85 (1H, d, J=7.8 Hz), 7.23-7.72 (7H, m), 6.68 (2H, s), 4.39 (2H, s), 2.65 (3H, s); Mass Spectrum (ESI) m/e=444.1 (M+1).
Reaction SMILES: C(N(CC)CC[OH:6])C.[CH:9]([N:12]([CH:15]([CH3:17])C)[CH2:13][CH3:14])([CH3:11])C.CS(Cl)(=O)=O.C([NH:26][C@:27]1([C:44](NC(C)(C)C)=[O:45])[C@@H:31]([CH2:32][CH2:33][CH2:34][B:35]2[O:39]C(C)(C)C(C)(C)[O:36]2)[CH2:30][NH:29][CH2:28]1)(=O)C>C(#N)C>[NH2:26][C@:27]1([C:44]([OH:45])=[O:6])[C@@H:31]([CH2:32][CH2:33][CH2:34][B:35]([OH:36])[OH:39])[CH2:30][N:29]([CH2:17][CH2:15][N:12]([CH2:9][CH3:11])[CH2:13][CH3:14])[CH2:28]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCN(CC)CCO
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Product: CCN(CC)CCN1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 76.1 %

Procedure:
A cooled (0° C.) solution of N,N-diethylethanolamine (82 mg, 0.70 mmol) and diisopropylethylamine (0.30 mL, 1.7 mmol) in anhydrous acetonitrile (12 mL) under nitrogen was treated with methanesulfonyl chloride (80.2 mg, 0.70 mmol), stirred 2.5 h, and treated with (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and heated to 60° C. for 15 h. The reaction mixture was concentrated, deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(2-(diethylamino)ethyl)pyrrolidine-3-carboxylic acid (120 mg, 57%) as a white foam. NMR (D2O) δ 3.97 (d, J=12.5 Hz, 1 H), 3.87 (m, 1 H), 3.65-3.80 (m, 3 H), 3.35-3.55 (m, 3 H), 3.19 (q, J=7.5 Hz, 4 H), 2.55-2.65 (m, 1 H), 1.50-1.65 (m, 1 H), 1.20 (t, J=7.5 Hz, 6 H), 1.15-1.35 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m−H2O+1): 298.3; MS (m−2H2O+1): 280.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:14].B([C:18]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:19]=1[O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])(O)O>C1COCC1>[Cl:30][C:28]1[CH:29]=[CH:18][C:19]([O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])=[C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:14])[CH:27]=1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Reactant: CN(C)S(=O)(=O)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1-c1ccc(S(=O)(=O)N(C)C)cc1F)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (i), the product from example 151 step (iv) and THF as solvent.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=O)[CH:15]=[C:16]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:17]([F:20])([F:19])[F:18])=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4].[OH-:30].[Na+].[NH2:32]O.Cl>CO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH2:15][C:16]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:30][N:32]=2)=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4]
Reactant: NO
Reactant: [OH-]
Reactant: COC(=O)c1sc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)c2c1CCCC2
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 89.6 %

Procedure:
Stir a mixture of 3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methyl ester (8.75 g, 18.9 mmol), NaOH (2.65 g, 66.1 mmol) and NH2OH—HCl (2.6 g, 37.8 mmol) in MeOH (60 mL) and water (15 mL) at room temperature for 2.5 hour. After removal of solvent under vacuum, dilute the residue with ice water (50 mL). Acidify the aqueous mixture with conc. HCl to pH=1 and extract the resultant mixture with EtOAc (50 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 50:1) to afford 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methyl ester as an orange solid (8.1 g, 93.1%). MS (m/z): 478 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:21][CH:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=[O:23]>O1CCCC1.O>[CH2:14]([O:13][CH2:12][CH:11]([OH:23])[CH:10]([OH:21])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(COCC2OC2COCc2ccccc2)cc1
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: OC(COCc1ccccc1)C(O)COCc1ccccc1
Temperature: 0 °C

Procedure:
4.2 g of the 1,4-bis(benzyloxy)-2,3-epoxybutane thus obtained was dissolved in a mixture comprising 120 ml of tetrahydrofuran and 30 ml of water. Then 30 ml of an aqueous solution containing 6 ml of 60% perchloric acid was added dropwise thereto under ice-cooling and stirring. After stirring at the same temperature for additional 4 hours, the reaction mixture was poured into ice/water and extracted with ether. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to thereby give 2.7 g of 1,4-bis(benzyloxy)-2,3-butanediol as a colorless liquid.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CN=C1.CCN(CC)CC.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl.O>[Si:21]([O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 1,4-cyclohexanediol (5 g, 43 mmol), imidazole (2.92 g, 43 mmol) and NEt3 (7 mL) in CH2Cl2 (100 mL) cooled in an ice bath was added tert-butyldimethylsilyl chloride (6.47 g, 43 mmol). The mixture was stirred at room temperature overnight. Water was added and the organic phase was separated. The aqueous layer was extracted with EtOAc. The combined organic phase was dried over MgSO4 and concentrated. Chromatography on silica gel eluting with 3:1 EtOAc/hexanes provided the title compound (4.2 g, 42%) as an oil. MS calculated (M+H)+231. Found 231.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[C:22]([C:27](O)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([N:62]2[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]2)=[O:28])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]1=[O:20]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccccc2-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.4 %

Procedure:
Charge a vial with 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-2-carboxylic acid (70 mg, 0.17 mmol), EDCI (65 mg, 0.34 mmol) and HOBt (23 mg, 0.17 mmol). Dissolve in DMF (0.1 M) and add triethylamine (95 μL, 0.68 mmol) and N-methyl piperazine (34 mg, 0.34 mmol). Stir at room temperature overnight. Pour into water and extract with ether. Dry over sodium sulfate, filter and concentrate. Purify over silica gel. Dissolve the residue in methylene chloride and acidify with 4N HCl in dioxane. Concentrate in vacuo which affords 57 mg (63%) of the title compound: Mass spectrum m/z=494.3 (M+H−HCl).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.CCCCCCC>C1(OC)C=CC=CC=1>[CH:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:34][C:23]([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:11][CH:12]=3)=[CH:21][N:20]=2)=[O:24])=[CH:33][CH:32]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: NCc1ccccc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 150 °C

Procedure:
The procedure for the amide formation described for the medium scale reaction worked well on large scale. Methyl ester 7 and benzylamine (3 equiv.) were dissolved in anisole and heated at 150° C. for almost 2 days. However, the isolation of the product using the medium-scale procedure can result in a solid mass of product. To avoid this issue, the reaction mixture was not cooled to room temperature, but cooled to 45-50° C. before adding the anti-solvent. Toluene and heptane were used as anti-solvent in the original procedure. Using n-heptane alone provided adequate purity and increased yields from 81 to 90%. Further, the use of a single isomer of heptane was essential to adequately quantitate the residual solvent.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:23]=[C:22](B(O)O)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:22]2[C:16]3[CH2:17][C:18]([CH3:20])([CH3:21])[O:19][C:15]=3[CH:14]=[C:13]([Cl:12])[CH:23]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Cc2c(cc(Cl)cc2B(O)O)O1
Reactant: Cc1c(Br)cnc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(Cl)cc3c2CC(C)(C)O3)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.7 grams (0.012 mole) of 6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 mL (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-(6-chloro-2,3-dihydro-2, 2-dimethylbenzofuran-4-yl)pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[CH2:30]Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:32][C:33]1[S:34][C:35]([CH3:38])=[N:36][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[CH2:30][S:32][C:33]2[S:34][C:35]([CH3:38])=[N:36][N:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nnc(S)s1
Reactant: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(CBr)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(CSc3nnc(C)s3)nc12
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of the product from Step A (137 mg, 0.28 mmol), 2-mercapto-5-methyl-1,3,4-thiadiazole (37 mg, 0.28 mmol), and potassium carbonate (77 mg, 0.56 mmol) in DMF (15 mL) was stirred at 50° C. for 17 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. The crude residue was purified using SiO2-gel chromatography using 50% EtOAc/hexanes to yield the desired product as a yellow solid. API-MS: 546 (M+1). 1H NMR (300 MHz, CDCl3): d 7.8 (d, 1 H), 7.4 (t, 1 H), 7.2 (d, 1 H), 4.95 (s, 2 H), 4.1 (t, 2 H), 4.0 (s, 3 H), 2.75 (s, 3 H), 2.8 (t, 3 H), 1.8-1.0 (m), 1.45 (s, 9 H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.[NH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[CH2:4]([CH2:3][C@H:2]([NH2:1])[C:15]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:17])[CH2:5][CH2:6][NH2:7]
Reactant: NCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Product: NCCCC[C@H](N)C(=O)NCC(=O)O

Procedure:
Lys-Gly-Amp was synthesized by a similar method except the amino acid starting material was Boc-Lys(Boc)-OSu and the starting drug conjugate was Gly-Amp (see Gly-Amp synthesis).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:27][CH:28]1[O:33][CH2:32][CH2:31][NH:30][CH2:29]1>C(Cl)Cl.CN(C=O)C.C(N(CC)C(C)C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:30]3[CH2:31][CH2:32][O:33][CH:28]([CH3:27])[CH2:29]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CC1CNCCO1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)CCO1
Temperature: 25 °C
Reaction time: 96 h
Yield: 44.9 %

Procedure:
To polymer N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (0.038 g) in an Alltech™ tube was added a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.007 g) in DCM (0.9 ml) followed by 2-methylmorpholine (0.004 g) in DMF (0.1 ml) and N,N-diisopropylethylamine (0.006 ml). The mixture was shaken at room temperature for 4 days. The tube was drained, the filtrate collected and the resin washed with DCM. The combined DCM solutions were concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.0038 g) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[CH:7][N+:8]([O-:10])=[O:9].[Br:11]Br>O>[Br:11][C:7]([N+:8]([O-:10])=[O:9])=[C:3]1[NH:4][CH2:5][CH2:6][N:2]1[CH3:1]
Reactant: CN1CCNC1=C[N+](=O)[O-]
Reactant: BrBr
Solvent: O
Product: CN1CCNC1=C(Br)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A stirred solution of 3.57 grams of 1-methyl-2(nitromethylene)imidazolidine (Compound 1) in 25 milliliters of water was treated dropwise with 3.99 grams of bromine at room temperature. After 30 minutes, the reaction mixture was extracted with methylene chloride. The extract was dried (MgSO4) and the solvent was evaporated to give 3.0 grams of crude product, melting point 100° (with vigorous decomposition). Recrystallization of the crude product from methylene chloride gave 15, melting point: 97° (explodes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=CC=C[CH:17]=1.C(=O)(OCC)OCC=C>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][O:14][CH2:21][CH:16]=[CH2:17])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: C=CCOC(=O)OCC
Solvent: C1CCOC1
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC

Procedure:
To a stirred solution of N-Boc-L-serine methyl ester (0.22 g, 1 mmol, 1 eq) in dry THF (2 ml) under N2 a mixture of n-allylpalladium chloride dimer (0.01 g, 0.02 mmol), triphenylphosphine (0.024 g, 0.09 mmol) and allyl ethyl carbonate (0.26 ml, 2 mmol, 2 eq) in dry THF (1 ml) was dropwise added at room temperature.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])(=[O:7])=[O:6].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1.C1N2CCN(CC2)C1>ClCCl>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([NH:20][C:18]([NH:17][S:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:5]([CH2:4][CH2:3][O:2][CH3:1])(=[O:7])=[O:6])(=[O:15])=[O:16])=[O:19])[N:22]=1
Reactant: COCCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COCCS(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 2-[(2-methoxyethyl)sulfonyl]benzenesulfonyl isocyanate (1.7 g, 0.0057 mol) in dichloromethane (10 ml) was added to 2-amino-4,6-dimethoxypyrimidine (0.70 g, 0.0045 mol) and DABCO (catalytic amount); the mixture was stirred at room temperature under nitrogen overnight. Filtration gave N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-[(2-methoxyethyl)sulfonyl]benzenesulfonamide (1.43 g) as a white powder, m.p. 187°-192°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[I:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(N(CC)CC)C.O>C(Cl)Cl>[I:11][C:12]1[CH:13]=[N:14][N:15]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH:16]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)n1cc(I)cn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94.3 %

Procedure:
Phenyl chloroformate (0.75 mL, 6.0 mmol) is added dropwise to a solution of 4-iodopyrazole (1.05 g, 5.4 mmol) and triethylamine (0.9 mL, 6.5 mmol) in 15 mL CH2Cl2. The reaction is stirred at RT. After 60 h, water is added. The mixture is extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. Hexane is added and the solvent is removed in vacuo. A white solid forms on standing to provide 1.6 g (95%) of phenyl 4-iodo-1H-pyrazole-1-carboxylate. MS (EI) m/z 315.1 (M+).