Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9](C(O)=O)[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3.C([N:31](CC)CC)C.C1(OP(=O)OC2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([NH2:31])[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Agent: O=[PH](Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(9,13)]tetracosa-1(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylic acid (0.40 g, 0.95 mmol) in tetrahydrofuran (10 mL) at 0° C. was treated with triethylamine (0.53 mL, 3.8 mmol) and diphenylphosphonic acid (0.45 mL, 2.1 mmol) and stirred at 20° C. for 2 h. The reaction mixture was poured into water (50 mL) and ethyl acetate (150 mL). The ethyl acetate layer was separated, diluted with water (50 mL) and heated at 100° C. for 8 h. The reaction mixture was filtered and the organic layer from the filtrate was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude yellow. This material was treated with ethyl acetate and filtered. The filtrate was concentrated to give the desired product (0.29 g, 78%) as a tan solid. LCMS for C18H17ClN5OS (M+H)+: m/z=385.9.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[H][H]>[Pd].C(OCC)(=O)C>[Cl:8][C:7]1[N:6]=[C:5]([NH2:9])[C:4]([O:10][CH3:11])=[N:3][CH:2]=1
Reactant: COc1nc(Br)c(Cl)nc1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ncc(Cl)nc1N
Yield: 82.2 %

Procedure:
A mixture of 5-bromo-6-chloro-3-methoxy-2-pyrazinamine (Example 125a) (0.6 g), triethylamine (0.72 mL), 10% palladium on carbon (0.05 g) and ethyl acetate (50 mL) were hydrogenated at 0.5 bar until reaction was complete as judged by hydrogen uptake. The reaction mixture was filtered and washed with water (25 mL), dried (MgSO4), filtered and evaporated to afford the sub-titled compound (0.33 g). Used Directly.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CCOC(=O)c1cccc(O)c1
Product: O=C(O)c1cccc(Oc2ccc(Cl)cn2)c1

Procedure:
Prepared from 2,5-dichloropyridine and ethyl 3-hydroxybenzoate. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (br. s., 1 H), 8.22 (d, 1 H), 8.00 (dd, 1 H), 7.81 (dd, 1 H), 7.60-7.64 (m, 1 H), 7.58 (t, 1 H), 7.43 (dd, 1 H), 7.18 (d, 1 H).
Reaction SMILES: Cl.[CH:2]1([N:7]2[C:11]3[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=3[C:9]3[CH:17]=[CH:18][N:19]=[CH:20][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:22]1[N:42]=[CH:41][CH:40]=[CH:39][C:23]=1[C:24]([N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)=[O:25]>>[CH:2]1([N:7]2[C:11]3[N:12]=[C:13]([NH:16][C:41]4[CH:40]=[CH:39][C:23]([C:24]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[O:25])=[CH:22][N:42]=4)[N:14]=[CH:15][C:10]=3[C:9]3[CH:17]=[CH:18][N:19]=[CH:20][C:8]2=3)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccnc2Cl)CC1
Agent: Cl
Product: O=C(c1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1)N1CCNCC1

Procedure:
Compound 350 was prepared as a light yellow solid (HCl salt) from compound 4 and compound 351 using chemistry similar to that described in example 200. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.06 (1 H, br. s.), 9.70 (1 H, s), 9.47 (1 H, s), 9.39 (2 H, br. s.), 8.67-8.75 (2 H, m), 8.51 (1 H, d, J=1.7 Hz), 8.37 (1 H, d, J=8.6 Hz), 8.02 (1 H, dd, J=8.7, 2.3 Hz), 5.43 (1 H, dq, J=8.9, 8.8 Hz), 3.77 (4 H, br. s.), 3.18 (4 H, br. s.), 2.42-2.48 (2 H, m), 2.02-2.20 (4 H, m), 1.70-1.83 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 443.2.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]3[C:18]4[C:19]([NH:25][C:16]=3[C:15](=O)[N:14](CC3C=CC(OC)=CC=3)[CH:13]=2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=4)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].O=P(Cl)(Cl)[Cl:38]>[Cl-].C[N+](C)(C)C>[Cl:38][C:15]1[C:16]2[NH:25][C:19]3[C:18]([C:17]=2[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)=[CH:13][N:14]=1)=[CH:23][C:22]([CH3:24])=[CH:21][N:20]=3
Reactant: CCS(=O)(=O)c1cccc(-c2cn(Cc3ccc(OC)cc3)c(=O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: CCS(=O)(=O)c1cccc(-c2cnc(Cl)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A 500 mL round bottom flask equipped with an N2 inlet and reflux condenser was charged with 5-[3-(ethylsulfonyl)phenyl]-7-(4-methoxybenzyl)-3-methyl-7,9-dihydro-8H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-8-one (19.3 g, 39.584 mmol), tetramethylammonium chloride (4.77 g, 43.542 mmol), and POCl3 (249.5 g, 1626.905 mmol) at room temperature, transferred to an oil bath and heated at 100° C. The reaction was monitored by HPLC, and determined to be complete after 2 h. The mixture was allowed to cool to ambient temperature. A separate 3 neck, 3 L flask was fitted with a cold thermometer, and two addition funnels. To this flask was added a solution of 33% by weight aqueous K3PO4 (1500 mL), cooled in a dry ice/acetone bath, followed by the drop-wise addition of the aryl chloride suspension. The internal temperature was kept between 5 to 20° C. and the pH was carefully monitored and maintained at 11.5 during the quench using a slow addition of 10M KOH when necessary. The suspension was allowed to stir for 10 min at 5° C. after the addition was complete, and at ambient temperature for 2 h. The crude product was extracted from the aqueous layer with DCM (5×500 mL), dried with MgSO4, filtered and concentrated in vacuo to a total volume of about 500 mL. The solution was allowed to sit at ambient temperature overnight. The precipitate was collected by filtration, washed with additional DCM and dried, affording a light grey solid (9.79 g) which was confirmed by analytical LCMS and 1H-NMR as the free base. The DCM mother liquor was concentrated and taken up with a methanol/DCM mixture (300 mL, 15/85). To the light green solution was slowly added 30 mL 4N HCl in dioxane and the mixture were stirred for one hour at ambient temperature. 1200 mL of MTBE was slowly added and the resultant suspension was filtered. Chromatography on silica gel plug with methanol/DCM (3/97) afforded a yellow solid. The solid was washed with warm methanol (30 mL) and the resulting product was collected by filtration and washed with additional diethyl ether, affording an additional 1.7 g of the product as a free base. (9.79+1.7=11.49 g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.33 Hz, 3H) 2.32 (s, 3H) 3.44 (q, J=7.33 Hz, 2H) 7.70 (d, J=1.26 Hz, 1H) 7.93 (t, J=7.71 Hz, 1H) 8.04-8.15 (m, 2H) 8.21 (d, J=10.61 Hz, 2H) 8.53 (d, J=1.52 Hz, 1H) 12.78 (br. s., 1H). ESI-MS: m/z 386.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[CH:15]1([N:21]([CH3:25])[CH2:22][CH2:23][NH2:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:12](=[O:14])[CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN(CCN)C1CCCCC1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Product: CN(CCNC(=O)CCc1c[nH]c2ccccc12)C1CCCCC1

Procedure:
Compound 12a was prepared using the amino acid coupling procedure described in Example 10 using 3-(1H-Indol-3-yl)-propionic acid and N1-Cyclohexyl-N1-methyl-ethane-1,2-diamine as the starting materials: LC-MS (Method B, retention time=0.427 min. MS calc'd for C20H30N3O (MH+): 328.2. Found 328.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:26][CH3:27])[C:15]2[C:16]([CH3:25])=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:70][CH2:71][C:72]1[C:73](=[O:80])[NH:74][C:75]([CH3:79])=[CH:76][C:77]=1[CH3:78]>CN(C=O)C.CCOC(C)=O>[Cl:24][C:22]1[CH:21]=[C:17]([C:18](=[O:19])[NH:70][CH2:71][C:72]2[C:73](=[O:80])[NH:74][C:75]([CH3:79])=[CH:76][C:77]=2[CH3:78])[C:16]([CH3:25])=[C:15]([N:14]([CH2:26][CH3:27])[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[CH:23]=1
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 89.1 %

Procedure:
To a solution of 3-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(ethyl)amino)-5-chloro-2-methylbenzoic acid (60 mg, 0.15 mmol) in DMF (2 ml) at room temperature under nitrogen was added PyBOP (94 mg, 0.18 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (40 μl, 0.23 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 28 mg, 0.17 mmol). After stirring for 1 hour at room temperature EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3(aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (2 g silica, Isolute cartridge, gradient of eluents; 100% EtOAc to 96:4 EtOAc:MeOH) to give 71 mg (88%) of the title compound as a pale yellow solid. LC-MS 97%, m/z=531.1/533.1, 1H NMR (250 MHz, Chloroform-d) δ ppm 11.17 (1H, br. s.), 7.11-7.18 (1H, m), 7.06 (2H, dd, J=7.46, 2.28 Hz), 5.96 (1H, s), 4.53 (2H, d, J=5.94 Hz), 3.93-4.14 (2H, m), 2.97-3.08 (2H, m), 2.78-2.88 (1H, m), 2.68 (2H, t, J=11.57 Hz), 2.39 (3H, s), 2.26 (3H, s), 2.24 (3H, s), 1.71 (2H, d, J=11.27 Hz), 1.52 (2H, br. s.), 1.45 (9H, s), 0.86 (3H, t, J=6.93 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CS(C)=O.[B-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [B-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
While cooling using a water bath, to a mixture of 1-benzyloxy-4-((E)-2-nitro-vinyl)-benzene described in Manufacturing Example 229-1-1 (60 g, 0.23 mol), acetic acid (27 mL) and dimethyl sulfoxide (400 mL) was added sodium borohydrate (8.9 g, 0.23 mol), which was stirred for 20 minutes at room temperature. Water (2.5 L) was added dropwise to the reaction mixture, and the deposited solids were filtered. Diethyl ether (300 mL) was added to the obtained solids to dissolve the title compound, and separation into filtrate and solids was carried out by filtration. The filtrate was concentrated under a reduced pressure to obtain the title compound (39 g). On the other hand, diethyl ether (300 mL) was added to the previously separated solid to dissolve the title compound, and separation into filtrate and solids was carried out by filtration. The filtrate was concentrated under a reduced pressure to obtain the title compound (12 g). This was combined with the previously obtained solids to obtain the title compound (51 g) as a crude product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1([CH2:6][CH2:7][C:8](O)=[O:9])[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH4+:19].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1.[Cl-].[Na+].O>[F:1][C:2]([F:12])([F:11])[C:3]1([CH2:6][CH2:7][C:8]([NH2:19])=[O:9])[CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: O=C(O)CCC1(C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)CCC1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of 3-(1-(trifluoromethyl)cyclopropyl)propanoic acid (0.2 g, 1.098 mmol) and oxalyl chloride (0.144 mL, 1.647 mmol) in DCM (5 mL) and DMF (1 drop) was stirred at RT for 2 h, then concentrated to dryness. The residue was co-evaporated with DCM (1×), then dissolved in THF (5 mL), added drop-wise to a solution of NH4OH (˜15 M, 1.07 mL, ˜16 mmol) in THF (5 mL) and stirred at RT for 0.5 h. The mixture was treated with brine, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 3-(1-(trifluoromethyl)cyclopropyl)propanamide (179 mg, 90%). 1H NMR (400 MHz, DMSO-d6): δ 7.30 (s, 1H), 6.77 (s, 1H), 2.16 (m, 2H), 1.75 (m, 2H), 0.85 (m, 2H), 0.71 (m, 2H).
Reaction SMILES: COC[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C1(CBr)CC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COCc1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Product: c1ccc2[nH]ccc2c1

Procedure:
6-methoxymethylindole, R5X=cyclopropyl-methylbromide; NH2A=(2-amino-thiazole-5-ylsulfanyl)-propionic acid ethyl ester
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]2[CH2:15][CH2:16][C:17]3([CH2:19][CH:18]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[O:8]=[C:9]1[NH:14][CH:13]=[C:12]2[CH2:15][CH2:16][C:17]3([CH2:19][CH:18]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]2=[CH:10]1
Reactant: CCOC(=O)C1CC12CCc1cnc(OCc3ccccc3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC12CCc1c[nH]c(=O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound H6.7 (200 mg, 618 μmol) was dissolved in 5 mL EtOH. To this solution was added palladium on carbon (65.8 mg, 618 μmol) and hydrogen was introduced by balloon. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the catalyst was filtered off and the solvent was removed to provide H6.8 (135 mg, 93.6%). MS ESI (pos.) m/e: 234.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH2:5][C:6]([Cl:9])([Cl:8])Cl)[CH:3]1[C:10]([O:12]C)=[O:11].[OH-].[Na+].[CH3:17]O>>[CH3:17][C:3]1([C:10]([OH:12])=[O:11])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:9])[C:2]1([CH3:1])[CH3:14]
Reactant: CO
Reactant: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C(C=C(Cl)Cl)C1(C)C(=O)O
Reaction time: 5 h
Yield: 78 %

Procedure:
A mixture of 9.0 g (0.035 mole) of methyl 2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropane-1-carboxylate (compound Z, C/T=75/25) in 30 ml of a 20% aqueous solution of sodium hydroxide (0.15 mole) and 10 ml of methanol was heated to 98° over 30 minutes. Heating was continued at this temperature for 5 hours. The reaction mixture was cooled, washed with ether, and the aqueous phase made acidic by the addition of concentrated hydrochloric acid. The acidic mixture was extracted with ether, and the ether extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated to give, after distillation, 5.68 g (78% yield) of methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylic acid, the acid corresponding to compound C, 95% purity, C/T=78/22.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[CH3:22][N:23]=[C:24]=[O:25]>>[F:21][C:8]([F:7])([F:20])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]2[CH2:15][N:16]([C:24]([NH:23][CH3:22])=[O:25])[CH2:17]2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: CN=C=O
Agent: O=C(O)C(=O)O
Product: CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h

Procedure:
The oxalic acid salt of 3-[4-(trifluoromethyl)phenoxy]azetidine, weighing 13.0 g (0.042 mole), was partitioned between 50 ml of benzene and 50 ml of potassium hydroxide solution. The benzene layer was dried with Drierite and filtered, and to this stirring filtrate was added 2.6 g (0.046 mole) of methyl isocyanate. Stirring was continued overnight. The mixture was concentrated in vacuo, and the solid residue was recrystallized from a mixture of isopropyl ether-ethyl acetate to give 7.5 g (65%), mp 154°-157°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[NH2:5].N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>CC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)CCc1ccc(N)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)CCc1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a stirred solution of 3-fluoro-4-(2-(methylsulfonyl)ethyl)aniline (200 mg, 0.92 mmol) in acetone/DMF (3 mL+1.27 mL), pyridine (0.222 mL, 2.76 mmol) was added dropwise phenyl chloroformate (0.152 mL, 1.197 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. The acetone was evaporated and the residue was diluted with DCM (30 mL). The mixture was washed with saturated NaHCO3 solution (15 mL) and the organic layer extracted with DCM (2×20 mL). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give pure phenyl 3-fluoro-4-(2-(methylsulfonyl)ethyl)phenylcarbamate (260 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([N:8]=[CH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].[BH4-].[Na+].CC1C=CC(NCC2C=C(OC)C(OC)=C(OC)C=2)=CC=1>>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N=Cc2cc(OC)c(OC)c(OC)c2)cc1
Agent: COc1cc(CNc2ccc(C)cc2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1ccc(NCc2cc(OC)c(OC)c(OC)c2)cc1
Yield: 81.4 %

Procedure:
From the imine 108d (5.6 g, 17.8 mmol) and NaBH4 (3.4 g, 88 mmol), a similar procedure as described for 109a gave 109d (4.6 g, 81.9%) as white crystals: mp 76°-8° C. after recrystallization from ethanol. 1H NMR (200 MHz, CDCl3) δ6.78 (d, J=8 Hz, 2H), 6.62 (d, J=8 Hz, 2H), 6.61 (s, 2H), 4.21 (s, 2H), 3.96 (q, J=6 Hz, 2 Hz), 3.84 (s, 9H), 1.37 (t, J=6 Hz, 3H). CIMS (isobutane) m/e 318 (MH+, 27).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21]CC)=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][C:36](B(O)O)=[CH:37][CH:38]=2)[C:33]([CH3:43])=[N:32]1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>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.CCO.O1CCOCC1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:36]3[CH:35]=[C:34]4[C:39](=[CH:38][CH:37]=3)[N:31]([CH3:30])[N:32]=[C:33]4[CH3:43])[S:3][C:4]=2[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:19]([OH:21])=[O:20])([CH3:26])([CH3:28])[CH3:27]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nn(C)c2ccc(B(O)O)cc12
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: C1COCCO1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(c3)c(C)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.202 mmol), 1,3-dimethylindazole-5-boronic acid (42 mg, 0.22 mmol), Pd(PPh3)4 (23 mg, 20 μmol), 2 M aq K2CO3 (800 μL), and dioxane (3.2 mL). The reaction was heated to 100° C. for 2 h. The reaction was treated with absolute EtOH (1.6 mL) and 10 M aq NaOH (800 μL). After heating to 100° C. for 2 h, the reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C29H28ClN3O3S: 534.2, 536.2 (M+H+). Found: 534.3, 536.3 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 8.08 (dd, J=8.9, 1.6 Hz, 1H), 7.81 (s, 1H), 7.75-7.64 (m, 1H), 7.62-7.52 (m, 4H), 5.26 (s, 1H), 4.01 (s, 3H), 2.61 (s, 3H), 2.57 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([CH3:9])[C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:8]([CH3:9])[C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(CBr)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 18.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-1-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.48 g, 1.02 mmol) was reacted with morpholine-3-carboxylic acid (0.4 g, 3.06 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.1 g, 20%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1)#[N:2].Br[CH:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH2:33][C:34]#[N:35])([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:21]1=O>C(O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2([CH2:33][C:34]#[N:35])[C:21]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([CH:4]=4)[C:1]#[N:2])[S:17][C:20]=3[CH2:25][CH2:24][CH2:23]2)=[CH:31][CH:30]=1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2C#N)cn1
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCC(Br)C1=O
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4(CC#N)c3ccc(Cl)cc3)cc2C#N)cn1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A suspension of [3-cyano-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (39.4 mg, 0.15 mmol) and of [3-bromo-1-(4-chloro-phenyl)-2-oxo-cyclohexyl]-acetonitrile (50.0 mg, 0.15 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol/concentrated aqueous NH4OH solution (9:1:0.1 v/v/v) as eluent to yield the title compound (34 mg, 46%) as a yellow gum. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.41 (s, 1H), 7.95 (s, 1H), 7.89 (d, 1H), 7.69 (s, 1H), 7.31 (t, 2H), 7.12 (d, 2H), 7.00 (d, 1H), 3.23 (d, 1H), 3.02 (d, 1H), 2.73 (m, 2H), 2.31 (s, 3H), 2.17 (m, 1H), 1.88 (m, 2H), 1.60 (m, 1H).