Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([CH3:51])=[CH:49][N:48]=[C:47]([NH:52][CH2:53][CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][NH:59][C@@H:58]([CH3:62])[CH2:57]4)[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]>>[ClH:3].[ClH:1].[ClH:3].[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([CH3:51])=[CH:49][N:48]=[C:47]([NH:52][CH2:53][CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][N:59]([CH3:4])[C@@H:58]([CH3:62])[CH2:57]4)[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN[C@@H](C)C4)ncc3C)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)[C@@H](C)C4)ncc3C)cc12

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (S)-2-{5-methyl-2-[3-(3-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 453 [M(free base)+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:11])[S:6][C:7]=1[C:8]([OH:10])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:7]5[S:6][C:5]([CH3:11])=[N:4][C:3]=5[O:2][CH3:1])=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: COc1nc(C)sc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1nc(C)sc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 54.5 %

Procedure:
In the same manner as in Example 259 and using 4-methoxy-2-methyl-1,3-thiazole-5-carboxylic acid (120 mg, 0.70 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (120 μL, 1.4 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (120 mg, 53%) was obtained as a white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][O:10][C:11](OC)([CH3:13])[CH3:12].CO.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[C:28]1(C)[CH:33]=CC=C[CH:29]=1>>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:28]([CH3:33])([CH3:29])[CH2:12][C:11]([O:10][CH3:9])([CH3:13])[O:5]2)=[CH:7][CH:8]=1
Reactant: Cc1ccccc1
Reactant: Oc1cccc(O)c1
Reactant: COC(C)(C)OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC1(C)CC(C)(C)c2ccc(O)cc2O1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
30 ml glass autoclave was charged with 2.2 g (20 mmol) of resorcin, 6.2 g (60 mmol) of acetone dimethyl acetal, 6.4 g (200 mmol) of methanol, 0.2 g (2 mmol) of conc. sulfuric acid and 10 ml of toluene, and sealed, and allowed to react at 100° C. for 4 hours. Then, the reaction mixture was cooled to room temperature, neutralized with saturated NaHCO3, washed with water, and toluene was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography on silicagel using hexane-ethyl acetate as an eluent to give 1.26 g (28.3%) of 7-hydroxy-2-methoxy-2,4,4-trimethylchroman as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:42]=[CH:41][C:18]([CH2:19][N:20]([C:24]2[S:25][C:26]([CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.[ClH:51]>CO.O>[ClH:51].[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:42]=[CH:41][C:18]([CH2:19][N:20]([C:24]2[S:25][C:26]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=1
Reactant: CCCN(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1nc(-c2ccccc2)c(CCC(=O)OC)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1nc(-c2ccccc2)c(CCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of methyl 3-[2-[N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-N-(1-propyl)amino]-4-phenyl-5-thiazolyl]propionate (537 mg), lithium hydroxide hydrate (116 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2.8 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the obtained colorless oil, 10% hydrochloric acid-methanol (3 ml) and diethyl ether (30 ml) was stirred at room temperature for 10 min. and concentrated to give 3-[2-[N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-N-(1-propyl)amino]-4-phenyl-5-thiazolyl]propionic acid hydrochloride (576 mg, yield 97%) as a colorless amorphous form.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.I[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1>CCCCCC.C(OCC)(=O)C>[CH3:14][C:9]1[CH:8]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:12]=[C:11]([CH3:13])[CH:10]=1
Reactant: c1cc[nH]c1
Reactant: Cc1cc(C)cc(I)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)cc(-n2cccc2)c1
Yield: 99 %

Procedure:
Using general procedure B, pyrrole (83 μL, 1.2 mmol) was coupled with 5-iodo-m-xylene to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 9:1) provided 0.170 g (99% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.07 (t, J=7.0 Hz, 2H), 7.02 (s, 2H), 6.89 (s, 1H), 6.33 (t, J=7.0 Hz, 2H), 2.37 (s, 6H).
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]([OH:30])=O)[CH:5]=[CH:6][CH:7]=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:65]([O:69][C:70](=[O:76])[NH:71][CH2:72][CH2:73][CH2:74][NH2:75])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:76])[NH:71][CH2:72][CH2:73][CH2:74][NH:75][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]1)=[O:30])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution 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 (800 mg, 1.74 mmol) in methylene chloride (10 mL), HATU (Aldrich, 662 mg, 1.74 mmol) was added followed by the addition of DIPEA (1.74 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (Aldrich, 1.74 mmol). The mixture was stirred at rt for 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, EtOAc/Hexanes, 20%) to give a white solid. 810 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(N(C(C)C)CC)(C)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)nn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(Cl)nn1
Temperature: 111 °C
Yield: 8.2 %

Procedure:
A suspension of 3-chloro-6-iodopyridazine (2.4 g, 10 mmol), ethyl acrylate (4.4 mL, 40 mmol), palladium(II) acetate (90 mg, 0.40 mmol) and tri(o-tolyl)phosphine (366 mg, 1.20 mmol) in DMF (10 mL) and diisopropylethyl amine (5 mL) was stirred with heating (111° C. oil-bath) for 3.5 h, cooled to room temperature, diluted with H2O (50 mL) and extracted with EtOAc (300 mL). The extract was washed (brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (14% to 20% EtOAc/hexane) to give 174 mg (8%) of ethyl(E)-3-(3-chloro-6-pyridazinyl)-2-propenoate as a brown solid, mp 106-110° C. IR 2928, 1715, 1186 cm−1; 1H NMR (CDCl3) δ 1.38 (t, J=7.5 Hz, 3H, CH2CH3), 4.33 (q, J=7.5 Hz, 2H, CH2CH3), 7.98 (d, J=16.2 Hz, 1H, CH═CHCO), 7.57 (d, J=8.4 Hz, 1H, 4-ArH), 7.63 (d, J=8.4 Hz, 1H, 5-ArH), 7.86 ppm (d, J=16.2 Hz, 1H, CH═CHCO). HRMS calcd C9H9ClN2O2 [M+H]+ 213.0425. found 213.0431.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@H:25]5[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]5)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CC[C@H](Nc2nc3ccc(Cn4cnc5cc(F)cnc54)cc3s2)CC1
Temperature: 110 °C

Procedure:
To a stirred suspension of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (119 g, 0.3 mmol) from Step 4 of Example 162 and trans-4-aminocyclohexanol (119 mg, 1.0 mmol) in anhydrous DMA (1 mL) was added DIEA (180 μL, 1.0 mmol). The mixture was heated in a sealed tube at 110° C. for 15 h. The mixture was cooled to rt and was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford trans-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 37%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 8.06 (dd, J=2.6, 9.3 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 5.48 (s, 2H), 4.55 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 1.93-2.03 (m, 2H), 1.78-1.87 (m, 2H), 1.19-1.30 (m, 4H); LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C(N)(N)=[O:18].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-:18])[CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: NC(N)=O
Reactant: O=c1c2cc(Br)ccc2oc2cccnc12
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2cc(Br)ccc2oc2ccc[n+]([O-])c12
Reaction time: 2 h

Procedure:
To a solution of 8-bromo-10H-chromeno[3,2-b]pyridin-10-one (60 g, 217 mmol) and urea peroxide (42.9 g, 456 mmol) in 120 mL of DCM at 0° C. was added dropwise trifluoroacetic anhydride (63.9 mL, 456 mmol). The resulting reaction was stirred for 2 h. The reaction was quenched with 10% Na2S2O3, extracted with DCM, dried over Na2SO4 and evaporated to dryness to give crude 8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[NH:4][CH2:5][C:6]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]CO)[CH:16]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.C(N(CC)CC)C.[C:36]([Cl:39])(Cl)=O.[O:40]1CCC[CH2:41]1>>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=1[N:4]1[CH2:5][C:6]2[C:7](=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:36][Cl:39])[CH:16]=2)[C:41]1=[O:40]
Reactant: C1CCOC1
Reactant: O=C(Cl)Cl
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2cccc(CCO)c2)n1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(c1cccc(CCCl)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Yield: 50 %

Procedure:
A solution of 1 g (2.3 mmol) of 5-(2,6-dichloroanilino)methyl-4-[3-(2-hydroxyethyl)phenyl]amino-2-methylthiopyrimidine in 60 ml of tetrahydrofuran was treated with 0.8 ml (6 mmol) of triethylamine and the mixture was added dropwise to a solution of 1.8 ml of phosgene (20% in toluene) in 40 ml of tetrahydrofuran. The cooling was removed. After 2 hours 100 ml of saturated aqueous ammonium chloride solution were added. The mixture was separated and the organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel using diethyl ether/hexane (1:2) for the elution. Product-containing fractions were combined and evaporated to give 0.5 g (50%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-[3-(2-chloroethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =479].
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:5]([C:6]=23)=[CH:4]1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:23]1([S:29]([N:3]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:12][NH:13][CH2:14][CH2:15][C:5]([C:6]=34)=[CH:4]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]c3cccc(c23)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CNCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60% in mineral oil, 66 mg, 0.4 mmol) was added to a solution of tert-butyl 1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 12 (51 mg, 0.2 mmol) in 800 of dry DMF). The reaction mixture was shaken at room temperature for 10 minutes and phenylsulfonyl chloride (66.2 mg, 0.4 mmol, in 600 uL of dry DMF) was added. The reaction mixture was shaken at room temperature for 10-20 minutes. The reaction was quenched by adding 4 mL of mixture a mixture of methanol and acetic acid (1:1). Boc-deprotection was carried out by adding 4 mL of solution of TFA/DCM (1:1). 2M NH3 in MeOH was added to the crude reaction (2×10 mL) and the solvent was removed under vacuum. The crude product was purified by preparative HPLC using System B, 100 mM NH4HCO3/MeCN (10-50% MeCN). 50 mg of the pure product was isolated as an off-white solid. MS m/z 313 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([Cl:9])=O)[CH2:2][CH3:3].Cl.C[O:18][C:19]1[C:24]([NH2:25])=[C:23]([NH2:26])[CH:22]=[CH:21][N:20]=1>>[ClH:9].[CH2:1]([O:4][C:5]1[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]1[N:25]=[C:24]2[C:19](=[O:18])[NH:20][CH2:21][CH:22]=[C:23]2[N:26]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cc(SC)ccc1C(=O)Cl
Reactant: COc1nccc(N)c1N
Agent: Cl
Product: CCCOc1cc(SC)ccc1C1=NC2=CCNC(=O)C2=N1

Procedure:
This compound was prepared analogous to Example 2 from 2-propoxy-4-methylmercapto-benzoyl chloride and 2-methoxy-3,4-diamino-pyridine hydrochloride. Melting point: above 260° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[N+:39]([O-])=O)[CH:12]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C(C(CCOCc1ccccc1)Oc1ccc(F)cc1[N+](=O)[O-])N(Cc1ccccc1)Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)ccc1OC(CCOCc1ccccc1)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1

Procedure:
9.30 g (17 mmol) racemic (2S,3R and 2R,3S)-5-Benzyloxy-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-pentanoic acid in 100 ml methanol were hydrogenated with 1.5 g Raney-Nickel. Filtration and removal of the solvent by distillation yielded 5.30 g (60%) (2S,3R and 2R,3S)-3-(2-amino-4-fluoro-phenoxy)-5-benzyloxy-2-dibenzylamino-pentanoic acid as foam, MS m/e (%): 529.0 (M+H+, 100).
Reaction SMILES: [ClH:1].C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[CH2:6][CH2:5]1)=O>CO>[Cl-:1].[Cl-:1].[Cl-:1].[N:7]1([CH2:10][C:11]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: Cl
Reactant: O=CN1CCN(Cc2ccc(O)c3ncccc23)CC1
Solvent: CO
Product: Oc1ccc(CN2CCNCC2)c2cccnc12
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of ˜16% HCl in methanol (25 ml) was added to a solution of compound 23 (300 ng, 1.23 mmol) in absolute methanol (5 ml). (Upon addition of the acid, all insoluble material was dissolved). The reaction mixture was stirred at room temperature. After 10 min, a yellow powder was precipitated; the mixture was stirred overnight. The product was then filtered and washed with absolute methanol (5 ml×2). The product was obtained as a yellow powder in quantitative yield. TLC and the m.p. showed the product to be identical to that obtained previously.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]4[CH2:30][CH2:31][N:26]([C:23](=[O:25])[CH3:24])[CH2:27][CH2:28]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CC(=O)N1CCNCC1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CC(=O)N1CCN(CCCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 1-Acetylpiperazine were converted to yield 1-(4-(4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl)-piperazin-1-yl)-ethanone as white solid, MS: 488 (MH+, 1Br).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=C=O.[CH:35]1([NH2:38])[CH2:37][CH2:36]1>>[CH:35]1([NH:38][C:24]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][N:8]2[C:6]([NH:27][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:7])=[O:26])[CH2:37][CH2:36]1
Reactant: CCCCCN=C=O
Reactant: NC1CC1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Product: CCCCCNC(=O)N1CC(=NOCc2ccc(OC)cc2)C[C@H]1C(=O)NC1CC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and cyclopropylamine the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=417.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[CH2:26]1[CH:35]2[N:30]([C:31](=[O:36])[O:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][NH:27]1.CCN(C(C)C)C(C)C>ClCCCl.CCOC(C)=O>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:27]2[CH2:28][CH2:29][N:30]3[C:31](=[O:36])[O:32][CH2:33][CH2:34][CH:35]3[CH2:26]2)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C1OCCC2CNCCN12
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(CN2CCN3C(=O)OCCC3C2)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.072 g, 0.16 mmol) and hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one trifluoro acetitic acid salt (Compound D, crude, 0.25 mmol) in 1,2-dichloroethane (5 mL) was added dropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirred at room temperature until the disappearance of starting material. The mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous NH4Cl solution and brine. The organic layer was separated and then dried over Na2SO4. The solvent was concentrated in vacuo and the crude product was purified by prep-HPLC to give methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-1,3,4,8,9,9a-hexahydropyrazino[1,2-c][1,3]oxazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Example 1) as a light yellow solid (11 mg). 1H NMR (400 MHz, METHANOL-d4) d ppm 7.97 (dd, J=3.01, 1.00 Hz, 1H), 7.81 (d, J=3.01 Hz, 1H), 7.46 (dd, J=8.66, 6.15 Hz, 1H), 7.26 (dd, J=8.78, 2.51 Hz, 1H), 7.00-7.13 (m, 1H), 6.19 (d, J=1.76 Hz, 1H), 4.19-4.48 (m, 4H), 4.11 (d, J=16.06 Hz, 1H), 3.76-3.94 (m, 1H), 3.62 (s, 3H), 3.18-3.31 (m, 2H), 2.37-2.80 (m, 3H), 2.11-2.30 (m, 1H), 1.90 (qdd, J=14.37, 14.37, 14.37, 9.22, 5.40 Hz, 1H). MS: calc'd 520 (MH+), measured 520 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1I.B([C:18]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:19]=1[O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])(O)O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[C:26]1[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[CH:18][C:19]=1[O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23]
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Reactant: CN(C)S(=O)(=O)c1ccc(I)c(Cl)c1
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)N(C)C)cc1Cl)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (ii) and the product from example 146 step (iv).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH2:20])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[O:28]=[C:29](Cl)OC(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[NH:20][C:29]2=[O:28])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(F)cc2N)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 4-(2-amino-4-fluoro-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.100 g, 0.36 mmol) and triethylamine (0.110 mg, 1.08 mmol) in methylene chloride (2 mL) at 0° C. was added a solution of diphosgene (0.71 mg, 0.36 mmol) in methylene chloride (4 mL) at room temperature. The reaction mixture was stirred for 18 h then quenched with a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and washed with brine. The organic phase was purified by passing it through a plug of silica gel, using ethyl acetate as the eluent. The filtrate was evaporated, in vacuo, to a residue. The residue was triturated with hexanes/dichlormethane (95:5) and the solid collected by filtration. Vaccum drying yielded 4-(5-fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester (77.8 mg, 71%) as a light tan solid.