Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N=C2CCCCC2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:8][C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[C:6]=2[CH:7]=1
Reactant: Brc1ccc(NN=C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 60 °C
Yield: 193.4 %

Procedure:
A 250-mL round-bottomed flask was charged with 1-(4-bromophenyl)-2-cyclohexylidenehydrazine (11 g, 41.35 mmol, 1.00 equiv) and conc. HCl (150 mL). The resulting mixture was heated to 60° C. in an oil bath for 4 hours. The reaction progress was monitored by TLC (EtOAc:PE=1:1). Upon completion, the reaction mixture was cooled down to room temperature. The pH was adjusted to 8 with aqueous sodium hydroxide. The resulting mixture was then extracted with ethyl acetate (5×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1/10) affording 3-bromo-6,7,8,9-tetrahydro-5H-carbazole as yellow solid (10 g, 97%).
Reaction SMILES: Cl[C@:2]12[C@@H:19]([F:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.C1([SnH](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@H:2]1[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](F)[C@@]12Cl
Agent: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12

Procedure:
1.2 g. of 9-chloro-11β-fluoro-4-androstene-3,17-dione is agitated for 2 hours at room temperature in 20 ml. of tetrahydrofuran and 3 ml. of triphenyltin hydride with the addition of 7 mg. of α,α'-azoisobutyrodinitrile. The solution is evaporated under vacuum and worked up as set forth in Example 1. After purification by preparative layer chromatography, 380 mg. of 11β-fluoro-4-androstene-3,17-dione is obtained; m.p. 162°-164°. UV: ε238 = 16,300 (methanol).
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.CC(C)([O-])C.[Na+].Cl[C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1>COCCOC>[O:6]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:1][O:7][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: OCC1CCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1nc(OCC2CCCO2)nc2c1ncn2C1CCCCO1
Temperature: 110 °C
Yield: 54.2 %

Procedure:
Tetrahydrofurfuryl alcohol (4.09 g) was diluted with 1,2-dimethoxyethane (20 mL). To this solution was added sodium tert-butoxide (3.84 g) gradually. The resultant reaction mixture was stirred until homogeneous (orange solution) before 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.53 g) was added. The reaction mixture was then heated to 110° C. (external) overnight under nitrogen. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL, 3 times). The organic layer was separated, combined and then dried by passing through a hydrophobic frit. This was evaporated under reduced pressure and the resultant material was then purified by silica chromatography eluting with 0-100% ethyl acetate: cyclohexane followed by methanol. An ISCO pump fault was detected whilst eluting with methanol, this line carried ethyl acetate previously and it was not known if the fault existed when eluting with ethyl acetate: cyclohexane. The appropriate fractions were evaporated to give the title compound as a solid (1.7258 g). This material was used in the next stage without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]2[C@H:36]([OH:37])[CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]3[C@H:36]([OH:37])[CH2:35][O:34][CH2:33][CH2:32]3)=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2CCOC[C@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCOC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 75 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.05 g) in 2-propanol (20 mL) were added 1,5-anhydro-2,3-dideoxy-3-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]-threo-pentitol (1.00 g) and piperidinium acetate (457 mg). The reaction mixture was stirred at 75° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained powder was washed with diisopropyl ether to give the title compound (571 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:12]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:13][C:14]2[O:18][C:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][C:15]=2[C:29]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=O)C.[Cl-].[NH4+].Cl>C(OC)(C)(C)C>[C:30]([C:29]1[C:15]2[CH2:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:18][C:14]=2[CH:13]=[C:12]([C:34]([CH3:35])([CH3:37])[CH3:36])[C:11]=1[OH:10])([CH3:31])([CH3:33])[CH3:32]
Reactant: CCCCCC1(CCCCC)Cc2c(cc(C(C)(C)C)c(OC(C)=O)c2C(C)(C)C)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: CCCCCC1(CCCCC)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 30 °C
Reaction time: 4.5 h
Yield: 75.2 %

Procedure:
In an argon atmosphere, 0.27 kg of lithium aluminum hydride was added to 18 L of methyl t-butyl ether and the mixture was heated under reflux for 0.5 hours. The solution was cooled to 30° C. and a solution of 2.8 kg of 5-acetoxy-4,6-di-tert-butyl-2,2-dipentyl-2,3-dihydrobenzofuran in 5 L of methyl t-butyl ether was added dropwise; thereafter, the mixture was stirred for 4.5 hours at 50° C. in an argon atmosphere. The solution was cooled to 10° C. and 1.4 L of a saturated aqueous solution of ammonium chloride was slowly added dropwise. Subsequently, 14 L of 10% aqueous hydrochloric acid was added and the mixture was extracted with 14 L of hexane. The aqueous layer was discarded and the organic layer was washed with 14 L of a saturated aqueous solution of sodium chloride; thereafter, the organic layer was concentrated under reduced pressure and the residue was dissolved in 12.5 L of hexane; 2.5 kg of silica gel was added to the solution which was then stirred for 1 hour. After filtering off the silica gel, the filtrate was concentrated under reduced pressure to give 1.9 kg (99.4% in purity) of 4,6-di-tert-butyl-5-hydroxy-2,2-dipentyl-2,3-dihydrobenzofuran.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[C:31]2([CH2:36][CH2:35][CH:34]([NH:37][C:38]3[NH:42][C:41]([CH3:43])=[N:40][N:39]=3)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[CH2:22]([C:21]1[N:39]2[N:40]=[C:41]([CH3:43])[N:42]=[C:38]2[N:37]([CH:34]2[CH2:33][CH2:32][C:31]3([O:27][CH2:28][CH2:29][O:30]3)[CH2:36][CH2:35]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 180 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (15 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (5 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL) and N,N-diethylaniline (80 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (6.4 g, 57%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][C:23]([OH:25])=O)([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(C)=O.O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][C:23]([N:32]=[N+:33]=[N-:34])=[O:25])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid (6A: 97 mg, 0.287 mmol) in acetone (1 mL) at 0° C. was added TEA (0.064 mL, 0.459 mmol), followed by ethyl chloroformate (0.044 mL, 0.459 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. A solution of NaN3 (37.3 mg, 0.573 mmol) in 0.5 mL water was added slowly and the mixture was stirred at 0° C. for another 1 h. The reaction mixture was then poured into ice-water (5 mL) and extracted with diethyl ether (3×2 mL). The combined extracts were washed successively with water (5 mL), saturated aqueous NaHCO3 (5 mL) and water (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (104 mg, 100% yield). LCMS, [M+Na]+=386.1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C>C1COCC1>[CH:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]1[N:4]3[CH2:16][CH2:17][CH2:18][N:19]([C:20]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:2][C:3]3=[N:15][C:6]=1[CH:7]=[N:8]2
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Yield: 90.4 %

Procedure:
A modification of the method described in Part D of Example 4 was used to treat tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (36.76 g, 98.1 mmol) with potassium tert-butoxide (107.9 mL of a 1 M solution in THF). Following the work-up procedure, the product was mixed with ethyl acetate. The resulting mixture was filtered to remove a solid, and the filtrate was concentrated under reduced pressure to provide 30.0 g of tert-butyl 11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]1[C:31]([O:32][CH3:33])=[CH:30][C:20]2[NH:21][C:22]([C:24]3[C:28]([NH2:29])=[CH:27][NH:26][N:25]=3)=[N:23][C:19]=2[CH:18]=1.[C:34]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([C:47](O)=[O:48])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C>[CH3:33][O:32][C:31]1[C:17]([O:16][CH3:15])=[CH:18][C:19]2[NH:23][C:22]([C:24]3[C:28]([NH:29][C:47]([CH:43]4[O:44][CH2:45][CH2:46][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]4)=[O:48])=[CH:27][NH:26][N:25]=3)=[N:21][C:20]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)C3CN(C(=O)OC(C)(C)C)CCO3)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of EDC (125 mg, 0.54 mmol) and HOAt (74 mg, 0.54 mmol) in DMF (2 ml) was added 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (117 mg, 0.45 mmol) (Example 15B) and (rac)-BOC-2-carboxymorpholine (125 mg, 0.54 mmol) and the mixture stirred at room temperature overnight. The mixture was then partitioned between EtOAc and water. The organic layer was then washed successively with saturated aqueous sodium bicarbonate, brine and then dried (MgSO4). The solution was evaporated to dryness in vacuo and the residue purified by flash column chromatography [SiO2, gradient elution: EtOAc-hexanes (1:1)-EtOAc-MeOH (80:20)] to give N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-rac-4-BOC-2-morpholine carboxamide (65 mg) as a colourless solid. (LC/MS (acidic method): Rt 2.65 min, [M+H]+ 473).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][S:16]([CH3:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][S:16]([CH3:18])(=[O:36])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(CCCS(C)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(CCCS(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylsulfinyl)pentyl]-1,4-difluorobenzene (66 mg, 0.15 mmol) obtained in Example 45 was dissolved in methylene chloride (5 ml). Under ice cooling, 3-chloroperbenzoic acid (32 mg, 0.19 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography (methylene chloride:methanol=100:1) to yield a white solid. The resulting white solid was washed with diethyl ether/methylene chloride, whereby the title compound (52 mg, 76%) was obtained as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7]#[N:8].O.[NH2:12][NH2:13]>C(O)C>[CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH2:8])[NH:13][N:12]=1
Reactant: CN(C)CCC(=O)CC#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCc1cc(N)[nH]n1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
To a solution of 5-(dimethylamino)-3-oxopentanenitrile (4.9 g) in ethanol (20 mL) at ambient temperature was added hydrazine monohydrate (1.72 mL, 35.5 mmol) and the reaction mixture was heated to 70° C. for 2 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to give 3.81 g of 3-(2-(dimethylamino)ethyl)-1H-pyrazol-5-amine (65% over 2 steps) which was carried on without further purification. 1H-NMR (400 MHz, DMSO-d6): δ 12.60 (bs, 1H), 6.52 (bs, 2H), 6.1 (s, 1H), 2.69 (m, 2H), 2.65 (m, 2H), 2.27 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12]([NH:14][CH3:15])=[O:13])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[OH:16][C:17]([C:20]1[CH:44]=[CH:43][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[C:28]=2[CH3:42])=[O:25])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[OH:16][C:17]([C:20]1[CH:44]=[CH:43][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:2]3[CH:3]=[C:4]([NH:11][C:12]([NH:14][CH3:15])=[O:13])[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)[C:28]=2[CH3:42])=[O:25])=[CH:22][CH:21]=1)([CH3:18])[CH3:19]
Reactant: CNC(=O)Nc1cc(Br)cn2ccnc12
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)O)cc2)cccc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: COCCOC
Product: CNC(=O)Nc1cc(-c2cccc(NC(=O)c3ccc(C(C)(C)O)cc3)c2C)cn2ccnc12
Yield: 13.8 %

Procedure:
A 5 mL Microwave Reactor Vessel was charged with 1-(6-Bromo-imidazo[1,2-a]pyridin-8-yl)-3-methyl-urea (85 mg, 0.317 mmol), 4-(1-Hydroxy-1-methyl-ethyl)-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (125 mg, 1 eq), tetrakis(triphenylphosphine)palladium (37 mg, 0.1 eq), 1M sodium carbonate (1 mL) and dimethoxyethane (2 mL). The reaction mixture was irradiated for 10 minutes at 150° C. on the Microwave Reactor. The reaction mixture was then partitioned between ethyl acetate (150 mL) and water (50 ml). Separated the layers and washed the organic layer with water (4×50 mL), then finally washed with brine (1×50 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by Preparative Thin Layer Chromatography, eluting with 50% acetone in hexanes to give 4-(1-Hydroxy-1-methyl-ethyl)-N-{2-methyl-3-[8-(3-methyl-ureido)-imidazo[1,2-a]pyridin-6-yl]-phenyl}-benzamide as an off-white powder (20 mg), ((M+H)+=458).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[CH:11][CH:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.ClCCOC(Cl)=O.CO>ClC(Cl)C>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:14][CH:10]1[CH:11]=[CH:12][CH2:13][NH:8][CH2:9]1
Reactant: Fc1ccc2[nH]cc(CC3C=CCN(Cc4ccccc4)C3)c2c1
Agent: O=C(Cl)OCCCl
Solvent: CO
Solvent: CC(Cl)Cl
Product: Fc1ccc2[nH]cc(CC3C=CCNC3)c2c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
A solution of 3-[(1-benzyl-1,2,3,6-tetrahydro-3-pyridinyl)methyl]-5-fluoro-1H-indole (500 mg, 1.57 mmol) in dichloroethane is treated with chloroethylchloro-formate (0.51 mL, 4.7 mmol), stirred at 80° C. for 4.5 hr, cooled and concentrated in vacuo to give a residue. The residue is treated with methanol, heated at reflux temperature overnight, cooled and concentrated in vacuo. The resultant residue is purified by column chromatography (10% MeOH/CH2Cl2+NH4OH) to give the title compound as a pale yellow solid, 240 mg (66%) mp 145° C. (dec.), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]([OH:15])(=[O:14])[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH2:9].OCC(CO)(CO)CO.[Sn+2]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:15])(=[O:14])[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH2:9]
Reactant: C[C@H](O)C(=O)O
Agent: C=C(CC(=O)O)C(=O)O
Agent: OCC(CO)(CO)CO
Agent: [Sn+2]
Product: CC(O)C(=O)O
Reaction time: 11 h

Procedure:
Reaction was performed in a 250 ml glass reactor where was added 227.8 g of aqueous L-lactic acid (88% water solution corresponding to 88 mole-%), 27.2 g of itaconic acid (8 mole-%), 13.6 g of pentaerythritol (4 mole-%) and 0.1 g of tin(II) octoate. Into the reaction vessel was led nitrogen and it was immersed partly into the oil bath with temperature of 90° C. and the mixing was start at a speed of 200 rpm. The temperature was increased at a rate of 25° C./h to 150° C. The temperature was evenly increased at a rate of 15° C./h to 180° C., where it was kept during the whole polymerisation. Bubbling of nitrogen was continued throughout the polymerisation and the formed water was collected as it evolved. Total polymerisation time was 11 hours. The product resin was hard, clear but brittle, yellowish in colour and it was observed to crosslink by radicals.
Reaction SMILES: O[CH:2]([C:34]1[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=1)[C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17]C3CCCCO3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=1.O[Li].O>C(O)=O.CC(=O)OCC.O.[Zn]>[OH:17][CH2:16][CH2:15][CH2:14][N:10]1[C:11](=[O:13])[C:12]2[C:3]([CH2:2][C:34]3[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=3)=[C:4]([O:26][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=3)[CH:5]=[N:6][C:7]=2[N:8]([CH3:25])[C:9]1=[O:24]
Reactant: Cc1cncc(Oc2cnc3c(c2C(O)c2ccc(C(F)(F)F)nc2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Agent: [Li]O
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cc1cncc(Oc2cnc3c(c2Cc2ccc(C(F)(F)F)nc2)c(=O)n(CCCO)c(=O)n3C)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
To a solution of 5-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (24 mg, 0.04 mmol) in HCOOH (1 mL) was added Zn dust (13 mg, 0.2 mmol). The reaction was heated at 100° C. for 1 h, cooled to RT and filtered. The filtrate was concentrated to a crude intermediate which was dissolved in THF (2 mL) and water (2 mL) then LiOH.H2O (33.6 mg, 0.8 mmol) was added. The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.0 mg, 20% yield) as a white solid. 1H NMR (CDCl3) δ: 8.68 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 4.86 (s, 2H), 4.25 (t, J=6.0 Hz, 2H), 3.74 (s, 3H), 3.57-3.61 (m, 2H), 2.96 (brd s, 1H), 2.34 (s, 3H), 1.92-1.97 (m, 2H). LCMS: MH+ 502 and TR=2.285 min.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].[C:13](=[O:15])=[O:14].CCOCC>O1CCCC1.CCCCCC>[C:1]1([C:7]2[S:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: O=C=O
Agent: [Li]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(-c2ccccc2)s1
Reaction time: 1 h

Procedure:
A solution of 2-phenylthiophene (16.0 g, 0.1 mole) in 100 ml anhydrous tetrahydrofuran (THF) is treated dropwise with a solution of n-bityl lithium (0.11 mole) in hexane (2 M solution). Thereafter the mixture is stirred for 1 hr. The resulting black solution is poured onto 50 g of solid CO2 covered with ether. When all the CO2 is evaporated, the mixture is treated with 200 ml of water, acidified with 10% HCl and extracted with ether. The extract is washed with 5% NaOH. The latter washings are cooled and rendered acidic with 20% HCl. The resulting precipitate is collected and recrystallized from 1000 ml CCl4 to give 5-phenyl 2-thiophenecarboxylic acid, mp 180° C, γmaxCHCl3 1665 cm -1, as yellow green crystals.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([CH:16]=[N:17]O)=[CH:15][C:3]1=2>C(OC(=O)C)(=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:3]1=2
Reactant: O=c1c2cc(C=NO)ccc2oc2ncccc12
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 25 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde oxime and 150 ml of acetic anhydride is stirred under reflux for 24 hours. After cooling, the crystals are filtered off, washed with water, dried, and recrystallized from dimethylformamide to give 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbonitrile melting at 260°C.