Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:37])[N:15]=[C:16]([NH:17][CH2:18][C@@H:19]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:11]=2[CH:10]=[CH:9]1)C.[NH:39]1[CH2:44][CH2:43][CH2:42][N:41]=[C:40]1[NH2:45]>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[C@@H:19]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:18][NH:17][C:16]1[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:45][C:40]3[NH:41][CH2:42][CH2:43][CH2:44][N:39]=3)[C:12]=2[N:13]=[C:14]([CH3:37])[N:15]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CCCn1ccc2c(NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)nc(C)nc21
Solvent: CN(C)C=O
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 104 mg (0.19 mmol) of 4-{4-[(2S)-2-tert-butoxycarbonyl-2-(benzenesulfonylamino)-ethylamino]-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl}-butyric acid ethyl ester (example 4a) in 1 ml of DMF was aded 100 mg (1.0 mmol) of 1,4,5,6-tetrahydro-pyrimidin-2-ylamine and the reaction mixture was stirred at room temperature for 4.5 hours. The solvent was removed in vacuo the residue was taken up in DCM and washed with a saturated NaCl solution. The organic phase was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/MeOH/AcOH/H2O (95:5:0.5:0.5). Yield: 70 mg.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([O:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([O:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:11][CH:9]2[CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: OC1CC(c2ccccc2)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OC2CC(c3ccccc3)C2)C1
Temperature: 120 °C
Yield: 51.7 %

Procedure:
The mixture of the title compound of Step A (80 mg), 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (200 mg) and cyanomethylenetri-n-butylphosphorane (1.0 mmol) in toluene (2 mL) was heated at 120° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (120 mg). The ester was re-dissolved into CH2Cl2 (10 mL), and TFA (2 mL) was added. The mixture was stirred at rt for 4 h then concentrated to give the title compound (168 mg). MS (ESI): mass calcd. for C19H20ClNO2, 329.1; m/z found, 330.1 [M+H]+. 1H NMR (MeOD): 7.26-6.64 (m, 8H), 5.30-5.15 (m, 2H), 4.95-4.83 (m, 2H), 4.60-4.52 (m, 1H), 3.78-3.65 (m, 1H), 2.68-2.58 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:29]([O:31][CH3:32])=[O:30])=[O:4].Cl[C:34]1[CH:35]=[CH:36][C:37]2[O:50][CH2:49][N:40]3[C:41]4[CH:42]=[CH:43][CH:44]=[C:45]([F:48])[C:46]=4[CH:47]=[C:39]3[C:38]=2[N:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:48][C:45]1[C:46]2[CH:47]=[C:39]3[C:38]4[N:51]=[C:34]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([C:29]([O:31][CH3:32])=[O:30])=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[C:9]=6[CH:10]=5)[CH:35]=[CH:36][C:37]=4[O:50][CH2:49][N:40]3[C:41]=2[CH:42]=[CH:43][CH:44]=1
Reactant: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To a mixture of compound methyl 3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylate (700 mg, 1.50 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (536 mg, 1.95 mmol) and K3PO4.3H2O (1.20 g, 4.50 mmol) in 1,4-dioxane (25 mL), Pd2(dba)3/XPhos (50 mg/50 mg) was added under N2 protection. After stirring at 100° C. for 3 h, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:MeOH=200:1) to give the product of methyl 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate (700 mg, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 9.41 (br s, 1H), 8.79 (s, 1H), 7.74 (s, 1H), 7.55˜7.45 (m, 2H), 7.24˜7.17 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.88˜6.81 (m, 1H), 6.01 (s, 2H), 4.10 (s, 3H), 3.40 (s, 3H), 3.05 (d, J=4.4 Hz, 3H), 2.69 (s, 3H). MS (M+H)+: 579.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:4])[C:6]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7]1)[CH3:2]
Reactant: CS(=O)(=O)Cc1cnc2ccccc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCn1cc(CS(C)(=O)=O)c(=O)c2ccccc21
Reaction time: 8 h

Procedure:
Ethyl iodide (2.93 g.) was added to a stirred mixture of 4-hydroxy-3-methylsulphonylmethylquinoline (1.93 g.), anhydrous potassium carbonate (2.3 g.) and 2-butanone (80 ml.) The mixture was boiled under reflux for 24 hours and the solvent was evaporated. The mixture was diluted with water (200 ml.) and left overnight. The mixture was filtered and the filtrate evaporated to dryness to give a white solid. This was purified by high pressure liquid chromatography over silica gel using ethyl acetate:isopropanol 9:1 as the eluant at a flow rate of 200 ml. per minute. There was obtained the novel compound 1-ethyl-3-methylsulphonylmethyl-4-quinolone, m.p. 162°-164°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[CH:9][C:10]=2[CH3:14])[NH:5][CH:4]=1.S(Cl)(Cl)=O.Cl[CH2:23]Cl>>[CH3:23][O:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[CH:9][C:10]=2[CH3:14])[NH:5][CH:4]=1
Reactant: ClCCl
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]cc(CO)c(=O)c12
Solvent: O=S(Cl)Cl
Product: COCc1c[nH]c2c([N+](=O)[O-])ccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1,4-dihydro-3-hydroxymethyl-5-methyl-8-nitro-4-oxoquinoline (1.12 g) in dichloromethane (10 ml) was dropwise added a solution of thionyl chloride (569 mg) in dichloromethane (5 ml) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature and for 2 hours at ambient temperature. The mixture was concentrated in vacuo, suspended in dichloromethane-methanol and refluxed for 2 hours. The mixture was evaporated in vacuo, and the residue was recrystalized from methanol to give 1,4-dihydro-3-methoxymethyl-5-methyl-8-nitro-4-oxoquinoline (889 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]([NH2:11])=O)=[N:2]1.[Cl-].[Na+].P(Cl)(Cl)(Cl)=O>C(#N)C>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:11])=[N:2]1
Reactant: NC(=O)c1n[nH]c2c1CCC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1n[nH]c2c1CCC2
Temperature: 80 °C

Procedure:
1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (0.210 g, 1.39 mmol) was added to anhydrous acetonitrile (12 cm3), heated to 80° C. and sodium chloride (2.0 g, 34-mmol) added. After 15 minutes phosphorus oxychloride (0.128 g, 0.83 mmol) was added and the solution heated to 80° C. overnight, cooled, filtered, and the collected solid washed with acetonitrile. Solvent was removed from the combined solutions under reduced pressure and the resulting solid purified by preparative HPLC to give 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carbonitrile as a deep purple coloured solid (0.031 g, 0.23 mmol, 17%). δH (CD3OD): 2.79 (t like, 2H, J=7.3), 2.73 (t like, 2H, J=7.1), 2.65-2.55 (m, 2H); m/z (ES+): 134 [M+H]+.
Reaction SMILES: C(=O)([O-])O.[K+].[NH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1.Br[CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[N:6]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: BrCCCCBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
25 mg of potassium hydrogen carbonate are added to a solution of tert-butyl cis-4-aminocyclohexanecarbamate (10 g, 46 mmol) and 1,4-dibromobutane (12.1 g, 56 mmol) in 400 ml of DMF, and the mixture is stirred at RT for 24 h. The reaction mixture is then evaporated and the residue is taken up in diethyl ether; this solution is washed with water. The organic phase is dried and evaporated in vacuo. Yield: 12 g.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1N.N([O-])=O.[Na+].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl.O>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:10][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: c1ccncc1
Reactant: Nc1ccccc1Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2ccccc2Sc2nc3ccccc3[nH]2)nc1

Procedure:
2-(1H-Benzimidazol-2-yl thio)benzenamine (8.5 g) in dilute hydrochloric acid (680 ml) was cooled (0° to -5°) with stirring and sodium nitrite (2.68 g) in water (85 ml) was added dropwise, keeping the temperature below 0°. The resulting diazonium salt solution was stirred at 0° for 0.5 hours, then added portionwise to pyridine (800 ml) with stirring at 80° for 1 hour. The pyridine was distilled off, and replaced with 880 ammonia which was in turn distilled off. The residue was treated with water and extracted into dichloromethane, washed, dried, evaporated under reduced pressure and purified by flash column chromatography using dichloromethane:ethyl acetate, 9:2 as eluant to give 3.07 g of the sub-title product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)OC(C)(C)C)=[C:8]([NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[CH:7]=1.Cl>CO.O1CCOCC1>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]=1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24]
Reactant: CCOC(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a stirred solution of tert-butyl ethyl (4-(thiophen-2-yl)-1,2-phenylene)dicarbamate (0.10 g, 0.28 mmol, 1.0 equiv.) in MeOH (2 mL) at 0° C. was added a 4M solution of HCl in dioxane (1.5 mL). The reaction was warmed to room temperature and stirred for 2 h, The reaction was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added. The obtained solid was filtered, washed with water and dried. The crude material was purified by column chromatography (silica gel, 15% EtOAc/hexanes) to give ethyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (0.05 g, 69% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35].CC(C)=O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:37][S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])(=[O:35])=[O:36])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)Cl)cc1OC)cn2C
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Temperature: 15 °C
Yield: 96.4 %

Procedure:
A solution of 4-(dimethylamino)pyridine (8.17 g, 66.9 mmole) in dichloromethane (20 ml) was added over 15 minutes to a stirred suspension of the product of step c) (9.94 g, 26.8 mmole) and 2-methylbenzenesulfonamide (6.87 g, 40.1 mmole) in dichloromethane (30 ml). After 45 minutes the solution was heated to reflux and 20 ml distillate collected. Acetone (150 ml) was added and a further 80 ml distillate collected. The mixture was allowed to cool overnight and finally stirred at 15° C. before collection of the solid by filtration. This was then slurry-washed with methanol (3×30 ml) to afford 16.22 g (96.4%) of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide, as its 4-(dimethylamino)pyridine salt; m.p. 185°-187° C. (with partial melting and resolidification at 138°-140° C.); NMR (250 MHz, DMSO-d6): 2.53 (s, 3H, ArCH3), 3.13 (s, 6H, N(CH3)2), 3.76, 3.83, 3.86 (each s, 3H, OCH3 plus NCH3 plus CO2CH3), 4.02 (s, 2H, ArCH2Ar'), 6.92 (d, 2H), 7.02 (d, 1H), 7.11-7.32 (m, 4H), 7.39-7.53 (m, 3H), 7.75 (dd, 1H), 7.88 (d, 1H), 8.20 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([C:11]2[C:12]([Cl:28])=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7][CH:6]=1)C.[OH-].[K+].Cl>C(O)C.O>[Cl:28][C:12]1[C:11]([C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([OH:29])=[O:3])=[CH:16][N:15]=[C:14]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:13]=12
Reactant: CCOC(=O)c1cncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)c(-c3cncc(C(=O)O)c3)cnc21
Reaction time: 16 h
Yield: 111.3 %

Procedure:
1.070 g (2.48 mmol) of 5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester was dissolved in 10 mL of ethanol. 2 mL of 50% w/v solution of potassium hydroxide in water and 10 mL of water were added and the resulting solution was left standing at ambient temperature for 16 h. Subsequently the pH was adjusted to approximately 4 by addition of concentrated aqueous hydrochloric acid and the mixture diluted with 100 mL of water. The resulting precipitate was filtered off and dried by suction to afford 1.1153 g (2.76 mmol, quant.) of 5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid. 1H-NMR [500 MHz, d6-DMSO] δ: 9.13 (d, 1H), 8.94 (d, 1H), 8.393 (m, 1H), 8.388 (m, 1H), 7.89 (d, 1H), 6.70 (d, 1H), 5.69 (s, 2H), 3.55 (t, 2H), 0.84 (t, 2H), 0.08 (s, 9H); MS [MH+] m/z: 404; [M−H−] m/z: 402.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([CH3:17])=[CH2:16])[C:6]([O:8][CH3:9])=[O:7].OS(O)(=O)=O.[CH3:23][OH:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]([O:24][CH3:23])([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CO
Reactant: C=C(C)COc1ccc(C(=O)OC)cc1OC
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OCC(C)(C)OC)c(OC)c1
Temperature: 100 °C
Yield: 59 %

Procedure:
To methyl 3-methoxy-4-(2-methylallyloxy)benzoate (313 mg, 1.33 mmol) in MeOH (2.5 mL) was added H2SO4 (71 μL, 1.3 mmol) and the mixture was heated in a microwave vial at 100° C. for 15.5 h. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate (208 mg, 59%). ESI-MS m/z calc. 268.1. found 269.5 (M+1)+; Retention time: 1.46 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.57 (dd, J=8.4, 2.0 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 3.90 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1C(=O)NN=C2COc3ccc(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A solution of 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #2, Step E; 5 g, 21.6 mmol) and 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (7.37 g, 43.1 mmol) in MeOH (90 mL) and HOAc (10 mL) was stirred at rt for 2 h. Sodium cyanoborohydride (2.7 g, 43.1 mmol) was added in portions and the resulting dark solution was stirred at rt for 2 h. The solvent was removed in vacuo and the residue was washed with aqueous Na2CO3 (100 mL) and extracted with EtOAc (4×100 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (4.48 g, 54%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.28 (brs, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.15 (s, 1H), 6.13 (d, J=8.4 Hz, 1H), 4.70 (m, 1H), 4.58 (d, J=13.2 Hz, 2H), 4.30 (m, 2H), 4.17 (m, 1H), 4.01 (m, 1H), 3.75 (m, 2H), 1.51 (d, J=6.8 Hz, 3H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:34])[C:18]([N:20]([CH3:33])[C:21]([CH3:32])([CH2:23][CH2:24][C:25]#[C:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[CH3:22])=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:35][CH3:36].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:34])[C:18]([N:20]([CH3:33])[C:21]([CH3:22])([CH2:23][CH2:24][C:25]#[C:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[CH3:32])=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:35][CH3:36]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(C)C(C)(C)CCC#Cc1cccs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(C)C(C)(C)CCC#Cc1cccs1)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 110 mg of 12i in 3 ml of dioxane a solution of 50 mg of KOH in 1 ml of water was added. The mixture was stirred at 50° C. for 2 hr. After cooling to RT, 15 ml of water was added and the reaction mixture was acidified to pH3 by addition of cold 0.5 N HCl. The product was extracted into ethyl acetate. The extract was once washed with water, dried and concentrated, to provide 100 mg of the acid 12j as colorless amorphous material, used without further purification in the next step; MS-ESI: [M+1] 546.98, 548.98).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].CC1C(C)=CC(C)=CC=1[OH:20]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:20])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: Cc1ccc(C)c(O)c1C
Product: Cc1cc(O)c(C)c(C)c1O

Procedure:
By following in the same manner as in Example 63, except that 100 g. (735 m. moles) of 2,3,6-trimethylphenol were used instead of 2,3,5-trimethylphenol, 2.05 g. (13.5 m. moles) of 2,3,6-trimethylhydroquinone were obtained. The yield of dihydric alkylphenol was 29.4 percent.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[F:11][C:12]([F:14])([F:13])[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[OH:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
4-Formylbenzonitrile (200 mg, 1.53 mmol) was dissolved in tetrahydrofuran (4.0 mL). To this, (trifluoromethyl)trimethylsilane (271 μL, 1.83 mmol) and tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 153 μL, 0.153 mmol) were added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a 1 mol/L aqueous hydrogen chloride solution (3.0 mL) was added and the mixture was further stirred for 0.5 minute. Then, the reaction mixture was neutralized with a saturated sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was subjected to slurry purification using hexane, to give 4-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile (Compound CL) (276 mg, yield: 90%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:24])[CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:24])[CH:4]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Solvent: Cc1ccccc1
Product: O=C(C=Cc1ccccc1)CCl

Procedure:
A mixture of 1-chloro-3-(triphenylphosphanylidene)-propane-2-one (2.8 g, 7.9 mmol) and freshly distilled benzaldehyde (0.7 g, 6.6 mmol) in toluene (10 ml) is heated at reflux for 20 hours. Evaporation to dryness yields a mixture containing the title compound that is used in the subsequent step without purification.
Reaction SMILES: [CH3:1][CH:2]1[N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6][CH2:5][N:4]2[C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=[C:3]12.[ClH:23]>O1CCOCC1>[ClH:23].[CH3:1][CH:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:16]([C:19]([F:22])([F:20])[F:21])=[N:17][N:18]=[C:3]12
Reactant: CC1c2nnc(C(F)(F)F)n2CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1NCCCn2c1nnc2C(F)(F)F

Procedure:
Compound from Step F (220 mg, 0.68 mmol) was treated with 4 N hydrogen chloride in dioxane at ambient temperature for 2 h. Concentration gave the title compound. MS 220.9 (M+1)
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1>C1COCC1.O>[CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:2]#[CH:3]
Reactant: C1CNCCN1
Reactant: C#CCBr
Solvent: C1CCOC1
Solvent: O
Product: C#CCN1CCNCC1
Yield: 22.9 %

Procedure:
Propargyl bromide (1.19 g, 10 mmol) and piperazine (8.61 g, 100 mmol) were dissolved in THF (90 ml). Stir under N2 and reflux for 4 h. Remove solvent and dissolve in 40 ml of H2O. Extracted with 4×40 ml of EtOAc, washed with 2×15 ml of brine, dried over MgSO4. After solvent was removed, brownish solid 29.83 (285 mg, 23% yield) was obtained. 1H NMR (CDCl3, 200 MHz): δ=2.28 (t, 1H, J=2.4 Hz), 2.56 (m, 4H), 2.92 (m, 4H), 3.30 (d, 2H, J=2.6 Hz).