Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](=[CH:11][CH3:12])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C[C:26]([CH3:29])([O-:28])[CH3:27].[Mg+2].[CH3:31][C:32](C)([O-:34])[CH3:33].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:47]([P:50](=O)(O)[OH:51])(C)C>CN(C=O)C>[CH:26]([O:28][P:50]([CH2:47][O:10][CH2:9][C:8]([C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:6][SiH2:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:11][CH3:12])(=[O:51])[O:34][CH:32]([CH3:33])[CH3:31])([CH3:29])[CH3:27]
Reactant: CC(C)(C)[O-]
Reactant: CC=C(CO)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: CC(C)P(=O)(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CC=C(COCP(=O)(OC(C)C)OC(C)C)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of 2-(tert-Butyl-diphenyl-silanyloxymethyl)-but-2-en-1-ol (see: J. Org. Chem. 58, 2151-2161, 1993), (660 mg (1.94 mmol)) in anhydrous DMF was added Magnesium t-butoxide 660 mg (3.88 mmol) followed by isopropylphosphonate tosylate 1.2 g (2.91 mmol). The reaction was stirred under Ar at 70° C. for 16 h, until the reaction was complete by TLC. Solvents were removed in vacuo and the residue (yellow gum) resuspended in EtOAc. Saturated NH4Cl— was added and the reaction extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (gradient elution, hexanes/ethyl acetate, 9:1 to 2:3) yielded the title compound 674 mg (1.3 mmol; 67% yield).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1.[ClH:22].N([O-])=O.[Na+].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>CC(C)=O.O.[Cu]Cl>[Cl:22][CH:28]([CH2:29][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1)[C:27]([O:31][CH3:32])=[O:30]
Reactant: C=CC(=O)OC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(N)cc2F)c1=O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(Cl)Cc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of 11.8 grams (0.039 mole) of 3-(4-amino-2-fluorophenyl)-1-methyl-6-trifluoromethyluracil and 25 mL of concentrated hydrochloric acid in 130 mL of acetone was cooled to below 10° C., and a solution of 2.7 grams (0.039 mole) of sodium nitrite in 10 mL of water was added dropwise. Upon completion of addition, the reaction mixture was stirred at below 10° C. for one hour. After this time 0.3 gram (0.003 mole) of copper(I) chloride was added in one portion. The reaction mixture was then cooled to 0° C., and 33.5 grams (0.390 mole) of methyl 2-propenoate was added slowly, portion-wise. The addition caused an exothermic reaction, which raised the reaction mixture temperature to about 15° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for about 16 hours. The reaction mixture was then poured into water, and the mixture was extracted with diethyl ether. The ether extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 heptane-methylene chloride and methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 10.4 grams of methyl 2-chloro-3-[3-fluoro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoate, mp 101°-103° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[NH:2][C:3](=[S:14])[CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br.Br[CH:17]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=O.[CH2:34](N(CC)CC)C>C(#N)C>[CH3:34][N:5]([CH2:4][C:3]1[S:14][C:17]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:2]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Reactant: CNC(=S)CNC(=O)c1ccccc1
Reactant: CCN(CC)CC
Agent: Br
Solvent: CC#N
Product: COc1ccc(-c2nc(CN(C)C(=O)c3ccccc3)sc2-c2cccnc2)cc1
Yield: 72 %

Procedure:
In 50 ml of acetonitrile was dissolved 2.3 g of N-methylbenzoylaminothioacetamide. In the solution was suspended 4.0 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added while stirring 1.5 ml of triethylamine, followed by further stirring under reflux. The reaction solution was left standing for cooling, then the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried, then, the solvent was evaporated off. The residue was purified by means of a silica-gel column chromatography (eluent: ethyl acetate) to give 3.2 g (yield 72%) of 2-(N-methylbenzoylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=1)[C@@H:13]([CH3:15])[CH2:12][O:11][CH2:10]3.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.Cl.N1C=CC=CC=1.C(Cl)(Cl)Cl>FC(F)(F)CO>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:2]2[C:7]3[N:8]=[C:9]4[N:14]([C:6]=3[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=2)[C@@H:13]([CH3:15])[CH2:12][O:11][CH2:10]4)=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nc(Cl)c2nc3n(c2c1C)[C@@H](C)COC3
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(C)c(C)c3c2nc2n3[C@@H](C)COC2)cc1
Temperature: 160 °C
Yield: 92.8 %

Procedure:
A conical microwave vial was charged with a solution of (4S)-9-chloro-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazine (270 mg, 1.07 mmol) dissolved in 3.5 mL of 2,2,2-trifluoroethanol. 4-Methoxybenzylamine (1.4 mL, 10.7 mmol) and pyridine hydrochloride (620 mg, 5.35 mmol) were added and the vial was sealed. The solution was heated in an Emrys Optimizer microwave (Personal Chemistry) at 160° C. for 120 minutes. The solvent was removed under reduced pressure, and the resulting residue was partitioned between 20 mL of CH2Cl2 and 20 mL of 10% aqueous Na2CO3. The layers were separated, and the organic portion was washed with 10% aqueous Na2CO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressures to give a crude oil. Chromatography (SiO2, 0-20% CMA/CHCl3) afforded (4S)—N-(4-methoxybenzyl)-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazin-9-amine (350 mg) as an orange syrup.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]1)[CH:19]=[CH:18]2.N1C=CC=CC=1>ClCCCl>[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:33]([NH:35][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:12])=[O:34])[CH2:30][CH2:31]1)[CH:19]=[CH:18]2
Reactant: NC(=O)NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1
Reactant: O=C(Cl)c1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(NC(=O)c1ccc2ncccc2c1)NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1

Procedure:
A mixture of 6-quinolinoyl chloride (4.77 g, 22 mmol), N-[[(6-fluoro-2-naphthalenyl)methyl]-4-piperidinyl]urea (6.02 g, 20 mmol), dry pyridine (2.5 ml) and 1,2-dichloroethane (30 ml) is stirred at reflux for 18 hours. The solution is then cooled, washed with aqueous sodium carbonate solution, dried and evaporated. The residue is crystallised from ethanol to give the title compound, mp 200°-201° C. (softens, maleate salt).
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.C([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:36])C=CC=CC=1>>[CH3:28][O:27][C:25]([C:20]1([C:21]([O:23][CH3:24])=[O:22])[C:12]2[C:11](=[CH:16][C:15]([N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=2)[NH:3][C:6]1=[O:36])=[O:26]
Reactant: CCN(CC)CC
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: COC(=O)C1(C(=O)OC)C(=O)Nc2cc([N+](=O)[O-])ccc21
Yield: 84.4 %

Procedure:
Triethylamine (8.64 mL, 62 mmol) was added to a solution of dimethyl (2-carboxy-4-nitrophenyl)malonate (18.43 g, 62 mmol) and diphenylphosphoryl azide (DPPA, 13.4 mL, 62 mmol) and the mixture stirred at reflux for 15 h. The orange-brown solution was cooled, concentrated to a small volume, and the solid filtered off, washing with 2N HCl then water. The solid was triturated with hot MeOH (ca. 80 mL) to give title compound as a pale yellow powder (15.4 g, 84%), mp 234-239° C. (dec.). 1H NMR ((CD3)2SO) δ11.43 (br s, 1H, NH), 7.97 (dd, J=8.3, 2.1 Hz, 1H, H-5), 7.66 (d, J=8.3 Hz, 1H, H-4), 7.62 (d, J=2.1 Hz, 1H, H-7), 3.76 (s, 6H, CO2Me); 13C NMR δ167.4, 163.9 (CO2Me, CONH), 148.4, 143.7, 130.4 (C-6,8,9), 126.7, 117.7, 104.6 (C-4,5,7), 65.7 (C-3), 54.0 (OMe); IR (KBr) 1767 (CONH), 1736 (CO2Me), 1524 (NO2), 1348 (NO2), 1246 cm-1; MS (DEI) 294 (85%, M+), 250 (100%, M--CO2); HRMS calcd. for C12H10N2O7 294.04880, found 294.04851. Anal. Calculated for C12H10N2O: C, 49.0; H, 3.4; N, 9.5. Found: C, 49.1; H, 3.4; N, 9.6%.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:7]=1[F:13])=[O:4].O1CCCC1.[CH2:27]([N:29](CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:27]#[N:29])=[CH:8][C:7]=1[F:13])=[O:4]
Reactant: CCN(CC)CC
Reactant: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(I)cc1F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(C#N)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To an argon degassed and dried flask was added (2S,3S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide (796 mg, 1.99 mmol), zinc cyanide (352 mg, 2.99 mmol), tetrakis-triphenylphosphine palladium (0) (116 mg, 0.1 mmol) and dry tetrahydrofuran (4 mL). After heating at 80° C. for 8 hours there was no reaction. To the cooled mixture was added 2-dicylohexylphosphino-2′-6′-dimethoxybiphenyl (42 mg, 0.1 mmol) and the reaction mixture heated again to 80° C. for 90 minutes, again no reaction occurred. To the cooled mix was added triethylamine (840 μl, 5.99 mmol) and the reaction mixture heated at 80° C. for 2 hours, again no reaction occurred. To the cooled mix was added 2-dicylohexylphosphino-2′-6′-dimethoxybiphenyl (84 mg, 0.2 mmol) and still no reaction occurred after 2 hours at 85° C. To the cooled mix was added rac-2-2′-bis(diphenylphosphino)-1-1′binaphthyl (125.6 mg, 0.2 mmol) and dry toluene (2 mL). After heating at 85° C. for 40 hours the reaction mix was dissolved in ethyl acetate (50 mL) and washed with 1.5 N aqueous potassium hydrogen sulfate solution, saturated aqueous sodium bicarbonate solution and the aqueous layers were back extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by chromatography over silica gel gradient eluted from 5 to 15% v/v ethyl acetate in hexanes to give (2S,3S)-2-amino-N-(4-cyano-2-fluoro-phenyl)-3-phenyl-butyramide as a yellow residue after concentration of the product containing fractions (120 mg, 20.2% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:12]2[CH:17]=[C:16]([CH:15]=[CH:14][N:13]=2)[C:18]#[N:19])[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2cc(C#N)ccn2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1-Methylpiperidin-4-ol (0.457 g, 3.97 mmol) was dissolved in 5 mL of DMSO under argon and NaH (0.173 g, 3.97 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 h and 30 min at 60° C. The mixture was allowed to cool and 2-chloro-4 pyridinecarbonitrile (0.500 g, 3.97 mmol) was added. The mixture was stirred for 2 h at ambient temperature and subsequently poured into 100 mL of water, extracted three times with EtOAc. The combined organic layer washed with water, dried over Na2SO4 and evaporated. The crude product was purified by preparative HPLC (Kromasil C8 50×250 mm, CH3CN/0, 2% HOAc 5/95-50/50). The product was freeze dried from water. Yield: 0.250 g (32%). 1H NMR (500 MHz, CD3OD) δ8.32 (d, 1H), 7.19 (dd, 1H), 7.12 (bs, 1H), 5.14 (m, 1H), 2.75 (m, 2H), 2.38 (m, 2H), 2.32 (s, 3H), 2.06 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][CH:15]=[C:16](Br)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:62])[NH:22][C@H:23]([C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]1[NH:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[C:46]4[S:52][CH:51]=[C:50](B5OC(C)(C)C(C)(C)O5)[C:47]=4[S:48][CH:49]=3)=[CH:41][CH:40]=2)[N:38]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]([C:50]2[C:47]3[S:48][CH:49]=[C:45]([C:42]4[CH:41]=[CH:40][C:39]([C:37]5[N:38]=[C:34]([C@@H:30]6[CH2:31][CH2:32][CH2:33][N:29]6[C:27](=[O:28])[C@@H:23]([NH:22][C:21]([O:20][CH3:19])=[O:62])[CH:24]([CH3:25])[CH3:26])[NH:35][CH:36]=5)=[CH:44][CH:43]=4)[C:46]=3[S:52][CH:51]=2)=[CH:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)c[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(B5OC(C)(C)C(C)(C)O5)csc34)cc2)c[nH]1)C(C)C
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: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)csc34)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Yield: 59 %

Procedure:
To a degassed mixture of compounds 48 (1.10 mmol), 50 (1.10 mmol), and sodium carbonate (4.42 mmol) in a mixture of DMF and water (33 mL/3 mL) was added Pd(PPh3)4 (0.11 mmol). The reaction mixture was heated at 80° C. for 2 hrs. Ethyl acetate and water were added. The dried organic layers were evaporated in vacuo and the residue was purified by silica gel chromatography (eluent: DCM first; then DCM/MeOH 9/1) to give compound 51 as a beige solid in 59% yield. MS (ESI, EI+) m/z=744 (MH+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([Mg]Br)[CH2:21][CH2:20]1.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH:1]([N:14]1[CH2:17][C:16]([CH:19]2[CH2:21][CH2:20]2)([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg of 1-benzhydrylazetidin-3-one dissolved in 3.8 ml of tetrahydrofuran was added to 2 ml of 1M cyclopropyl magnesium bromide/tetrahydrofuran solution under ice water cooling, and the mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction solution was poured into a saturated aqueous solution of sodium carbonate and the mixture was subjected to extraction with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 334 mg of the objective compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]2([CH3:24])[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[N:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([OH:35])=[C:30](B(O)O)[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.C(O)(C)(C)C.[Pd]>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C@:8]3([CH3:24])[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[N:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[C:29]([OH:35])=[CH:28][CH:27]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: CN1C(=O)C[C@@](C)(c2cccc(Br)c2)NC1=NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: CN1C(=O)C[C@@](C)(c2cccc(-c3cc(Cl)ccc3O)c2)NC1=NC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF2; R1=R6=Me) (0.25 g, 0.6 mmol), 5-chloro-2-hydroxyphenylboronic acid (R21=5-chloro-2-hydroxyphenyl; 0.2 g, 1.2 mmol, 2 eq), Fibrecat (4.26% of Pd, 0.7 g) and 1N aq. K2CO3 (0.5 mL) in dimethoxyethane (DME, 10 mL) or tert-butanol (10 mL) in a 20 mL Smith process vial equipped with stir a bar was sealed and heated in an Emrys optimizer at 110° C. for 15 min. After cooling, the reaction mixture was transferred to a pre-packed Si-Carbonate column and eluted with MeOH/CH2Cl2 (1:1). The eluant was collected and concentrated under reduced pressure to give 0.32 g of the crude product as an oil. The crude product was purified by silica gel chromatography (20-50% EtOAc/hexanes gradient) to yield 0.13 g (0.3 mmol, 48%) of (S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)-phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.48-4.32 (m, 2H), 7.20 (m, 3H), 6.84 (m, 2H), 5.68 (br s, 1H), 3.28 (d, J=15.7 Hz, 1H), 3.21 (s, 3H), 2.96 (d, J=15.3 Hz, 1H), 1.68 (s, 3H), 1.53 (s, 9H). MS (ESI): MH+=443.7, 445.7; M+−56=388.0. HPLC Rt (A)=6.99 min.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:24])=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C@H:41](O)[C@H:40]([F:45])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C@@H:41]([N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=3[C:27]([F:28])([F:30])[F:29])[N:8]=[C:9]4[CH3:24])[S:21][C:20]2=[O:22])[C@H:40]([F:45])[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)NC3=O)cc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(=O)N([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4F)C3=O)cc12

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-3-methyl-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-(trans)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 36) and (cis)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (prepared as described in U.S. Pat. Pub. No. 2007/0249589) following General Procedure J.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11](C(O)=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CC(C)(C)C(Cl)=O.Cl.[CH3:35][O:36][C:37](=[O:40])[CH2:38][NH2:39]>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11]([NH:39][CH2:38][C:37]([O:36][CH3:35])=[O:40])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncc(-c2cccc(Cl)c2)cc1O
Reactant: COC(=O)CN
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)CNc1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 3 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A 20 L reactor equipped with a mechanical stirrer, condenser, thermometer and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (380 g, 1.52 mol) and diisopropylethylamine (DIPEA) (295 g, 2.28 mol). With agitation, the solution was cooled to 3° C. and charged with trimethylacetyl chloride (275.7 g, 2.29 mol) while maintaining a temperature of less than 11° C., The mixture was then agitated at ambient temperature for 2 hours. The mixture was then cooled to 10° C. and charged with a slurry of glycine methyl ester HCl (573.3 g, 4.57 mol) and THF (1689 g, 1900 mL), then charged with DIPEA (590.2 g, 4.57 mol) and agitated at ambient temperature for 16 hours. The mixture was then charged with EtOH (1500 g, 1900 mL) and concentrated under reduced pressure to a reaction volume of about 5.8 L. The EtOH addition and concentration was repeated twice more. Water (3800 g) was then added and the mixture was agitated for 16 hours at ambient temperature. The resulting solid product was isolated by filtration and washed with a mixture of EtOH (300 g, 380 mL) and water (380 g), followed by water (3800 g), dried under reduced pressure for 18 hours at 50° C. to afforded 443 g (91% yield) of the desired product as an off-white solid. Purity by HPLC was 98.9%. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[C:19](=[O:31])[C:20]([CH2:24][CH:25]([OH:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:3][C:4](=[O:7])[O:5][N:46]=3)=[CH:37][CH:38]=2)[C:19](=[O:31])[C:20]([CH2:24][CH:25]([OH:30])[C:26]([CH3:28])([CH3:29])[CH3:27])=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)c(CC(O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)c(CC(O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogen carbonate (0.36 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-(2-hydroxy-3,3-dimethylbutyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-carbonyldiimidazole (0.057 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.082 g, 37%).