Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:17]1[CH2:21][CH:20]([CH2:22][CH3:23])[CH:19]=[N:18]1)=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([NH:3][C:4]([N:17]1[CH2:21][CH:20]([CH2:22][CH3:23])[CH:19]=[N:18]1)=[N:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:2]
Reactant: CCNC(=NS(=O)(=O)c1ccc(OC)cc1)N1CC(CC)C=N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1ccc(O)cc1)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
In 20 mL DCM, 0.28 g N-[Ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methylene]-4-methoxy-benzenesulfonamide was dissolved, and 3.32 mL of a 1M solution of BBr3 in DCM was added. The mixture was stirred overnight at room temperature, extracted with 5% aqueous NaHCO3, dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography (stepwise gradient DCM→DCM/MeOH 95:5) to yield 0.186 g (59%) of N-[Ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methylene]-4-hydroxy-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J=7.52 Hz, 3H), 1.13 (t, J=7.22 Hz, 3H), 1.50 (dq, J=14.20, 7.00 Hz, 1H), 1.60 (dq, J=14.22, 7.00 Hz, 1H), 3.01-3.16 (m, 1H), 3.43-3.50 (m, 2H), 3.66 (dd, J=11.44, 7.52 Hz, 1H), 4.05 (t, J=11.29 Hz, 1H), 6.80 (br.s., 1H), 6.87 (d, J=8.73 Hz, 2H), 6.91 (d, J=1.50 Hz, 1H), 7.78 (d, J=8.73 Hz, 2H) [guanidine NH invisible].
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH:16][O:17]C3CCCCO3)=[O:15])[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH:16][OH:17])=[O:15])[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Agent: Cl
Solvent: CO
Product: CC(=O)N1CCc2cc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.2 %

Procedure:
A mixture of 150 mg of 2-acetyl-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 1 ml methanol and 1.5 ml of an aqueous, 0.1 N hydrochloric acid is stirred for 3 h at ambient temperature. The reaction mixture is lyophilized. 40 mg of the title compound are obtained as colorless oil. MH+=235.0
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=4)=[C:16]([F:30])[C:15]=3[F:31])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:32])[CH:6]=1)=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:15]([F:31])=[C:16]([F:30])[C:17]([C:22]4[CH:23]=[CH:24][C:25]([CH:28]=[O:29])=[CH:26][CH:27]=4)=[C:18]([F:21])[C:19]=3[F:20])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:32])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(CO)cc4)c(F)c3F)nc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(C=O)cc4)c(F)c3F)nc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.1 %

Procedure:
To a solution of 6-methyl-2-(2,3,5,6-tetrafluoro-4′-hydroxymethyl-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid methyl ester (0.55 g, 1.22 mmol) in dry tetrahydrofuran (50 mL) was added pyridinium dichromate (0.2 g) portion wise. The reaction mixture was stirred at room temperature in nitrogen atmosphere for 14 hours. TLC shows completion of the reaction. The reaction mixture was filtered over celite bed and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography using 20% ethyl acetate in hexane to get to get the title compound as colorless solid (0.4 g, 74.07%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](N(OC)C)=[O:11])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: CON(C)C(=O)c1oc2ccc(Cl)cc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C=O)oc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution (40 mL) of 5-chloro-N-methoxy-N,3-dimethyl-1-benzofuran-2-carboxamide (2.15 g) synthesized above in tetrahydrofuran was added lithium aluminum hydride (322 mg) at 0° C., and the mixture was stirred for 1 hr. Water (320 μL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (320 μL) was added, and the mixture was stirred at room temperature for 1 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (tetrahydrofuran) to give a pale-yellow solid. The obtained solid was washed with diisopropyl ether to give the title object compound (1.21 g, 73%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1C2C(=CC(B(O)O)=CC=2)[CH:23]=[CH:22]1>>[NH:21]1[C:4]2[C:5](=[CH:6][C:1]([C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=3[C:14]=45)=[CH:2][CH:3]=2)[CH:23]=[CH:22]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc4[nH]ccc4c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (530 mg, 2.00 mmol) and indole-5-boronic acid (354 mg, 2.20 mmol) were coupled to yield 2-(1H-indol-5-yl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 396 mg (66%) as a beige solid: m.p. 315-317° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.10 (m, 2H), 3.41 (m, 2H), 6.54 (m, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.42 (m, 2H), 7.55 (m, 2H), 7.68 (d, J=7.5 Hz, 1H), 7.83 (br s, 1H), 8.05 (br t, 1H), 11.26 (br s, 1H), 11.48 (br s, 1H). MS (electrospray, MH+) 302. Anal. (C19H15N3O.0.25 H2O) C, H, N.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:49])[C:19]([CH3:48])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:33]([O:42][CH3:43])[CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:49])[C:19]([CH3:48])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:33]([O:42][CH3:43])[CH2:34][C:35]([OH:37])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:20])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a stirring solution of #127 (4.2 g, 6.1 mmol, 1.0 eq.) in 21 mL of dichloromethane under nitrogen, (7 mL, 90 mmol, 10 eq.) of TFA was added. The reaction was allowed to stir at room temperature for −4 hours. Reaction was concentrated in vacuo, azeotroped once with heptane, and then placed underneath high vacuum yielding #128 as a white slight yellow solid (3.8 g, quant.). LC-MS (Protocol Q): m/z 624.2 [M+H+] retention time=2.01 minutes.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([O:21][CH3:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([O:21][CH3:22])[CH:12]=2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc([C@@H](CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A solution of (R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acid (60 mg, 0.18 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 110 μL, 0.21 mmol) which produced gas evolution and it was then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 2 mL. In a separate round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 31 mg, 0.20 mmol), 2,6-lutidine (32 μL, 0.28 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise the above solution acid chloride. The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 70% ethyl acetate/hexanes to 85% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionamide (61 mg, 73%) as a white foam: [α]28589=−26.0° (c=0.10, methanol); ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2211; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.10 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.11 (m, 1H, CH), 3.20 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.90 (br, 1H, ArCHCO), 3.95 (s, 3H, OCH3), 4.65 (s, 1H, OH), 6.46 (s, 1H, Ar), 7.15 (d, Jo=8.2 Hz, 1H, Ar), 7.27 (s, 1H, Ar), 7.50 (s, 1H, Ar), 7.74 (d, Jo=8.2 Hz, 1H, Ar), 10.73 (s, 1H, NH).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([N:9]([OH:11])[CH3:10])=[O:8].[OH:25]OS([O-])=O.[K+]>CO.O>[CH3:1][S:2]([C:3]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([N:9]([OH:11])[CH3:10])=[O:8])=[O:25]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(CCCc2ccccc2)cc1C=CC(=O)N(C)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(O)C(=O)C=Cc1cc(CCCc2ccccc2)ccc1S(C)=O
Reaction time: 0.58 h

Procedure:
In methanol (15 ml) is placed 2-(methylthio)- 5-(3-phenylpropyl)-N-hydroxy-N-methylcinnamamide (0.35 g, 1.02 mmol) prepared according to Example 27 and the solution cooled in an ice bath. In 3 ml of water is placed oxone (0.33 g, 0.533 mmol) which is then added to the cooled methanol solution and stirred for 35 minutes. The reaction mixture is poured into 80 ml of water and extracted twice with 75 ml portions of ethyl acetate. The organic layers are washed with brine and dried over MgSO4 to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20]Br>C(O)(=O)C.O>[Br:20][C:9]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[C:8]=1[NH2:10]
Reactant: BrBr
Reactant: COc1cccc(C)c1-n1nc(C(C)(C)C)cc1N
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C)c1-n1nc(C(C)(C)C)c(Br)c1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108.2 %

Procedure:
To a solution of 3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-amine (2.00 g, 7.71 mmol) (Intermediate C) in acetic acid (15 mL) was added bromine (1170 mg, 0.38 mL, 7.33 mmol) dropwise. The reaction mixture was stirred for 5 min at rt, and then diluted with water (100 mL), causing a solid to precipitate. The solid was collected by filtration, then dissolved in EtOAc. The organic phase was then washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford product (2683 mg, 102%) containing minor impurities. ES-MS m/z 338.2 (MH+); HPLC RT (min) 3.06.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1.CCOC(C)=O>CN(C=O)C>[CH:25]1([CH2:24][N:2]([CH3:1])[CH2:3][C:4]#[C:5][CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[O:29][CH:28]=[CH:27][O:26]1
Reactant: CNCC#CCN1CCCC1
Reactant: BrCC1OCCO1
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CN(CC#CCN1CCCC1)CC1OC=CO1

Procedure:
A solution of N-Methyl-4-(1-pyrrolidinyl)-2-butynamine (83.4 mg, 0.548 mmol), TEA (153 μL, 1.098 mmol), HMPA (114 μL, 0.657 mmol), and 2-(bromomethyl)-1,3-dioxolane (68 μL, 0.657 mmol) in DMF (2 mL) was stirred at 50 ° C. for 20 h or until complete by TLC. The mixture was poured into EtOAc (20 mL) then washed with 1N NaOH saturated with NaCl (3×20 mL). The organic layer was dried over Na2SO4, and the EtOAc removed in vacuo to give a crude orange oil (102.8 mg, 79% yield). This oil was vacuum distilled to give N-(2,5-dioxolylmethyl)-N-methyl-4-(1-pyrrolidinyl)-2-butynamine as a clear oil: bp 90° C. (0.2 mm Hg); MS (CI-NH3), m/e 239 (MH+); 1H NMR (CDCl3) δ1.74 (br s, 4 H), 2.33 (s, 3 H), 2.58 (br H), 3.37 (s, 2 H), 3.38 (s, 2 H), 3.79 (m, 2 H), 3.92 (m, 2 H), 4.90 (t, J=4.6 Hz, 1 H).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[NH3:25]>CO>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][NH2:25])[S:7]1(=[O:24])=[O:23]
Reactant: N
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccc(F)cc1F
Solvent: CO
Product: NC/C=C/CN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.14 g, 0.33 mmol) was treated with 7N ammonia in methanol to give (2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-en-1-amine which was treated with 1N hydrochloric acid in ether to give hydrochloride salt as a white solid (0.052 g, 40%). MS (ES) m/z 351.9 ([M+H]+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:15][CH2:14][O:13][C:12]2[CH:16]=[C:17]([O:20][C:21]3[CH:22]=[C:23]([C:33]([NH:35][C:36]4[CH:40]=[CH:39][N:38](C(OC(C)(C)C)=O)[N:37]=4)=[O:34])[CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)[CH:18]=[CH:19][C:11]=2[S:10]1(=[O:49])=[O:48]>C(Cl)Cl>[CH3:8][N:9]1[CH2:15][CH2:14][O:13][C:12]2[CH:16]=[C:17]([O:20][C:21]3[CH:22]=[C:23]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)[C:33]([NH:35][C:36]3[CH:40]=[CH:39][NH:38][N:37]=3)=[O:34])[CH:18]=[CH:19][C:11]=2[S:10]1(=[O:49])=[O:48]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)S3(=O)=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)S3(=O)=O)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 1,1-dimethylethyl 3-{[(3-[(2-methyl-1,1-dioxido-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate (50 mg, 0.08 mmol) in DCM (8 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo and DCM (20 mL). The mixture was washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL), brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (31 mg). 1H NMR δ (CDCl3): 1.33 (d, 3H), 2.80 (s, 3H), 3.40 (s, 3H), 3.51-3.61 (m, 2H), 3.71-3.73 (m, 2H), 4.17-4.22 (m, 2H), 4.57-4.65 (m, 1H), 6.72-6.74 (m, 1H), 6.79-6.84 (m, 2H), 6.86 (s, 1H), 7.20 (s, 1H), 7.41 (s, 1H), 7.49 (s, 1H), 7.78 (d, 1H), 9.59 (s, 1H), 10.20 (s, 1H); m/z 503 (M+H)+
Reaction SMILES: [CH3:1][CH:2]1[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:9]([O:11]CC)=[O:10].C1(C(OCC)=O)C2(CCCCC2)C1>>[CH3:1][CH:2]1[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1C(C)C12CCCC2
Agent: CCOC(=O)C1CC12CCCCC2
Product: CC1C(C(=O)O)C12CCCC2

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 27A for the product from Example 1A. MS m/z 154 (M)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([C:23](O)=[O:24])[CH2:18]2)[CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:23]([C@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:3]4[N:2]([CH3:1])[C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[N:4]=4)[CH:12]=3)[CH2:18]2)=[O:24])[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1c(-c2cccc(N3CCC[C@H](C(=O)O)C3)c2)nc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1c(-c2cccc(N3CCC[C@H](C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)C3)c2)nc2ccccc21
Temperature: 35 °C
Yield: 26.5 %

Procedure:
Method A—Step a To a vial with (S)-1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid (0.10 g, 0.30 mmol) (obtained as described in general method 1, step d), HATU (0.12 g, 0.31 mmol), TEA (0.09 mL, 0.66 mmol) and tert-Butyl-1-piperazinecarboxylate (0.07 g, 0.37 mmol) dichloromethane (2 mL) was added and the reaction mixture was heated at 35° C. overnight. Reaction was cooled to room temperature, solvent removed and the crude purified by preparative HPLC and NH2 column filtration, to obtain 0.04 g of the title compound (27%).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[C:18]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[N:24][CH:25]=2)=[CH:17][CH:16]=[C:15]([CH:26]2[CH2:28][CH2:27]2)[N:14]=1)=[O:12].[OH-].[Na+]>CO.O>[CH:26]1([C:15]2[N:14]=[C:13]([C:11]([NH:10][C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:29])=[O:2])=[O:12])[C:18]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[N:22][CH:21]=3)=[CH:17][CH:16]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1

Procedure:
To stirred suspension of 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid methyl ester (330 mg, 0.84 mmol) in MeOH (5 ml) was added a solution of NaOH (84.5 mg, 2.1 mmol) in water (2 ml) at 0-5° C. After the addition the reaction mixture was stirred at rt for 8 hrs. The solvent was removed in vacuo, the residue was dissolved in water (7 ml), and was washed with EtOAc (2×10 ml). The aqueous layer was then acidified with 1N HCl (pH˜2), and concentrated to obtain the title compound (containing NaCl) as a yellowish sticky solid which was directly used as such for the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C(=O)N([Br:22])C(=O)C1>C1COCC1.CN1C(=O)CCC1>[Br:22][C:12]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1nc2ccccc2n2ccnc12
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Clc1nc2ccccc2n2c(Br)cnc12
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a stirred suspension of 4-chloro-imidazo[1,2-a]quinoxaline (28.9 g, 141.8 mmol) in THF/NMP 2:1 (300 mL) was added NBS (25.2 g, 141.8 mmol) in one portion at rt. After 18 h stirring, additional 12.6 g (70.9 mmol) NBS were added and the mixture was stirred for additional 2 h at rt. After removal of the THF portion of the organic phase by vacuum evaporation, water was added (500 mL). The precipitate was filtered and the residue was washed with water and dried to give 1-bromo-4-chloro-imidazo[1,2-a]quinoxaline as an off-white solid (35 g, 78.6%): 1H-NMR (300 MHz, d6-DMSO): δ=12.42 (1H, s), 8.19 (1H, s), 7.75 (1H, d), 7.44 (2H, m) ppm. UPLC-MS: RT=1.14 min; m/z 284.6 [MH+]; required MW=283.5.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](Br)=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:40]3[CH:39]=[N:38][C:37]([CH3:36])=[N:42][CH:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1ncc(Br)cn1
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-methyl-5-bromopyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.221 min, m/z=468.2; 1H NMR (CDCl3) 1.06 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.11-2.28 (m, 4H), 2.31-2.42 (m, 1H), 2.70 (s, 3H), 2.82 (m, 1H), 5.65 (m, 1H), 7.00 (d, 2H), 7.21-7.34 (m, 7H), 8.19 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[O:20][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1nc2c(Cl)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Cl)c(Oc3cc(Cl)ncn3)ccc2[nH]1

Procedure:
270 mg (1.81 mmol) 4,6-dichloropyrimidine, 330 mg (1.81 mmol) 4-chloro-5-hydroxy-2-methyl-1H-benzo[d]imidazole and 270 mg (1.95 mmol) potassium carbonate in 1.5 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)[C:14]([NH:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1)=[O:15]>C(#N)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=1)[C:14]([NH:16][C:17]1[C:18]([N:1]2[CH2:6][CH2:5][CH:4]([CH:7]([OH:9])[CH3:8])[CH2:3][CH2:2]2)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1)=[O:15]
Reactant: CC(O)C1CCNCC1
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: CC(O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 0.200 g (1.55 mmol) of 1-piperidin-4-yl-ethanol and 0.200 g (0.663 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide in acetonitrile (10 mL) is heated at 175 C in a microwave reactor for 14 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to give 0.170 g (65.0%) of 3-chloro-N-[5′-chloro-4-(1-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide as a yellow oil.