Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(Br)ccc21
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: Cc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(Cl)cc4)cc23)CC1

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 5-bromo-3-(1-methylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (0.500 g, 1.11 mmol), 4-chlorophenylboronic acid (0.183 g, 1.17 mmol), tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol), and 2M aqueous sodium carbonate solution (2 mL) in toluene (15 mL) to give 0.200 g of 5-(4-chlorophenyl)-3-(1-nethylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (40%) as a white solid, which was desilylated by dissolving in 1 mL of tetrahydrofuran and treating with tetrabutylammonium fluoride (1M in tetrahydrofuran, 4 mL) to give the title compound (0.112 g, 83%) as an amorphous solid. FDMS m/e=325 (M+). EA calculated for C20H21N2Cl.½ H2O: C, 71.95; H, 6.64; N, 8.39. Found: C, 72.09; H, 6.68; N, 8.48.
Reaction SMILES: [Br-].[C:2]([NH:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)(CC)C.CO>[C:2]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:16]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cc[n+](CCc2c[nH]c3ccccc23)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: CCC(C)O
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccccc1

Procedure:
A suspension of 4-benzamido-1-[2-(3-indolyl)ethyl]-pyridinium bromide (10.5g) and sodium borohydride (2.8 g) in sec-butanol (100 ml) was stirred and refluxed for 6 hours. The reaction mixture was cooled to 25° and diluted with aqueous methanol. The product was separated by filtration and washed with aqueous methanol then with water and finally with methanol, and dried to give the crude title compound. This was purified as described in Example 5 to give the title compound mp 203°-5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=[C:5]([CH2:13][CH:14]=[O:15])[CH:4]=1.[BH4-].[Na+]>CO>[OH:15][CH2:14][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=1
Reactant: COc1cc(CC=O)cc2c1C(=O)OC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCO)cc2c1C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (7-methoxy-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (0.12 g, 0.58 mmol) was treated with sodium borohydride (0.05 g, 1.45 mmol) and methanol (10 mL); the resulting mixture was stirred at room temperature for 1 h. The solution was concentrated to dryness, dissolved in EtOAc and washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give 5-(2-hydroxyethyl)-7-methoxy-2-benzofuran-1(3H)-one. LC/MS: [(M+1)]+=209.
Reaction SMILES: OO.[NH2:3][C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(O)(=O)C>[CH2:10]([C:8]1[CH:7]=[CH:6][C:5]2=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:13][N:3]=[C:4]2[CH:9]=1)[CH3:11]
Reactant: CCc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: OO
Solvent: CC(=O)O
Product: CCc1ccc2c(-c3ccccc3)onc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
A solution of 300 ml of 30% hydrogen peroxide in 700 ml of glacial acetic acid was heated on a steam bath for 1 hr. To the cooled solution was added a solution of 64.0 g (0.284 mole) of (2-amino-4-ethylphenyl)phenylmethanone in 150 ml of glacial acetic acid. The dark reaction mixture was heated at 50°-70° C. for 0.5 hr, poured into 3 liters of ice water and let stand at ambient temperature overnight. The reaction mixture was extracted with six 200 ml portions of carbon tetrachloride. The combined carbon tetrachloride extracts were washed with three 200 ml portions of water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to 200 ml, treated with charcoal and filtered. The filtrate was evaporated under reduced pressure to give a dark oil as residue. A 9.0 g sample was purified by chromatography (3.5×60 cm glass column; 175 g of silica gel; benzene). Fractions containing the title compound were combined and the solvent evaporated under reduced pressure to give 6.2 g (57%) of oil. The oil was dissolved in 2-propanol and cooled to dry ice acetone temperatures to give light yellow crystals, m.p. 41°-43° C.
Reaction SMILES: [CH3:1][C:2]1([NH2:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1)=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1cc(N2CCC(C)(N)CC2)ncn1
Solvent: ClCCl
Product: Cc1cc(N2CCC(C)(N=C=S)CC2)ncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
To a solution of 4-methyl-1-(6-methylpyrimidin-4-yl)piperidin-4-amine (1.09 g, 5.28 mmol) in dichloromethane (17.2 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (1.84 g, 7.92 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After cooling to room temperature the mixture was evaporated. Purification by chromatography (silica gel, 3×70 g, 50 to 100% ethyl acetate in heptane) afforded the title compound (1.2 g, 91%) as a light yellow solid. MS ISP (m/e): 249.1 [(M+H)+].
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=5)[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Reactant: Cc1cccc(CBr)c1
Product: Cc1cccc(CN2Cc3ccc(N4CCN(CCC(c5ccccc5)c5ccccc5)CC4)cc3C2=O)c1
Yield: 101.3 %

Procedure:
In the same manner as in Example 51, the title compound (48 mg) was prepared from the compound (50 mg) obtained in Example 50 and a-bromo-m-xylene (17 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11].[OH-].[Na+]>O1CCCC1>[CH3:7][NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11]
Reactant: CN[C@@H](C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium aluminum hydride (1.84 g, 43 mmol) was suspended in 30 ml of tetrahydrofuran and cooled in an ice-bath. A solution of (R)-methylamino-phenyl acetic acid (1.0 g, 6 mmol) in 10 ml of tetrahydrofuran was slowly added over a period of 20 minutes. The resulting mixture was stirred for 1 hour at 0°, 4 hours at room temperature and then refluxed overnight. The mixture was cooled and carefully hydrolysed by addition of 50 ml 15% aqueous sodium hydroxide. Extraction with ethyl acetate gives a crude oil which was purified by chromatography on silica gel using heptane/ethyl acetate 9:1 v/v to give the title compound as a slightly yellowish oil (0.36 g, yield=39%).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.Cl.CN.C(N(CC)CC)C>C(OCC)(=O)C.O>[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][NH:2][CH3:1])[S:9][CH:10]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.1 %

Procedure:
25.2 g (360 mmol) of sodium cyanoborohydride are added to a solution of 35 g (180 mmol) of 4-bromothiophene-2-carbaldehyde, 62 g (640 mmol) of methylamine hydrochloride and 119 ml (846 mmol) of triethylamine. The reaction medium is stirred at room temperature for 3.5 hours. After addition of water and ethyl acetate and washing with aqueous 1M sodium hydroxide solution, the organic phase is extracted. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 90/10 to 70/30 heptane/ethyl acetate mixture. 19.7 g (52%) of (4-bromothiophen-2-ylmethyl)methylamine are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
2.5 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine were dissolved in 50 ml of pyridine and treated at room temperature with a solution of 1.7 g of benzoyl chloride in 20 ml of tetrahydrofuran. After stirring at room temperature for two hours the reaction mixture was poured on to ice-water and, after acidification with 3N hydrochloric acid, extracted with ethyl acetate. The oil obtained after drying and evaporating the organic phase was crystallized from hexane/ethyl acetate and gave 3 g of N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)benzamide in white crystals, m.p. 146°-148° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[I:8][C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1.C1COCC1.CCOCC>O>[I:8][C:9]1[S:13][C:12]([CH:14]=[C:1]2[C:2](=[O:3])[CH2:4][O:5][C:6]2=[O:7])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(I)s1
Reactant: O=C1COC(=O)C1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C1COC(=O)C1=Cc1ccc(I)s1
Reaction time: 0.08 h

Procedure:
0.59 gm of tetronic acid (FW=100, 0.056 mole) and 3.65 gm of 5-iodo-2-thiophenecarboxaldehyde (FW=238, 15.3 mmole) were added to a 25 mL roundbottom flask and 2.5 mL of THF were added and the solution was stirred for five minutes. The sludge was allowed to react for 30 minutes, occasionally helping the stirring with a glass rod. The precipitate was then treated with 10 mL of ether and 10 mL of water and swirled. The yellow crystals were then collected on a buchner funnel, washing them with ether, water and ether again. The excess 5-iodo-2-thiophenecarboxaldehyde was then recovered by extracting to aqueous layer with ether and resublimed. The crude adduct was dissolved in hot CHCl3 (approximately 250 mL) and passed through a silica plug (approximately 5 cm). The crystals obtained after solvent evaporation were recrystallized from ethyl acetate/igroin and the yield was 0.85 gm (46%). The material melted at 211°-212° C. (dec.) C9H6IO3S: %C 33.77; %H 1.57; found %C 33.53; %H 1.83 NMR results: 1HNMR (d6DMSO,(H20)/TMS) 6 4.69 (2H, d, 4.8 Hz); 7.53 (1H, m); 8.08 (1H, m).
Reaction SMILES: Cl.[K].[C:3]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:8]([Cl:17])[N:7]=1)([OH:5])=[O:4].[CH3:18]O>>[CH3:18][O:4][C:3]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:8]([Cl:17])[N:7]=1)=[O:5]
Reactant: CO
Reactant: CCCCc1c(Cl)cc(C(=O)O)nc1Cl
Agent: Cl
Agent: [K]
Product: CCCCc1c(Cl)cc(C(=O)OC)nc1Cl

Procedure:
300 ml of 5 N hydrochloric acid in methanol are added to 28.6 g (0.1 mol) of the potassium salt of 2-carboxy-4,6-dichloro-5-n-butyl-pyridine and the mixture is heated for 8 hours under reflux. It is then evaporated to dryness and hydrochloric acid which still adheres is distilled off with toluene. The residue is rendered alkaline with 2 N sodium carbonate solution and extracted with ether. The ether phases are combined, dried with sodium sulphate and evaporated. Distillation of the residue in a bulb tube at a temperature of 140°-160° at 0.3 mm Hg yields 2-methoxycarbonyl-4,6-dichloro-5-n-butyl-pyridine of the formula ##STR31##
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([O:21]C)=[O:20])[C:7]=2[C:6]([CH3:23])=[N:5]1)([CH3:3])[CH3:2].BrC1C=C(C(OC)=O)C2C(C=O)=NNC=2C=1.O[Li].O>C1COCC1.O>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([OH:21])=[O:20])[C:7]=2[C:6]([CH3:23])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cccnc2)cc2c1c(C)nn2C(C)C
Agent: COC(=O)c1cc(Br)cc2[nH]nc(C=O)c12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(C(C)C)c2cc(-c3cccnc3)cc(C(=O)O)c12
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylate, 1 (0.5 g, 1.618 mmol) in a mixture of THF and H2O (30 mL) was added LiOH.H2O (0.2 g, 4.85 mmol) and the mixture was refluxed at 80° C. for 8 h. THF was distilled off and the aqueous layer was adjusted to pH˜5 with 10% HCl at 0° C. and the precipitated solid was collected by filtration and dried to afford 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylic acid as an off-white solid (0.51 g). LCMS (ES+) m/z: 296.7.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]3[CH2:19][NH:20][CH2:21][CH2:22][N:11]3[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].Cl>C(Cl)(Cl)Cl.CCOCC>[C:3]1([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]3[CH2:19][N:20]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:21][CH2:22][N:11]3[CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc([C@@H]2CN3CCNC[C@H]3c3ccccc32)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a stirred solution is cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride (7.0 g, 0.20 m) and triethylamine (8.4 g, 0.08 m) in chloroform (100 ml) maintained at 0° under nitrogen was added dropwise propionyl chloride (2.9 g, 0.031 m). The mixture was allowed to warm to ambient temperature and stirred for 16 hours, then treated with 10% HCl (50 ml). The layers were separated and the organic phase washed with 10% HCl (2×50 ml), water (50 ml), and dried over MgSO4. Evaporation of the solvent gave a solid residue, which was slurred with ether and filtered to give 2.1 g cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2-propionyl-2H-pyrazino[2,1-a]isoquinoline, m.p. 250°-251° . An additional 3.2 g of good purity product was recovered from the ether to give a total of 5.3 g (82%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[CH:7]1[CH2:12][CH:11]=[N:10][C:9]([Cl:13])=[N:8]1>CCOC(C)=O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[N:8]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1C1CC=NC(Cl)=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
4-(4-Bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-4,5-dihydropyrimidine (21.65 g, 50.1 mmol) and manganese dioxide (43.6 g, 501 mmol) in EtOAc (240 mL) was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrates were concentrated and the residue purified by flash column chromatography (10-40% EtOAc in heptane) to afford 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine as a yellow oil (17.8 g, 41.4 mmol, 83%). LCMS (m/z) 429.0 (MH+), tR=1.24 minutes; 1H NMR (400 MHz, CDCl3) δ −0.06 (s, 9H), 0.82-0.90 (m, 2H), 1.04-1.11 (m, 2H), 1.14-1.20 (m, 2H), 2.06 (m, 1H), 3.55-3.62 (m, 2H), 5.92 (s, 2H), 7.92 (d, J=5.5 Hz, 1H), 8.62 (d, J=5.5 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[C:9]=2[N:10]=[C:11](Cl)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC>[CH2:18]([NH:21][C:11]1[N:12]=[C:7]([NH:6][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[C:9]=2[N:10]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: Cc1csc2c(NNC(C)(C)C)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCNc1nc(NNC(C)(C)C)c2scc(C)c2n1
Yield: 31.6 %

Procedure:
270 mg (1.0 mmol) of 4-(2-t-butylhydrazino)-2-chloro-7-methylthieno[3,2-d]pyrimidine and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/4] to give 92 mg (yield: 31.6%) of the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=[C:18]([CH:26]([NH2:33])[C:27]4[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=4)[C:17]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:16]3=4)[CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=C1CCC(=O)N1[O:46][C:47](=O)[O:48][C:49]1([CH:52]2[CH2:54][CH2:53]2)[CH2:51][CH2:50]1>ClCCl.C(N(CC)CC)C>[CH:1]1([O:6][C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH:15]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=[C:18]([CH:26]([NH:33][C:47]([O:48][C:49]4([CH:52]5[CH2:54][CH2:53]5)[CH2:51][CH2:50]4)=[O:46])[C:27]4[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=4)[C:17]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:16]3=4)[CH2:13][CH2:14]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1cncc1C(N)C1=Cc2cccnc2C(N2CCN(C(=O)OC3CCCC3)CC2)c2ccc(Cl)cc21
Reactant: O=C(ON1C(=O)CCC1=O)OC1(C2CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cncc1C(NC(=O)OC1(C2CC2)CC1)C1=Cc2cccnc2C(N2CCN(C(=O)OC3CCCC3)CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
4-{6-[Amino-(3-methyl-3H-imidazol-4-yl)-methyl]-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl}-piperazine-1-carboxylic acid cyclopentyl ester (60 mg, 0.11 mmol) was dissolved in 5 ml of dichloromethane and 0.2 ml of triethyl amine. Carbonic acid bicyclopropyl-1-yl ester 2,5-dioxo-pyrrolidin-1-yl ester (45 mg, 0.19 mmol) was added and the reaction mixture stirred for 18 hours at ambient temperature under a dry nitrogen atmosphere. The reaction mixture was washed with brine and evaporated to a solid. The solid was chromatographed on silica gel using 5% methanol/dichloromethane as eluent to obtain 49 mg of title product.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:13][OH:14].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]=[O:14]
Reactant: O=c1c(Br)c(CO)nc2ccccn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1nc2ccccn2c(=O)c1Br

Procedure:
To a suspension of 3-bromo-2-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1 equiv) and NaHCO3 (6 equiv) in DCM was added Dess-Martin periodinane (1.5 equiv) at rt with stirring. The reaction mixture was stirred at rt for 3 h, monitered by MS and TLC. The mixture was diluted with DCM and filtered off through Celite™, and the filtrate was cond under vacuum. The crude was purified by silica gel column chromatography using 80% EtOAc in hexane as eluent to give the 3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde as a yellowish solid: 1HNMR (400 MHz, DMSO-d6): δ10.12 (s,1H), 9.00-9.01 (dd,1H), 8.03-8.12 (m,1H), 7.89-7.91 (dd,1H), 7.50-7.54 (m,1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:45]/[O:46][C:47]([CH3:52])([CH3:51])[C:48]([OH:50])=[O:49])/[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]([S:16]([OH:19])(=[O:18])=[O:17])[C@@H:12]2[CH2:20][N:21]2[CH:25]=[C:24]([CH2:26][NH:27][C:28]([NH:37]C(OC(C)(C)C)=O)=[N:29]C(OC(C)(C)C)=O)[N:23]=[N:22]2)=[O:9])[N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:45]/[O:46][C:47]([CH3:52])([CH3:51])[C:48]([OH:50])=[O:49])/[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]([S:16]([OH:19])(=[O:17])=[O:18])[C@@H:12]2[CH2:20][N:21]2[CH:25]=[C:24]([CH2:26][NH:27][C:28]([NH2:37])=[NH:29])[N:23]=[N:22]2)=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)N=C(NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nn1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(CNC(=N)N)nn1)c1csc(N)n1)C(=O)O
Yield: 3.1 %

Procedure:
To a solution of 2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (0.15 mmol, assumed quantitative conversion) In DCM (1.5 mL) at 0° C. was added TFA (689 μL, 9 mmol). The cold bath was removed after 10 min. After 4 h at rt it was diluted with DCM (1.5 mL) and concentrated in vacuo. The crude residue was purified by reverse phase prep HPLC (X-Bridge, 30×100 mm, 5 μm, C18 column; acetonitrile-water with 0.1% formic acid modifier, 1 mL/min) to afford the title compound (2.7 mg, 3%). LCMS: m/z=572.0 (M−1); 1H NMR (400 MHz, D2O): δ 1H NMR (400 MHz, D2O): δ 7.91 (s, 1H), 6.80 (s, 1H), 5.31 (d, J=5.2 Hz, 1H), 4.54 (s, 1H), 4.35 (s, 2H), 3.50-3.35 (m, 2H), 1.19 (s, 3H), 1.18 (s, 3H).