Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([Cl:20])[CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][N:26]([CH2:3][C:4]2[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=2)[CH2:25][CH2:24]3)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Clc1cc(Cl)cc(-c2ccc3c(c2)CCNC3)c1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3cc(-c4cc(Cl)cc(Cl)c4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 38.1 %

Procedure:
A suspension of 1.85 g (0.0095 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 105 ml of dimethylformamide was treated with 250 g (0.00795 mol) of 6-(3,5-dichlorophenyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 3.66 ml (0.026 mol) of triethylamine and stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water. 30 ml of a 1N aqueous sodium hydroxide solution were added dropwise thereto, the mixture was extracted and chromatographed over silica gel with ethyl acetate/isopropyl alcohol 9:1 as the eluent. Crystallization was then carried out, firstly from methanol/ethyl acetate/n-hexane and then from hot ethyl acetate. 1.21 g (38%) of 5-[6-(3,5-dichlorophenyl)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as white crystals; m.p. 205°-211°.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C@@H:13]([NH:15][S@@](C(C)(C)C)=O)[CH3:14])[C:10]([CH3:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23]>O1CCOCC1>[ClH:23].[CH2:1]([N:8]1[CH:12]=[C:11]([C@@H:13]([NH2:15])[CH3:14])[C:10]([CH3:22])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccccc2)cc1[C@H](C)N[S@](=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn(Cc2ccccc2)cc1[C@H](C)N
Temperature: 25 °C

Procedure:
(R)—N—((S)-1-(1-benzyl-3-methyl-1H-pyrazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide was dissolved in dioxane (5 ml) and 4N HCl in dioxane (1.2 ml, 10 eq.) was added. Stirred 1H at room temperature. The solvents were removed and co-yapped twice with CH2Cl2. Some t-butyl observed by NMR. Resubmitted to reaction conditions and work-up to give title compound.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:11][CH:10]1[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]2[O:13][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1cccc(Cl)c1Cl

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:3]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[N:41]1([C:2]2[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])=[O:7])=[C:4]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[CH:3]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCOCC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 129 °C
Yield: 57.1 %

Procedure:
The 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (203 mg, 0.35 mmol) was diluted with morpholine (4 mL, 45.9 mmol). The mixture was heated to 129° C. for 2 days. The reaction was diluted with methylene chloride (100 mL) and washed with water (2×10 mL). The aqueous layers were combined and extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 25 g silica, 10% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2) to give the desired product (125 mg, 0.20 mmol, 56%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.Cl.C(NN)[C:28]1[CH:33]=[CH:32]C=[CH:30][CH:29]=1>>[CH2:23]([N:14]1[C:4]2=[N:5][N:6]=[C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]([Cl:1])=[C:3]2[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:15]1)[C:24]1[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1
Reactant: CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NNCc1ccccc1
Agent: Cl
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1ccccc1
Reaction time: 16 h

Procedure:
Compound 31 was synthesised following similar procedures outlined in Example 31 (Compound 18), using benzyl hydrazine dihydrochloride instead of ethyl hydrazine in Step 3. As a slightly modified procedure, Step 3 was performed at 50° C. for 16 h. The crude residue was purified by column chromatography (silica gel, gradient 5 to 10% ethyl acetate/isohexane), followed by preparative HPLC, yielding Compound 31 as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH2:12][CH2:13][CH3:14].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:22](=[O:23])[NH:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[S:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCSc1cc2c(cc1Br)NCC2
Reactant: O=C=Nc1cccnc1
Product: CCCSc1cc2c(cc1Br)N(C(=O)Nc1cccnc1)CC2
Yield: 65 %

Procedure:
6-Bromo-5-propylthioindoline (D83) (0.095 g, 0.35 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol/diethyl ether to give the title compound (0.089 g, 65%) as a white crystalline solid m.p. 224°-226° C.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCC.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.Cl.N[C@@H:37]([CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[C@@H:38]([OH:48])[CH:39]([OH:47])[CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][CH:40]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[CH:39]([OH:47])[CH:38]([OH:48])[CH2:37][CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: CCCC[C@H](N)C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: -15 °C

Procedure:
25.6 mg of L-N-[(2S or R)-2-ethylsulfonylmethyl-4-methylpentanoyl]norleucine was dissolved in 0.5 ml of dry DMF, and a dry DMF solution of 30.8 mg of triethylamine, 25.2 mg of DPPA and 38.5 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was added thereto at -15° C. under stirring. The mixture was stirred at the same temperature for one hour and at room temperature overnight. The reaction solution was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue thereby obtained was purified silica gel column chromatography (chloroform/methanol=50/1) to obtain 21.7 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-2-ethylsulfonylmethyl-4-methylpentanoyl]norleucyl}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[N:26]=[CH:25][C:24]([C@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:29][C@@H:27]([C:24]4[CH:25]=[N:26][C:21]([C:20]([F:31])([F:19])[F:30])=[CH:22][CH:23]=4)[CH3:28])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2c1CN(c1ccc(Cl)cn1)CC2)c1ccc(C(F)(F)F)nc1
Temperature: 200 °C
Yield: 20.1 %

Procedure:
4-Bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (250 mg, 0.768 mmol), (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (219 mg, 1.15 mmol), N,N-diisopropylethylamine (401 μL, 2.30 mmol), and acetonitrile (0.75 mL) were added to a 0.5-2 mL microwave vial. The reaction was heated in the microwave reactor at 200° C. for 2.5 hours. The solids were filtered from solution and washed with acetonitrile (2×0.5 mL) and ether (2×3 mL) (219 mg of a light yellow solid). The filtrate was evaporated and the residue was redissolved in CH2Cl2 (10 mL) and washed with 1M NaH2PO4 (2×8 mL). The organic layer was dried with Na2SO4, filtered and evaporated to give an orange solid. The crude product was purified by column to give 67 mg of a light yellow solid. The 2 products that were obtained were combined (219 mg+67 mg). To remove some of the yellow colored impurity, ethyl ether (3 mL) was added and the mixture was stirred for about 1 hour then the solution was decanted from the solids. The solids were washed with ethyl ether (2×2 mL) to yield a light beige solid (264 mg, 79% yield).
Reaction SMILES: [C:1]([C:5]1[C:6](C#N)=[C:7]2[N:11]([N:12]=1)[C:10]([C:13]1[C:18]([CH3:19])=[C:17]([CH3:20])[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:15]([CH3:31])[C:14]=1[CH3:32])=[N:9][NH:8]2)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.O>CO>[C:1]([C:5]1[CH:6]=[C:7]2[N:11]([N:12]=1)[C:10]([C:13]1[C:14]([CH3:32])=[C:15]([CH3:31])[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:17]([CH3:20])[C:18]=1[CH3:19])=[N:9][NH:8]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCCCCCc1c(C)c(C)c(-c2n[nH]c3c(C#N)c(C(C)(C)C)nn23)c(C)c1C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCCCCCCCCc1c(C)c(C)c(-c2n[nH]c3cc(C(C)(C)C)nn23)c(C)c1C
Temperature: 0 °C
Yield: 85 %

Procedure:
The nitrile from part (b) (20 g) was added in one portion to 75% sulfuric acid (from concentrated H2SO4 [270 g]) and ice (90 g) with stirring at 140°-150° C. 15-20 minutes later, ice (1000 g) was added. After decantation, the sticky solid was dissolved in methanol (200 ml) and hot water (5 ml) added. On cooling, the precipitate was collected, washed with 90% methanol (2×50 ml) and dried to give the product (85-90%), m.p. 194°-195° C.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Na].[CH2:11]([O:13][P:14]([CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].[H-].[Na+]>O1CCOCC1>[C:5]([CH:4]=[CH:3][CH2:2][C:19]([P:14]([O:13][CH2:11][CH3:12])([O:16][CH2:17][CH3:18])=[O:15])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/CBr
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1COCCO1
Product: CCOC(=O)C=CCC(C)(C(=O)OCC)P(=O)(OCC)OCC

Procedure:
Ethyl 4-bromocrotonate (19.3 parts) was added dropwise at 25°-30° C. to a solution of the sodium salt of ethyl 2-diethylphosphonopropionate, prepared from 23.8 parts of ethyl 2-diethylphosphonopropionate and 5.3 parts of sodium hydride (50% in oil) in dioxan. The resulting solution was heated at reflux for 18 hr., after which time the sodium bromide was removed by filtration and the solution concentrated in vacuo. The residual oil was distilled to give 12.7 parts of ethyl 5-carboethoxy-2-diethylphosphono-2-methylpent-4-enoate boiling at 158°/0.2 mm. Hydrogenation of 12 parts of this material over 5% palladium on carbon gave 7.2 parts of diethyl 2-diethylphosphono-2-methyladipate boiling at 146°-52° C./0.05 mm; subsequent hydrolysis of 5 parts of this in concentrated hydrochloric acid gave 3.7 parts of 2-methyl-2-phosphonoadipic acid as a glassy solid which had a 31P chemical shift of -24 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH3:29])[C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[C:22]([CH3:29])=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-3-methyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=413.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[Si]([C:14]([F:17])([F:16])[F:15])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O.[Cl-].[Na+].O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cccc(Br)n1)C(F)(F)F
Temperature: 0 °C

Procedure:
6-Bromopyridine-2-carbaldehyde (1.0 g, 5.38 mmol) was taken up in 35 mL THF and cooled to 0° C. TMSCF3 (1.0 mL, 6.45 mmol) was added followed by tetrabutylammonium fluoride (6.45 mL of 1.0M in THF). The reaction was stirred allowed to warm to room temperature and maintained at that temperature for 4.5 hours. The mixture was then diluted with water and brine, and extracted with ethyl acetate (3×). The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate/hexanes) afforded the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13](=[O:16])[CH2:14]Br)[CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13](=[O:16])[CH2:14][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1
Reactant: O=C(CBr)Nc1cc(F)c(F)cc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1cc(F)c(F)cc1C(=O)O
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A solution of 4,5-difluoro-2-((bromoacetyl)amino)benzoic acid (31.0 g 105.4 mmol) and aniline (24 mL, 24.5 g, 263.4 mmol) in anhydrous DMF (100 mL) was heated to 95°-100° C. overnight with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then a solution of 5% KOH was added until the pH of the solution was 10. The solution was extracted with 3×150 mL of CH2Cl2, and then the aqueous layer was separated and acidified to pH=3 using 2N HCl. The yellow precipitate which formed was filtered, washed with water, and then dried in a vacuum desiccator to yield 32.01 g (99%) of the title compound as a light-yellow solid, mp 124°-126° C.: 1H NMR (DMSO-d6) δ12.10 (s, 1H), 8.75 (dd, J=14.0, J=7.6, 1H), 7.86 (dd, J=11.6, J=1.2, 1H), 7.09 (t, J=7.2, 2H), 6.63-6.40 (m, 4H), 3.85 (s, 2H); 13C NMR (DMSO-d6) δ171.40, 167.44, 152.18 (dd, J=249, J=12.7), 148.02, 144.02 (dd, J=242, J=12.6), 138.18 (dd, J=10.6, J=2.1), 129.01, 119.66 (d, J=19), 117.22, 113.10, 112.48, 108.21 (d, J=23), 48.82; MS (El, m/z) 306 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=1[CH3:27])=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:26]([CH3:27])=[N:25][C:24]([O:28][CH3:29])=[N:23][C:22]=1[CH3:30]
Reactant: COc1nc(C)c(N=C=S)c(C)n1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(C)nc(OC)nc2C)c1NCCCO
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (11.4 g, 44.2 mmol) and 5-isothiocyanato-2-methoxy-4,6-dimethylpyrimidine (17.3 g, 88.4 mmol) in tetrahydrofuran (170 mL) was stirred at 65° C. for 3 days. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow amorphous (13.1 g, 28.9 mmol, 65%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:35])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[C:31]([F:34])([F:33])[F:32])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:35])=[C:16]([C:31]([F:34])([F:32])[F:33])[CH:17]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)c(C(F)(F)F)c1
Yield: 99.5 %

Procedure:
2-(2′-Methanesulfonyl-3-trifluoromethyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.97 g, 1.9 mmol) was dissolved in 10 mL DCM and 5 mL trifluoroacetic acid and stirred at ambient temperature overnight and concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO3, separated layers, washed organics with brine, dried with MgSO4, filtered and concentrated to yield title compound as an oil (0.78 g, 100%) APCI (AP−): 411.0 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[CH2:12][NH:11][C:10]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[N:18][C:9]2=3)[CH2:4][O:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:21])[O:3][CH2:4][CH:5]([N:8]2[C:13](=[O:14])[CH:12]=[N:11][C:10]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[N:18][C:9]2=3)[CH2:6][O:7]1
Reactant: COc1ccc2c(n1)N(C1COC(C)(C)OC1)C(=O)CN2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(C3COC(C)(C)OC3)c2n1
Yield: 69.1 %

Procedure:
4-(2,2-Dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (25.37 g) and activated manganese dioxide (120 g, ˜15 eq.) were stirred in DCM (500 ml) at room temperature for 2 hours then overnight. The mixture was filtered with suction and the solids were washed with DCM (2×100 ml). The combined filtrate plus washings were evaporated under reduced pressure to give a brown foam; this was purified by column chromatography on silica (eluting with 0%-100% ethyl acetate in petroleum ether (40-60°)). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a light tan solid (17.40 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15](O)[CH2:16][CH2:17][C:13]=3[N:12]=[C:11]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:22]([O:24][C:25]([CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])[CH3:23].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16][CH2:17][C:13]=3[N:12]=[C:11]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)C)n(Cc3ccc(Cl)c(Cl)c3)c21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 22 (660 mg) and triethylmethanetricarboxylate (0.86 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added dropwise trimethylphosphine, 1M in toluene (4.06 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.799 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 2 hours. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere for 30 mins. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (40 ml) and washed with water (40 mL). The 2 phases were separated; the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (750 mg). LC/MS MH+ 539, 541, Rt 2.19 min (5 minute run).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([C@H:14]([OH:23])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([C@H:14]([OH:23])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](C/C=C/c1ccccc1)[C@H](O)C(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1

Procedure:
A solution of (E)-(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pent-4-enoic acid methyl ester (1.55 g, 4.65 mmol) in methanol (15 ml) was hydrogenated at 50 psi over Pd/C for 4 hrs. The catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure to give (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester as pale, brown solid (1.45 g); 1H NMR (CDCl3) δ 1.90–1.65 (m, 4H), 2.62–2.75 (m, 3H), 3.75–3.40 (m, 11H), 4.0 (d, J=15 Hz, 1H), 4.47–4.4.39 (m, 1H), 7.38–7.15 (m, 5H); MS: 336(M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]([OH:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]>Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]([OH:29])[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:31])[F:32]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1ccncc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: O=S(=O)(Nc1cc(Cl)cnc1C(O)c1ccncc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
4-Chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg, 0.06 mmol) in 50% aqueous of MeOH (10 mL) was treated with 5-10 drops of conc. HCl and heated at 80° C. for 3 days. The resulting mixture was cooled to room temperature, concentrated under reduced pressure and neutralized with aqueous NaHCO3 to pH 7. It was then extracted with EtOAc to provide crude 4-chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide which was purified by preparative HPLC. 1H NMR (400 MHz, CDCl3) δ 8.34 (br, 2 H), 8.29 (d, J=2.0 Hz, 1 H), 7.97 (s, 1 H), 7.91 (s, 1 H), 7.44 (d, J=8.4 Hz, 1 H), 7.38 (d, J=8.4 Hz, 1 H), 7.11 (d, J=5.6 Hz, 2 H), 5.98 (s, 1 H); MS m/z: 478.0 (M+H).