Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=O)[C:5]([CH2:11][OH:12])=[CH:4][N:3]=1.Cl.[C:14]([NH:18][S:19]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])([CH3:17])([CH3:16])[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[C:14]([NH:18][S:19]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][CH2:9][C:6]3[C:5]([CH2:11][OH:12])=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=3[OH:8])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1ncc(CO)c(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
In a 250 mL three-necked round bottom flask fitted with a condenser and a Dean-Stark trap, a mixture of pyridoxal hydrochloride (330 mg, 1.62 mmol), 4′-amino-biphenyl-2-sulfonic acid tert-butylamide (494 mg, 1.62 mmol), p-toluenesulfonic acid monohydrate (68 mg, 0.36 mmol) in toluene (150 mL) was heated at 100° C. under nitrogen atmosphere for 3 hours. The solvent was then evaporated and the crude product was dissolved in dichloromethane (70 mL), cooled down to 0° C. and then sodium borohydride (163 mg, 4.32 mmol) and methyl alcohol (15 mL) were added. The reaction mixture was stirred at room temperature overnight, after which the solvent was removed. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel using a mixture of dichloromethane:methyl alcohol (9:1) as eluant to give 4′-[(3hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (7) (178 mg, 24% overall yield for two steps) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:33]CCBr)[CH:29]=2)[CH:24]=1)[C:16]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:16][CH2:15][O:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]4)[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: BrCCOc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccc2cc(OCCN3CCC(Cc4ccc(F)cc4)CC3)ccc2c1

Procedure:
The title compound was prepared from 4-(4-Fluoro-benzyl)-piperidine and 2-benzyloxy-6-(2-bromo-ethoxy)-naphthalene and potassium carbonate in two steps as a solid, mp184-185° C. Analysis calculated for C24H26FNO2 : C, 75.96; H, 6.91; N, 3.69; F, 5.01. Found: C, 75.52; H, 6.86; N, 3.50; F, 5.15.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][C@H:18]([CH3:22])[C:19](O)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)([Cl:27])=O.CN(C=O)C>CCOCC>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][C@H:18]([CH3:22])[C:19]([Cl:27])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[C@@H](Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@@H](Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.06 g (2.94 mmol) of (R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid in 5 ml of dry ether under a nitrogen atmosphere and cooled to 0° is added 400 μl (5.50 mmol, 0.66 g) of thionyl chloride and 50 μl of DMF. After 5 hours at 0°, the reaction is stirred at RT overnight. The ether solution of acid chloride is then removed from the oily residue, and the ether and excess thionyl chloride are removed by rotoevaporation to give (R)-2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([O:21]CC4C=CC=CC=4)[CH:19]=3)[C:14]([OH:31])=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:12]=2[C:36]([O:38][CH3:39])=[O:37])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>O1CCCC1.CO.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([OH:21])[CH:19]=3)[C:14]([OH:31])=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:12]=2[C:36]([O:38][CH3:39])=[O:37])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(OCc3ccccc3)c(OC)cc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(O)c(OC)cc2c1O
Yield: 90.3 %

Procedure:
2 g of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxy-carbonyl)-4-hydroxy-6-methoxy-7-benzyloxynaphthalene obtained in Example 6 are dissolved in a mixture of 200 ml of tetrahydrofuran and 50 ml of methanol. The solution is stirred in the presence of 2 g of 10% palladium-charcoal in hydrogen atomsphere at 40 psi for 2 hours. After the reaction, the catalyst is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. The resultant crude crystals are triturated with methanol, whereby 1.5 g of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)4-hydroxy-6-methoxy-7-hydroxynaphthalene is obtained.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:33])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][CH:24]=3)[CH:11]=2)[C:6]([CH3:35])([CH3:34])[CH2:5]1)(=O)C.Cl>CCO>[CH3:34][C:6]1([CH3:35])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14](=[O:33])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3ccccc3NCc3ccnc4ccccc34)cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)CNc2cc(NC(=O)c3ccccc3NCc3ccnc4ccccc34)ccc21
Reaction time: 2 h

Procedure:
N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(quinolin-4-ylmethyl)-amino]-benzamide (Example 9) (150 mg, 0.32 mmol) was dissolved in EtOH (15 mL) and concentrated aqueous HCl (5 mL) and the mixture was heated to 50° C. overnight, then 80° C. for 2 h. After drying in vacuo, the residue was partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was collected, washed with brine, and dried over Na2SO4. After concentrated in vacuo, the desired product was isolated as a white solid. MS: (ES+) 423, (M+H). Calc'd. for C27H26N4O-422.53.
Reaction SMILES: C([O:3][C:4]([CH:6]1[N:10]([C:11](=[S:21])[NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH2:9][CH2:8][S:7]1)=O)C>Cl>[Cl:20][C:15]1[CH:14]=[C:13]([N:12]2[C:4](=[O:3])[CH:6]3[S:7][CH2:8][CH2:9][N:10]3[C:11]2=[S:21])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: CCOC(=O)C1SCCN1C(=S)Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: O=C1C2SCCN2C(=S)N1c1cc(Cl)cc(Cl)c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
A mixture of 2.19 g of the obtained 3-(3,5-dichlorophenylthiocarbamoyl)thiazolidine-2-carboxylic acid ethyl ester and 20 ml of concentrated hydrochloric acid was stirred at 120° C. for 1.5 hours. After the reaction mixture was cooled, the precipitate was separated, followed by recrystallization from a mixed solvent of ethyl acetate and n-hexane to give 1.43 g (yield 74.7%) of 6-(3,5-dichlorophenyl)perhydroimidazo[5,1-b]thiazole-5-thion-7-on (Compound No. 2). The resulting point and the elementary analysis were as given in table 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.C([N-]C(C)C)(C)C.[Li+].[Si:40]([O:47][C:48]1[C:49]([F:58])=[C:50]([CH:53]=[C:54]([CH2:56][CH3:57])[CH:55]=1)[CH:51]=[O:52])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:51]([C:50]2[CH:53]=[C:54]([CH2:56][CH3:57])[CH:55]=[C:48]([O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:49]=2[F:58])[OH:52])[N:11]([C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
To a solution of Intermediate 217.1 (650 mg, 1.40 mmol) in 10 mL THF at 0° C., was added a solution of lithium diisopropylamide (2M in heptane/THF/ethylbenzene, 0838 mL, 1.68 mmol). The mixture was stirred at 0° C. for 30 min, then a solution of Intermediate 188.3 (356 mg, 1.26 mmol) in 2 mL THF. The mixture was stirred at 0° C. for 2 h, then was quenched with sat. NH4Cl and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 510 mg of Intermediate 217.2 as a pale yellow solid. LCMS (50 to 100% B, 4 min gradient, A=95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=5.61 min, 747.67 (M+H)+.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:11][CH:12](O)[CH:13]=[CH2:14].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[CH:12]=[CH:13][CH3:14]
Reactant: O=C1CCc2ccccc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccccc2C1=O
Yield: 48 %

Procedure:
A solution of 29.5 g of 1-indanone, 73.5 ml 3-buten-2-ol, 77.0 ml of 2,2-dimethoxypropane and 400 mg of p-toluenesulfonic acid in 400 ml of toluene was boiled under reflux for 24 hours. After cooling, the solution was washed with 100 ml of saturated sodium hydrogen carbonate solution. The aqueous washing was extracted with 150 ml of ethyl acetate and the organic phases were combined, dried with magnesium sulfate and evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 7:1) yielded 19.8 g (48%) of (RS)-2-(2-buten-1-yl)-1-indanone as a pale yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[O:16][CH:15](/[C:18](=[N:22]\[OH:23])/[O:19][CH2:20][CH3:21])[CH2:14][C:13]=2[CH:12]=[C:11]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:10]=1[OH:33]>>[C:1]([O:23]/[N:22]=[C:18](\[CH:15]1[CH2:14][C:13]2[CH:12]=[C:11]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:10]([OH:33])=[C:9]([Cl:8])[C:17]=2[O:16]1)/[O:19][CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: CCO/C(=N/O)C1Cc2cc(C(=O)c3ccccc3F)c(O)c(Cl)c2O1
Reactant: CC(=O)OC(C)=O
Product: CCO/C(=N/OC(C)=O)C1Cc2cc(C(=O)c3ccccc3F)c(O)c(Cl)c2O1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To acetic anhydride (8 ml.) was added (8h) (400 mg., 1.06 mmole). After stirring for 1 hour at 90° C. the mixture was left to stand at room temperature for 18 hours, then evaporated to dryness under high vacuum. The product, an oil, was triturated in absolute ethanol, giving crystalline (9h), m.p. 111°-112° C. in 58.4% yield. Analysis (C20H17ClFNO6) C,H,N.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Yield: 85 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5.83 g, 15 mmol), 4-fluorophenylboronic acid (3 g, 22 mmol), PdCl2(PPh3)2 (1 g, 1.4 mmol), and aqueous Cs2CO3 solution (2 M, 8.0 mL) in 1,4-dioxane (50 mL) was heated to reflux for 2 h. The mixture was filtered, and the filtrate was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5.3 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Cl)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-chloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=596.1)=97%.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[N:17][CH:18]=[C:19]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])[CH:20]=3)[N:12]=[C:11]([CH3:38])[N:10]=2)=CC=1.OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[CH3:37][O:36][C:33]1[N:32]=[CH:31][C:30]([NH:29][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:38])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])=[CH:18][N:17]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CNc2nc(C)nc(-c3cc(C(=O)N4CCOCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(=O)N3CCOCC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
A solution of N,N-b is (4-methoxybenzyl)-4-(2-((6-methoxy-3-pyridinyl)amino)-5-(4-morpholinylcarbonyl)-3-pyridinyl)-6-methyl-1,3,5-triazin-2-amine (0.128 g, 0.193 mmol) in TFA (2.00 mL) at ambient temperature was treated with triflic acid (0.051 mL, 0.579 mmol) and heated for 4 h at 80° C. The reaction mixture was concentrated, but not to dryness. A few ice cubes were added and saturated NaHCO3 (aq.) was added until pH was about 7. The solid was collected by filtration, washed with water and CH2Cl2, and dried under vacuum to give 4-(2-((6-methoxy-3-pyridinyl)amino)-5-(4-morpholinylcarbonyl)-3-pyridinyl)-6-methyl-1,3,5-triazin-2-amine (0.056 g, 0.133 mmol, 68.6% yield) as a brown solid. 1H NMR (400 MHz, d6-DMSO) δ 11.92 (s, 1H); 8.87 (s, 1H); 8.52 (s, 1H); 8.38 (s, 1H); 8.11-8.22 (m, 1H); 7.92 (br. s., 1H); 7.78 (br. s., 1H); 6.85 (d, J=8.80 Hz, 1H); 3.84 (s, 3H); 3.54-3.65 (m, 8H); 2.44 (s, 3H). m/z (ESI, +ve ion) 423.1 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:15]4([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH2:17][CH2:16]4)[S:13][CH:14]=3)=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br.CO.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]([C:15]3([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:16][CH2:17]3)[S:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: c1ccc(C2(c3nc(-c4ccc5c(c4)OCO5)cs3)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(-c2csc(C3(c4ccccc4)CC3)n2)cc1O
Temperature: -78 °C
Reaction time: 12 h

Procedure:
4-(1,3-benzodioxol-5-yl)-2-(1-phenylcyclopropyl)-1,3-thiazole (3-1 [synthesized by the method described in Scheme 1], 0.04 g, 0.121 mmol) in methylene chloride (5.0 mL) was cooled to −78° C. and treated with BBr3 (1.0M solution in methylene chloride, 0.60 mL, 0.60 mmol). The reaction stirred 12 h at −78° C. and was subjected directly to reverse phase HPLC (C-8, 5-95% MeOH—H2O w/0.1% TFA) to provide pure 4-(3,4-dihydroxyphenyl)-2-(1-phenylcyclopropyl)-1,3-thiazole (3-2). 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=7.1 Hz, 2H), 7.39 (m, 3H), 7.51 (d, J=7.6 Hz, 2H), 7.14 (br s, 1H), 7.02 (s, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 2.05 (m 2H), 1.70 (m, 2H); MS 309.9 found 310.4 (M+H+) required.
Reaction SMILES: Cl[Sn]Cl.Cl.S(=O)(=O)(O)[OH:6].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][C:12]=1[F:19]>O.C(OCC)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:6])=[CH:13][C:12]=1[F:19]
Reactant: N#Cc1ccc(Br)c(F)c1
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 59 g (0.31 mol) of anhydrous SnCl2 and 320 cm3 of diethyl ether was placed on an ice water bath and saturated with hydrogen chloride gas generated by the drop-wise addition of concentrated sulfuric acid to concentrated hydrochloric acid until the SnCl2 assumed a liquid state and the mixture was dried with concentrated sulfuric acid. 31 g (0.16 mol) of 4-bromo-3-fluorobenzonitrile was added to the mixture and the resulting mixture was stirred at room temperature for 1 hour and allowed to stand overnight. 300 cm3 of water was added to the reaction product and the mixture was stirred over a hot water bath at 50° C. The diethyl ether was distilled off. The oily layer was separated out and the aqueous layer was extracted with ether. The two layers were combined, washed with water, and dried overnight with anhydrous Na2SO4. Diethyl ether was distilled off the resulting dried mixture. Diethyl ether was distilled off the distillation residue. The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg) to yield 26 g (0.13 mol) of 4-bromo-3-fluorobenzaldehyde.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH2:16][OH:17].C(Cl)(Cl)Cl>CO>[OH:17][CH2:16][CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCO
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Add 6.0 g (0.03 moles) 4-chloro-3-nitrobenzamide to 60 ml 2-aminoethanol and stir at ambient temperature. When TLC (silica support; 9:1 CHCl3 :MeOH eluent) shows no starting material, ca. 3 hrs., pour onto ice. Filter, wash (3×15 ml) with cold H2O, and recrystallize from MeOH/IPA. Yield is 4.5 g (66%) of orange crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>>[F:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:42])[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Yield: 62 %

Procedure:
In a manner analogous to that described in Example 2b), the reaction of (R)-5-[5-(5,6-difluoro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (130 mg, 284 μmol) with Lawesson's reagent (126 mg, 312 μmol) yielded the title compound (83 mg, 62% yield as a white solid. MS (ISP): m/z=475.1 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:44])[C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:35])[CH:28]=2)=[CH:23][CH:22]=1)[C:17](O)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:45]1[CH2:50][CH2:49][CH:48]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:47][CH2:46]1>>[CH2:54]([O:53][C:51]([CH:48]1[CH2:49][CH2:50][N:45]([C:17](=[O:18])[C@@H:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:44])[C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:35])[CH:28]=3)=[CH:23][CH:22]=2)[CH2:46][CH2:47]1)=[O:52])[CH3:55]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Reactant: CCOC(=O)C1CCNCC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)N3CCC(C(=O)OCC)CC3)cc2)c1
Yield: 107.7 %

Procedure:
In a similar manner, using 20 mg (33.8 μmol) of the (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2) and 4.8 mg (30.5 μmol) of ethyl piperidine-4-carboxylate, 24 mg of expected product are obtained with a quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[Br:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([Br:8])=[CH:10][CH:11]=1)=[O:5]
Reactant: Brc1cccc2ccccc12
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 37 %

Procedure:
To a suspension of ALCl3 (3.20 g, 24 mmol) in 100 mL DCM at 0° C., methylchloroglyoxylate (2.2 mL, 24 mmol) was added. The resulting solution was stirred for 5 min., after which 1-bromo-naphthalene (5 g, 24 mmol) was added. After stirring for 2 hrs at room temperature, water was added and the phases were separated, after which the organic layer was washed with water and dried over MgSO4. The residue obtained after evaporation of the organic solvent was purified by column chromatography (0-30% EtOAc/Hex), to afford 2.6 g of the target compound. 1H NMR (CDCl3): 8.92 (1H, d, J=9.3 Hz, H-arom); 8.31 (1H, d, J=9.3 Hz, H-arom); 7.82 (1H, d, J=8.8 Hz, H-arom); 7.72 (1H, d, J=8.8 Hz, H-arom); 7.57-7.68 (2H, m, H-arom); 3.94 (3H, s, OMe).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:42]([O:49][C:50](=[O:56])[NH:51][CH2:52][C:53](=[NH:55])[NH2:54])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.ClCCl>[CH2:42]([O:49][C:50](=[O:56])[NH:51][CH2:52][C:53]([NH:55][C:8]([C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10])=[NH:54])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: N=C(N)CNC(=O)OCc1ccccc1
Reactant: O=C(O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N=C(CNC(=O)OCc1ccccc1)NC(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen, 3-chloro-2-pyrazinecarboxylic acid (76 mg), TBTU (168 mg), and diisopropylethylamine (310 mg) were added to a solution of carbamimidoylmethyl-carbamic acid benzyl ester [77390-81-9] (99 mg) in DMF (6 ml). The reaction mixture was stirred for 2 h at ambient temperature, diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The obtained, crude title compound (220 mg) was used without further purification in the next step.