Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)OCC3C=CC=CC=3)=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1.CO.O(C(C)(C)C)[Li].[C:30]([O:33][C@H:34]([CH2:40]Cl)[CH2:35][NH:36][C:37](=[O:39])[CH3:38])(=[O:32])C>CN(C=O)C>[CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:40][C@H:34]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:33][C:30]3=[O:32])=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Reactant: O=C(Nc1ccc2c(c1)CCOC2)OCc1ccccc1
Agent: [Li]OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCOC3)C(=O)O1
Temperature: 25 °C
Reaction time: 66 h
Yield: 50.5 %

Procedure:
A solution of phenylmethyl (3,4-dihydro-1H-2-benzopyran-6-yl)carbamate (Step 1, 1.60 g, 5.65 mmol) and MeOH (0.458 mL, 11.3 mmol) in dry DMF (5.6 mL) under N2 is cooled in an ice bath and treated with LiOtBu (1M in THF, 16.95 mL, 16.95 mmol) dropwise over 2 mins. Then, the (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate (2.19 g, 11.3 mmol) is added all at once, the cooling bath is removed and the mixture is stirred at ambient temperature for 2.75 days and is then diluted with H2O (20 mL) and extracted with EtOAc (4×50 mL). The combined organic phase is washed with brine (25 mL), dried over MgSO4 and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-2/98). Those fractions with an Rf=0.23 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated and the product triturated with EtOAc to give 828 mg (50%) of the title compound as a white solid, mp 142-145° C. [α]25D=−24° (c 1.01, DMSO).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)[CH:16]=1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1C

Procedure:
58.3 mg of the target compound (0.16 mmol, 20.0%) was obtained using 1-(2,3-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>N1C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NS(=O)(=O)c2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (50 mg, 0.17 mmol) in 5 mL of pyridine was added 3-fluorobenzene-1-sulfonyl chloride (41 mg 0.21 mmol) below 0° C. The mixture was stirred at room temperature under nitrogen overnight. Pyridine was removed in vacuo and the residue was purified by preparative thin layer chromatography to afford 2-(4-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 43 mg, yield: 62%. MS (ESI+APCI) M+1=455.50.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.CN(C)C=O>O>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:28]=1[O:29][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8])[CH:22]=[O:21]
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyl-1,3-thiazole (1.0 g), potassium carbonate (0.57 g), vanillin (0.62 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.28 g, 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 133-134° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]([O:27][C:28](=[O:43])[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][C:37]([NH2:39])=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:40][CH2:41][CH3:42])([CH3:26])([CH3:25])[CH3:24]>ClCCCl.O>[C:23]([O:27][C:28](=[O:43])[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][C:37]([NH:39][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:40][CH2:41][CH3:42])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=Cc1ccccc1
Reactant: CCCc1nc2cc(N)ccc2n1CC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (1.8 g, 8.4 mmol) was added to a solution of benzaldehyde (0.68 mL, 6.5 mmol) and (5-amino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (1.8 g, 6.5 mmol) in DCE (15 mL), and stirred overnight at room temperature. The reaction solution was diluted with H2O. The organic solution was washed with brine, dried over MgSO4, and concentrated to afford the subtitle compound that was used without further purification. MS calculated for C23H29N3O2+H: 380, observed: 380.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[N:14][C:13]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[N:20]=1>N1C=CC=CC=1>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[N:17]=[C:16]([NH:18][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH:15]=[N:14][C:13]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[N:20]=1
Reactant: Cc1nccc(-c2ncc(N)nc2-c2ccco2)n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1nccc(-c2ncc(NC(=O)C3CC3)nc2-c2ccco2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
Cyclopropanecarbonyl chloride (0.028 mL, 0.30 mmol) was added to a stirred solution of 6-(2-furyl)-5-(2-methylpyrimidin-4-yl)pyrazin-2-amine (Example 9, 38 mg, 0.15 mmol) in pyridine (0.5 mL). The mixture was heated to 80° C. in a sealed tube and stirred for 3 h. The crude reaction was concentrated to dryness and the residue was diluted with ethyl acetate and washed with aqueous sodium bicarbonate 4%. The organic layer was dried (Na2SO4) and evaporated. The residue was purified with flash silica gel chromatography (30% ethyl acetate in hexanes). Concentration in vacuo of the product-rich fractions provided the titled compound as a pale-yellow solid (12 mg, 25%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[OH-].[K+].[N+:11]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[O:8][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:3][CH:2]=1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Reactant: O=Cc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccncc1)N1CCCC1
Yield: 98 %

Procedure:
SLA 07092 was prepared in accordance with method D using pyridine-4-carbaldehyde (1.88 mL, 19.76 mmol), KOH (1.01 g, 18.00 mmol) in methanol (18 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (2.73 g, 19.76 mmol). The residue was partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer was combined with additional ethyl acetate extracts (2×150 mL), washed with aqueous sodium chloride (2×150 mL) and dried over MgSO4, filtered and evaporated. Trans-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(pyrrolidin-1-yl)methanone Compound 19 was obtained as a white solid (4.32 g, 98% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:8]([C:7]1[C:2]2[N:1]=[CH:12][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cccc2ocnc12

Procedure:
Compounds of Formula I also can be prepared as illustrated by exemplary reaction in Scheme 3. Reaction of 2-amino-3-nitro-phenol and triethyl orthformate in the presence of a acid such as p-toluenesulfonic acid produced 4-nitrobenzooxazole. The nitro group was reduced to give the 4-amino-benzooxazole, which was converted to the methylamino-benzooxazole in two steps. Treatment of the compound with base, such as sodium ethoxide converted the 4-methylamino-benzooxazole into a 4-hydroxy-1-methylbenzimidazole. Reaction of 4-hydroxy-1-methylbenzimidazole with an aryl-aldehyde such as 5-bromoveratraldehyde and malononitrile in the presence of a base, such as piperidine produced the substituted 7-methyl-imidazo[4,5-h]chromene.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]3([CH3:17])[CH2:16][CH2:15]3)=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.CCN(CC)CC.Cl[C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]3([CH3:17])[CH2:15][CH2:16]3)=[O:12])=[CH:9][N:10]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:5]2=[N:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(NC(=O)c2c[nH]c3ncc(Br)nc23)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(NC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Br)nc23)CC1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
To a solution of 2-bromo-N-(1-methylcyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (600 mg, 2.1 mmol) in 20 mL of dry THF was added Et3N (0.42 mL, 4.2 mmol) and reaction mixture stirred for 5 mins, then (chloromethanetriyl)tribenzene (540 mg, 2.53 mmol) was added and reaction mixture stirred for 10 mins. Then, the reaction was heated to 60° C. and stirring continued for 3 hrs. The reaction was quenched with brine (10 mL), product extracted with ethyl acetate (3×20 mL), organics combined dried with sodium sulfate, filtered and concentrated to give 2-bromo-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (400 mg, 37%) as yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 1H), 8.01 (s, 1H), 7.31-7.26 (m, 15H), 1.51 (s, 3H), 1.25 (s, 2H), 0.90-0.74 (m, 2H). LCMS: (M+H)+=537/539.
Reaction SMILES: O[CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].P(Br)(Br)[Br:18]>C(OCC)C>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:2][Br:18]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Yield: 215.5 %

Procedure:
A solution of 1.00 g (4.5 mmol) of (E,E)-farnesol (Aldrich, further purified by flash chromatography) in 10 ml of distilled diethyl ether at 0° C. under argon in the dark was treated dropwise with a solution of 195 μL (2.05 mmol, 0.45 eq.) of PBr3 in 2 ml of diethyl ether. The resultant mixture was stirred at 0° C. for one hour, then quenched with water and separated. The organic phase was washed with 5 ml of H2O, 5 ml of saturated NaHCO3, and 5 ml of brine, dried over Na2SO4 and evaporated to give 1.26 g (98%) of crude bromide as a clear oil.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.O>C1COCC1>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:17]1([OH:20])[CH2:18][CH2:19][C:14]2([O:21][CH2:11][CH2:12][O:13]2)[CH2:15][CH2:16]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A solution of n-butyllithium (8.1 mL of 1.6 M solution in hexane, 12.92 mmol) was added to thiazole (1.0 g, 11.75 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (1.84 g, 11.75 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe and stirred for 3 h at −78° C. Water (5 mL) was added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and chromatographed to yield 2.531 g of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol in 89% yield. MS (EI) calcd: (M+H)+=242.1; found: 242.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1O
Yield: 88.6 %

Procedure:
A mixture of 4-chloro-2-hydroxybenzoic acid (200 g, 1.16 mol) and 40 ml conc. sulfuric acid in 400 ml of methanol was heated under reflux for 201/2 hours. The solvent was evaporated under reduced pressure, the residue poured into aqueous saturated Na2CO3, and then extracted with ethyl ether (3×500 ml). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to give 2f (191.6 g, 88.6% yield) as an oil. This was used for the next reaction without purification. IR (neat) 3150 (OH), 1728 (C=0), and 1678 (C=0) cm-1. NMR (CDCl3) δ 10.27 (br s, 1H, OH), 7.47 (d, 1H, JBC =8 Hz, HC), 6.80 (d, 1H, JAB =2 Hz, HA), 6.63 (d of d, 1H, HB), and 3.85 (s, 3H, CH3).
Reaction SMILES: [NH3:1].CO.[Br:4][C:5]1[C:6]([F:17])=[C:7]2[C:11](=[C:12]([C:14](O)=[O:15])[CH:13]=1)[NH:10][CH:9]=[CH:8]2>C(Cl)Cl>[Br:4][C:5]1[C:6]([F:17])=[C:7]2[C:11](=[C:12]([C:14]([NH2:1])=[O:15])[CH:13]=1)[NH:10][CH:9]=[CH:8]2
Reactant: O=C(O)c1cc(Br)c(F)c2cc[nH]c12
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(Br)c(F)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A solution of 2 M NH3/MeOH (0.6 mL, 1.2 mmol) was added to a solution of 5-bromo-4-fluoro-1H-indole-7-carboxylic acid (20 mg, 0.078 mmol) in DCM. The reaction was stirred at room temperature overnight. The mixture was washed with water, and the organic layer was concentrated. The residue was purified by flash chromatography, giving 4 mg (20%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11])=[O:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCCC[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
(1R,2S)-2-Amino-cyclohexanecarboxylic acid methyl ester (1 g, 6.4 mmol) was dissolved in methanol (70 mL). 4-Fluoro-benzaldehyde (0.794 g, 6.4 mmol) was added followed by acetic acid (1 mL). The solution was stirred at 25° C. for 10 min. Sodium cyanoborohydride (1 g, 16 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into 1/2 saturated aqueous sodium bicarbonate solution (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1R,2S)-2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (0.8 g, 3 mmol, 47%), as a light yellow oil. LC-MS (ESI) calcd for C15H20FNO2 265.15, found 266.2 [M+H+].
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[NH2:5][CH2:4][CH2:3][CH:2]([O:1][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1=COCCC1
Reactant: CCCCCC(O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCC(CCN)OC1CCCCO1
Yield: 93.6 %

Procedure:
A mixture of 3-hydroxycaprylonitrile (5.2 g., 36.8 millimole), dihydropyran (3.8 g., 45 millimole), and p-toluenesulfonic acid.hydrate (catalytic amount) is stirred at 25° C. for 16 hours, then diluted with ether (100 ml.). The resulting solution is washed with 5% aqueous sodium hydroxide (25 ml.) and water (2×25 ml.), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo affords the title compound as a pale yellow oil (7.9 g., 95%), pmr (CDCl3) δ0.93 (3H, t), 2.54 (2H, q) and 4.68 (H, m).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(N(CC)CC)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
4-Fluoro-4′-phenylethynylbenzophenone was synthesized by the cuprous iodide catalyzed coupling of 4-bromo-4′-fluorobenzophenone. More specifically, 4-bromo-4′-fluorobenzophenone (30 grams, 0.11 mol), phenylacetylene (11 grams, 0.11 mol), triphenylphosphine (0.2 gram), cuprous iodide (0.1 gram), bis(triphenylphosphine) palladium dichloride (0.1 gram) and 450 milliliters of triethylamine were charged to a 500 milliliter flask equipped with a mechanical stirrer, N2 inlet, and reflux condenser. The mixture was heated to reflux for 4 hours, cooled to 23° C., and stirred for an additional 16 hours. The mixture was then poured into water acidified with HCl and the precipitate was collected by filtration. Recrystallization from acetone gave 23 grams (75 percent yield) of the desired product.
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][CH2:4][CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10]C)=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[CH2:19]([N:21]([CH2:22][CH3:23])[C:8](=[O:10])[CH2:7][C:6](=[O:12])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH3:20]
Reactant: CCNCC
Reactant: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Product: CCN(CC)C(=O)CC(=O)CCC=C(C)CCC=C(C)C

Procedure:
5.4 g of the product of Example 3 and 10.8ml of diethylamine were stirred in a closed auto clave at 110° C. for 70 hours and after cooling, the reaction mixture was recovered and evaporated under reduced pressure. The residue was chromatographed over silica and was eluted with a 1-1 ethyl etherpetroleum ether (b.p.= 40°-75° C.) mixture to obtain 3.6 g of N,N-diethyl-7,11-dimethyl-3-oxo-6,10-dodecadienamide in the form of an orange oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27].O>CN1C(=O)CCC1>[CH2:25]([NH:29][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CN
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)CNc1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (1 g, 2.629 mmol) and isobutylamine(0.52 ml) in NMP (10 ml) was stirred at ambient temperature for 18 h. Water (100 ml) was then added and the resulting precipitate was collected by filtration and dried (0.85 g). Trituration of this material with ether/cyclohexane gave the title compound as a colourless solid (0.62 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11](O)=[O:12])=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[N:6][C:5]=2[N:4]([CH:27]([CH3:29])[CH3:28])[N:3]=1.[NH2:30][CH2:31][C:32]1[C:33](=[O:40])[NH:34][C:35]([CH3:39])=[CH:36][C:37]=1[CH3:38].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[C:10]2[C:9]([C:11]([NH:30][CH2:31][C:32]3[C:33](=[O:40])[NH:34][C:35]([CH3:39])=[CH:36][C:37]=3[CH3:38])=[O:12])=[CH:8][C:7]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:18][CH:19]=3)=[N:6][C:5]=2[N:4]([CH:27]([CH3:29])[CH3:28])[N:3]=1
Reactant: CC(C)n1nc(Br)c2c(C(=O)O)cc(-c3ccc(CN4CCOCC4)cc3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)nc3c2c(Br)nn3C(C)C)c(=O)[nH]1
Reaction time: 12 h
Yield: 39 %

Procedure:
A solution of 3-bromo-1-isopropyl-6-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.8 g, 1.74 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.531 g, 3.49 mmol) in DMSO (8 mL) and was stirred at room temperature for 15 min. Then PYBOP (1.36 g, 2.62 mmol) was added to it and stirring was continued for 12 hr. After completion of the reaction, reaction mass was poured into ice to obtain solid, which was filtered and solid was purified by silica gel column chromatography to obtain the desired compound (39% yield). LCMS: 593.20 (M+1)+; HPLC: 97.49% (@ 254 nm) (Rt;5.338); 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (bs, 1H), 8.67 (t, 1H, J=4.8 Hz), 8.18 (d, 2H, J=8.4 Hz), 7.73 (s, 1H), 7.47 (d, 2H, J=8.4 Hz), 5.87 (s, 1H), 5.33-5.30 (m, 1H), 4.40 (d, 2H, J=4.4 Hz), 3.58 (bs, 4H), 3.53 (s, 2H), 2.38 (bs, 4H), 2.26 (s, 3H), 2.11 (s, 3H), 1.52 (d, 6H, J=6.4 Hz).
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].CO.[OH-].[Na+]>O>[CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3cccc(OC)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)c1
Temperature: 50 °C

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 3-(isopropyl(methyl)amino)-2-(3-methoxyphenyl)quinoxaline-6-carboxylate (50 mg, 0.14 mmol, 1.00 equiv), methanol (10 mL), sodium hydroxide (27.4 mg, 0.69 mmol, 5.00 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 20 mg (41%) of 3-(isopropyl(methyl)amino)-2-(3-methoxyphenyl)quinoxaline-6-carboxylic acid as a yellow solid.