Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:31][C@H:32]1[C@@H:39]2[N:35]([C:36](=[O:53])N(C3C4CCCCC=4C(C#N)=CC=3)[C:38]2=[O:40])[CH2:34][CH2:33]1>>[OH:31][C@H:32]1[C@@H:39]2[N:35]([C:36](=[O:53])[N:7]([C:6]3[CH:5]=[C:4]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:3]([C:1]#[N:2])=[CH:9][CH:8]=3)[C:38]2=[O:40])[CH2:34][CH2:33]1
Reactant: N#Cc1ccc(N)cc1-c1ccccc1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)cc1-c1ccccc1

Procedure:
The title compound was prepared from compound 47A by procedures analogous to those described in Experiment 2E and 2F. HPLC: 96% at 3.24 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 334 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH2:12][CH2:13]O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].C(N(CC)CC)C.C(OCC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>O>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH2:12][CH2:13][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc2c(CCO)cccc2c1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: Cc1oc2c(CCS(C)(=O)=O)cccc2c1C
Temperature: -30 °C
Reaction time: 1 h
Yield: 111.9 %

Procedure:
5.1 g (26.5 mmol) of 2,3-dimethyl-7-(2-hydroxyethyl)benzofuran, 5.91 ml (42.5 mmol) of triethylamine and 500 ml of anhydrous ethyl ether are introduced, under an inert atmosphere, into a 1 l round-bottomed flask. The mixture is cooled to -30° C. and 3.3 ml (42.5 mmol) of mesyl chloride are added dropwise. The reaction mixture is stirred for 1 h 30, while being allowed to return to 0° C. 200 ml of water are added and extraction is carried out with ethyl ether. The organic phases are combined and concentrated under vacuum. 7.48 g of 2,3-dimethyl-7-(2-(methylsulphonyl)ethyl)benzofuran are obtained in the form of an oil. 7.18 g (26 mmol) of 2,3-dimethyl-7-(2-(methylsulphonyl)ethyl)benzofuran and 200 ml of diethylamine are introduced into a 500 ml round-bottomed flask equipped with a reflux condenser. The reaction mixture is stirred for 16 h at reflux and concentrated under vacuum and the residue is purified by silica column chromatography (elution solvent: 9/1 dichloromethane/methanol).
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:14]2[C:13](=[CH:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=3)[C:12]3[CH:34]=[CH:35][CH:36]=[CH:37][C:11]=3[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C>[CH:3]1[C:14]2[C:13](=[CH:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:12]3[CH:34]=[CH:35][CH:36]=[CH:37][C:11]=3[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3OCOc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCC=C2c3ccccc3OCOc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 15% aqueous solution of NaOH (4 ml) was added to a solution of ethyl 3-(4-(2-(12H-dibenzo(d,g)-1,3-dioxocine-12-ylidene)ethoxy)phenyl)-2-ethoxypropionate (0.95 g, 2.0 mmol) in ethanol (15 ml), and the mixture stirred at room temperature for 2 h, then left to stand overnight. The resulting solution was evaporated, water (20 ml) and benzene (25 ml) were added, and the mixture acidified to pH 6 with acetic acid. The benzene layer was separated, and the water layer further extracted with benzene (2×10 ml). The combined benzene extracts were washed with water (20 ml), brine (15 ml), dried (MgSO4) and evaporated to give 3-(4-(2-(12H-dibenzo(d,g)-1,3-dioxocine-12-ylidene)ethoxy)phenyl)-2-ethoxypropionic acid: 0.79 g (83.2%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[BH3-][C:26]#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH3:26])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2ccccc2)COC1(C)C
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CN(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (500 mg; example 2.a) at r.t. in methanol (10 ml) under an argon atmosphere were added formaldehyde (37% solution in H2O; 0.62 ml), zinc chloride (890 mg) and NaBH3CN (308 mg). The mixture was heated to 40° C. and stirring at that temperature was continued for 2 h. The mixture was concentrated and the residue was taken up in EtOAc/H2O. The biphasic mixture was filtered. The aqueous layer from the filtrate was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:cyclohexane->cyclohexane/EtOAc 85:15) to give (S)-2,2-dimethyl-4-[(methyl-phenyl-amino)-methyl]-oxazolidine-3-carboxylic acid tert-butyl ester (462 mg, 88%) as colorless viscous oil. MS (ISP): 321.4 ([M+H]+)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[C@@H:8]12[CH2:14][C@@H:11]([CH2:12][CH2:13]1)[CH2:10][C@H:9]2[N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[C:25](Br)[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH2:17][CH2:16]1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)O1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C>[C@@H:8]12[CH2:14][C@@H:11]([CH2:12][CH2:13]1)[CH2:10][C@H:9]2[N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[C:25]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1ccc(Br)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(-c2ccncc2)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1

Procedure:
Dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium(II)dichloromethane adduct (12 mg, 0.015 mmol), acetonitrile (500 μL), 2.0 M sodium carbonate (aq) (250 μL), 1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(5-bromo-2-methoxyphenyl)piperidine hydrochloride (compound no. 187) (60 mg, 0.15 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (31 mg, 0.15 mmol) were combined in a microwave vial. The vial was flushed with nitrogen, capped and microwaved at 140° C. for 20 min. The reaction was diluted with methanol (750 μL), mixed well and then filtered (Whatman 0.20 μM PTFE) and subjected to reverse-phase HPLC purification (2-40% CH3CN/0.08% TFA) to yield [4-(3-(1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)piperidin-4-yl)-4-methoxyphenyl) pyridine] (compound no. 124) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 363.4 [M+H]+, retention time 1.67 min.
Reaction SMILES: C[Si]([Br:5])(C)C.[F:6][C:7]1[C:8]([C:15]2[S:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[C:21]([F:24])[C:22]=3[N:23]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C(=O)(O)[O-].[Na+]>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:8]3[C:7]([F:6])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]#[N:11])=[N:23][C:22]=2[C:21]([F:24])=[CH:20][N:19]=1
Reactant: N#Cc1cccc(F)c1-c1nc2c(F)cnc(Cl)c2s1
Reactant: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1cccc(F)c1-c1nc2c(F)cnc(Br)c2s1
Temperature: 50 °C
Yield: 94.7 %

Procedure:
Trimethylsilyl bromide (0.92 mL, 6.85 mmol) was added to a suspension of 3-fluoro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile (0.70 g, 2.28 mmol) in propionitrile (20 mL) at room temperature, under argon. The reaction mixture was heated at 50° C. for 16 hours. The reaction mixture was adjusted to pH 7 by careful addition of a saturated aqueous solution of sodium bicarbonate. The resultant mixture was extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resultant solid was triturated with diethyl ether and dried under vacuum to afford the title compound as an off-white solid (0.76 g, 95% yield). LCMS (Method D): RT=3.87 min, m/z: 352 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.B([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29])(O)O.C([O-])([O-])=O.[Cs+].[Cs+].Cl>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.O.O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=[O:29])=[CH:7][N:6]3[C:8]=2[C:18](=[O:19])[NH:20][CH3:21])=[CH:12][CH:13]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)O)c3)cn12
Temperature: 100 °C
Yield: 77.7 %

Procedure:
6-Bromo-2-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (150 mg, 0.431 mmol) and 3-boronobenzoic acid (107 mg, 0.646 mmol) were slurried into dioxane (5 mL) and water (1 mL). To the reaction mixture was added Cs2CO3 (211 mg, 0.646 mmol) followed by Pd(PPh3)4 (50 mg, 0.043 mmol). The reaction was sealed and heated at 100° C. overnight. The reaction solution was cooled to rt, filter to remove solids, diluted with water (˜10 mL) and acidified with 1N HCl (aq) (1.5 mL, 1.5 mmol). The white precipitate that formed was collected by filtration, washed with water and dried to yield 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (174 mg, 0.335 mmol, 78% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 13.15 (br s, 1H), 9.01 (s, 1H), 8.25-8.17 (m, 2H), 8.00 (t, J=7.5 Hz, 2H), 7.87 (d, J=8.7 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.65-7.59 (m, 1H), 7.59-7.53 (m, 1H), 7.32 (d, J=8.9 Hz, 2H), 2.82 (d, J=4.0 Hz, 3H). LC-MS retention time 1.18 min: m/z 388 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u 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 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(OC([O:6][C:7]1[C:8]2[N:9]([CH:28]=[CH:29][N:30]=2)[C:10]2[C:19](C([O-])=O)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:11]=2[N:12]=1)=O)C.[ClH:31].C(OCC)(=O)C>O1CCCC1.O>[ClH:31].[CH:28]1[N:9]2[C:10]3[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:11]=3[NH:12][C:7](=[O:6])[C:8]2=[N:30][CH:29]=1
Reactant: CCOC(=O)Oc1nc2c(n3ccnc13)C(C(=O)[O-])(C(=O)OCC)c1ccccc1-2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 8 h

Procedure:
To a solution of 0.22 g of ethyl 4-ethoxycarbonyloxy-10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-10,10-dicarboxylate in 20 ml of tetrahydrofuran are added 5.5 ml of 1N hydrochloric acid at a temperature in the region of 20° C. After reacting overnight at the same temperature, the tetrahydrofuran is evaporated off under reduced pressure (15 mmHg; 2 kPa) and the aqueous solution thus obtained is diluted with 5 ml of distilled water. The addition of 10 ml of ethyl acetate causes formation of a cream-coloured precipitate which is filtered off, washed and dried to give 0.15 g of ethyl 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-10-carboxylate hydrochloride in the form of a cream-coloured solid (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 1.23 (t, J=7.5 Hz, 3H: --CH3 ethyl); from 4.00 to 4.40 (mt, 2H: --OCH2 -ethyl); 5.41 (s, 1H: --CH-- 10); 7.43 and 7.51 (2 broad t, J=8 Hz, 1H each: --H 7 and --H 8); 7.75 and 7.97 (2 broad d, J=8 Hz, 1H each: --H 6 and --H 9); 7.82 and 8.14 (2s, 1H each: --H of the imidazole); 12.95 (mult., 1H: --CONH--)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]1[C:11](=[O:12])[NH:10][C:9](=[S:13])[NH:8][C:7]1=[O:14].[C:19](=O)([O-])[O-].[K+].[K+].CI.Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([OH:14])=[N:8][C:9]([S:13][CH3:19])=[N:10][C:11]=1[OH:12]
Reactant: COc1ccccc1OC1C(=O)NC(=S)NC1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: COc1ccccc1Oc1c(O)nc(SC)nc1O
Reaction time: 4 h
Yield: 61.9 %

Procedure:
19.8 g 5-(o-methoxyphenoxy)-2-thioxo-dihydro-pyrimidine-4,6-dione was dissolved in 100 ml DMSO and 10.28 g potassium carbonate was added. After 30 min 4.36 ml methyl iodide was added in portions within 10 min. Stirring was continued for 4 h followed by the addition of 250 ml water. The solution was acidified with 25% hydrochloric acid. The precipitated product was filtered off, washed with diethylether and dried in vacuo to give 12.9 g 5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidine-4,6-diol. LC-MS: tR=3.01 min, [M−1]−=279.15.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:92]=[C:93]1[CH:97]=[CH:96][C:95](=[O:98])[N:94]1[CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][C:104]([NH:106][NH2:107])=[O:105]>CN(C=O)C>[O:98]=[C:95]1[CH:96]=[CH:97][C:93](=[O:92])[N:94]1[CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][C:104]([NH:106][NH:107][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:105]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
38 mg (47 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[2-(1H-indol-3-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 37 ml of DMF and then admixed with 71 mg (187 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 33 μl of N,N-diisopropylethylamine and with 37 mg (140 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT for 1 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 12.2 mg (26% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Mg+2].[Cl-].[Cl-].C([O-])(=O)CC([O-])=O.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCOCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-chlorophenyl)tetrahydro-2H-pyran-4-carboxylic acid (0.500 g, 2.08 mmol) in IPAc (2.5 mL) was added DMF (0.050 mL). Oxalyl chloride (0.277 g, 0.19 mL, 2.18 mmol) was then added at ambient temperature over a period of 20 minutes. The resulting solution was stirred at room temperature for a period of 2 hours. In a separate flask, a solution of diethyl malonate (0.420 g, 0.40 mL, 2.60 mmol) in IPAc (3.5 mL) was treated with MgCl2 (0.247 g, 2.60 mmol). The resulting slurry was aged at room temperature for 30 minutes and subsequently treated with TEA (0.704 g, 0.97 mL, 2.60 mmol). After a further 2 hours at ambient temperature, the malonate slurry was cooled to 5° C. and treated with the acyl chloride solution. The resulting mixture was aged at room temperature for 2 hours then treated with a 5N HCl solution (2.5 mL). The organic layer was separated, and the aqueous layer was extracted 3 times with IPAc (2.5 mL). The organic phases were combined, dried (MgSO4), and concentrated under reduced pressure to afford the title compound as an orange oil. MS m/e=383.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]3[OH:29])=[O:21])[C:12](=[O:19])[N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[N:6][CH:7]=1.[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)[C@@H]1CCCC[C@H]1N>CS(C)=O.[Cu]I>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[NH:22][C:20]([C:11]1[C:12](=[O:19])[N:13]2[C:18]([CH:17]=[CH:16][CH:15]=[CH:14]2)=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[CH:7][N:6]=2)[CH:10]=1)=[O:21]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Br)cn2)c2ccccn2c1=O
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(-n3cccn3)cn2)c2ccccn2c1=O
Temperature: 120 °C

Procedure:
To a solution of 1-[(5-bromopyridin-2-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide (Example 2, 0.045 g, 0.099 mmol) and pyrazole (0.020 g, 0.30 mmol) in 2 mL of DMSO under an atmosphere of nitrogen was added aqueous cesium carbonate (1 M, 0.20 mL, 0.20 mmol), trans-N, N-dimethylcyclohexane-1,2-diamine (0.014 g, 0.10 mmol), and copper(I) iodide (0.014 g, 0.076 mmol). The mixture was heated at 120° C. for 15 h, cooled to rt, and subjected to purification via reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 444.0 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.46 (d, J=7.6 Hz, 1H), 8.93 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.17-8.08 (m, 2H), 7.85-7.82 (m, 1H), 7.75 (s, 1H), 7.49-7.44 (m, 2H), 6.56-6.55 (m, 1H), 4.53 (s, 2H), 3.86-3.82 (m, 1H), 3.74-3.70 (m, 1H), 2.13-2.02 (m, 2H), 1.89-1.73 (m, 13H), 1.43-1.33 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Br:16][CH2:17][CH2:18]Br.[OH-].[Na+].C1C=C2C3C=CN=CC=3NC2=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:18][CH2:17][Br:16])[C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCBr)C(=O)CCC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
199 g. (1 mole) of 6-methyl-1,2,3,4-tetrahydrocarbazol-1-one (m.p.: 199° C., as given in literature: 194°-195° C., 195°-196° C., 195° C., cf. Bloink and Pausacker loc. cit. page 1330), 1520 g. (8.1 moles), 1.2-dibromoethane and 1000 ml. (7.5 moles) of aqueous sodium hydroxide solution (30% strength) are taken initially and admixed, while stirring at room temperature, with 4.25 g. (12.5 m mole) of tetrabutylammoniumhydrogensulfate dissolved in 25 ml of water. With a slight temperature rise, the reaction sets in and while continuously stirring, comes to an end after some seven hours' time. For working up, the aqueous alkaline layer is separated, the organic layer washed with water and the excess dibromoethane distilled off in vacuo. The residue is recrystallized from 200 ml. of ethanol. Obtained are 281 g.=92% of the theoretical of 6-methyl-9-(2-ethylbromide)-1,2,3,4-tetrahydrocarbazol-1-one melting at 103° C. The amount of the tetrabutylammoniumhydrogensulfate used as catalyst can be reduced to 5 m moles per 1 mole of the carbazoline employed. During the procedure the reaction takes twice as long.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:37]3[N:36]=[C:30]([NH:31][C:32](=[S:35])[NH:33][CH3:34])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:47]1([N:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:37]3[N:36]=[C:30]([NH:31][C:32](=[S:35])[NH:33][CH3:34])[N:29]=[C:27]([O:28][C:54](=[O:55])[N:53]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CNC(=S)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-methylthiocarbamoyldeoxyguanosine (1.0 g, 1.76 mmol) was azeotroped with anhydrous pyridine three times and dissolved in anhydrous pyridine (17 mL). To the resulting solution, diisopropylethylamine (511 μL, 3.16 mmol) and then diphenylcarbamoyl chloride (489 mg, 2.11 mmol) were added. The mixture was stirred at room temperature for 0.5 hours, and then sodium bicarbonate water (5 mL) was added thereto to terminate the reaction. Then, the reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (120 mL) once and then with ethyl acetate (150 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with ethyl acetate/40% to 50% hexane to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (1.09 g, 81%).