Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)/[CH:14]=[CH:15]\[O:16][CH2:17][CH3:18])CCC>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.C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:4]=[CH:3][C:2](/[CH:14]=[CH:15]\[O:16][CH2:17][CH3:18])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCO/C=C\c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 32.7 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (800 mg), CIS-tributyl[2-ethoxyethenyl] tin (1.80 g), PdCl2(PPh3)2 (30 mg), and toluene (10 mL) was stirred under a nitrogen atmosphere at an outside temperature of 100° C. for 4 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (SNAP Cartridge KP-NH: 28 g, mobile phase: n-hexane/EtOAc=100/0 to 85/15 (v/v)) to yield 2-chloro-5-[(Z)-2-ethoxyethenyl]pyrimidine (250 mg, colorless solid).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][CH2:5][CH:6]([OH:10])[CH2:7][CH:8]=[CH2:9].[H-].[Na+].[CH3:15]I.O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:15][O:10][CH:6]([CH2:5][CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[CH2:7][CH:8]=[CH2:9]
Reactant: CI
Reactant: C=CCC(O)CCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CCC(CCC(OC)OC)OC
Reaction time: 0.17 h

Procedure:
7,7-Dimethoxyhept-1-en-4-ol obtained in Preparation Example 59-(1) (6.16 g) was dissolved in 1-methyl-2-pyrrolidinone (60 mL), and the solution was cooled in an ice bath under a nitrogen atmosphere. Then, sodium hydride (60%, 2.12 g) was added, followed by stirring for 10 minutes. Methyl iodide (6.61 g, 2.28 g/cm3) was further added and the mixture was further stirred for two hours and 10 minutes. After slowly adding water, ethyl acetate was added, followed by further stirring. The aqueous layer was separated and then the organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (5.83 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:36]O>>[CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH2:16][CH2:17][CH2:18][S:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:36])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: OO
Reactant: COc1ccc(SCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Product: COc1ccc(S(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(3,4-dimethoxyphenylthio)-propyl]-methylamine and hydrogen peroxide analogously to Example 4.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:19][N:18]=1.CC(O)CC.C1C2C(=CC=CC=2)C=NN=1>CCCCCC>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:19][N:18]=2)=[CH:9][N:10]=1
Reactant: Nc1cnc(Oc2ccccc2Br)nc1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Agent: c1ccc2cnncc2c1
Solvent: CCCCCC
Solvent: CCC(C)O
Product: Brc1ccccc1Oc1ncc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
2-(2-Bromophenoxy)pyrimidin-5-amine (3.01 g, 11.3 mmol), 1-chloro-4-phenylphthalazine (2.72 g, 11.3 mmol), and butan-2-ol (56.6 ml, 11.3 mmol) were placed in a sealed tube. The reaction vessel was sealed and mixture heated to 120° C. After 1.5 h, LCMS showed mainly product as [M+H]+=470 and a small amount of bromo starting material. 200 mg of phthalazine was added. After another 3.5 h, the reaction was cooled to RT. Hexane was added to allow a yellow solids to precipitate. The yellow solids were filtered and recrystallized with DCM and hexanes. The resulting dark brown solids were dried under vacuum overnight, affording the product, N-(2-(2-bromophenoxy)pyrimidin-5-yl)-4-phenylphthalazin-1-amine.
Reaction SMILES: [C:1]([C:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:11]([N:14]=[C:15]=[S:16])[CH:12]=[CH2:13]>O1CCCC1>[CH2:11]([NH:14][C:15]([N:8]1[CH2:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]1)=[S:16])[CH:12]=[CH2:13]
Reactant: CC(C)(C)C1=CCNCC1
Reactant: C=CCN=C=S
Solvent: C1CCOC1
Product: C=CCNC(=S)N1CC=C(C(C)(C)C)CC1

Procedure:
In 20 ml. of anhydrous tetrahydrofuran there is dissolved 5.0 grams of 4-t-butyl-1,2,3,6-tetrahydropyridine, and with stirring there is added 3.5 grams of allylisothiocyanate in 10 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 24 hours at room temperature and the tetrahydrofuran is evaporated in vacuo. The resulting solid is dried at 50°C/20 mmHg. to remove any unreacted allylisothiocyanate to give N-allyl-4-t-butyl-1,2,3,6- -tetrahydro-1-pyridinethiocarboxamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][C:23]=1[F:32]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][C:23]=3[F:32])=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Reactant: CC(C)(O)c1ccc(CN)c(F)c1
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1

Procedure:
Prepared from 2-(Benzo[1,3]dioxol-5-yloxy)-nicotinic acid and and 2-(4-Aminomethyl-3-fluoro-phenyl)-propan-2-ol.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:26]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:3])[C:7]=2[OH:26])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(F)cc2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 403 (M+H)+.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Cl.CNC.[BH4-].[Na+]>C(O)C.CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([N:3]([CH3:4])[CH3:1])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1
Reactant: O=C1CCN(c2ccc(Br)cc2)CC1
Reactant: CCN(CC)CC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CNC
Solvent: CCO
Solvent: CO
Product: CN(C)C1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of triethylamine (0.987 mL, 7.08 mmol) in ethanol (6.2 mL) and methanol (4.2 mL) was treated with 1-(4-bromophenyl)piperidin-4-one (0.9 g, 3.54 mmol) and dimethylamine hydrochloride (0.578 g, 7.08 mmol). Titanium(IV) isopropoxide (2.075 mL, 7.08 mmol) was added and a thick mixture formed. The suspension was stirred at ambient temperature for 18 hours. Sodium borohydride (0.2 g, 5.31 mmol) was then added portion-wise over 5 minutes and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction was quenched with 70 mL 10% aqueous ammonia and the resulting suspension was extracted with 250 mL dichloromethane. The aqueous layer was extracted with 150 mL additional dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash chromatography on a silica gel column eluting with a gradient of from 0% to 7% methanol in dichloromethane to provide the title compound. MS ESI(+) m/z 284.8 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH:17]=[CH:18]4)=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:6])[CH2:2][CH3:3].[H][H]>C(O)C.[Pd]>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH2:17][CH2:18]4)=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4C=CC3C4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC3C4)nc2n(CCC)c1=O
Yield: 39.1 %

Procedure:
1.0 g (3.1 mmol) of 1,3-dipropyl-8-(5-norbornen-2-yl)xanthine are hydrogenated under pressure in 30 ml of ethanol, with the addition of palladium/charcoal, until no further uptake of hydrogen can be detected. The catalyst is filtered off, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel (Ch2Cl2 /CH3OH 99:1). 0.4 g of the title compound are obtained in the form of white crystals (39% of theory), m.p. 136°-138° C.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([Br:23])[C:3]=12
Reactant: Oc1nc[nH]c2nccc1-2
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Oc1nc[nH]c2ncc(Br)c1-2
Temperature: 40 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 1.0 g of 4-hydroxypyrrolo[2,3-d]pyrimidine in 20 ml of DMF, 3.8 g (2.5 eq) of bis(trimethylsilyl)acetamide was added, and the resulting solution was stirred at 40° C. in an oil bath for about two hours. Completeness of silylation was indicated by NMR analysis of an aliquot showing disappearance of the N-3 proton signal. The reaction was cooled to ambient temperature and 1.6 g (1.2 eq) of N-bromosuccinimide (NBS), was added in one portion. The reaction mixture was protected from light and stirred at ambient temperature until completion was indicated by NMR analysis (disappearance of pyrrole C-H doublets and emergence of a single, finely split doublet at δ7.16, about 2 h). The mixture was poured into 50 mL of water, with stirring. After 1-2 hours, the product was collected by filtration, washed with water, dried, and reslurried in 10 volumes of 10% methanol in chloroform. Filtration and drying gave 1.2 g of 4-hydroxy-5-bromopyrrolo-[2,3-d]pyrimidine (75% yield), mp 269-°271° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ7.16 (d, J=2.0 Hz, 1 H), 7.80 (d, J=2.1 Hz, 1 H), 11.87 (s, 1 H), 12.15 (s, 1 H). 13C NMR (75.5 MHz, DMSO-d6) 89.3, 105.5, 120.4, 144.3, 147.4, 157.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:5]([C:6]([O:8]C)=O)[C:4]=1[NH2:17]>COC(OC)N(C)C>[OH:8][C:6]1[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=2)[N:17]=[CH:12][C:3]=1[C:4]#[N:17]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Agent: COC(OC)N(C)C
Product: COc1cc2c(O)c(C#N)cnc2c(OC)c1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 159.2 %

Procedure:
A mixture of 4.82 g of methyl 3,4,5-trimethoxyanthranilate in 20 ml of N,N-dimethylformamide dimethyl acetal was refluxed for 18 hours and concentrated in vacuo. The crude amidine product was used in the next step without further purification. To 25 ml of tetrahydrofuran at -78° C. was added 17.6 ml of 2.5M n-butyllithium in hexanes. Then 2.35 ml of acetonitrile in 45 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 15 minutes. Then a solution of the crude amidine in 30 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for minutes, then 5.7 ml of acetic acid was added. The mixture was warmed to room temperature, and 100 ml of water was added. The product was collected, washed with water, and dried to give 4.14 g of 4-hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 280° C. (decomposed); mass spectrum (electrospray, m/e): M+H 261.2.
Reaction SMILES: NC(N)=S.ClCC([NH:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:49]/[O:50][CH3:51])/[C:16]([NH:18][CH:19]2[C:47](=[O:48])[N:21]3[C:22]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[C:23]([CH:27]=[N:28][O:29][CH3:30])[C@@H:24]([CH3:26])[S:25][C@H:20]23)=[O:17])[N:14]=1)=O>O.O1CCCC1>[NH2:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:49]/[O:50][CH3:51])/[C:16]([NH:18][CH:19]2[C:47](=[O:48])[N:21]3[C:22]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[C:23]([CH:27]=[N:28][O:29][CH3:30])[C@@H:24]([CH3:26])[S:25][C@H:20]23)=[O:17])[N:14]=1
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(NC(=O)CCl)n3)[C@H]2S[C@@H]1C
Agent: NC(N)=S
Solvent: O
Solvent: C1CCOC1
Product: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2S[C@@H]1C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A solution of 84 mg of thiourea in 1 ml of H2O was added to a solution of 713 mg of diphenylmethyl 7-[2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate in 10 ml of tetrahydrofuran, and the mixture was stirred overnight to distill off the solvent under reduced pressure. The residue was dissolved in CH2Cl2, washed with H2O and saturated aqueous NaCl solution, successively, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.acetone (9:1) were collected to distill off the solvent, thus yielding 180 mg (28%) of diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.Cl.[C:16](=N)([O:18][CH2:19][CH3:20])[CH3:17]>O>[CH2:16]([O:18][C:19](=[N:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:20])[CH3:17]
Reactant: CCOC(C)=N
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(C)=NNc1ccc([N+](=O)[O-])cc1
Yield: 85 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 15 parts of 1-(4-nitrophenyl)hydrazine and 160 parts of absolute ethanol were added 13.5 parts of ethyl ethanimidate hydrochloride. After stirring for 3 hours while cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dried, yielding 19 parts (85%) of 1-(1-ethoxyethylidene)-2-(4-nitrophenyl)hydrazine; mp. 101.8° C. (int. 18).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH3:24])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:29]([O-])=O.[Na+]>Cl.O>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=4)[N:10]=3)=[CH:3][C:2]=2[N:1]=[N:29]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(N)c(N)c3)c(N3CCC[C@@H]3C)nc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]nnc4c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.1 %

Procedure:
To a solution of (S)-methyl 2-(3,4-diaminophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (600 mg, crude) in HCl (60 mL, 2N) was added sodium nitrite (164.7 mg, 2.39 mmol) in water (1 mL) dropwise at 0-5° C. The resulting solution was stirred for 15 min at 0° C., then diluted with water (150 mL), extracted with dichloromethane (3×80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (1.25% methanol in dichloromethane) to afford (S)-methyl 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (130 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH:21]([CH3:23])[CH3:22])[C:9]1=[O:24])C1C=CC=CC=1>C1COCC1>[CH:21]([CH:10]1[C:9](=[O:24])[NH:8][CH2:13][CH2:12][N:11]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])([CH3:23])[CH3:22]
Reactant: CC(C)[C@@H]1C(=O)N(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a three-necked bottle containing THF (10 mL) was bubbled with NH3 (gas) at −78° C. for 5 mins. Then Na (300 mg, 13.0 mmol) was added to the mixture slowly at −78° C. After stirring for 30 min, (R)-tert-butyl 4-benzyl-2-isopropyl-3-oxopiperazine-1-carboxylate (700 mg, 2.11 mmol) was added dropwise at −78° C. The mixture was stirred at −78° C. for 30 min. The mixture was quenched with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC with petroleum ether/EtOAc 1/1 to afford tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (300 mg, 59% yield) as a white solid. The product was found to be a racemic mixture. The cause of racemization was not investigated. LC-MS m/z 187.1 [M-56+H]+, 265.1 [M+Na]+. 1H NMR (CDCl3 400 MHz): δ 6.29 (s, 1H), 4.55-3.99 (m, 2H), 3.51-3.36 (m, 1H), 3.32-3.12 (m, 2H), 2.34-2.29 (m, 1H), 1.46 (s, 9H), 1.09 (d, J=6.8 Hz, 3H), 0.99 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C(O)=O.[C:26]1(C)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Resin-bound aryl silane intermediate 4-Scheme 1 (2 g) was suspended in toluene (15 mL) and allowed to swell for 30 minutes. To this was added tetrkistriphenylphosphine (275 mg, 0.25 mmol), phenylboronic acid (500 mg, 4.1 mmol), ethanol (2 mL), sodium carbonate, aq (2 mL, 2M), all of which was heated in an oil bath maintained at 90° for 16 h. The reaction mixture was cooled, filtered washed with methanol, water, methylene chloride and methanol to give a black solid which was taken for the next step. A portion of the above resin (1 g) was treated with trifluoroacetic acid (3 mL) and stored at room temperature for 24 h. Methylene chloride (10 mL) was added and filtered, washed with methylene chloride. Removal of solvents gave a slight brown oil which was triturated with hexane (50 mL). Evaporation of the hexanes yielded biphenyl (78 mg) which was come with an authentic sample.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[C:36](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:37][C:38]([CH3:45])([C:41]([F:44])([F:43])[F:42])[C:39]=1[CH3:40])#[N:34]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=[CH:40][C:39]2[C:38]([CH3:45])([C:41]([F:44])([F:42])[F:43])[O:37][C:36](=[C:46]([C:47]#[N:48])[C:49]#[N:50])[C:35]=2[C:33]#[N:34])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84 %

Procedure:
In 10 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 730 mg (1.63 mmol) of 5-[2-(2-benzyloxy-4-dibutylaminophenyl)vinyl]thiophene-2-carboaldehyde and 380 mg (1.5 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at room temperature for 19 hours and further stirred with heating at 50° C. for 6 hours. The solvent was evaporated off and the residue was washed with ethanol to give 860 mg of a dark reddish brown crystal (yield: 94.0%; mp: 184-185° C.)
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([CH:24]([S:45]CC2C=CC(OC)=CC=2)[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([N:35]([CH3:44])[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:34])[CH:28]=2)[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([CH:24]([SH:45])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([N:35]([CH3:44])[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:34])[CH:28]=2)[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: COc1ccc(CSC(CCc2cccc(C(=O)N(C)CCc3ccccc3)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(CCc1ccccc1)C(=O)c1cccc(CCC(S)C(Cc2ccc(N)nc2)C(=O)O)c1
Temperature: 60 °C
Yield: 126.4 %

Procedure:
tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-(3-{[methyl(2-phenylethyl)amino]carbonyl}phenyl)pentanoate (80 mg, 0.106 mmol) was dissolved in triethylsilane (0.4 mL) and trifluoroacetic acid (3.0 mL). The solution was heated to 60° C. for 1 h and was then concentrated. Purification of the residue by reversed-phase HPLC (C-8 column, linear gradient 20%→100% of MeCN in 5% aqueous MeCN containing 0.15% trifluoroacetic acid) gave the title diastereomeric compound as the trifluoroacetic salt (64 mg, 100%) after freeze-drying.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14]1[CH:35]=[CH:34][C:17](/[CH:18]=[CH:19]/[C@H:20]3[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[N:21]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:16][CH:15]=1)[C:7]2=[O:13]>CO.[Pt]>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14]1[CH:35]=[CH:34][C:17]([CH2:18][CH2:19][C@H:20]3[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[N:21]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:16][CH:15]=1)[C:7]2=[O:13]
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2ccc(N3CCc4c(ccc(Cl)c4Cl)C3=O)cc2)COC1(C)C
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N3CCc4c(ccc(Cl)c4Cl)C3=O)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred suspension of (S,E)-tert-butyl 4-(4-(5,6-dichloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)styryl)-2,2-dimethyloxazolidine-3-carboxylate (220 mg) in methanol (8 ml) was added 10% platinum on charcoal (42 mg) and the mixture was then stirred under an atmosphere of hydrogen at room temperature for 2 hours. The mixture was then filtered through celite and the filtrate was concentrated in vacuo to afford (S)-tert-butyl 4-(4-(5,6-dichloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)phenethyl)-2,2-dimethyloxazolidine-3-carboxylate (166 mg, 75%) as a white amorphous solid. MS (ISP): 538.3 ([{37Cl35Cl}M+NH4]+), 536.2 ([{35Cl}M+NH4]+), 521.3 ([{37Cl35Cl}M+H]+), 519.2 ([{35Cl}M+H]+), 465.3 ([{37Cl35Cl}M+H—C4H8]+), 463.1 ([{35Cl}M+H—C4H8]+).