Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH:19][C@@H](C3C=CC(OC)=CC=3)C)[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3].FC(F)(F)C(O)=O>CC(O)C.Cl>[ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH2:19])[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3]
Reactant: CCOc1cc([C@H]2CSCC[C@H]2N[C@H](C)c2ccc(OC)cc2)ccc1OC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOc1cc([C@H]2CSCC[C@H]2N)ccc1OC
Temperature: 25 °C

Procedure:
A mixture of (3R,4R)-3-(3-Ethoxy-4-methoxy-phenyl)-N-[(1R)-1-(4-methoxy-phenyl)-ethyl]-tetrahydro-2H-thiopyran-4-amine hydrochloride (1.0 g; compound C14) and trifluoroacetic acid (2 ml) is stirred at reflux temperature for 30 min yielding a dark red solution. Cooled to RT the solution is evaporated, the dark viscous residue is dissolved in a mixture of diethylether (5 ml) and water (5 ml) and the pH of the solution is increased up to 10 by adding some drops of a 40% aqueous solution of sodium hydroxide. The mixture is extracted with diethylether, the organic phase is washed with a saturated aqueous solution of NaHCO3 and then extracted two times with a 20% aqueous solution of citric acid. The pH of the collected aqueous acid solutions of about 2.4 is increased up to 10 by adding a 40% NaOH solution and the basic mixture is extracted with diethylether. The organic phase is washed two times with water, dried over sodium sulfate and then evaporated to give an oily residue. This is dissolved in 2-propanol (10 ml) and to the stirred solution a 5-6 M solution of hydrogen chloride in 2-propanol (1 ml) is added dropwise at RT inducing a spontaneous crystallization. The slurry is concentrated to about half of the volume and stirred for 15 h at RT. The crystals are filtered off, washed with 2-propanol (2 ml), dried in vacuo at 40° C. to give the title compound. M.p. 233° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:49]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[CH2:50]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:49]3[CH2:53][CH2:52][CH:51]([C:54]4[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=4)[CH2:50]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: c1cncc(C2CCNC2)c1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1Cl
Yield: 65.1 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyrrolidin-3-ylpyridine (6 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z 384 (M+1); HRMS, calcd for C20H18ClN3O3: 383.1037, found 383.1033.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([O:17]CC)=O)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].CC[O-].[Na+]>CCO>[O:17]=[C:15]1[CH2:14][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OCC)CC1=O
Temperature: 80 °C

Procedure:
Intermediate (e) (18.0 g, 65.2 mmol) was added to an ice bath cooled solution of NaOEt (32.6 mL) (21% by weight in EtOH) in absolute EtOH (41.7 mL) under a nitrogen atmosphere. The ice bath was removed and the mixture was heated at 80° C. for about 12 h until the condensation was complete as observed by TLC. The mixture was poured onto ice/water and extracted into EtOAc. The solvent was dried with Na2SO4, filtered, and evaporated to afford crude intermediate (f) as an off white solid (14.05 g) which was carried on without purification.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:13]1([C:25]2[C:26]([O:31][CH2:32][CH3:33])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=2)[NH:15][C:14]1=[O:24].Cl>CN(C)C=O.ClCCl.CCCCCCC.C(OCC)(=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:13]1([C:25]2[C:26]([O:31][CH2:32][CH3:33])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=2)[NH:15][C:14]1=[O:24])[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(C#N)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOc1ncccc1C1(C(C(=O)OC)C(=O)OC)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105 %

Procedure:
5.68 ml (49.75 mmol) of dimethyl malonate were slowly added dropwise to a suspension, cooled to 10° C., of 1.808 g (45.23 mmol, 60% w/w) of sodium hydride in 100 ml of dimethylformamide. The reaction mixture was then stirred at room temperature for 30 minutes and subsequently 4.73 g (15.08 mmol) of 3-chloro-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile from example 1.3 were added in portions undiluted. The reaction solution became dark red in color and was stirred at room temperature for a further 15 minutes. The progress of the reaction was checked by thin-layer chromatography (silica gel, heptane/ethyl acetate 1:1). The mixture was worked up by stirring into cold 1 N HCl and adding dichloromethane. The phases were separated, and the aqueous phase was extracted with dichloromethane (1×). The combined organic phase was washed firstly with water (1×) and then with saturated sodium chloride solution (1×), dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. The residue was again partly dissolved in a little dichloromethane, and pentane was added. Several crystalline fractions were obtained. A total of 6.48 g (15.83 mmol, 100%) of the title compound was obtained as a yellow solid which was only slightly impure.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([CH2:27][OH:28])[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:23]1[CH2:24][CH2:25][C:20]2[C:19](=[O:26])[O:18][C:17]([CH2:27][OH:28])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]=2[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(CO)(c2ccccc2)C2=C1CCNC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C1OC(CO)(c2ccccc2)C2=C1CCN(C(=O)NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Benzyl isocyanate (0.069 g, 0.52 mmol) was added to a solution of 3-phenyl-3-hydroxymethyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.128 g, 0.52 mmol prepared in a manner analogous to compound 2) in dichloromethane (10 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.101 g, 51%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.18-2.47 (m, 2H), 3.19-3.31 (m, 1H), 3.63 (dt, J=13.75, 4.99 Hz, 1H), 3.94-4.07 (m, 3H), 4.07-4.18 (m, 1H), 4.35 (d, J=5.65 Hz, 2H), 4.47 (d, J=18.84 Hz, 1H), 5.50 (t, J=5.65 Hz, 1H), 7.15-7.25 (m, 4H), 7.27-7.42 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH3:41])[C:32]2[NH:37]C(=O)[O:35][C:34](=O)[C:33]=2[CH:40]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O.C(#N)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH3:41])[C:32]2[N:37]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]=3)[O:15][C:34](=[O:35])[C:33]=2[CH:40]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Reactant: O=C(O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylic acid (i.e. product of Step C) (7.9 g, 24 mmol) stirred in dichloromethane (100 mL) was added N,N-dimethylformamide (4 drops). Oxalyl chloride (4.45 g, 35 mmol) was added dropwise over a period of 45 minutes. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. The isolated acid chloride was dissolved in dry acetonitrile (10 mL) and added to a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (i.e. product of Step D) (4.9 g, 23 mmol) stirred in dry acetonitrile (14 mL). Pyridine (10 mL) was added, and the solution heated at reflux 6 hours. After cooling using an ice bath, a precipitate of white solid (9.15 g) was collected. The 1H NMR spectrum of the collected precipitate showed peaks consistent with the title compound and residual 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione starting material. A small portion of the collected precipitate was recrystallized from acetonitrile to yield the pure title product melting at 178-180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:12])[NH:8][CH2:9][C:10]=2[N:11]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([N:8]1[CH2:9][C:10]2[N:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCc2nc(F)ccc2N1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccc2)Cc2nc(F)ccc2N1c1ccccc1
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 6-fluoro-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (120 mg, 0.5 mmol, 1.0 equiv) in DMF (3 mL) was added sodium hydride (60% in mineral oil, 24 mg, 0.6 mmol, 1.2 equiv) and the reaction mixture was stirred for 1 h. Benzyl bromide (70 μL, 0.6 mmol, 1.2 equiv) was added and the mixture was stirred for 16 h. H2O was added and the product was extracted with EtOAc. The organic phase was washed with, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-40%) to afford 3-benzyl-6-fluoro-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (112 mg). MS: [M+H]+=334.
Reaction SMILES: OP(O)(O)=O.[Br:6][C:7]1[CH:8]=[N:9][C:10]([O:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O>O>[Br:6][C:7]1[CH:15]=[C:11]2[C:12](=[O:14])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([I:23])[CH:21]=3)[O:16][C:10]2=[N:9][CH:8]=1
Reactant: O=C(O)c1cc(Br)cnc1Oc1ccc(I)cc1
Agent: O=P(O)(O)O
Solvent: O
Product: O=c1c2cc(I)ccc2oc2ncc(Br)cc12
Temperature: 117.5 °C
Reaction time: 17 h
Yield: 85.3 %

Procedure:
A 5 L 3-neck flask equipped with an overhead stirrer, a thermometer and nitrogen inlet was charged with PPA (4 Kg, 1942 mL) (115% H3PO4) and heated to 115-120° C. 5-Bromo-2-(4-iodophenoxy)nicotinic acid (400 g, 952 mmol) was charged portion wise to the hot PPA. The viscous mixture was then allowed to stir overnight (16-18 h) at 115-120° C. The dark viscous mixture was cooled to 60-65° C. and poured slowly onto a mixture of ice (3000 g) and water (2000 mL) under mechanical stirring. The light brown slurry was allowed to stir overnight and filtered at RT. The wet cake was washed with water (2×1000 mL) followed by IPA (1500 mL) and hexane (2×1000 mL). The solid was dried to obtain 326.4 g of 3-Bromo-7-iodo-5H-chromeno[2,3-b]pyridine-5-one as a grey solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.[CH3:20][O-:21].[Na+]>CO>[CH3:20][O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(OCCCCCCCBr)cc1
Agent: [Na+]
Solvent: CO
Product: COCCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
A solution of methyl 4-[7-bromo-n-heptyloxy)benzoate (2.3 g) in methanol (50 ml) and a solution of 28% sodium methoxide in methanol (3.5 ml) was refluxed for 12 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to the residue and adjusted to pH 1 using hydrochloric acid. The precipitates were collected by filtration, washed with water and dried in vacuo to give an oil. The oil was subjected to column chromatography on silica gel (silica gel 60 F254, Merck: 100 g) and eluted with a mixture of ethyl acetate and n-hexane (1:5). The fractions containing the objective compound were combined and concentrated under reduced pressure to give methyl 4-(7-methoxyheptyloxy)benzoate (1.6 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][NH2:49])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][NH:49][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[CH2:26][CH:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:11])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(O)CNC(=O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)CNC(=O)CC2c3ccccc3-c3ccccc3N2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from {2-[5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetylamino}-acetic acid (Example 12b) and 4-(2-amino-ethyl)-piperidine-1-carboxylic acid tert-butyl ester according to the method described in Example 1e.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[C:11]1([C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH2:4][OH:3])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ncsc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ncsc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
Prepare a cold (0° C.) solution of 5-phenylthiazole-4-carboxylic acid ethyl ester (3.0 g, 12.9 mmol) in tetrahydrofuran (150 mL). Add LiAlH4 (488 mg, 12.9 mmol). Allow the reaction to slowly warm to room temperature and stir for 3 hours. Quench with water (25 mL) and filter through Celite®. Concentrate the filtrate in vacuo to a residue. Chromatograph (silica gel, 3:7 hexane/ethyl acetate) to afford (5-phenylthiazol-4-yl)methanol (1.4 g). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.40-7.55 (m, 5H), 4.80 (d, J=4 Hz, 2H), 3.15-3.22 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30]>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([N:27]5[CH2:34][CH2:33][CH2:32][C@H:28]5[C:29]([OH:31])=[O:30])[CH:26]=[CH:25][C:5]=43)[CH:9]=2)[N:15]([CH2:20][C:21]([F:23])([F:22])[F:24])[N:16]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(CC(F)(F)F)n1
Reactant: O=C(O)[C@@H]1CCCN1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CCC[C@H]4C(=O)O)cc2OCC3)n(CC(F)(F)F)n1

Procedure:
8-bromo-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene and L-proline were reacted to give (S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-pyrrolidine-2-carboxylic acid. LCMS: RT=3.06 min, [M+H]+=463.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].CCOCC.[C:17](O)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CS(O)(=O)=O>>[C:17]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)Oc1ccc2ccccc2c1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 1197.03 g (2.11 moles) of the Alkoxylate from example 18 and 402.97 g (2.01 moles) of Lauric Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[N:5][N:6]([C:8](=[NH:10])[NH2:9])[CH:7]=1.C[O-].[Na+].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C.[OH-].[K+].Cl>CCO.CCOCC>[OH:16][C:17]1[C:18]([C:19]([OH:21])=[O:20])=[CH:24][N:9]=[C:8]([N:6]2[CH:7]=[C:3]([CH3:2])[CH:4]=[N:5]2)[N:10]=1
Reactant: Cc1cnn(C(=N)N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cnn(-c2ncc(C(=O)O)c(O)n2)c1
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
The product of step A (9 g, 46.8 mmol), NaOMe (16.0 mL, 70.2 mmol, 25% wt in MeOH) and diethyl ethoxymethylenemalonate (9.55 mL, 46.8 mmol) was dissolved in EtOH (100 mL). The reaction was heated for 1 h at 78° C. and became very thick. The mixture was slightly cooled and KOH (5.25 g, 94 mmol, 4.5 M in water) was added and the reaction became a cake. EtOH (20 mL) was added and the reaction was reheated at 78° C. for 90 min. Additional KOH (0.88 g, 15.7 mmol, 1 M in water) and EtOH (15 mL) were added and the reaction was heated 1 h. The mixture was cooled and HCl (20.9 mL, 265 mmol, 12 N) was added slowly and the slurry was diluted with Et2O. The solids were filtered, suspended in HCl (0.6 M) and re-filtered. The product was washed with Et2O:EtOH (1:1) and then hexane affording the titled compound. HPLC/MS: 221.1 (M+1); Rt=1.41 min.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO[C:18](OC)([N:20]([CH3:22])[CH3:21])[CH3:19]>C1C=CC=CC=1>[C:1](/[C:9](=[C:18](/[N:20]([CH3:22])[CH3:21])\[CH3:19])/[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(OC)N(C)C
Reactant: N#CCC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: C/C(=C(/C#N)C(=O)c1ccccc1)N(C)C

Procedure:
To a solution of 14.5 g. (0.10 m) of benzoylacetonitrile in 100 ml. of chloroform, cooled in an ice-salt bath, was added 13.3 g. (0.1 m) of N,N-dimethylacetamide dimethylacetal in 20 ml. chloroform. The reaction mixture was stirred in the ice-salt bath for 2 hours, then evaporated in vacuo to an orange oil. The oil was dissolved in 150 ml. benzene and passed through Magnesol®. The filtrate was evaporated and the oil thus obtained was dissolved in 50 ml. benzene to which pet ether was added until the solution became cloudy. The precipitate which formed upon cooling was collected. The solid was recrystallized twice from benzene-pet ether, with charcoal treatment to yield 5.8 g. (27%) of light yellow crystals, m.p. 105°-106° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][CH:15]1[CH2:20][O:19][CH2:18][CH:17]([CH3:21])[NH:16]1.O>C(#N)C>[CH3:14][CH:15]1[N:16]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:17]([CH3:21])[CH2:18][O:19][CH2:20]1
Reactant: CC1COCC(C)N1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1C(C)COCC1C
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (0.311 g, 2.25 mmol) and ethyl bromoacetate (0.319 g, 1.91 mmol) was added to the solution of 3,5-dimethylmorpholine (0.2 g, 1.73 mmol) in acetonitrile (4 mL) at room temperature. The reaction mixture was stirred at 60° C. for 12 h. The reaction mixture was transferred into iced-water and extracted with ethyl acetate (20 mL×3). The combined organic layers was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification (Crude Yield: 54%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH:3]=1.C(O)=O.C(N(CC)CC)C.[OH-].[Na+]>>[CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH2:3]1
Reactant: Cc1cc2c(cn1)nnn2-c1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC1Cc2c(nnn2-c2cnccn2)CN1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
To a solution of 6-methyl-1-(pyrazin-2-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine (245 mg, 1.15 mmol) in formic acid (0.70 mL, 18.5 mmol) was added dropwise triethylamine (1.28 mL, 9.24 mmol). The resulting mixture was heated to 140° C. for 24 h. The reaction was cooled and 1M NaOH was added until the pH was 7-9. The water layer was extracted with CH2Cl2 three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated. The residue was dissolved in 3:1 isopropanol/concentrated HCl (4 mL) and stirred at 50° C. for 16 h. The reaction was cooled and 1M NaOH was added until pH 12 was reached. The water layer was extracted with 1:4 isopropanol/CH2Cl2 three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated to a yellow solid (230 mg, 92%). MS (ESI) mass calcd. C10H12N6, 216.11. m/z found, 217.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.51-9.47 (m, 1H), 8.64-8.60 (m, 1H), 8.49-8.46 (m, 1H), 4.26-4.08 (m, 2H), 3.37-3.28 (m, 1H), 3.14-3.04 (m, 1H), 2.85-2.74 (m, 1H), 2.23-2.02 (br s, 1H), 1.36 (d, J=6.3 Hz, 3H).