Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([CH2:21][OH:22])[CH:20]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH:21]([C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([Cl:11])[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:22]
Reactant: O=C(O)c1cc(Cl)cc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)cc(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 2 liter 4-necked round-bottomed flask were placed 500 ml of methylene chloride and cooled down to -78° C. 44.6 g (0.35 mole) of oxalyl chloride were added slowly, followed by dropwise addition of 57.7 g (0.74 mole) of dry dimethylsulfoxide in 40 ml of methylene chloride, keeping the temperature below -70° C. After the addition was completed, the reaction mixture was stirred at -78° C. for 30 minutes and 71.5 g (0.38 mole) of the previously prepared 3-chloro-5-hydroxymethylbenzoic acid were added in 1 portion and 60 ml more of methylene chloride followed by dropwise addition of 149.5 g (1.48 mole) of triethylamine, keeping the temperature below -65° C. The reaction mixture was then warmed up slowly to room temperature and stirred during 90 minutes and washed with 2% aqueous sodium hydroxide (4×500 ml). The combined basic layers were washed with hexane once, then acidified with concentrated hydrochloric acid and then extracted with ethyl acetate (4×500 ml). The combined organic layers were washed with water (1×500 ml) and then with brine (1×300 ml) and dried over anhydrous magnesium sulfate. The solvent was then eliminated in a rotavap, yielding 52 g of 3-formyl-5-chlorobenzoic acid.
Reaction SMILES: [OH:1]O.[OH:3][CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH2:10][S:9](=[O:13])[CH:8]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(Cl)(Cl)Cl>CO.O>[OH:3][CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH2:10][S:9](=[O:1])(=[O:13])[CH:8]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Reactant: OO
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CCCCCC(O)CCN1C(=O)CS(=O)(=O)C1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
30% Hydrogen peroxide (2.0 ml., 20 millimole) is added slowly to a stirred solution of 7-[3-(3-hydroxyoctyl)-1,4-dioxo-2-thiazolidinyl]heptanoic acid (1.98 g., 4.69 millimole) and ammonium molybdate. tetrahydrate 0.1 g., catalyst) in methanol (25 ml.) maintained at 0° to 5° C. The resulting solution is allowed to warm to room temperature and then is stirred at room temperature for 64 hours. After diluting with water, the reaction mixture is extracted with chloroform three times. The combined organic extract is washed with water until free of peroxides, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo at 40° to 50° C. leaves a viscous oil which is applied to a silica gel (20 g.) column with chloroform. Elution with chloroform-acetic acid (25:1; v:v) provides the title compound as a tlc homogeneous oil.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[S:3]1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@@H:23]([CH2:36][NH:37][CH:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:4]3[S:3][C:2](=[NH:1])[NH:6][C:5]3=[O:7])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: N=C1NC(=O)C(Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: N=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound: was prepared from 1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-one (which was obtained in Example 45) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 73 as a pale yellowish solid; mp>155° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.90 (m, 6 H), 3.24 (dd, J=14.1, 4.0 Hz; 1 H), 3.50–3.75 (m, 2 H), 3.80–4.05 (m, 3 H), 4.50 (dd, J=9.8, 4.0 Hz, 1 H), 4.88 (brs, 1 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.80–6.90 (m, 3 H), 7.04 (d, J=8.7 Hz, 2 H), 8.73 (brs, 1 H); MS (ES) m/z: 256.3 ((M+2H)2+, 100%), 511.2 (MH+, 10%); HRMS Calcd. for C25H31N6O4S (MH+): 511.2128. Found: 511.2122.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH2:39][C:40](O)=[O:41])[CH:36]=[CH:37][CH:38]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:32][C:33]1[CH:34]=[C:35]([CH2:39][C:40]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]4[N:14]=[C:15]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]6[CH2:28][CH2:29][CH2:30][CH2:31]6)=[CH:20][CH:19]=5)[N:16]=[C:12]4[CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[O:41])[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(Cc1cccc(Cl)c1)Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 8 h

Procedure:
[5-(3-Amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (50 mg, 0.121 mmol), 3-chlorophenylacetic acid (25 mg, 0.145 mmol) and di-isopropylethylamine (25 μL, 0.145 mmol) were dissolved in dimethylacetamide (1 ml). HBTU (55 mg, 0.145 mmol) was subsequently added and the mixture was stirred overnight. The product was purified by preparatory HPLC. RT: 2.9 min, MI: 567, Method: 2.
Reaction SMILES: COC(CS[C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:41])[NH:15][CH2:16][C:17]([N:19]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:22]([C:30](OC)=O)[CH2:21][CH:20]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:18])[CH:10]=[CH:11][CH:12]=1)=O.[OH-:42].[K+].[CH3:44][OH:45]>O>[CH2:30]([C@H:22]1[C@H:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:19]([C:17](=[O:18])[CH2:16][NH:15][C:14](=[O:41])[NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:44]([OH:45])=[O:42])[C@H:20]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:21]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: COC(=O)CSc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)OC)C2c2ccccc2)c1
Reactant: CO
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](Cc2ccccc2)[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 2.6 g of 2-tert-butyl 4-methyl (2RS,4RS,5SR)-1-{2-[3-(3-(methoxycarbonylmethylthio)phenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate and 0.5 g of potassium hydroxide in a mixture of 15 cm3 of distilled water and 50 cm3 of methanol. After treatment, there are obtained 1.8 g of 2-tert-butyl hydrogen (2RS,4RS,5SR)-1-{2-[3-(3-(carboxymethylthio)phenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate [Rf =0.1; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2>>[ClH:1].[CH3:13][N:12]([CH3:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CN(C)c1ccc2ncnc(Cl)c2c1
Product: CN(C)c1ccc2ncnc(Nc3ccc4[nH]ncc4c3)c2c1
Product: Cl
Yield: 92 %

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-6-dimethylaminoquinazoline was reacted with 5-amino-1H-indazole to give 6-dimethylamino-4-(1H-indazol-5-ylamino)quinazoline hydrochloride in 92% yield, m.p. >300° C.;
Reaction SMILES: COC1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2SC=C(C(OC)=O)N=2)CC1)=O.Cl.[Br:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][N:38]=[C:37]2[C:43]([NH:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:44].Cl[CH2:54][C:55]1[O:59][C:58]([C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:57][CH:56]=1>>[Br:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][N:38]=[C:37]2[C:43]([NH:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([CH2:54][C:55]2[O:59][C:58]([C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:57][CH:56]=2)[CH2:51][CH2:52]1)=[O:44]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: O=C(NCC1CCNCC1)c1n[nH]c2ccc(Br)cc12
Agent: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Agent: Cl
Product: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1

Procedure:
Ethyl 5-{[4-({[(5-bromo-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}furan-2-carboxylate 15 was prepared, according to the procedure described for compound 7, from 11b and ethyl 5-(chloromethyl)furan-2-carboxylate. Yield: 300 mg, 62%.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[S:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])C.[OH-].[Na+]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:15]([C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([F:13])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:27])=[O:3])=[S:26])=[C:19]([F:25])[CH:20]=1
Reactant: CCOC(=O)COc1cc(F)c(C)cc1C(=S)NCc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=S)NCc2ccc(Br)cc2F)c(OCC(=O)O)cc1F
Yield: 98.7 %

Procedure:
A stirring solution of [2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.79 g, 1.53 mmol) in ethanol (7.6 mL, 0.2 M) and treated with aqueous NaOH (2 N, 7.4 mL, 9.15 mmol) in an analogous fashion to Example 45, Step 9 to provide [2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid (0.65 g, 98%) as a yellow solid: mp 162-164° C.; Rf 0.41 (20% methanol in methylene chloride); 1H NMR (DMSO-d6, 300 mHz) δ 10.64 (t, J=5.0 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.52 (dd, J1=9.6 Hz, J2=1.7 Hz, 1H), 7.45-7.36 (m, 2H), 7.00 (d, J=11.4 Hz, 1H), 4.89 (bd d, J=5.1 Hz, 2H), 4.78 (s, 2H), 2.15 (d, J=1.2 Hz, 3H); ESI-LC/MS m/z calcd for C17H14BrF2NO3S: 428.98; found 428.0 (M−1)−; Anal. calcd for C17H14BrF2NO3S: C, 47.45; H, 3.28; N, 3.26; S, 7.45. Found C, 47.54; H, 3.19; N, 3.11; S, 7.33.
Reaction SMILES: [CH3:1][C@@:2]([S:14]([CH3:17])(=[O:16])=[O:15])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)[C:3]([OH:5])=O.CN1CCOCC1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].O>C1COCC1>[CH3:1][C@@:2]([S:14]([CH3:17])(=[O:16])=[O:15])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]1)[C:3]([NH:32][O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1)=[O:5]
Reactant: NOC1CCCCO1
Reactant: Cc1cnn(CC[C@](C)(C(=O)O)S(C)(=O)=O)c1
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cnn(CC[C@](C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoic acid (20 mg, 0.077 mmol, 1 eq) and CDMT (17.6 mg, 0.10 mmol, 1.3 eq) in THF (1 mL) was added N-methylmorpholine (10.9 mg, 0.108 mmol, 0.0120 mL, 1.4 eq) and the reaction mixture was stirred at RT for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (9.00 mg, 0.077 mmol, 1 eq) was added to the reaction mixture which was stirred overnight at RT. Water was added and the organic phase was separated. The aqueous phase was extracted with Et2O. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to give (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, (19 mg, 68%).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[NH2:14][CH2:13][CH2:12][NH:15][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: CCOC(=O)c1cccnc1
Reactant: NCCN
Product: NCCNC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of ethyl nicotinate (21.9 g.) and ethylenediamine (30 ml.) was heated to 100° C. for 16 hours under an atmosphere of argon. Excess ethylenediamine was removed by distillation in vacuo and the residue was dissolved in water (100 ml.) The insoluble material [bis(carboxamido)derivative] was removed by filtration. Evaporation of the filtrate, addition of toluene (50 ml.) followed by re-evaporation gave crude N-(2-aminoethyl)pyridine-3-carboxamide (26.5 g.) as its oily free base, essentially pure by TLC (SiO2 : 10% MeOH/CHCl3) and which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=N1.CN(C=[O:57])C.CCN(CC)CC>CCOC(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:35]3[CH2:36][CH2:41][CH:40]([OH:57])[CH2:39]3)=[O:10])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:14])=[O:13])=[CH:16][C:17]=1[C:22]([F:23])([F:24])[F:25]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CN(C)C=O
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCC(O)C1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a vial containing 5-chloro-3-(4-chloro-3-trifluoromethyl benzenesulfonylamino)-pyridine-2-carboxylic acid (20 mg, 0.05 mmol) were added 3-(±)-pyrrolidinol hydrochloride (13 mg, 0.11 mmol), BOP (25 mg, 0.06 mmol), DMF (0.3 mL) and NEt3 (40 μL, 0.29 mmol). The solution was maintained at room temperature for 24 h, then diluted with EtOAc (30 mL), washed with saturated aqueous NaCl (3×5 mL), and dried over MgSO4. The volatiles were removed in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (10 mg, 43% yield): HPLC retention time=2.49 minutes. MS (ES) [M+H]+ expected 484.0. found 484.0. 1H NMR (400 MHz, CDCl3) δ 11.38 (s, 1H), 8.21-8.24 (m, 1H), 8.11-8.13 (m, 1H), 8.02-8.04 (m, 1H), 7.91-7.93 (m, 1H), 7.60-7.62 (m, 1H), 4.50-4.53 (m, 1H), 3.82-4.01 (m, 2H), 3.65-3.76 (m, 3H), 1.95-2.04 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][C:33]([O:42][CH2:43][C@@H:44]1[CH2:46][O:45]1)([CH3:41])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][C:33]([O:42][CH2:43][C@@H:44]1[CH2:46][O:45]1)([CH3:32])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:36]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(Cn1ccc(N)n1)OC[C@@H]1CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.12 g, 0.28 mmol), 1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine (52.4 mg, 0.248 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 0.212 g, 0.56 mmol) and iPr2NEt (0.25 mL, 1.4 mmol) in CH2Cl2 (3 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by column chromatography (4 g column, 1-100% ethyl acetate/heptane) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((5)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (58 mg, 35.4%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H37Cl2F2N5O3+H [(M+H)+]: 660.2315. found: 660.2316.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:22])[CH:20]=[CH2:21]>>[CH2:19]([O:22][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:20]=[CH2:21]
Reactant: C=CCO
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: C=CCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 118-120° C. and MS: m/e=295 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and allyl alcohol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:19][C:20]1[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC1(c2ccccc2)C(=O)Nc2ccc(Br)cc21
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 5-Bromo-3-methyl-3-phenyl-1,3-dihydro-indol-2-one (602 mg, 2 mmol), compound 3,5-dimethylisoxazole-4-boronic acid (564 mg, 4 mmol), Pd(PPh3)4 (440 mg, 0.4 mmol) and Cs2CO3 (1.624 g, 5 mmol) in dioxane (10 mL) and H2O (5 mL) is stirred at 80° C. under nitrogen for 20 hours. The mixture is poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate:petroleum ether=1:2) to give the desired compound.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.1 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.45 g, 4.2 mmol/g loading, 10.29 mmol) followed by 4-bromobenzenesulfonyl chloride (2.60 g, 10.2 mmol). The resulting solution was stirred at room temperature overnight (˜24hours)and then the resin filtered off with methanol and the solvent evaporated in vacuo. The residue was passed through an SCX column eluting first with methanol followed by 2M ammonia in methanol. The relevant fractions were collected, combined and the solvent evaporated in vacuo. The crude product was purified by Flashmaster causing an elution gradient of 0 to 10% methanol in dichloromethane. The relevant fractions were collected, combined and the solvent evaporated to afford the title compound (E106). MS (ES+) m/e 454/456 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2N.N([O-])=[O:16].[Na+].O>C(O)(=O)C>[OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:9](=[O:16])[NH:8][CH:7]=[N:6][C:5]1=2
Reactant: CC(O)Cn1cnc2c(N)ncnc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(O)Cn1cnc2c(=O)[nH]cnc21
Reaction time: 3 h

Procedure:
9-(2-Hydroxy-1-propyl)adenine (I, 4.0 g, 20.7 mmol) was suspened in 50% acetic acid (20 ml) and sodium nitrite (4 g, 58 mmol), was slowly added. The mixture was stirred at 25° for 3 hr. The resulting solution was evaporated to dryness and isopropanol added; this operation was repeated once. The solid residue was boiled in isopropanol and filtered. The filtrate was evaporated and crystallized by addition of acetone. Recrystallization was made from iso-propanol/methanol (98:2); a colorless crystalline product was obtained. Yield 3.3 g (82%); M.P. 244°-250°; uv (H2O; pH 5.5), λmax 250 nm.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.Br[C:30]1[CH:31]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=1>C(Cl)Cl.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>[NH2:23][C:14]1[CH:15]=[C:16]([C:30]2[CH:31]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=2)[CH:17]=[C:18]2[C:13]=1[CH:12]=[N:11][N:10]2[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
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: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Temperature: 120 °C
Yield: 19.8 %

Procedure:
Four identical reactions were carried out in a 20 ml microwave vial, each using one quarter of the quantities stated. They were then combined for work-up and purification. A solution of a quarter of 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (4.329 g, 9.93 mmol) in a quarter of DMF (24 ml) was treated with a quarter of N-(5-bromo-2-chloro-3-pyridinyl)methanesulfonamide (3.26 g, 11.42 mmol) followed by a quarter of Pd(PPh3)4 (1.032 g, 0.893 mmol). Each vial was heated at 120° C. for 50 mins in a Biotage Initiator. The orange solutions were combined and loaded onto a 20 g silica cartridge, and the vials washed with methanol (10 ml) which was also loaded onto the cartridge which was then eluted with methanol. Then eluants were evaporated to leave an orange oil. This was diluted with DCM (10 ml) and loaded directly and evenly onto 2×100 g silica cartridges. These were eluted with 0-100% ethyl acetate/cyclohexane over 80 mins using the Flashmaster II. Appropriate pure fractions were combined and evaporated to give the title compound as a yellow solid (0.939 g).