Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)[CH3:21].Cl>>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:35]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: CCN(CC)CCOCCC1CCCCN1
Agent: Cl
Product: CCN(CC)CCOCCC1CCCCN1C(=O)N1c2ccccc2NC(=O)c2cccnc21
Yield: 86 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-[2-(diethylamino)ethoxy]ethyl]piperidine in a yield of 86% of theory. The colourless hydrochloride melted at 186°-187° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CC(N(C)C)=O>[C:32]([O:36][C:37](=[O:38])[NH:39][CH2:40][C:41](=[O:42])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 150 °C

Procedure:
Cyclopropanecarboxylic acid [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (0.05 g, 0.17 mmol) was dissolved in dimethylacetamide (1 mL), diisopropylethylamine (0.036 mL, 0.204 mmol) and N-(tert-butoxycarbonyl)glycine (0.036 g, 0.204 mmol) were added followed by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (0.078 g, 0.204 mmol) and the mixture was heated to 150° C. for 10 min in a microwave. The reaction mixture was transferred to a vial and purified by prep LCMS. LCMS method: 1, RT: 4.08 min, MI: 451 [M+1].
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:30]=1>>[CH2:39]([O:38][C:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:34][CH:33]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and ethyl 4-aminophenylacetate
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[S:6][CH:7]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)cs2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3)cs2)cc1
Yield: 76.7 %

Procedure:
Method A. Reaction of chloride 51 (402 mg, 1.5 mmol) and sodium 4-methylbenzenesulfinate (294 mg, 1.7 mmol) in dry DMF (10 mL) gave benzoate 52 (446 mg, 77%) as a white powder: mp (EtOAc) 160-161° C.; 1H NMR (CDCl3) δ 8.05 (ddd, J=8.6, 1.9, 1.7Hz, 2.H, H-2, H-6), 7.77 (ddd, J=8.6, 1.9, 1.7Hz, 2 H, H-3, H-5), 7.64 (ddd, J=8.3, 1.9, 1.7Hz, 2 H, H-2″, H-6″), 7.42 (s, 1 H, H-5′), 7.27 (br d, J=8.3Hz, 2 H, H-3″, H-5″), 4.60 (s, 2 H, CH2SO2), 3.94 (s, 3 H, OCH3), 2.41 (s, 3H, CH3); MS m/z 388.6 (MH+, 100%). Anal. calcd for C19H17NO4S2: C, 58.90; H, 4.42; N, 3.61. Found: C, 58.83; H, 4.33; N, 3.55%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Product: O=C(Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl

Procedure:
A solution of 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (3.22 g, 13.2 mmol) in thionyl chloride (9 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride as a yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
Reaction SMILES: [O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C:18]2=[O:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C[C:43](C)=[O:44]>>[O:1]1[C:19]2=[C:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C:18]2=[O:21])[C@@H:14]2[C@H:4]([C@H:5]4[C@:11]([CH3:23])([CH2:12][CH2:13]2)[C@@H:8]([CH:9]([CH:43]=[O:44])[CH3:10])[CH2:7][CH2:6]4)[C@@H:3]2[O:24][C@:2]123
Reactant: CC(C)=O
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 55 %

Procedure:
In 10 ml of acetone was dissolved 44.2 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one, followed by addition of 5 mg (0.02 mmole) of pyridinium p-toluenesulfonate. The mixture was refluxed for 2 hours., The reaction mixture thus obtained was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was diluted with methylene chloride and this methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:5, v/v) to recover 19.6 mg of 1α,2α;6α,7α-diepoxy-3-oxopregn-4-ene-20-carbaldehyde (yield: 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[O:26]([CH2:33][CH2:34][NH2:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:35][CH2:34][CH2:33][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCOc1ccccc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCCOc1ccccc1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-phenoxyethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.85 (1H, br s), 10.49 (1H, br s), 8.49 (1H, br s), 7.42 (1H, br s), 7.32-7.25 (4H, m), 7.14 (2H, t, J=8.7 Hz), 6.97-6.91 (3H, m), 4.14-4.08 (4H, br m), 3.72 (2H, br); HRMS calcd for C24H20FN3O4+H+: 434.1516. Found 434.1519.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10]([N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16])=[O:11])([CH3:8])([CH3:7])[CH3:6]>>[C:5]([O:9][C:10]([N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH3:16])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: C=CC#N
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Product: CN(CCC#N)CCN(C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
530 mg of acrylonitrile were slowly added to 1.88 g of N-(tert-butoxycarbonyl)-N,N'-dimethyl-ethylenediamine, while cooling with ice. The mixture was stirred at 0° C. for 1 hour, at RT for 14 hours and at 60° C. for 2 hours. The volatile constituents were removed in vacuo and the residue was purified by chromatography over silica gel (EA:MeOH 9:1). 1.92 g of product were obtained. MS(Cl): 242 (M+H)⊕, 186, 142
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:4][C:3]3[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=3[F:1])=[O:21])[N:19]=2)[CH:16]=1
Reactant: Nc1cc(F)ccc1F
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1cc(F)ccc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 2,5-difluoroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([C:34](O)=[O:35])=[CH:6][N:7]2[CH2:32][CH3:33].C(N(CC)CC)C.ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([CH2:34][OH:35])=[CH:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1cc(CO)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.1 %

Procedure:
To a suspension of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (24 g, 41.7 mmol) in Tetrahydrofuran (THF) (450 mL) was added triethylamine (8.71 mL, 62.5 mmol), followed by careful addition of isobutyl chloroformate (7.66 mL, 58.4 mmol). The resulting mixture was stirred at r.t. for 2.5 h. Then the mixture was cooled down to −40° C. and a solution of DIBAL-H (69.5 mL, 104 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 3.5 h. After completion, the reaction was quenched with sat. NH4Cl (aq.), warmed up to r.t., diluted with sat. NH4Cl (aq.), filtered through Celite to remove gummy precipitate, and extracted with dichloromethane twice. The combined organic extracts were then saturated with brine and then dried over sodium sulfate, filtered and the resulting filtrate was concentrated in vacuo to afford 5-chloro-1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (19 g, 30.9 mmol, 74.2% yield) as a yellow solid, which was used in the next oxidation step. LCMS: (M+H)+: 510.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2O[C:8]32[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]3=O)=[CH:3][CH:2]=1.[NH2:20][NH2:21]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:21][N:20]=[C:10]3[C:11]4[C:16]([CH2:17][CH2:18][C:8]=23)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2CCC12OC2c1ccncc1
Reactant: NN
Product: c1ccc2c(c1)CCc1c-2n[nH]c1-c1ccncc1

Procedure:
Following the procedure of step B of Example 1 , the above 3'-(4-pyridyl)-spiro[1,2,3,4-tetrahydronaphthalene-2,2'-oxirane]-1-one is treated with hydrazine to yield 4,5-dihydro-3-(4-pyridyl)-2H-naphtho[ 1,2-c]pyrazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][CH2:12][CH2:11]O2)=[CH:5][CH:4]=1)#[N:2].Br[C:15]1C=[CH:19][C:18]([F:21])=[CH:17][C:16]=1COCOC>>[F:21][C:18]1[CH:17]=[CH:16][C:15]2[B:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[O:13][CH2:12][C:11]=2[CH:19]=1
Reactant: N#Cc1ccc(B2OCCO2)cc1
Reactant: COCOCc1cc(F)ccc1Br
Product: N#Cc1ccc(B2OCc3cc(F)ccc32)cc1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(4-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ccccc3n2)CC1

Procedure:
A mixture of 6.1 mmol 2-chloroquinoline, 6.7 mmol piperazine-1-carboxylic acid tert-butyl ester and 12.2 mmol potassium carbonate in 15 ml acetonitrile was refluxed overnight. The reaction mixture is concentrated, water is added and the compound extracted with ethyl acetate. Chromatography (SiO2; cyclohexane/ethyl acetate 9/1) gave the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[NH:20][C:17]([C:3]1[C:4]([CH3:16])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:18]
Reactant: Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Cl
Reactant: Nc1nccs1
Product: Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1

Procedure:
Using the procedure of Example 1, the product of Step D and 2-aminothiazole were reacted to obtain N-(2-thiazolyl)-4-hydroxy-2-methyl-8-trifluoromethyl-quinoline-3-carboxamide melting at 267° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[O:7]=[C:8]1[NH:16][CH:15]=[N:14][C:13]2[N:12]([CH2:17][CH2:18][C:19](OCC)=[O:20])[CH:11]=[N:10][C:9]1=2>C(#N)C.CO>[O:7]=[C:8]1[NH:16][CH:15]=[N:14][C:13]2[N:12]([CH2:17][CH2:18][C:19]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[O:20])[CH:11]=[N:10][C:9]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCC(O)CO
Solvent: CO
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCC(O)CO
Temperature: 110 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
0.500 g (5.49 mmol) of 3-amino-1,2-propanediol was placed into a 10 ml round bottom flask with a magnetic stirring bar. The flask was heated to 110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was stirred at 100°-110° C. for one hour. The flask was allowed to cool to room temperature and 10 ml of 1:1 acetonitrile/methanol was added and the solution was stirred vigorously for 30 minutes. The resulting white precipitate was collected using Buchner funnel filtration to yield 272 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2,3-dihydroxyprop-1-yl)propanamide (AIT-0062) as a white solid. 91% yield.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]C6CCCCO6)[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:42])C(=O)C1.O1CCOCC1>C(Cl)Cl.Cl>[Br:42][C:3]1[N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: CC(c1ccc2nccn2c1)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(c1ccc2ncc(Br)n2c1)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(rac)-3-(1-Imidazo[1,2-a]pyridin-6-yl-ethyl)-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (obtained by analogy of Stage 185.1 by replacing (rac)-6-chloro-3-[1-(3-methyl-3H-benzoimidazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine with (rac)-6-chloro-3-(1-imidazo[1,2-a]pyridin-6-yl-ethyl)-imidazo[1,2-b]pyridazine (Example 292), 150 mg, 0.328 mmol) was dissolved in DCM (3.3 mL) and NBS (64.2 mg, 0.984 mmol) was added. It was stirred at rt for 3 h then the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated and dissolved in DCM (1 mL) with 4 N HCl in dioxane (0.246 mL, 0.984 mmol). The RM was stirred at rt for 2 min. The solvent was removed and the residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.7 min (conditions 2), MH+=452, 1H-NMR in DMSO-d6: 8.46 (s, 1H); 8.40 (s, 1H); 8.04 (m, 2H); 7.78 (s, 1H); 7.67 (s, 1H); 7.52 (m, 2H); 7.33 (d, 1H); 4.95 (t, 1H); 4.76 (q, 1H); 4.18 (t, 2H); 3.75 (q, 2H); 1.80 (d, 3H)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][CH3:24])=[O:22]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([O:13][C:21]([O:23][CH3:24])=[O:22])[C:9]([NH:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CNC(=O)N(O)c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CNC(=O)N(OC(=O)OC)c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-1-hydroxy-3-methylurea (10 grams; 0.05 mol) in isopropyl alcohol (40 ml), and pyridine (6 ml) were charged into a glass reaction flask equipped with a mechanical stirrer. Methyl chloroformate (5 ml; 0.06 mol) was added to the flask with stirring, at a temperature of about 10° to 15°C. After the addition was completed the reaction mixture was stirred for an additional one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture was poured onto ice and the precipitate was recovered by filtration and dried. The dried precipitate was then recrystallized from a methyl alcohol-water mixture to yield 1-(4-chlorophenyl)-1-methoxycarbonyloxy-3-methylurea having a melting point of 145° to 146°C and having the following elemental analysis as calculated for C10H11ClN2O4 :
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]1([C:31]2[CH:35]=[C:34]([NH:36][C:37](=O)[O:38]C3C=CC=CC=3)[O:33][N:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>>[CH:26]1([C:31]2[CH:35]=[C:34]([NH:36][C:37]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH:20]=3)=[O:38])[O:33][N:32]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(Nc1cc(C2CCCC2)no1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCCC5)no4)c3)c2cc1OC
Yield: 28 %

Procedure:
The title compound was prepared as described in Example 113C by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (104 mg, 0.35 mmol), phenyl 3-cyclopentylisoxazol-5-ylcarbamate described in Example 163A (124 mg, 0.45 mmol) and N,N-diisopropylethylamine (73 μl, 0.42 mmol) to give 1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (51.72 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.50-7.35 (m, 2H), 7.30 (d, 1H), 7.00 (d, 1H), 5.95 (s, 1H), 4.34 (bs,2H), 3.99 (s, 3H), 3.77 (bs, 2H), 3.34 (s, 3H), 3.11-2.99 (m, 1H), 2.10-1.80 (m, 2H), 1.75-1.50 (m, 6H); LC-MS (ESI) m/z 520 (M+H)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[ClH:5].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14]([NH:17][CH2:18][CH:19]=[CH2:20])(=[O:16])=[O:15])=[CH:9][CH:8]=1>O.Cl>[ClH:5].[NH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14]([NH:17][CH2:18][CH:19]=[CH2:20])(=[O:16])=[O:15])=[CH:9][CH:8]=1)[NH2:1]
Reactant: C=CCNS(=O)(=O)Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CCNS(=O)(=O)Cc1ccc(NN)cc1
Reaction time: 1.33 h

Procedure:
A solution of sodium nitrite (1.06 g) in water (2.5 ml) was added dropwise to a stirred suspension of the product from stage (b) (3.5 g) in 5N hydrochloric acid (28 ml) between -8° and -3° under nitrogen and stirring was continued at ca -3° for 80 min. The mixture was filtered, and the clear yellow filtrate was added dropwise from an ice-cooled, jacketed dropping funnel to a stirred solution of stannous chloride dihydrate (17.5 g) in concentrated hydrochloric acid (17.5 ml) between -2° and +1° over 35 min. After warming up to 10° over 15 min, the mixture was filtered, and the residue was washed with concentrated hydrochloric acid (4×30 ml) and dry ether (4×30 ml) and dried to give the title compound as a very pale yellow solid (2.44 g), m.p. 163°-166°, containing 5% inorganic material.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[C:5]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:34][CH2:33][C:32]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:31]=4[NH:30][C:29]3=[O:41])[CH2:24][CH2:23]2)=[CH:6][C:7]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1.CN(C=O)C>O1CCOCC1.O.[Cu](I)I>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([C:10]([C:7]1[CH:6]=[C:5]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:34][CH2:33][C:32]5[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:31]=5[NH:30][C:29]4=[O:41])[CH2:24][CH2:23]3)[C:4]([I:1])=[CH:9][N:8]=1)=[O:11])[CH2:13][CH2:14]2
Reactant: [I-]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncc3Br)CC1)C(=O)N2
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncc3I)CC1)C(=O)N2
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere 91 mg (0.61 mmol) sodium-iodide, 6 mg (0.03 mmol) copper iodide and 0.09 mL (0.01 mmol) N,N-dimethylene-ethylene-diamine were added to 0.18 g (0.30 mmol) 3-[5′-bromo-2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 1.0 mL 1,4-dioxane and the mixture was stirred overnight at 110° C. Then an additional 0.3 mL DMF was added and the reaction mixture was stirred for a further 10 days at 110° C. After being diluted with water the precipitate formed was suction filtered and dried.
Reaction SMILES: C1CCCCCCCCCCC=1.C1CCC=CCCC=CCCC=1.[CH:25]1([CH:37]([CH3:40])[CH:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][CH2:31][CH2:30][CH:29]=[CH:28][CH2:27][CH2:26]1>>[CH:25]1([CH:37]([CH3:40])[CH2:38][OH:39])[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][CH2:31][CH2:30][CH:29]=[CH:28][CH2:27][CH2:26]1
Reactant: CC(C=O)C1CCC=CCCC=CCCC1
Agent: C1=CCCC=CCCC=CCC1
Agent: C1=CCCCCCCCCCC1
Product: CC(CO)C1CCC=CCCC=CCCC1

Procedure:
An alternative approach to synthesis of QRM 2172 would be to utilise a cheaper starting material in place of cyclododecene. In this respect, 1,5,9-cyclododecatriene is worthy of investigation. As shown in FIG. 3. the desired reaction product, 2-(4.8-cyclododecadienyl)propan-1-al (5) (referred to herein as QRM 2669) could be hydrogenated to give QRM 2172. It could also be reduced to give 2-(4,8-cyclododecadienyl)propan-1-ol (6) (referred to herein as QRM 2671), a novel molecule, which would have a strong possibility of exhibiting amber properties, together with improved biodegradability.