Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:9])(N)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH2:7].[C:10](OC)(=O)[C:11](OC)=O>>[N:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[CH:11][CH:10]=1
Reactant: COC(=O)C(=O)OC
Reactant: NC1CCCCC1(N)N
Product: c1ccc2nccnc2c1

Procedure:
By the reaction of the cyclohexanetriamine with dimethyl oxalate to give a quinoxaline derivative in step d) of the process according to the invention, a racemate comprising two enantiomers is formed.
Reaction SMILES: C1N2CCN(CC2)C1.I[C:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]=1.C[Si](Cl)(C)C.[CH2:21]([PH:25](=[O:29])[O:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH3:24].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)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>[OH:15][CH:12]1[CH2:13][CH2:14][C:10]([CH2:24][CH2:23][CH2:22][CH2:21][PH:25](=[O:29])[O:26][CH2:27][CH3:28])=[CH:11]1
Reactant: OC1C=C(I)CC1
Reactant: CCCC[PH](=O)OCC
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCO[PH](=O)CCCCC1=CC(O)CC1
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
A solution of DABCO (11.8 g, 0.105 mol) in anhydrous toluene (300 cm3) was heated at reflux for 1 hour with continual stirring. The solution was allowed to cool to room temperature, to which (±)-3-iodo-2-cyclopenten-1-ol (6) (6.35 g, 30.4 mmol) was added. Following this, trimethylsilyl chloride (4 mL) was added slowly, after which the reaction mixture was allowed to stir for 15 minutes. On the side, a solution of ethyl butylphosphinate (3) (21.0 g, 0.140 mol) in DCM (150 cm3) was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Following this, ethyl butylphosphinate (6.83 g, 45.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (876 mg, 2.5 mol %) were then added to the reaction mixture. The reaction mixture was heated at 70° C. for 24 hours after which a second portion of tetrakis(triphenylphosphine)-palladium(0) (876 mg, 2.5 mol %) was added and heating continued for a further 24 hours. The reaction mixture was filtered while still hot and aqueous ethanol (100 cm3), followed by acetic acid (10 cm3) were added to the filtrate, which were then concentrated in vacuo. The product was isolated by short column vacuum chromatography on silica gel (10% ethanol/ethyl acetate) to yield the title compound (7) as a pale yellow oil (4.74 g, 67%; 4.45 g, 63%): 1H-NMR (300 MHz, CDCl3) δH 0.87 (3H, 2×t, J=7.2 and 7.2 Hz & 7.2 and 7.2 Hz, PCH2CH2CH2CH3), 1.17-1.89 (10H, m, C(5)—H′, POCH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3, PCH2CH2CH2CH3), 2.37 (2H, m, C(5)—H and C(4)—H′), 2.62 (1H, m, C(4)—H), 3.45 (1H, br. s, C(3)—OH), 4.02 (2H, m, POCH2CH3),4.95 (1H, m, C(3)—H), 6.62 (1H, d, J=9.7 Hz, C(2)—H); 13C-NMR (75 MHz, CDCl3) δC 13.45 (s, PCH2CH2CH2CH3),16.39 and 16.47 (d, 3JPOCC=6.23 Hz, POCH2CH3), 23.32 and 23.36 (d, 2JPC=3.38 Hz, PCH2CH2CH2CH3), 23.64 and 23.86 (d, 3JPC=15.98 Hz, PCH2CH2CH2CH3), 27.10 and 28.30 (d, JPC=90.23 Hz, PCH2CH2CH2CH3), 31.65 and 31.80 (d, 3JPC=11.70 Hz, C(4)), 33.89 and 33.95 (d, 2JPC=4.58 Hz, C(5)), 60.55 (s, POCH2CH3), 76.61 and 77.03 (d, 3JPC=31.58 Hz, C(3)), 136.94 and 138.51 (d, JPC=117.3 Hz, C(1)), 148.81 (s, C(2)); 31P-NMR (121 MHz, CDCl3) δP 43.93 and 44.18; MS (CI, CH4) m/z 233.1 (100%) (MH+), 215.2 (47), 464.9 (39), 261.2 (18). Synthesis of (±)-ethyl [3-(t-butyldimethylsilyloxy)cyclopentenyl]butylphosphinate (8)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1ccc(Cl)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(CBr)ccc1Cl
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a solution of 5-methyl-2-chlorobenzonitrile (200 mg, 1.32 mmol) in carbon tetrachloride (12 mL) was added N-bromosuccinimide (235 mg, 1.32 mmol) and benzoyl peroxide (32 mg, 0.132 mmol). The mixture was heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate and evaporated to give an orange oil. The oil was purified by silica gel chromatography eluting with 50% heptanes in DCM to afford the title compound (192 mg) as a 2:1:1 mixture with 5-methyl-2-chlorobenzonitrile and 2-chloro-5-(dibromomethyl)benzonitrile respectively, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=4[NH2:43])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][S:45](Cl)(=[O:47])=[O:46].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:37]([NH:43][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:38][CH:39]=[CH:40][C:41]=4[Cl:42])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3NS(C)(=O)=O)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{3-[4-(2-amino-6-chloro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (257 mg, 0.42 mmol) in 4 mL of CH2Cl2 was treated with 32 □L (0.42 mmol, 1.0 eq) of methanesulfonyl chloride and 116 □L (0.83 mmol, 2 eq) of triethylamine and the reaction mixture stirred at 25° C. for 1 h. EtOAc (40 mL) and sat. NaHCO3 (20 mL) were added. The organic layer was separated and washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, and concentrated to afford the crude 1-{3-[4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C32H40ClF3N6O4S, 696.25; m/z found, 697.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]([CH2:8][C@@:9]12[CH2:21][CH2:20][CH2:19][N:10]1[C@@H](C(Cl)(Cl)Cl)[O:12][C:13]2=O)[CH3:7].[NH3:25].CO>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]([CH2:8][C@@:9]1([C:13]([NH2:25])=[O:12])[CH2:21][CH2:20][CH2:19][NH:10]1)[CH3:7]
Reactant: N
Reactant: CN(Cc1cccc(F)c1)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Solvent: CO
Product: CN(Cc1cccc(F)c1)C[C@@]1(C(N)=O)CCCN1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
(3R,7aR)-7a-{[(3-Fluoro-benzyl)-methyl-amino]-methyl}-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (Stage K.1, 385 mg, 0.973 mmol) was added to 7 M ammonia in MeOH (6.950 mL, 48.7 mmol) under argon and heated in a sealed vessel at 50° C. for 6 days and then at 75° C. for 5 days. The RM was then evaporated and the residue purified by flash chromatography using a 12 g RediSep® silica gel column (eluent 5% MeOH in DCM) to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].[N-:8]=[N+:9]=[N-:10].[Na+].Cl>C(O)C.O>[C:1]([N:5]1[C:6](=[S:7])[NH:10][N:9]=[N:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=S
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)n1nn[nH]c1=S
Reaction time: 5.5 h
Yield: 30.5 %

Procedure:
Combined solutions of 50.0 g (0.435 mol) tert-butyl isothiocyanate in 125 ml ethanol and 56.6 g (0.850 mol) sodium azide in 900 ml water were heated under reflux with stirring for 5.5 hours. After cooling, the solution was acidified to pH 1 with hydrochloric acid and extracted with ether. The extracts were washed with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to yield 21 g of colorless oil which later crystallized. The product of a repeat of this preparation was triturated with ligroine to yield colorless crystals of Ia mp 92°-94°, confirmed by NMR, infrared, and mass spectral data as well as elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[O:6].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O.Cl>O1CCOCC1.[OH-].[Na+]>[CH3:11][S:8]([NH:7][C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=1)=[O:6])(=[O:10])=[O:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CS(=O)(=O)NC(=O)c1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.1 %

Procedure:
To a solution of N-(3-aminobenzoyl)methanesulfonamide (400 mg) in dioxane (4 ml) and 1N sodium hydroxide solution (3.73 ml) was added phenyl chloroformate (351 mg) under ice-cooling, and the mixture was stirred for 2.5 hours at ambient temperature. Water was added thereto, the mixture was adjusted pH 3 with hydrochloric acid. The mixture was extracted with chloroform-methanol, and the extract was dried over magnesium sulfate and concentrated in vacuo to give phenyl 3-(methanesulfonylaminocarbonyl)phenylcarbamate (600 mg) as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([NH:5][O:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH3:4].N1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19]>C(#N)C>[CH2:2]([N:5]([O:6][CH2:7][CH2:8][CH3:9])[C:18](=[O:19])[CH2:17][Br:16])[CH2:3][CH3:4]
Reactant: O=C(Br)CBr
Reactant: CCCNOCCC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCON(CCC)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 197.8 %

Procedure:
N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to -20° C. Pyridine (0.2 mL) was added. Bromoacetyl bromide (0.15 g) was added dropwise over 5 min. The solution was stirred at -20° C. for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1×25 mL), 1 N phosphoric acid (3×25 mL), and brine (1×25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.35 g). The product is a mixture of chloro- and bromoacetamides in a ratio of ~3:1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([N:23]1[CH2:24][CH2:25][C:26]([F:30])([F:29])[CH2:27][CH2:28]1)[C:17]1[CH:18]=[N:19][C:14]([C:13]([F:12])([F:31])[F:32])=[CH:15][CH:16]=1)=[O:6]
Reactant: NCC(c1ccc(C(F)(F)F)nc1)N1CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(C(F)(F)F)nc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-(trifluoromethyl)-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][N:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:33])([F:34])[F:32])=[CH:24][CH:23]=2)[N:26]=[N:27]1)[CH3:13]
Reactant: O=c1[nH]nnn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nnn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 69.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.962 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.19 g of 1-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone, 1.31 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].O>O1CCOCC1.C(OO)(C)(C)C.[Br-].[Al+3].[Br-].[Br-]>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: CC(C)(C)OO
Agent: [Al+3]
Agent: [Br-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
In a 50 ml flask, there were charged (-)-cis-chrysanthemic acid (2.0 g), dioxane (17.5) and t-butyl hydroperoxide (0.011 g) under nitrogen. A solution of aluminum bromide (0.032 g) in dioxane (0.5 g) was added thereto at 15°-20° C. with stirring. After 30 minutes, water (0.5 g) was added to the reaction mixture with stirring. The reaction mixture was treated in the same manner as described in Example 1 and 1.91 g of chrysanthemic acid was obtained. The composition was as follows: (+)-cis, 3.3%; (-)-cis, 4.2%; (+)-trans, 46.2%; (-)-trans, 46.2%.
Reaction SMILES: [Si]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[OH:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1ccc(-c2ccc(-c3cccc4c3CCC4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2ccc(-c3cccc4c3CCC4O)s2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
To a stirred solution of 5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile (80 mg, 0.16 mmol) in 1,4-dioxane (1 mL) was added 4N HCl solution in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. Solvent was evaporated and the crude product was purified by chromatography (EA/hexanes) to afford 26 mg (40%) of 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile 223 as a white solid. LCMS-ESI (m/z) calculated for C23H21NO2S: 375.1; found 398.1 [M+Na]+, tR=3.96 min. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.3 Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.53-7.45 (m, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.19 (q, J=3.8 Hz, 2H), 6.97 (d, J=8.9 Hz, 1H), 5.28 (t, J=6.1 Hz, 1H), 4.66 (dt, J=12.2, 6.1 Hz, 1H), 3.28 (ddd, J=16.2, 8.5, 4.7 Hz, 1H), 3.11-2.91 (m, 1H), 2.53 (dddd, J=13.1, 8.2, 6.9, 4.7 Hz, 1H), 2.08-1.92 (m, 1H), 1.57 (s, 1H), 1.41 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 159.37, 146.65, 142.74, 141.52, 140.36, 131.55, 131.08, 130.96, 130.79, 127.79, 127.54, 126.67, 123.82, 116.57, 114.40, 103.82, 76.59, 72.43, 36.07, 30.88, 22.08.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[N:15][NH:14][C:13](=[O:17])[CH:12]=2)=[N:7][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([OH:36])[CH3:35])=[CH:30][C:29]=1[CH3:37])=[O:27].BrC(Br)=O>CS(C)=O.O>[OH:36][CH:34]([C:31]1[CH:32]=[CH:33][C:28]([C:26](=[O:27])[CH2:25][N:14]2[C:13](=[O:17])[CH:12]=[C:11]([O:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)[CH:16]=[N:15]2)=[C:29]([CH3:37])[CH:30]=1)[CH3:35]
Reactant: COc1ccc(COc2cn[nH]c(=O)c2)nc1
Reactant: Cc1cc(C(C)O)ccc1C(=O)CBr
Agent: O=C(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)O)cc3C)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9b, 2.00 g, 8.58 mmol) in DMSO (20 mL) is added cesium carbonate (5.59 g, 17.2 mmol) and the mixture is stirred 10 min at room temperature. Then 2-bromo-1-[4-(1-hydroxy-ethyl)-2-methyl-phenyl]-ethanone (preparation 10b, 2.21 g, 8.58 mmol) is added in portions and the mixture is stirred overnight at room temperature. An additional 0.5 g of the bromoketone is added and the mixture is stirred for 3 h at room temperature. After addition of water, the reaction mixture is extracted with ethyl acetate. The combined organic layer is dried over MgSO4 and evaporated under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:27]([CH:30]1[C:35]2[N:36]=[CH:37][NH:38][C:34]=2[CH2:33][CH2:32][N:31]1[C:39](OCC1SC=CN=1)=[O:40])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:27]([CH:30]1[C:35]2[N:36]=[CH:37][NH:38][C:34]=2[CH2:33][CH2:32][N:31]1[C:39]([O:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1)=[O:40])([CH3:29])[CH3:28]
Reactant: OCC1CCO1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1nccs1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC1CCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 8.6 %

Procedure:
2-Hydroxymethyloxetane (0.71 g, 8.10 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (0.89 mL, 8.10 mmol) and 4-nitrophenyl chloroformate (1.63 g, 8.10 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. A solution of Intermediate 1 (1.16 g, 3.90 mmol) and DIPEA (2.69 mL, 15.4 mmol) in DCM (20 mL) was added and the resulting solution was stirred for 18 h. The solvents were removed in vacuo, the residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (120 mL), the organic layer was washed with 1M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4% and 5% MeOH in DCM (200 mL)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (93.4 mg, 8.7%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=N1.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C)C=O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:23])=[O:14])=[CH:8]2
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (17.20 g), 1H-1,2,3-benzotriazol-1-ol (8.29 g) and N,N-dimethylformamide (150 ml) was added N-[3-(dimethylamino)propyl]-N,N-ethylcarbodiimide hydrochloride (11.8 g) at room temperature, and the mixture was stirred at 50° C. for 20 min. The mixture was allowed to cool to room temperature, and 28% aqueous ammonia (3.4 ml) was added. The reaction mixture was stirred at room temperature for 2 hr, and water was added. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, washed with cooled ethyl acetate, and dried to give the title compound (11.47 g, yield 67%) as colorless crystals. melting point 244-245° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1.Br[C:17]1[CH:22]=[CH:21][N:20]2[CH:23]=[CH:24][N:25]=[C:19]2[CH:18]=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.O>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][N:20]3[CH:23]=[CH:24][N:25]=[C:19]3[CH:18]=2)[CH:8]=1
Reactant: Brc1ccn2ccnc2c1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1cncc(-c2ccn3ccnc3c2)c1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
A suspension of potassium carbonate (0.351 g, 2.54 mmol), pyridin-3-ylboronic acid (68.6 mg, 0.558 mmol), 7-bromoimidazo[1,2-a]pyridine (0.100 g, 0.508 mmol) and tetrakis(triphenylphosphine)palladium (0) (29.3 mg, 0.025 mmol) in 6.5 ml of a 1:1:4.5 mixture of water:dimethylformamide:acetonitrile was degassed thoroughly under a nitrogen atmosphere, and heated at 60° C. for 18 hours. The reaction mixture was poured in water (50 ml) and extracted with dichloromethane and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford a solid. The solid was purified by silica gel chromatography (eluting with 6% MeOH-chloroform) to afford the desired compound (74.1 mg, 75% yield). MS APCI (+) m/z 196.3 (M+1) detected.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]1[N:16]=[C:17]([C:21]([O:23]CC)=O)[NH:18][C:19](=[O:20])[C:8]1=[CH:7]2>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]1[N:16]=[C:17]([C:21]([NH2:1])=[O:23])[NH:18][C:19](=[O:20])[C:8]1=[CH:7]2
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Reactant: N
Solvent: CCO
Product: COc1cc2cc3c(=O)[nH]c(C(N)=O)nc3nc2cc1OC
Temperature: 95 °C

Procedure:
Anhydrous ammonia is bubbled into a mixture of ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (300 mg., 9.00 millimoles) in absolute ethanol (75 ml.) for fifteen minutes. A clear solution formed followed after a few minutes by formation of a precipitate. The reaction mixture is transferred to a pressure bomb (Monel) and heated in a 95° C. oil bath overnight. The bomb is then cooled to room temperature and the contents removed. The bomb is washed with ethanol and the combined reaction mixture plus wash filtered to recover the product. The filter cake is washed with ethanol and then dried in air. Yield = 260 mg. (95%). M.P. 310° C. (dec.).