Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4](/[CH:5]=[CH:6]\[C:7]#[N:8])[C@H:3]1[C:9](Cl)=[O:10].[CH3:13][OH:14].C1C=CC=CC=1.N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:12])[C@@H:4](/[CH:5]=[CH:6]\[C:7]#[N:8])[C@H:3]1[C:9]([O:14][CH3:13])=[O:10]
Reactant: CO
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1/C=C\C#N
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1[C@H](/C=C\C#N)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1.85 g of (1R,cis) 2,2-dimethyl-3-[(Z)-cyanoethenyl]-cyclopropane-1-carboxylic acid chloride were added at 0° to solution of 2 ml of methanol, 10 ml of benzene and 1 ml of pyridine and the reaction solution was stirred at 20° C. for 16 hours and was poured into water. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with benzene to obtain 0.511 g of methyl (1R,cis) 2,2-dimethyl-3[(Z)-2-cyanoethenyl]cyclopropane-1-carboxylate.
Reaction SMILES: [C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Ni]>[C:1]1([NH:7][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][NH2:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: c1ccc(C2CCNN2c2ccccc2)cc1
Agent: [Ni]
Solvent: CO
Product: NCCC(Nc1ccccc1)c1ccccc1
Yield: 34.5 %

Procedure:
2,3-Diphenylpyrazolidin (133.9 g, 620 mmoles, described in Example 1) is dissolved in methanol (1.7 liters) and the solution is heated at 60° C. in the presence of Raney nickel (37 g) under 50 atmospheres of hydrogen for 5 hr. The catalyst is removed by filtration through diatomaceous earth and the filtrate is evaporated. The residue is crystallized from cyclohexane-hexane to give the title compound (48.4 g) mp 104°-105° C.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].[Br:10]Br>CCOCC>[Br:10][CH:4]([CH:5]([O:8][CH3:9])[O:6][CH3:7])[CH:3]=[O:2]
Reactant: BrBr
Reactant: COC=CC(OC)OC
Solvent: CCOCC
Product: COC(OC)C(Br)C=O
Reaction time: 0.5 h

Procedure:
To a solution of 25.0 g (0.19 mole) of 1,3,3-trimethoxy- 1-propene in 75 ml of ether at 5° C is added 22.4 g (0.14 mole) of bromine (bromine color begins to persist at this point) over a period of 40 minutes. The solvent is removed in vacuo at 25° C and the colorless liquid residue is added dropwise with stirring to a mixture of 25 g of sodium bicarbonate and 80 ml of 75% v/v dioxane at 0°-5° C. Stirring is continued for 30 minutes and the mixture is extracted with 200 ml and 150 ml portions of ether. The extract is dried over magnesium sulfate, evaporated in vacuo and the residue distilled through a Vigreux head to afford 2-bromo-3,3-dimethoxypropionaldehyde, b.p. 70°-73° C/8 mm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][C@@H:13]([CH3:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:4][C:5]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.Cl.N[C@H](C)/C=C/C(OC)=O>>[NH2:1][C:2]1[C:3]([NH:12][C@H:13]([CH3:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:4][C:5]([NH:8][CH:9]([CH3:10])[CH3:11])=[N:6][CH:7]=1
Reactant: COC(=O)CC[C@H](C)Nc1nc(NC(C)C)ncc1N
Agent: COC(=O)/C=C/[C@@H](C)N
Agent: Cl
Product: COC(=O)CC[C@@H](C)Nc1nc(NC(C)C)ncc1N
Yield: 75 %

Procedure:
The title compound was prepared as methyl (4S)-4-({5-amino-2-[(methylethyl)amino]pyrimidin-4-yl}amino)pentanoate with methyl (2E)(4R)-4-aminopent-2-enoate hydrochloride (1.7 g, 10.31 mmol) to give the title compound (2.17 g, 75%): ES-MS (m/z) 282 [M+1]+.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14]>>[F:9][C:8]([F:11])([F:10])[C:7]([C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])[S:6][CH:5]=1)=[O:12]
Reactant: O=C(c1csc(Br)c1)C(F)(F)F
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: O=C(O)c1cccc(-c2cc(C(=O)C(F)(F)F)cs2)c1
Yield: 16 %

Procedure:
This compound was synthesized from 1-(5-bromothiophen-3-yl)-2,2,2-trifluoroethanone and 3-carboxyphenylboronic acid as described in example 88 step 3 (150 mg, yield 16%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.26 (br s, 1H), 8.85 (s, 1H), 8.19 (s, 1H), 8.07-8.05 (m, 2H), 7.96-7.93 (d, J=7.9 Hz, 1H), 7.62-7.57 (t, J=7.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C(N)CC.[N+:15]([CH3:18])([O-:17])=[O:16].C(O)(=O)C>C1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH:18][N+:15]([O-:17])=[O:16]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: C[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: O=[N+]([O-])C=Cc1ccc(O)c(Br)c1
Reaction time: 3 h

Procedure:
3-Bromo-4-hydroxybenzaldehyde (20.1 g.) and n-propylamine (7.6 g.) were refluxed in dry benzene (150 ml.) using Dean-Stark water separator for 3 hours. Benzene phase was concentrated to get the crude aldimine as an oily product. The aldimine (24.2 g), nitromethane (24 ml.) and glacial acetic acid (72 ml.) were refluxed for 45 minutes. The reaction mixture was diluted with cold water. The solid was filtered off and crystallised from aqueous ethanol to obtain the title product; m.p. 132°-34° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[F:25][C:26]1[CH:27]=[C:28]([CH:51]=[CH:52][CH:53]=1)[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][C:35]([NH:39][C:40]3[C:41]4[CH:49]=[C:48]([NH2:50])[N:47]=[CH:46][C:42]=4[N:43]=[CH:44][N:45]=3)=[CH:36][CH:37]=2)[CH:32]=[N:31]1.CC(N(C)C)=O>C1COCC1.O.C(Cl)Cl.ClCCl.CO>[F:25][C:26]1[CH:27]=[C:28]([CH:51]=[CH:52][CH:53]=1)[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][C:35]([NH:39][C:40]3[C:41]4[CH:49]=[C:48]([NH:50][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:47]=[CH:46][C:42]=4[N:43]=[CH:44][N:45]=3)=[CH:36][CH:37]=2)[CH:32]=[N:31]1
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Nc1cc2c(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)ncnc2cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)ncnc2cn1)OCC
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
To a stirred mixture of CDI (1.41 g, 8.73 mmol) and dry THF (6 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (1.56 g, 7.94 mmol) in THF (4 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A solution of compound 220 (1.53 g, 3.97 mmol) in a mixed solvents of dry THF (4 mL) and DMA (5 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=15:1). After stirred overnight (16 h), it was found only ca. 70% reaction occurred. Thus, another batch of reagent was prepared from CDI [0.42 g, 2.62 mmol; DCM (3 ml)] and 2-(diethoxyphosphoryl)acetic acid [0.47 g, 2.38 mmol); DCM (2 mL)] and added to the reaction. It was stirred further for 4 h at 40° C. The reaction mixture was poured into water (200 mL) and stirred with petroleum ether (400 mL) at room temperature for 20 min. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (200 mL). The sticky solid was collected by suction filtration; washed with water (5×30 mL). It was dissolved in acetone (50 mL) and stirred with water (100 mL) and petroleum ether (200 mL) at room temperature for 68 h. The solid was collected, washed with acetone/water=1:10 (5×30 mL) and dried to give diethyl 2-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (229) (1.95 g, 87%); mp 111-114° C.; 1H NMR δ [(CD)2SO]: 10.81 (s, 1H), 10.36 (s, 1H), 8.98 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1 H), 8.16 (d, J=0.7 Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.68 (dd, J=9.0, 1.8 Hz, 1H), 7.42-7.32 (m, 1H), 7.15-7.00 (m, 3H), 5.70 (s, 2 H), 4.17-4.03 (m, 4H), 3.32 (d, partially obscured by water peak, 2H), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C27H27FN7O4P.1.6H2O: C, 54.75; H, 5.14; N, 16.55%. Found C, 54.60; H, 5.21; N, 16.60%.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO>[N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc2[nH]cc(C=C[N+](=O)[O-])c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]cc(CC[N+](=O)[O-])c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of 3-(2-nitrovinyl)-5-methoxycarbonyl-1H-indole (57 mg, 0.23 mmol) in 9 mL THF and 2 mL MeOH with NaBH4 (26 mg, 0.69 mmol). Stir at ambient temperature overnight, concentrate to dryness and partition between conc. NH4OH (10 mL) and dichloromethane. Extract the aqueous layer with dichloromethane, acidify with conc. HCl and extract twice with dichloromethane. Combine the organic layers, concentrate, and chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give the title compound as a solid: 1H NMR (CDCl3) 8.35 (bs, 1H), 8.32 (s, 1H), 7.92–7.90 (m, 1H), 7.38–7.36 (d, 1H), 7.12–7.11 (m, 1H), 4.69–4.65 (t, 2H), 3.93 (s, 3H), 3.51–3.48 (t, 2H); ISMS 248 (M+).
Reaction SMILES: [OH-].[Na+].[N:3]1([C:9]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[C:12]=2[C:17]([O:19]C)=[O:18])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[N:3]1([C:9]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[C:12]=2[C:17]([OH:19])=[O:18])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1c(C)noc1C(=O)N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(C(=O)N2CCCCC2)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
Under a nitrogen blanket and at -15° to -10° C., 1.0 g (25.0 mmol) of sodium hydroxide in 20 ml of water was dripped over a period of 4 hours into a solution of 5.7 g (22.6 mmol) of methyl 5-piperidinocarbonyl-3-methylisoxazole-4-carboxylate in 20 ml of methanol, and the mixture was stirred for 12 hours at room temperature. The solution was evaporated down, the residue was taken up in 100 ml of water, the pH was adjusted to 8-9, and the mixture was extracted once with 100 ml of diethyl ether. The mixture was acidified to a pH of 2 with 6N HCl, and extracted four times, each time with 100 ml of dichloromethane. The combined organic phases dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 91%; mp.: 128°-130° C.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C@@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:25][C@@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH:2]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: c1ccc(-c2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
[1,1′-Biphenyl]-3-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:35][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1>[Al].ClCCCl.CCOC(C)=O>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)[O:35][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Agent: [Al]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 8 h

Procedure:
The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0.983 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (289 mg, 0.800 mmol) in DCE (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) the expected product consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1H, d, J=2.01 Hz), 8.16-8.26 (2H, m), 8.06 (1H, d, J=2.26 Hz), 7.95 (1H, dd, J=8.03, 1.76 Hz), 7.87 (1H, d), 7.45-7.57 (3H, m), 3.86 (3H, s), 2.34 (3H, s). LC-MS retention time: 2.85 min; m/z (MH+):440, 442. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13]C)[CH:12]=1)[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[OH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(c(OC)c1)C(=O)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(O)c2c(c1)CCCC2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
A solution of 6,8-dimethoxy-3,4-dihydro-2H-naphthalen-1-one (15 g, 72.8 mmole), prepared according to the procedure of J. Chem. Soc., London 2782 (1955), which is incorporated herein by reference, in methylene chloride (150 mL) at 0° C. was treated portionwise with AlCl3 (14.3 g, 107 mmole), stirred for 20 h at room temperature, poured onto ice with stirring and extracted with methylene chloride when the ice melted. The extracts were washed with water and brine, dried (MgSO4) and concentrated to provide 13.8 g of the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].I[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[C:16]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(C#N)cc2)CC1

Procedure:
The title compound was synthesized in analogy to example 116, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone and 4-iodobenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:25]\[OH:26])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCC2)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)C2CCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-cyclobutyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=389.1 [M+H]+.
Reaction SMILES: [OH-:1].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[S:14][CH:13]=[CH:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:4]([C:15]1[CH:16]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3](=[O:2])[N:7]2[C:6]=1[C:11]1[CH:12]=[CH:13][S:14][C:10]=1[CH2:9][CH2:8]2)(=[O:1])[CH3:3]
Reactant: [OH-]
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1sccc1-2
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccsc1CC2

Procedure:
A solution of 1 g of 5,6-dihydro-3-hydroxy-2-phenyl-thiazolo[3,2-a]thieno[3,2-c]pyridinium hydroxide (internal salt) and 0.23 g of 3-butyl-2-one in 10 ml of toluene was stirred at room temperature for 48 hours. The solution was evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). There was obtained pure 10-acetyl-4,5-dihydro-8-phenyl-7H-thieno-[3,2-a]quinolizin-7-one of m.p. 181°-182° (from ethyl acetate).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:48]([NH:50][C@H:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53](=[O:55])[NH2:54])=[O:49])[CH2:27][S:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C(NCC)C>CN(C)C=O>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:48]([NH:50][C@H:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53](=[O:55])[NH2:54])=[O:49])[CH2:27][S:28][C:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)CC(N)=O
Reaction time: 0.25 h

Procedure:
1.9 g (1.74 mmol) of Fmoc-Asn-Tyr(tBu)-Cys(Trt)-Asn-OtBu are dissolved in 50 ml of dimethylformamide. To this are added 1.8 ml of diethylamine, and the mixture is left to stand at room temperature for 15 minutes. It is then concentrated under high vacuum, and the residue is triturated with ethyl acetate and dried in vacuo. Yield 0.98 g (65%). C47H58N6O8S (867.081), [α]D21 =-7.2° (c=1, in methanol)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:16][C:17]([F:20])([F:19])[F:18])[C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:21]([NH2:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:16][C:17]([F:20])([F:19])[F:18])[C@H:11]([C:13]([NH:23][CH2:21][CH3:22])=[O:15])[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1
Reactant: CCN
Product: CCNC(=O)[C@H](C)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3-chloro-4-cyanophenyl)-N-(2,2,2-trifluoroethyl)alanine and ethylamine: MS (ES) m/z 334 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)c3ccccc3)ccc2[nH]1
Reaction time: 1 h

Procedure:
To a stirred solution of 2.00 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 100 ml of tetrahydrofuran, cooled at 0° C., is added 13.0 ml of 2.0M phenyllithium and stirring continued is for 1 hour. The cooling is removed and the reaction allowed to reach room-temperature followed by an additional 30 minutes at room temperature. The reaction is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried, evaporated to a residue, which is purified by chromatography on silica gel by elution with 0.25:100 methanol-chloroform to give 0.932 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)CC1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of N-(tert-butoxycarbonyl)-piperidin-4-ol (800 mg, 3.98 mmol), 3-hydroxypyridine (378 mg, 3.98 mmol) and triphenylphosphine (1.148 g, 4.38 mmol) in dry tetrahydrofuran (20 mL) was treated drop-wise via syringe with diethyl azodicarboxylate (0.75 mL, 830 mg, 4.76 mmol). The mixture was allowed to stir and warm to ambient temperature over 16 h. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography over silica gel, eluting with hexane-ethyl acetate-(9:1, v/v). Selected fractions were collected and concentrated to produce 800 mg (72%) of a thick syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 308 (M+H)+.