Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BH4-].[Na+]>CO>[F:14][C:2]([F:1])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH:3]([O:5][CH3:6])[OH:4]
Reactant: COC(=O)C(F)(F)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(O)C(F)(F)c1ccc(F)cc1
Temperature: -57.5 °C
Reaction time: 1.25 h
Yield: 94.6 %

Procedure:
A solution of methyl difluoro(4-fluorophenyl)acetate (2.04 g, 10.0 mmol, from EXAMPLE 155, Step E) in CH3OH (10.0 mL) was cooled to −60° C. Sodium borohydride (380 mg, 10.0 mmol) was added in 5 portions at 10 to 15 min. intervals. The mixture was cooled to −60 to −55° C. prior to each addition and allowed to warm to −45° C. following each addition. After the last addition, the mixture was stirred 1.25 h at −50 to 45° C. The mixture was cooled to −60° C. and quenched with 1 N HCl (30 mL), with the temperature rising to −20° C. near the end of the addition. After warming to 0° C., the mixture was extracted with ether (3×20 mL). The combined ether layers were washed with H2O (2×20 mL), dried (Na2SO4), decanted, and evaporated to give 1.95 g of crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:17])=[C:7]([O:13][CH2:14][CH2:15][CH3:16])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C1COCC1>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:17])=[C:7]([O:13][CH2:14][CH2:15][CH3:16])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: CCCOc1oc(=O)c2cc(N)ccc2c1Cl
Solvent: C1CCOC1
Product: CCCOc1oc(=O)c2cc(NC(=O)NCC)ccc2c1Cl
Yield: 45 %

Procedure:
This compound was synthesized by the reaction of an equimolar amount of 7-amino-4-chloro-3-propoxyisocoumarin and ethyl isocyanate in small amount of dry THF. The reaction mixture was stirred at r. t. for a few days. During this time the yellow crystals slowly crystallized out. After filtration, the compoumds were recrystallized once more from THF-pentane, yield 45%; mp 189°-191° C.; TLC, Rf =0.43 (CH3Cl:MeOH=9:1); MS, m/e 324 (M+). Anal. Calc. for C15H17O4N2Cl: C, 55.42; H, 5.23. Found: C, 55.31; H, 5.28.
Reaction SMILES: ICC1CCC(=O)N1[C:9]1[C:10]([I:23])=[C:11]([C:20]([NH2:22])=[O:21])[C:12]([I:19])=[C:13]([C:16]([NH2:18])=[O:17])[C:14]=1[I:15].C([O-])(=O)C.C([N+](CC)(CC)CC)C>C(#N)C>[I:19][C:12]1[C:13]([C:16]([NH2:18])=[O:17])=[C:14]([I:15])[CH:9]=[C:10]([I:23])[C:11]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1c(I)c(C(N)=O)c(I)c(N2C(=O)CCC2CI)c1I
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CC#N
Product: NC(=O)c1c(I)cc(I)c(C(N)=O)c1I
Reaction time: 18 h
Yield: 15.8 %

Procedure:
To a solution of N,N'-bis[2-(acetyloxy)-1-(acetyloxy)methyl]ethyl]-5-[2-(iodomethyl)-5-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (12.00 g, 110 mmol) in acetonitrile (150 ml) was added tetraethylammonium acetate (5.74 g, 22 mmol) and the mixture stirred at 50° for 18 hours. Acetonitrile was removed in vacuo at 60°, the residue dissolved in ethyl acetate (200 ml), and the resulting solution washed with brine (2×100 ml) and with water (100 ml). The ethyl acetate layer was dried and removal of the solvent afforded the crude product as a colorless glassy solid. This material was purified by column chromatography over silica gel, using 20% hexane in ethyl acetate as eluent, to obtain N, N-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[2-(acetyloxy)methyl)-5-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a colorless solid (9.4 g, 83.6% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].[CH2:25]([O:27][CH2:28][CH2:29]Br)[CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:26][CH2:25][O:27][CH2:28][CH2:29][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 90 °C

Procedure:
Mix [1H-benzimidazol-2-yl][1-(t-butyloxycarbonyl)-4-piperidinyl]methanone (4.25 g, 12.91 mmol), 2-bromoethyl ethyl ether (2.34 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [Br-].C[PH3+].[CH3:4]C(C)([O-])C.[K+].[C:10]1([N:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.ClCCl>[C:10]1([N:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[CH2:4])=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[PH3+]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
19 g of methylphosphonium bromide is suspended in dried THF under protective gas, and 6 g of potassium tert-butoxide are added in portions at 0° C. An immediate colour change to orange occurs. 14 g of N,N-diphenyl-p-aminobenzaldehyde are added to the reaction solution at 0° C. The mixture is warmed to room temperature and stirred for a further 20 hours. The solvent is stripped off in vacuo, the residue is taken up in dichloromethane, and the solution is extracted with water dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1.[CH3:20][C:21]([S:24](Cl)=[O:25])([CH3:23])[CH3:22].Cl>C(OCC)(=O)C>[CH3:20][C:21]([S:24]([NH:9][C@@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:15]1)=[O:25])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)(C)S(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@@H](NS(=O)C(C)(C)C)CC1

Procedure:
Triethylamine (272 mL) was added dropwise to a suspension of methyl cis-4-amino-1-cyclohexane carboxylate hydrochloride (7) (151 g, 0.78 mol) and 2-methylpropane-2-sulfinyl chloride (3) (120.8 g, 1.1 eq) in ethyl acetate (755 mL) at 6 to 9° C. The mixture was stirred for an hour at the same temperature and poured into diluted hydrochloric acid. The mixture was extracted with ethyl acetate (750 mL×2) and each of organic layers was washed with water, 5% aqueous solution of sodium bicarbonate, water and brine, successively. The solvent was concentrated under reduced pressure to obtain oily (14) (222.7 g, 1.09%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23](SC)=[N:22][C:21]4=[O:27])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=[O:4])=[O:3].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][S:2]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[N:22][C:21]4=[O:27])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:30]([F:31])([F:32])[F:33])[CH:6]=1)(=[O:3])=[O:4]
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(S(C)(=O)=O)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [Cl-].[CH:2]1([CH2:6][NH2+:7][CH2:8][CH2:9]Cl)[CH2:5][CH2:4][CH2:3]1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]1[N:7]([CH2:6][CH:2]2[CH2:5][CH2:4][CH2:3]2)[CH2:8][CH2:9][S:21]1
Reactant: Cc1cccc(N=C=S)c1C
Reactant: ClCC[NH2+]CC1CCC1
Agent: [Cl-]
Product: Cc1cccc(N=C2SCCN2CC2CCC2)c1C

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[C:9]([OH:23])[CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)C(=O)O1.[C:26]([O:30][C:31]([O:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:37]([O:36][C:35]([N:34]([O:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[C:6](=[O:8])[CH2:5][C:9]([CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1)=[O:23])=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)=C2C(=O)OC(C)(C)OC2=O)CC1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)ON(C(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Reaction time: 36 h

Procedure:
A solution of tert-butyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl]piperidine-1-carboxylate (8.99 g, 25.3 mmol) and t-butyl N-(t-butoxycarbonyloxy)carbamate (5.90 g, 25.3 mmol) in toluene (200 mL) was stirred at 65° C. for 14 h, then at rt for 36 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (silica, 25% ethyl acetate/hexanes) to afford tert-butyl 4-(3-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}-3-oxopropanoyl)piperidine-1-carboxylate. H NMR analysis was consistent with product but complex due to carbamate rotamers.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9](N)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCCCCCN
Reactant: NC(=O)c1ccccc1
Product: NCCCCCCNC(=O)c1ccccc1
Yield: 62 %

Procedure:
Using the general method of Example 9 Part A, hexamethylenediamine (348.63 g, 3 mol) was reacted with benzamide (121.14 g, 1 mole) to provide 136.5 g of N-(6-aminohexyl)benzamide.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[NH2:21][C:22]1[CH:27]=[C:26]([C:8]2[C:7]3[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=3[C:5]3[C:4]4[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH:9]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: Nc1cccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)c1
Yield: 62 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 3-aminobenzeneboronic acid according to the procedure described in example 8 gave 4-(3-aminophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (15) (I, Ar=3-aminophenyl) in a 62% yield; mp 279–284° C. 1H NMR δ [(CD3)2SO] 11.70 (s, 1H), 10.96 (s, 1H), 9.22 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.10–7.03 (m, 2H), 6.77–6.74 (m, 1H), 6.72–6.68 (m, 1H), 6.61 (dd, J=8.1, 2.3 Hz), 1H), 5.11 (br s, 2H). Found: C, 69.41; H, 4.12; N, 10.73. C20H13N3O3 requires C, 69.96; H, 3.82; N, 12.24.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:19]([C:21]1([C:24]2[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=2)[CH:29]=O)[CH2:23][CH2:22]1)[CH3:20])(=[O:18])[CH3:17].C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[C:16]([N:19]([C:21]1([C:24]2[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=2)[CH2:29][NH:15][C@H:14]2[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:23][CH2:22]1)[CH3:20])(=[O:18])[CH3:17]
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1ccc(C2(N(C)C(C)=O)CC2)cc1C=O
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C2(N(C)C(C)=O)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 3 and Compound 10 in the same manner of Compound 4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCNC(=O)C3)=O)C=2)C=C(F)C=1.[S:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:54]3[CH2:55][CH2:56][S:52][CH2:53]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccn1
Reactant: C1CSCN1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Product: Cc1cc(-n2nc(C(=O)N3CCSC3)cc2-c2cc(F)cc(Cl)c2)ccn1

Procedure:
150 mg (0.45 mmol) of the compound of Example 30A is reacted analogously to the synthesis of the compound of Example 4 with 43 mg (0.48 mmol) of thiazolidine. 137 mg (74% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](OC(ON=C(C#N)C(OCC)=O)=O)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(OCC)(=O)C>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:14][C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: CCOC(=O)C(C#N)=NOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 53.8 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-proline (1.25 g) and triethylamine (0.70 ml) in ethyl acetate (15 ml), ethyl 2-p-nitrophenyloxycarbonyloxyimino-2-cyanoacetate (1.55 g) in powder form is added at room temperature while stirring. The resulting mixture is stirred for 4 hours and then extracted with ethyl acetate. The extract is washed with water, dried and concentrated. The residue is recrystallized from an ethanol-petroleum ether mixture to give N-benzyloxycarbonyl-L-proline p-nitrophenyl ester (1.0 g). M.P. 94° - 96°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[O:24]1[CH2:25][CH2:26][N:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:16]=[CH:15][S:14][C:13]=3[C:17]([O:19][CH3:20])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
To a solution of 74 (1.02 g; 2.7 mmol) in anhydrous toluene (13.3 mL) were added morpholine (0.28 mL; 3.2 mmol), sodium tert-butoxide (0.52 g; 5.4 mmol), bis(dibenzylideneacetone)palladium(0) (79 mg; 0.1 mmol), and racemic-BINAP (104 mg; 0.2 mmol), sequentially. Additional toluene (13.3 mL) was added to aid in stirring. The reaction mixture was put under nitrogen atmosphere (flush×3) and then heated at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture was extracted with dichloromethane (70 mL) and washed with aqueous hydrochloric acid (30 mL×2; 2N), water (30 mL), and aqueous saturated sodium chloride (30 mL). The dichloromethane extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a yellow gel. The crude product was purified by silica gel chromatography (16% to 25% to 33% to 66% ethyl acetate in hexanes to 10% methanol in dichloromethane gradient) to yield the title compound as a pale yellow solid (307 mg).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH2:34][O:35][CH2:36][CH3:37])=[CH:28][C:27]=2[O:38][CH3:39])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])O.[Na+].O.[F:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:48]=1[C:49](Cl)=[O:50]>C(OCC)(=O)C>[F:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:48]=1[C:49]([NH:12][C@@H:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([O:38][CH3:39])=[CH:28][C:29]([CH2:34][O:35][CH2:36][CH3:37])=[CH:30][C:31]=2[O:32][CH3:33])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:50]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](N)C(=O)OCC)cc2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)OCC)cc2)c(OC)c1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a mixture of ethyl (αS)-α-amino-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate p-toluenesulfonate (29.0 g), sodium hydrogen carbonate (15.2 g), water (290 ml) and ethyl acetate (290 ml) was added dropwise 2,6-difluorobenzoyl chloride (9.6 g) at 15° C. or below and the mixture was stirred for 30 minutes at the same temperature. The ethyl acetate layer was washed with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was recrystallized from isopropanol-water to yield ethyl (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate (26.4 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[N:6][C:5]=2[S:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[N:3][S:4][C:5]=2[N:6]=[C:7]1[CH2:12][CH2:13][CH3:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2snc(C)c2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-6-propyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 7) (800 mg, 3.8 mmol) in 20 mL of anhydrous DMF was added 1.38 g (10 mmol) of anhydrous 10 K2CO3 followed by benzyl bromide (655 mg, 3.8 mmol) and the mixture was stirred at room temperature overnight. The TLC of the reaction mixture showed the complete disappearance of the SM. The reaction mixture was poured into ice cold water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried (Na2SO4) and concentrated. The TLC and the 1H NMR showed the presence of two products N alkylated as well as O-alkylated products in a ratio of 1:1. The products were separated by column (silica gel, 116 g) chromatography using 10-20% EtOAc in hexanes. The desired N-alkylated product 5-benzyl-3-methyl-6-propyl-5H-isothiazolo[5,4-d]pyrimidin-4-one was isolated as white crystalline solid (369 mg, 32%). 1H NMR (300 MHz) δ 0.96 (t, 3H), 1.71-1.84 (m, 2H), 2.73 (t, 3H), 2.81 (s, 3H), 5.38 (s, 2H), 7.14-7.38 (m, 5H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].[ClH:39]>O1CCOCC1>[ClH:39].[NH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:7]2[N:8]=[C:9]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:16]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1ncc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
To a solution of (R)-tert-butyl 1-(5-cyano-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (88) in MeOH (15 mL) and DMSO (1.5 mL) was added solid NaOH (200 mg) and 30% H2O2 (1.5 mL). The mixture was stirred at RT for 20 min, diluted with acetonitrile (10 mL), and EtOAc (200 mL) 10 min later. The organic phase was washed with water ×2, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 7% MeOH in DCM to isolate (R)-tert-butyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (89) (yield >95%). (R)-tert-butyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (89) was treated with 4N HCl in dioxane (30 mL) for 40 min. The mixture was concentrated in vacuo to dryness to afford (R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (90).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O:12][C:13]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][C:14]=1[C:15]([O:17]CC)=[O:16])(=O)C>N1C=CC=CC=1>[OH:12][C:13]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:8][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1OC(C)=O
Solvent: c1ccncc1
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)O)c2)cc1
Reaction time: 18 h

Procedure:
3-methyl-2-pyridinamine (1.3 g, 12 mmol) was dissolved in dry pyridine (20 ml) and ethyl 2- acetyloxy-5-[(4-chlorosulfonylphenyl)ethynyl]-benzoate (4.1 g, 10 mmol) was added. The solution was kept at ambient temperature for 18 h. The solvent was evaporated and the residue dissolved in a small amount of tetrahydrofuran. The solution was added to a refluxing solution of potassium hydroxide (6 g) in water (100 ml) and ethanol (50 ml). After 15 min the solution was acidified with formic acid to produce a precipitate. The solid was collected by filtration, washed with water and dried. Yield 1.2 g, 29%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](O)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].P(Cl)(Cl)([Cl:20])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([Cl:20])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccnc(O)c1Oc1cc(Cl)cc(Br)c1
Product: Cc1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C

Procedure:
A suspension of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-ol (340 mg, 1.081 mmol) in phosphorus oxychloride (10 mL, 107 mmol) was heated at 100° C. for 24 hours, after which the solvent was removed in vacuo. The resulting oil was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (100 mL). The organic extract was washed with water (20 mL), dried over MgSO4, filtered, and the solvent removed on a rotary evaporator. This residue was purified using Waters PrepPak and eluting with a gradient of 5-95% ACN/H2O with 0.1% TFA. The desired fractions were combined and the solvent removed in vacuo to give the title compound. LRMS (M+1)=333.8.