Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: Fc1ccccc1N1CCNCC1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ccccc2F)CC1
Yield: 9.9 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2-fluoro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (6.8 mg, 9.9%) as light yellow oil. MS m/e=509.4 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH:9]1[NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C>C(#N)C.ClCCl>[NH2:33][CH2:32][CH2:31][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH:9]([NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[CH:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)NC1Cc2ccc(O)cc2C1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)NC1Cc2ccc(OCCN)cc2C1Cc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl 1-benzyl-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate (620 mg, 1.991 mmol) and caesium carbonate (1298 mg, 3.98 mmol) in acetonitrile (15 ml) was stirred at 80° C. under argon for 1 h, cooled down to 50° C. and tert-butyl 2-bromoethylcarbamate (669 mg, 2.99 mmol)dissolved in acetonitrile was slowly added. Stirred at 80° C. for 2 h. Evaporated acetonitrile, re-dissolved in dichloromethane, washed with water, co-extracted aqueous layer twice with dichloromethane and the combined organic layers were dried, filtered and evaporated and purified by flash silica gel chromatography on 40 g SiO2-cartridge using 30% ethyl acetate in cyclohexane to afford the titled compound as a brown oil. m=624 mg
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH:25]([CH:26]1[N:10]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][O:1]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CNC(CO)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(c2ccccc2)COC1C(c1ccccc1)c1ccccc1

Procedure:
Scheme 4 and 5 show routes for preparation of compound of formula 2b. The protected amino acid is either commercially available material or prepared as described in known literature. For example, the CBZ protected (2S,3S)-hydroxyleucine (CBZ: benzyloxycarbonyl) is prepared according to the analogous procedure to that described in the literature (Panek, J., J. Org. Chem., 1998, 63, 2382). As shown in scheme 4, phenylglycinol is alkylated with tert-butyl bromoacetate in the presence of base such as triethylamine in a solvent such as anhydrous tetrahydrofuran, to provide tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate. Reaction of tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate and diphenylacetaldehyde in the presence of a drying agent such as magnesium sulfate in a solvent such as anhydrous methylene chloride provides tert-butyl (2-benzhydryl-4-phenyl-oxazolidin-3-yl)-acetate. The oxazolidine is treated with a nucleophile such as lithium diisopropylamide in an anhydrous solvent such as anhydrous tetrahydrofuran at low temperature such as −78° C., followed by addition of an electrophile such as isopropylaldehyde, to provide tert-butyl 2-(2-benzhydryl-4-phenyl-oxazolidin-3-yl)-3-hydroxy-4-methyl-pentanoate. The oxazolidine ring is cleaved by treatment with acid such as formic acid in a solvent such as a mixture of water and tetrahydrofuran to provide tert-butyl 3-hydroxy-2-(-2-hydroxy-1-phenyl-ethylamino)-4-methyl-pentanoate. The amine is freed by hydrogenolysis using catalyst such as 5-10% palladium on carbon in a solvent such as methanol or ethanol, to provide tert-butyl 2-amino-3-hydroxy-4-methyl-pentanoate. The resulting free amine is protected by treatment with an agent such as (benzyloxycarbonyloxy)succinimide or benzyloxycarbonyl chloride in a solvent such as anhydrous methylene chloride, then the ester is cleaved by treatment with an acid such as trifluoroacetic acid to provide 2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoic acid. Optically pure compound can be prepared by using an optically pure starting material. For example, optically pure (S)-phenylglycinol provides (2S,3S)-2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(C)C>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[N:15]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2csc(N)n2)cc1

Procedure:
At room temperature, methyl 4-bromoacetylbenzoate (1.00 g) and thiourea (296 mg) were dissolved in isopropanol (100 ml), followed by heating under reflux for 15 minutes. Under stirring at the same temperature, anhydrous sodium carbonate (206 mg) was added to the reaction mixture. The resulting mixture was heated under reflux for 20 minutes. After completion of the reaction, water (50 ml) was added under ice cooling and the solid so precipitated was collected by filtration. The solid was dissolved in water and dichloromethane. The organic layer so separated was dried over anhydrous sodium sulfate. The solvent was then distilled off. The pale yellow solid so precipitated was washed with ether, whereby the title compound (634 mg, 70%) was obtained.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)Cl>C(Cl)(Cl)Cl>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:29])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: O=C(Cl)N1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)N4CCCCC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.075 g, 0.25 mmol, Preparation #9) and TEA (0.041 mL, 0.29 mmol) in CHCl3 (1.2 mL) to give a brown suspension. Piperidine-1-carbonyl chloride (0.040 g, 0.27 mmol) was added and the reaction was stirred at ambient temperature for about 3 h. The reaction mixture was heated to about 45° C. for about 16 h. The mixture was cooled to ambient temperature, DCM (25 mL) was added, and the solution was washed with water and brine (about 5 mL each). The layers were separated and the organic solution was dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)piperidine-1-carbohydrazide (0.11 g, 100%): LC/MS (Table 2, Method a) Rt=2.09 min; MS m/z: 415 (M+H)+.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([N:24]3[C:29](=[O:30])[NH:28][C:27](=[O:31])[CH:26]=[N:25]3)=[CH:19][C:18]=2[Cl:32])[CH:13]=[CH:12][C:11]=1[OH:33].C(N(CC)CC)C.[CH3:42][C@H:43]1[CH2:48][C@@H:47]([CH3:49])[CH2:46][NH:45][CH2:44]1>C(COC)OC>[Cl:32][C:18]1[CH:19]=[C:20]([N:24]2[C:29](=[O:30])[NH:28][C:27](=[O:31])[CH:26]=[N:25]2)[CH:21]=[C:22]([Cl:23])[C:17]=1[O:16][C:14]1[CH:13]=[CH:12][C:11]([OH:33])=[C:10]([C:9]([N:45]2[CH2:46][C@H:47]([CH3:49])[CH2:48][C@H:43]([CH3:42])[CH2:44]2)=[O:8])[CH:15]=1
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)ccc1O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H](C)CN(C(=O)c2cc(Oc3c(Cl)cc(-n4ncc(=O)[nH]c4=O)cc3Cl)ccc2O)C1
Reaction time: 2 h

Procedure:
To solution of 5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (320 mg) and triethylamine (265 μL) in dimethoxyethane (1.3 mL) was added 3,5-cis-dimethylpiperidine (189 mg). After 2 h, the reaction solution was concentrated in vacuo and flash chromatographed on silica gel (50% ethyl acetate/hexanes) to afford the title compound of this Example as a colorless solid, 130 mg. MS Calc.:505.3 Found:505.2.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(N)cc1OC
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1OC
Yield: 74 %

Procedure:
Prepared from VII and 3,4-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 74%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3267, 2839, 2226, 1644, 1610, 1583, 1507, 1460, 1443, 1379, 1308, 1260, 1227, 1201, 1166, 1150, 1129, 1020, 967, 935, 861, 839; 1H NMR (300 MHz, DMSO-d6) δ 8.34 (m, 1H), 7.79 (m, 1H), 7.71 (m, 1H), 6.90 (d, 1H, J=8.1 Hz), 6.54 (m, 2H), 4.26 (s, 6H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0850.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Yield: 100.4 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-n-butyl-3-L-rhamnopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.5 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-L-rhamnopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[NH2:19]>CC(C)=O>[N:19]1[C:3]([C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)=[CH:2][N:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=12
Reactant: Nc1ncccn1
Reactant: O=Cc1ccc(C(=O)CBr)cc1
Solvent: CC(C)=O
Product: O=Cc1ccc(-c2cn3cccnc3n2)cc1
Reaction time: 8 h

Procedure:
4-(bromoacetyl)benzaldehyde is dissolved in acetone. To it is added pyrimidin-2-amine (1 eq). The reaction mixture is stirred overnight. The precipitated solid is filtered off and dried to obtain the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22](=[O:35])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.Br[C:53]1[CH:58]=[CH:57][C:56]([Br:59])=[CH:55][N:54]=1>>[Br:59][C:56]1[CH:57]=[CH:58][C:53]([C:40]2[CH:39]=[CH:38][C:37]([CH2:36][C:11]3[N:12]([C:14]4[CH:19]=[CH:18][C:17]([N:20]5[S:24](=[O:25])(=[O:26])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[C:22](=[O:35])[CH2:21]5)=[CH:16][CH:15]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:42][CH:41]=2)=[N:54][CH:55]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)N(COCC[Si](C)(C)C)S4(=O)=O)cc3)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cn4)cc3)cc2)S1(=O)=O

Procedure:
5-(4-{4-(2,4-Dichloro-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (154 mg, 0.2 mmol) was treated as described in general procedure G using 2,5-dibromopyridine (95 mg, 0.4 mmol) to give 5-{-4-[2-[4-(5-bromo-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one, which was again treated as described in general procedure G using cyclohexen-1-ylboronic acid (51 mg, 0.4 mmol) to give 5-{-4-[2-[4-(5-cyclohex-1-enyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>O>[Na+:5].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CS(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
To a solution of sodium sulfite (14.3 g 113 mmol) in water (60 mL) was added 4-methylbenzyl chloride (15.0 mL, 113 mmol). The mixture was stirred under reflux for 12 hours, and cooled to rt. The precipitate was collected by filtration, and washed with water and ether to give 4-methylphenylmethanesulfonic acid sodium salt (12.5 g, 60 mmol, 53%).
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[F:24])[CH:13]=2)=[CH:6][CH:5]=1.[C:28]([O-:31])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([N:10]3[CH2:7][CH2:6][C@@H:28]([OH:31])[CH2:11]3)=[C:14]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[F:24])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(-c2[nH]ncc2F)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-3-(4-fluoro-1H-pyrazol-5-yl)benzamide (Stage 24.1, 62 mg, 0.147 mmol), R-3-hydroxypyrrolidine (0.031 mL, 0.206 mmol) and TEA (0.062 mL, 0.442 mmol) in DMSO (0.5 mL) was stirred at 100° C. for 16 h. The RM was diluted with EtOAc (30 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was removed under reduced pressure. The aq. residue was extracted with DCM and the combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was dissolved in DCM and treated with n-hexane to give the title product as a white solid. HPLC (Condition 5) tR=6.61 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=467.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.95 (m, 2H) 2.79 (d, J=10.56 Hz, 1H) 3.06-3.20 (m, 2H) 3.22-3.35 (m, 1H) 4.13-4.30 (m, 1H) 4.79-4.96 (m, 1H) 6.75-6.92 (m, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.86 (m, J=9.38 Hz, 5H) 10.11 (s, 1H) 12.67-13.12 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:32]([N:34]([CH2:35][CH3:36])[CH:17]1[CH2:16][CH2:15][CH:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:21][C:22]([C:24]3[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=3)=[O:23])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:1])([CH3:31])[CH2:3][CH:4]=3)[CH:13]=2)[CH2:19][CH2:18]1)[CH3:33]
Reactant: CC1(C)CC=C(c2cc(C3CCC(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCN(CC)C1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1

Procedure:
The title compound is prepared from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-oxo-cyclohexyl)-phenyl]-amide (as prepared in Example 23) and diethylamine using NaBH(OAc)3 according to literature procedure (J. Org. Chem., 61, 3849-62 (1996)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1B(O)O.Br[C:19]1[S:23][C:22]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1[C:19]1[S:23][C:22]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:21][N:20]=1
Reactant: COc1c(B(O)O)c(=O)n(C)c2ccccc12
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2nnc(N(C)C3CC(C)(C)NC(C)(C)C3)s2)c(=O)n(C)c2ccccc12
Temperature: 100 °C
Yield: 25.3 %

Procedure:
A degassed reaction mixture of (4-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (500 mg, 2.15 mmol), 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (858 mg, 2.57 mmol), tetrakis(triphenylphosphine)palladium(0) (248 mg, 0.215 mmol) and Na2CO3 (682 mg, 6.44 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated via microwave irradiation at 100° C. for 1 h. After cooling to room temperature, the mixture was filtered through celite, washed with MeOH then the filtrate was concentrated. The residue was purified by silica gel chromatography (2%˜10% 2M NH3 in MeOH/DCM) to give 4-methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one (240 mg, MS: 442.1 [M+H+].) (4 mg, MS: 442.0 [M+H+], LCMS Rt=1.25 min (LCMS method D); 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.55 (s, 1H), 8.14 (dd, J=8.08, 1.52 Hz, 1H), 7.72-7.81 (m, 1H), 7.61-7.69 (m, 1H), 7.33-7.45 (m, 1H), 4.61 (br. s., 1H), 3.94 (s, 3H), 3.78 (s, 3H), 3.11 (s, 3H), 1.95 (d, J=12.13 Hz, 2H), 1.79 (br. s., 2H), 1.50 (s, 6H), 1.39 (br. s., 6H).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li+].CC([N-]C(C)C)C.CN([CH:19]=[O:20])C.O>C1COCC1>[Br:1][C:2]1[S:3][C:4]([CH:19]=[O:20])=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1ccsc1Br
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)sc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-methylthiophene (2.66 g, 15.0 mmol) in dry THF (10 mL) at −65° C. was added LDA solution (15.0 mmol) dropwise. After stirring for 30 min, DMF (3.0 g, 10.0 mmol) in dry THF (3 mL) was added dropwise and the reaction was stirred at −65° C. for 2 h. The reaction was warmed to room temperature and water was added. The quenched mixture was extracted with EtOAc (3×100 mL). The combined extract was washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>ClCCl>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:42](=[O:44])(=[O:43])[N:41]([CH3:46])[CH3:40])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CNS(=O)(=O)N(C)C)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (25 mg, 0.057 mmol) in dichloromethane (DCM) (1 mL) was treated with Et3N (0.012 mL, 0.086 mmol) and dimethylsulfamoyl chloride (7.33 μL, 0.069 mmol), stirred for 15 min, and then warmed to rt for 1 hour. Additional Et3N (25 uL) and dimethylsulfamoyl chloride (15 uL) were added, the reaction was stirred at rt overnight. The reaction was concentrated and purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-(((N,N-dimethylsulfamoyl)amino)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (22.6 mg, 0.042 mmol, 72.6% yield) as clear oil. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-(((N,N-dimethylsulfamoyl)amino)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (18.4 mg, 0.034 mmol, 82% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1 H), 7.54 (td, J=1.9, 8.2 Hz, 1 H), 7.41-7.30 (m, 1 H), 7.30-7.23 (m, 1 H), 7.16 (dd, J=8.4, 12.9 Hz, 1 H), 7.09-6.99 (m, 1 H), 5.35 (s, 1 H), 4.53 (br. s., 1 H), 4.36 (br. s., 2 H), 3.69 (d, J=1.0 Hz, 3 H), 2.81 (s, 3 H), 2.80 (s, 3 H), 2.36 (s, 3 H), 2.32 (s, 3 H), 1.07 (s, 4.5 H), 1.06 (s, 4.5 H); LCMS (m/z) ES+=530 (M+1).