Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][S:9][C:8]=2[CH:20]=1)([O-])=O.O.NN>CO.[Ni]>[N:15]1([CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][S:9][C:8]3[CH:20]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)SCCN2CCN1CCCC1
Temperature: 25 °C
Yield: 106.6 %

Procedure:
To a solution of 7-nitro-4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.637 g, 2.172 mmol) in MeOH (30 mL) was added Raney-Nickel (slurry in water) (˜30 mg, 2.172 mmol) followed by hydrazine hydrate (1.056 mL, 21.72 mmol), and the mixture was immersed in a preheated oil bath and refluxed for 1 hour. The solution was cooled to room temperature, filtered through a pad of Celite, and washed with 100 mL of MeOH. The crude material was filtered through a silica plug (3.5-10% 2M NH3 in MeOH/CH2Cl2). The solvent was evaporated to give the title product as a dark brown oil (0.61 g, quantitative). 1H NMR (DMSO-d6) δ 6.49 (d, J=8.7 Hz, 1H), 6.26-6.23 (m, 2H), 4.42 (brs, 2H), 3.38-3.35 (m, 2H), 3.21 (t, J=7.2 Hz, 2H), 2.97-2.94 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.45 (brs, 4H), 1.66 (brs, 4H); ESI-MS (m/z, %): 266, 264 (MH+, 100), 98 (34).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][OH:24])[CH:17]=[C:16]([C:29]([O:31]CC)=[O:30])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:7]=1)[CH3:2].[OH-].[Li+].Cl>O1CCCC1.CO.O>[CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][OH:24])[CH:17]=[C:16]([C:29]([OH:31])=[O:30])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[N:39]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)C(C)(C)C)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3[C@H](CO)C(C)(C)C)cn1
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 104, 212.7 mg, 0.34 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2 M lithium hydroxide (0.253 mL, 0.51 mmol). The reaction mixture was heated at 100° C. for 15 min in a microwave reactor. The reaction mixture was cooled to room temperature and diluted with water. 1 N HCl was added until pH 3-4 was reached. The precipitate that formed was collected by filtration, washed with water and hexanes. Purification via column chromatography (silica, 95:5 methylene chloride/methanol) provided (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (72.3 mg, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1ccc(Br)c(I)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Br)c(-c2cccnc2)c1
Temperature: 120 °C
Yield: 69.8 %

Procedure:
A solution of Pd(Ph3P)4 (1.410 g, 1.220 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (3.94 ml, 24.41 mmol), pyridin-3-ylboronic acid (3.00 g, 24.41 mmol), and potassium carbonate (13.49 g, 98 mmol) in 32 mL dioxane and 16 mL water was heated to 120° C. overnight. LC/MS showed incomplete conversion, so an additional portion of pyridin-3-ylboronic acid (3.00 g, 24.41 mmol) and potassium carbonate (13.49 g, 98 mmol) were added and the reaction mixture was heated to 120° C. for 3 hours. LC/MS showed no further conversion, so the reaction mixture was poured into water and was extracted with DCM. The organics were then concentrated. Purification of the crude residue by column chromatography (0-100% EtOAc/heptane) gave 3-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (5.150 g, 17.05 mmol, 69.8% yield) as a yellow solid. m/z (ESI) 303.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[C:27]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:47][O:48][C:49]([CH3:55])([CH3:54])[C:50]([NH:52][OH:53])=[O:51]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:47]/[O:48][C:49]([C:50](=[O:51])[NH:52][OH:53])([CH3:55])[CH3:54])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[C:27]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NO
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nc(-c5ccccc5)ncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(-c4ccccc4)ncc3-c3ccc(O)c(O)c3)CS[C@H]12)c1csc(N)n1)C(=O)NO
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.2 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (33 mg) (0.05 mmol) and 11 mg (0.065 mMol) 2-(aminooxy)-N-hydroxy-2-methylpropionamide hydrochloride are dissolved in 0.8 ml of absolute dimethylacetamide. After stirring at room temperature for 22 hours the mixture is concentrated in a high vacuum and the residue is crystallized with water. The product is filtered off, washed with water, ethanol and diethyl ether and dried in a high vacuum at room temperature. There are obtained 32 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(hydroxycarbamoyl)-1-methylethoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:10]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Nc1cc(-c2cccnc2)ncn1
Temperature: 125 °C
Yield: 34.8 %

Procedure:
6-Chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-4-ylboronic acid (0.384 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) were suspended in a mixture of DME/EtOH/water (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (5-25% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine (0.15 g, 0.871 mmol, 35% yield) as an off-white solid. LCMS R.T.=0.30; [M+H]+=173.11.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[NH2:22][C:23]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)([CH3:27])[C:24]([OH:26])=[O:25]>CCOCC>[NH2:22][C:23]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:32][CH:33]=1)([CH3:27])[C:24]([OH:26])=[O:25]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CC(N)(C(=O)O)c1ccc(N)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(N)(C(=O)O)c1ccc(NC=C2C(=O)NC(=O)c3ccc(Br)cc32)cc1
Temperature: 110 °C
Yield: 33 %

Procedure:
A mixture of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (191 mg, 0.50 mmole), N,N-dimethylformamide (2 mL) and 2-Amino-2-(4-amino-phenyl)-propionic acid (90 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is diluted with ether, filtered, washed with acetonitrile and dried to give a dull yellow solid 71 mg (33%), mp 250-253° C.; MS (ESI): m/z 428.2, 430.2 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:29]=[C:30]([CH2:35][CH2:36][NH2:37])[CH:31]=[C:32]([Cl:34])[CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:37][CH2:36][CH2:35][C:30]3[CH:29]=[C:28]([Cl:27])[CH:33]=[C:32]([Cl:34])[CH:31]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cc(Cl)cc(Cl)c4)cc3)c(Cl)cc21
Reaction time: 24 h
Yield: 96.5 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (54.2 mg, 0.144 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 2-(3,5-dichlorophenyl)ethanamine (30.1 mg, 0.158 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.1 mg, 0.173 mmol), 1-Hydroxy-7-azabenzotriazole (5.87 mg, 0.0432 mmol), and N,N-diisopropylethylamine (27.9 mg, 0.216 mmol) at ambient temperature. After 24 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (76.4 mg, 0.139 mmol, 96.8% yield) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH2:22][CH2:23][C:19]=2[CH:18]=1.C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:49][CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=N2)C=1)(C)(C)C>O1CCCC1.[Cl-].[NH4+]>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH2:22][CH2:23][C:19]=2[CH:18]=1)[CH2:49][CH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: COC(=O)Cc1ccc2c(c1)CCS2
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCC1)c1ccc2c(c1)CCS2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
A round bottom flask with a stir bar and argon inlet was charged with tetrahydrofuran (10 mL) and cooled to −78° C. Diisopropyl amine (155 μL, 1.10 mmol) was then added followed by the dropwise addition of a solution of n-butyl lithium (2.5M solution in hexanes, 422 μL, 1.06 mmol) and it was stirred at −78° C. for 15 min. After this time, a solution of (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid methyl ester (200 mg, 0.96 mmol) in tetrahydrofuran (3 mL) and 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added dropwise. It was then stirred for 1 h at −78° C. It was then treated with a solution of iodomethylcyclopentane (prepared in PCT WO2004/052869 A1 Example 1, 302 mg, 1.44 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) dropwise. The reaction was then stirred at −78° C. and gradually allowed to warm to 25° C. and stirred at 25° C. for 16 h. The reaction was then diluted with a saturated aqueous ammonium chloride solution (30 mL). The aqueous layer was and extracted with ethyl acetate (3×20 mL). The organics were then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 2% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid methyl ester (193 mg, 69).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:21][CH2:20][C:17]2([CH2:19][CH2:18]2)[C@H:16]([OH:22])[CH2:15]1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:21][CH2:20][C:17]2([CH2:19][CH2:18]2)[C@H:16]([OH:22])[CH2:15]1
Reactant: O=C(NCCCN1CCC2(CC2)[C@H](O)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCN1CCC2(CC2)[C@H](O)C1
Yield: 88.9 %

Procedure:
A solution of [3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-carbamic acid benzyl ester (590 mg, 1.85 mmol) in MeOH (14 mL) was stirred under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 200 mg), then after 90 min insoluble material was removed by filtration and the filtrate evaporated to afford the title compound (303 mg, 89%). Yellow liquid, MS: 185.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][CH:6]=[C:7]([Br:9])[N:8]=1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C1COCC1>[Br:3][C:4]1[N:5]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:6]=[C:7]([Br:9])[N:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1c[nH]c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(Br)nc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 1.2 eq) was added portionwise to a solution of 2,4-dibromoimidazole (1 eq.) in THF at 0° C. After 1 hr, SEM-Cl (1.2 eq.) was added and the mixture was stirred at RT for 12 hr. The reaction was carefully quenched with H2O and the aqueous phase was extracted with EtOAc (3×). The combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 5-33% EtOAc/pentane yielded the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ: 7.09 (1H, s), 5.22 (2H, s), 3.54 (2H, t, J=8.1 Hz), 0.92 (2H, t, J=8.1 Hz), 0.00 (9H, s). MS (ES) C9H16Br2N2OSi requires: 354/356/358, found: 355/357/359 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCl>[Br:14][CH2:12][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CBr)c1

Procedure:
A mixture of [3-methylphenyl]acetic acid ethyl ester (5g), N-bromosuccinimide (5 g) and benzoyl peroxide (0.1 g) in dichloromethane (200 ml) was irradiated under a 500 W halogen lamp for 6 hours. The solvent was evaporated and the residue partitioned between diethyl ether and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 5-10% ethyl acetate in isohexane. Yield 5.14 g.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.C=O.C1CCN2C(=NCCC2)CC1.[Cl-].[Li+]>O1CCCC1.C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 mL of anhydrous tetrahydrofuran, add paraformaldehyde (80 mg, 2.6 mmol), DBU (434 mg, 2.8 mmol) and anhydrous Lithium chloride (186 mg, 4.4 mmol), reflux overnight under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 20 mL of toluene, wash with 5% HCl(aq), saturated Na2CO3 and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([OH:38])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[OH-].[Zn+2:40].[OH-]>>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:40].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([OH:38])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: [OH-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
Stearic acid and palmitic acid were mixed at a mass ratio of 65:35 to prepare a mixture, and zinc hydroxide was mixed and melted with the resulting mixture to be reacted therewith, and then dried to produce particles in which zinc stearate and palmitic acid were dissolved in each other (particle diameter: 11 μm to 23 μm). A part of the particles thus produced was dissolved in a hydrochloric acid-methanol solution, and the product was heated to 80° C. to methylate the stearic acid and palmitic acid. The methylation product was analyzed by gas chromatography to determine the zinc stearate content and the palmitic acid content and to express them in terms of the equivalent ratio of zinc stearate to zinc palmitate, and the ratio was found to be 64:34 (mass ratio).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[N:28]1([C:33]2[N:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][N:34]=2)[CH:32]=[N:31][N:30]=[N:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[N:28]1([C:33]2[N:34]=[CH:35][C:36]([CH2:39][C:40]([N:18]3[CH2:17][CH2:16][N:14]4[CH2:15][C@H:10]([C:5]5[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[C:4]=5[CH3:27])[N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:12][C@@H:13]4[CH2:19]3)=[O:41])=[CH:37][N:38]=2)[CH:32]=[N:31][N:30]=[N:29]1
Reactant: O=C(O)Cc1cnc(-n2cnnn2)nc1
Reactant: Cc1c([C@H]2CN3CCNC[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (46 mg, 0.123 mmol) and 2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)acetic acid (30.4 mg, 0.147 mmol) in DMF (2 mL) was added HATU (70.1 mg, 0.184 mmol) and diisopropylethylamine (64.4 μl, 0.369 mmol) and the resulting solution was stirred at rt for 1 h. Ethyl acetate (50 mL) was added and the organic phase was washed with brine (3×50 mL), dried over sodium sulphate, concentrated and the residue was purified on TLC using 10% methanol/methylene chloride to give title compound, LC/MS: [(M+23)]+=585.23; [(M+1-100-28)]+=435.20.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[C:3]=1[C:4]#[N:5].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13]>>[S:12]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[C:3]=1[C:4]#[N:5])(=[O:15])(=[O:14])[NH2:13]
Reactant: CSc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CSc1cccc(NS(N)(=O)=O)c1C#N

Procedure:
Prepared as in Example 1 from 2-amino-6-(methylthio)benzonitrile (Example 8b) and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.26 (s, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.59 (t, J=8.40 Hz, 1H), 9.51 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8]C(C#N)(O[Si](C)(C)C)[C:6]=2[CH:18]=1.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][CH:20]([C:19]([OH:22])=[O:21])[C:6]=2[CH:18]=1
Reactant: CC(=O)O
Reactant: C[Si](C)(C)OC1(C#N)CCSc2ccc(Cl)cc21
Agent: Cl
Product: O=C(O)C1CCSc2ccc(Cl)cc21

Procedure:
Following the procedure of Example 2, 6-chloro-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-1-benzothiopyran (5.8 g.) was reacted with stannous chloride dihydrate in glacial acetic acid (25 ml.) and concentrated hydrochloric acid (25 ml.). Recrystallization from benzene:cyclohexane gave 6-chloro-3,4-dihydro-2H-1-benzothiopyran-4-carboxylic acid (2.59 g.), m.p. 153°-154° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]2[C:10]=1[C:9](=O)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:6]2.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:9]1[C:10]2=[C:2]([CH3:1])[N:3]=[C:4]([CH3:18])[N:5]2[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C)n2nc(-c3ccccc3)[nH]c(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(C)n2nc(-c3ccccc3)nc(Cl)c12

Procedure:
700 mg (2.9 mmol) of 5,7-dimethyl-2-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 15A) were dissolved in 8 ml of phosphoryl chloride and stirred at reflux for 12 h. The reaction mixture was poured into 170 ml of saturated sodium bicarbonate solution, and solid sodium bicarbonate was added until a pH of 7 had been reached. Ethyl acetate was added, and the mixture was extracted. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. This gave 657 mg (80% of theory) of the product as a solid.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[N:15]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:13]([F:21])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>[Pd].CO>[F:21][C:13]1[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[N:15][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COCCOc1nc(Cl)c(C(=O)OC)cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COCCOc1ncc(C(=O)OC)cc1F
Yield: 28.4 %

Procedure:
10% Pd/C (200 mg) and ammonium formate (200 mg) were added to an MeOH (10 ml) solution containing methyl 2-chloro-5-fluoro-6-(2-methoxyethoxy)nicotinate (1.07 g) obtained in the 1st step, followed by reflux for 1 hour. Next, insoluble matter was removed using Celite. The solvent was distilled away under reduced pressure. Then, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:5). A white solid of methyl 5-fluoro-6-(2-methoxyethoxy)nicotinate (264 mg) was thus obtained.