Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:2]1[C:4]([O-])=[O:5].[CH:11]1([NH2:14])[CH2:13][CH2:12]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH:11]1([NH:14][C:4]([CH:2]2[CH2:3][CH:1]2[C:7]([O:9][CH3:10])=[O:8])=[O:5])[CH2:13][CH2:12]1
Reactant: COC(=O)C1CC1C(=O)[O-]
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1CC1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9.3 g of monomethyl (1RS,2RS)-1,2-cyclopropanedicarboxylate, 4.0 ml of N-cyclopropylamine and 11.6 g of N(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 210 ml of methylene chloride is treated at 0° C. with 0.7 g of dimethylaminopyridine and subsequently stirred at room temperature for 2 hrs. The reaction solution is worked-up with methylene chloride/10% potassium hydrogen sulphate solution. The organic phase is washed with saturated sodium bicarbonate solution, dried and concentrated to give 10.6 g of methyl (1RS,2RS)-2-cyclopropylcarbamoyl-cyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][C:15]([OH:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:14][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:28][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N(CCC(O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COC(c2ccccc2)(c2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
The solution of 19.3 g of N-benzyl-N-chloroacetyl-3hydroxy-3,3-diphenylpropylamine in 150 ml of dimethylformamide is added dropwise to the suspension of 1.2 g of sodium hydride in 50 ml of dimethylformamide while stirring and cooling with an ice-bath. The mixture is allowed to warm up to room temperature, stirred for 15 hours and evaporated. The residue is partitioned between 150 ml methylene chloride and 50 ml of N hydrochloric acid, the organic layer separated, washed with water, dried, filtered and evaporated. The residue is triturated with diethyl ether and recrystallized from ethanol, to yield the 4-benzyl-3-oxo-7,7-diphenyl-hexahydro-1,4-oxazepine of the formula ##STR7## melting at 185° to 186°.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[C:5]([NH:10][C:11](=[O:24])[C:12]([CH3:23])([CH3:22])[CH2:13][O:14]CC2C=CC=CC=2)=[C:4]([C:25]#[N:26])[C:3]=1[CH3:27].[H][H]>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[C:5]([NH:10][C:11](=[O:24])[C:12]([CH3:23])([CH3:22])[CH2:13][OH:14])=[C:4]([C:25]#[N:26])[C:3]=1[CH3:27]
Reactant: [H][H]
Reactant: Cc1c(Br)c(F)c(O)c(NC(=O)C(C)(C)COCc2ccccc2)c1C#N
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(F)c(O)c(NC(=O)C(C)(C)CO)c1C#N
Yield: 50.3 %

Procedure:
N-(4-Bromo-2-cyano-5-fluoro-6-hydroxy-3-methylphenyl)-2,2-dimethyl-3-[(phenylmethyl)oxy]propionamide (I-105) (5.82 g, 13.37 mmol) was dissolved in ethyl acetate (120 ml), carbon-held palladium catalyst (5% wet, 580 mg) was added, followed by vigorously stirring at room temperature under atmospheric pressure of hydrogen for 18 hours. After the reaction, the insoluble matter was separated by filtration through Celite, the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (2.32 g, 50%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][CH:8]=[CH:9][CH2:10]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[OH-].[Na+].[Br-].C(OC(C=CC=CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)C.[O:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[O:68][CH:69]1[CH:73]([O:74][CH:75]2[CH2:80][CH2:79][CH2:78][CH2:77][O:76]2)[CH2:72][CH:71]([CH:81]=O)[CH:70]1[CH2:83][CH2:84][CH:85]([O:91][CH:92]1[CH2:97][CH2:96][CH2:95][CH2:94][O:93]1)[CH2:86][CH2:87][CH2:88][CH2:89][CH3:90]>O.C(Cl)(Cl)Cl>[O:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[O:68][CH:69]1[CH:73]([O:74][CH:75]2[CH2:80][CH2:79][CH2:78][CH2:77][O:76]2)[CH2:72][CH:71]([CH:81]=[CH:10][CH:9]=[CH:8][CH:7]=[CH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:70]1[CH2:83][CH2:84][CH:85]([O:91][CH:92]1[CH2:97][CH2:96][CH2:95][CH2:94][O:93]1)[CH2:86][CH2:87][CH2:88][CH2:89][CH3:90]
Reactant: CCOC(=O)C=CC=CC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC(CCC1C(C=O)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Agent: CCOC(=O)C=CC=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCC(CCC1C(C=CC=CC=CC(=O)OCC)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Reaction time: 18 h

Procedure:
A solution of 5-ethoxycarbonylpenta-2,4-dienyltriphenylphosphorane [prepared by adding N aqueous sodium hydroxide solution (40 ml.) to a stirred solution of 5-ethoxycarbonylpenta-2,4-dienyltriphenylphosphonium bromide (16.4 g.) in water (1000ml.) at 1°-3° C., extracting with chloroform and concentrating the extract to about 250 ml.] was treated at 2° C. under nitrogen with a solution of 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbaldehyde (8.5 g.) [prepared as described in (m) above]in chloroform (20 ml.). The solution was allowed to stand at room temperature for 18 hours, the chloroform was removed in vacuo and the residue extracted three times with hot petroleum ether (b.p. 40°-60° C.). The combined petroleum extracts were cooled and filtered to remove precipitated triphenylphosphine oxide. The filtrate was evaporated in vacuo and the residue separated by chromatography on silica gel. Elution with petroleum ether (b.p. 40°-60° C.) gave ethyl 7-{3,4-di(2-tetrahydropyranyloxy)-2-[3 -(2-tetrahydropyranyloxy)octyl]cyclopentyl}-hepta-2,4,6-trienoate (6.4 g.), νmax : 1700 cm-1, 1610 cm-1 (liquid film).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([O:13]C)[C:4]=1[OH:15].Cl.N1C=CC=CC=1.Cl>>[C:9]([C:7]1[CH:8]=[C:3]([OH:2])[C:4]([OH:15])=[C:5]([CH:6]=1)[OH:13])([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1cc(C(C)(C)C)cc(OC)c1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(O)c(O)c(O)c1

Procedure:
2,6-Dimethoxy-4-t-butylphenol (16.5 g, 0.08 mole) and pyridine hydrochloride (60 g) were heated at 200°-210° C. for 2 hours. The mixture was then added to iced dilute hydrochloric acid and the aqueous solution extracted twice with petroleum ether (b.p. 40°-60° C.) to remove any unchanged starter. The aqueous phase was saturated with salt and extracted three times with ether. Drying and running down gave 12.5 g title product (88%) m.p. 137°-9° C.
Reaction SMILES: [NH2:1][C@:2]([CH3:26])([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][O:17][C:16]3([CH3:23])[CH3:22])=[CH:8][CH:7]=1)=[O:4].C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[CH3:23][C:16]1([CH3:22])[C:15]2[CH:14]=[C:13]([O:12][C:9]3[CH:8]=[CH:7][C:6]([N:5]4[C:3](=[O:4])[C@:2]([CH2:24][CH3:25])([CH3:26])[NH:1][C:32]4=[O:33])=[CH:11][CH:10]=3)[CH:21]=[CH:20][C:19]=2[CH2:18][O:17]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2ccc3c(c2)C(C)(C)OC3)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc4c(c3)C(C)(C)OC4)cc2)C1=O
Reaction time: 8 h

Procedure:
(2R)-2-amino-N-[4-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]phenyl]-2-methyl-butanamide (Intermediate 71, 140 mg, 0.39 mmol) was dissolved in ethyl acetate (2 mL) and the resulting solution was added drop wise to a suspension of CDI (1.4 equiv) in ethyl acetate (0.5 mL). The resulting suspension was stirred overnight. A new solution of CDI was freshly prepared (60 mg in 0.5 mL of ethyl acetate) and added drop wise to the mixture. A third portion of CDI (50 mg) was added and the reaction mixture was left stirring over week-end at room temperature. The mixture was treated with 10% w/w aqueous citric acid solution, two layers were separated and the organic layer washed with water and brine, then dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 80:20 to 60:40 as eluent. The fractions containing the product were combined, evaporated to dryness and further purified by crystallization from ethyl acetate/n-heptane. The slurry was stirred for 2 hours, and then the solid collected, washed with n-heptane and dried under vacuum. The residue was re-purified by flash chromatography on silica gel using dichloromethane/methanol from 100:0 to 90:10. The fractions containing the product were combined, evaporated to dryness and the residue further purified by crystallization from methyl tertbutyl ether/n-heptane to afford the title compound (47 mg) as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[O:17][CH2:16][CH:15]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[C:14]=3[C:13]([CH3:28])=[C:12]([NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:11]=2[CH3:37])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[O:17][CH2:16][CH:15]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][CH:20]=4)[C:14]=3[C:13]([CH3:28])=[C:12]([NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:11]=2[CH3:37])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc([N+](=O)[O-])c1)OCC2c1ccc(C(C)C)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N)c1)OCC2c1ccc(C(C)C)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of N-(7-(3-nitrophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (2.50 g, 5 mmol) obtained in Example 109 and ammonium formate (1.26 g, 20 mmol) in ethanol (50 mL) was added 10% palladium on carbon (water content: 50%, 0.25 g), and the resulting mixture was heated at 65° C. and stirred for 2 hours. The reaction solution was cooled to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2.15 g (yield: 92%) of the title compound. Melting point: 170-172° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(Cl)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)c(Br)c1

Procedure:
To a 500 ml 3-necked pyrex round bottomed flask equipped with a magnetic stirring bar, reflux condenser and argon inlet was added 2-bromo-4-chlorotoluene (10.00 g, 48.67 mmol), N-bromosuccinimide (18.66 g, 48.67 mmol) and dry, degassed carbon tetrachloride (200 ml). The stirred mixture was heated at reflux while being irradiated at a distance 10 cm by a 150 watt Hanovia low pressure mercury Lamp for 4 hours. The cooled reaction mixture was diluted with carbon tetrachloride and washed with water (2×200 ml) and brine (400 ml). Drying (MgSO4), filtration, and removal of the solvent in vacuo left compound (2a) as a colorless oil. HPLC analysis indicates the material to be approximately 80% of the monobromo and 20% of the dibromo material. 'H NMR (CDCl3) δ4.55 (s, 2H), 7.00-7.65 (m, 3H).
Reaction SMILES: Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:14][CH:15]=[CH:16][C:17]1[C:18]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12>>[CH3:27][C:26]1([CH3:28])[C:18]2[C:17](=[C:21]3[N:20]([N:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22]3)[CH2:16][CH:15]([OH:14])[O:29]1
Reactant: COC=Cc1c(C(C)(C)O)nn2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: CC1(C)OC(O)Cc2c1nn1ccccc21
Yield: 60.2 %

Procedure:
Following procedures analogous to those described in Example 6 Step b, using concentrated hydrochloric acid (0.5 mL, 6 mmol) in lieu of p-toluenesulfonic acid, 2-[3-(2-methoxy-vinyl)-pyrazolo[1,5-a]pyridin-2-yl]-propan-2-ol (1.23 g, 5.30 mmol) was converted to 1,1-dimethyl-3,4-dihydro-1H-2-oxa-8a,9-diaza-fluoren-3-ol (0.697 g, 3.19 mmol, 60% yield) as a light yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=O)[CH2:9]1.O.[OH-].[Na+]>O1CCCC1>[C:14]1([CH2:13][N:12]2[CH2:8][CH2:9][CH:10]([CH2:20][NH:22][CH:23]([CH3:25])[CH3:24])[CH2:11]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 8.2 g (0.2 mole) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran was added portionwise, 18.3 g (70.0 mmole) of solid 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide. When the addition was compete, the reaction mixture was stirred at room temperature for 18 hours and then refluxed for two hours. After cooling to room temperature, the mixture was treated dropwise, successively, with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml of water, titrating the final addition to produce a granular precipitate. The solid was removed by filtration, washed with tetrahydrofuran and the filtrate evaporated in vacuo to give 15.6 g of 1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinemethanamine as a heavy syrup.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)(=[O:20])=[O:19]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:26]1[C:25]2[C:29](=[CH:30][C:22]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:23][CH:24]=2)[NH:28][C:27]1=[O:31])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)NC(=O)C2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(NS(C)(=O)=O)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-methylsulfonylamino-2-oxindole to give 0.4 g of N-[3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-methanesulfonamide as a yellow-orange solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]C2C(O)=CC=CC=2)=[CH:3][CH:2]=1.[C:15]1([CH2:21][C:22]2[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]=[O:26])[C:23]=2[OH:30])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:4]1([CH2:7][O:30][C:23]2[C:22]([CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=[O:26])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Oc1ccccc1Cc1ccccc1
Reactant: O=Cc1cccc(Cc2ccccc2)c1O
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(Cc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Yield: 71 %

Procedure:
Using the method of Tramposch, Kung and Blau (J. Med. Chem. (1983) 26, 121), 2-hydroxydiphenylmethane was converted to 3-(phenylmethyl)salicylaldehyde in 56% yield: NMR (CDCl3) 11.35 (s, 1H), 9.35 (s, 1H), 7.45-6.85 (m, 8H), 4.00 (s, 2H); Mass spec (CI) 213. This hydroxyaldehyde (31.3 g, 0.147 mole) was treated with benzyl bromide (25.2 g, 0.147 mole) and potassium carbonate (22.1 g, 0.16 mole) in N,N-dimethylformamide (180 mL) at 100° overnight. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Distillation of the residue (170°-185°, 0.1 torr) provided the title material as a pale yellow viscous oil in 71% yield. NMR (CDCl3) 10.3 (s, 1H), 7.8-7.1 (m, 13H), 4.9 (s, 2H), 4.05 (s, 2H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1)=[CH2:2].[C:9]([O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])(=[O:12])[CH2:10][SH:11].N(C(C)(C)C#N)=NC(C)(C)C#N>>[O:8]=[C:5]1[O:4][CH:3]([CH2:1][CH2:2][S:11][CH2:10][C:9]([O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:12])[CH2:7][O:6]1
Reactant: CCCCC(CC)COC(=O)CS
Reactant: C=CC1COC(=O)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(CC)COC(=O)CSCCC1COC(=O)O1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
3.07 grams (26.9 mmol, MW: 114.10) 4-vinyl-1,3-dioxaolane-2-one, 5.0 grams (24.5 mmol, MW: 204.13) 2-ethylhexyl thioglycolate and 0.402 grams (2.45 mmol, MW: 164.21) 2,2′-azobis(2-methylpropionitrile) (AIBN) were charged in 25 milliliter thick sealed glass reactor. After addition, the reaction mixture was stirred for 22 hours at 110° C. The reaction was then stopped and cooled down to room temperature. The excess of unreacted 4-vinyl-1,3-dioxaolane-2-one was removed by air bath oven at 180° C. under vacuum for 1 hour. The final product was determined by IR, 13C NMR. Yield: 6.0 grams (77%). IR: (cm−1) 3046, 2957, 2926, 2870, 2857, 1596, 1510, 1458, 1394, 1378, 1260, 1219, 1165, 1077, 1016, 779, 730. 13C NMR (CDCl3): 170.4, 154.7, 75.5, 69.2, 67.8, 38.4, 33.7, 33.5, 30.3, 28.9, 27.8, 23.6, 22.9, 14.3, 10.7.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([O:32]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH3:28][O:27][C:24]1[N:23]=[C:22]([O:29][CH3:30])[C:21]([C:20]2[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:10][CH:9]=3)[O:12][C:13]3[C:18]([C:19]=2[CH3:31])=[CH:17][CH:16]=[C:15]([OH:32])[CH:14]=3)=[CH:26][N:25]=1
Reactant: C1COCCN1
Reactant: COc1ncc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)c(OC)n1
Product: COc1ncc(C2=C(C)c3ccc(O)cc3OC2c2ccc(OCCN3CCOCC3)cc2)c(OC)n1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and morpholine as the starting material.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[N:18]=[N:17]1>>[NH:16]1[C:20]2[CH:21]=[CH:22][C:23](/[CH:25]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=4)=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2[nH]nnc2c1
Product: CS(=O)(=O)Nc1ccc2c(c1)/C(=C\c1ccc3[nH]nnc3c1)C(=O)N2

Procedure:
According to the method of Example A20, except substituting N-(2-oxoindolin-5-yl)methanesulfonamide (12 mg, 0.053 mmol) and 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (9 mg, 0.058 mmol), the title compound was obtained as an orange solid (8 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 2.86 (s, 3H); MS ESI 356.0 [M+H]+, calcd for [C16H13N5O3S+H]+ 356.1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClCCl.C(OCC)C>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH:10]=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: OCc1ncn2cc(Br)sc12
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ncn2cc(Br)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
A solution of 2-bromo-7-hydroxymethylimidazo [5,1-b]thiazole (27 mg, 0.11 mmol) in dichloromethane (3.5 ml) was added to a suspension of pyridinium chlorochromate (38 mg, 0.18 mmol) and sodium acetate (4.8 mg, 0.06 mmol) in dichloromethane (1.5 ml). The mixture was stirred at room temperature for 30 min. After the completion of the reaction, the reaction solution was diluted with diethyl ether. Celite was added to the diluted solution, and the mixture was stirred at room temperature for additional 20 min. The procedure consisting of filtering the reaction mixture through Celite, adding ethyl acetate to the residue, stirring the mixture, and filtering the stirred mixture through Celite was repeated a few times. The filtrates were combined, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (5 mg, 20%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[CH:25]1([O:24][C:22]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][C:12]3[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cn2ccc3ccc(N)cc32)o1
Product: COC(=O)c1ccc(Cn2ccc3ccc(NC(=O)OC4CCCC4)cc32)o1
Yield: 53 %

Procedure:
Using a similar procedure to that described in Ex. 22, but starting from methyl 5-(6-aminoindol-1-ylmethyl)furan-2-carboxylate and cyclopentyl chloroformate, there was obtained methyl 5-[6-(cyclopentyloxycarbonyl)aminoindol-1-ylmethyl]furan-2-carboxylate in 53% yield, as an off-white solid; partial NMR: 1.5-2.0 [br m, 8H, (CH2)4 ], 6.2 (d, 1H, CH.CH=C), 6.6 (br.s, 1H,NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[N:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][C:23]=2[CH:24]=1>>[Br:14][C:15]1[CH:16]=[N:17][C:18]2[CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:22][C:23]=2[CH:24]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Brc1cnc2c(c1)CNCC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ncc(Br)cc2C1
Yield: 62 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Bromo-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound.
Reaction SMILES: C([CH:3]([C:7]1([CH3:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-])=O)[NH:9][C:8]1=S)[C:4]([O-:6])=[O:5])C.[BH4-].[Na+].[CH2:23]1COC[CH2:24]1>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:3][C:4]([O:6][CH2:23][CH3:24])=[O:5])([CH3:20])[CH2:8][NH:9]2
Reactant: CCC(C(=O)[O-])C1(C)C(=S)Nc2cccc([N+](=O)[O-])c21
Reactant: C1CCOC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC1(C)CNc2cccc(N)c21
Reaction time: 0.17 h

Procedure:
To a solution of (±)-ethyl (3-methyl-4-nitro-2-thioxo-2,3-dihydro-1H-indol-3-yl)acetate from Step A (3.65 g, 12.4 mmol) and nickel (II) chloride hexahydrate (23.6 g, 99.2 mmol) in MeOH (30 mL) and THF (30 mL), at 0° C., was added NaBH4 (11.3 g, 298 mmol) in portions over 1 h. The resulting mixture was stirred for 10 min, then filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—90:10, to give the title compound. MS: m/z=235 (M+1).