Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]([CH2:57][CH2:58][CH3:59])([C@@H:10]([C:34](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)OC1=S)=[O:35])/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:23][CH2:22][CH2:21][O:20]1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:60][C@@H:61]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][C:75]#[C:76][CH3:77])=[CH:69][CH:68]=1)[C:62]([O:64][CH3:65])=[O:63]>ClCCl>[CH2:74]([O:73][C:70]1[CH:69]=[CH:68][C:67]([CH2:66][C@H:61]([NH:60][C:34]([C@@H:10](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2([CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:20][CH2:21][CH2:22][O:23]2)[C@@:2]([OH:1])([CH2:57][CH2:58][CH3:59])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:35])[C:62]([O:64][CH3:65])=[O:63])=[CH:72][CH:71]=1)[C:75]#[C:76][CH3:77]
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Reactant: CCC[C@@](O)(C(=O)OC(C)(C)C)[C@H](/C=C/CCCCCCC1(CCCCc2ccccc2)OCCO1)C(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCc3ccccc3)OCCO2)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
tert-Butyl (E)-(2S,3S)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-11-[2-(4-phenyl-butyl)-[1,3]dioxolan-2-yl]-2-propyl-undec-4-enoate (124 mg, 0.150 mmol) and methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate (70.0 mg, 0.283 mmol) were dissolved in dichloromethane (3.0 mL). Dichloromethane was distilled off under reduced pressure. The residue was then stirred at an outer temperature of 50° C. for 24 hours. The reaction mixture was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 72.0 mg (0.0928 mmol, 62% yield, purity 78%) of tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-11-[2-(4-phenyl-butyl)-[1,3]dioxolan-2-yl]-2-propyl-undec-4-enoate (ESI (LC/MS positive mode) m/z 776 (M+H); Rt 2.47 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH3:13])=[CH:6][C:3]=1[CH2:4][NH:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: NCC1CC1
Reactant: COCCc1ccc(Cl)c(C=O)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCc1ccc(Cl)c(CNCC2CC2)c1
Temperature: 70 °C

Procedure:
To a solution of 2-chloro-5-(2-methoxyethyl)benzaldehyde from Amine 7, Step 6 (1 eq.) in methanol (0.8 M) was added 1-cyclopropylmethanamine (1.2 eq.) and sodium bicarbonate (1.5 eq). The vessel was sealed and heated at 70° C. for 2 h. The insolubles were removed via filtration and to the filtrate was then added sodium borohydride (1.5 eq.) at 0° C. The reaction mixture was allowed to warm slowly to RT overnight. The volatiles were removed in vacuo and the resulting residue was partitioned between 1 N aq. NaOH and ether. The aqueous layer was separated and back extracted with ether. The combined ethereal extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:18].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.P([O-])([O-])([O-])=O.[Na+].[Cl-]>CN(C=O)C.O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:18])=[O:16]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: OCCCCCCOCCc1ccccn1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)CCCCCOCCc1ccccn1
Yield: 51.8 %

Procedure:
A solution of 6-[2-(2-pyridinyl)ethoxy]hexanol (1.0 g) and pyridinium dichromate (5.90 g) in DMF (12 ml) was stirred at room temperature for 24 h. The solution was diluted with water (100 ml) and extracted with ether (2×100 ml). The combined organic extracts were washed with water (100 ml), dried and evaporated in vacuo to give a colourless oil. The original aqueous washes were combined and re-extracted with dichloromethane (2×150 ml), washed with water (100 ml), dried and evaporated in vacuo to give a brown oil. The original aqueous washes were then buffered to pH 6.5 using phosphate buffer and solid NaCl added. The saturated solution was extracted with dichloromethane (2×100 ml), washed with water (100 ml), dried and evaporated in vacuo to give a brown oil. The three oils were combined and purified by FCC eluting with hexane-ether (1:1) followed by methanol to afford a yellow oil, which was dissolved in dichloromethane (50 ml) and filtered. The filtrate was evaporated in vacuo to give the title compound as a green oil (0.55 g), t.l.c. (System A 40:10:1) Rf 0.6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a suspension of 25.6 g (100 mmol) of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid in 75 ml of dichloromethane was added 14.0 g (110 mmol) of oxalyl chloride. This mixture was treated with four drops of dry N,N-dimethylformamide, and the rapidly bubbling solution was stirred overnight at room temperature. The mixture was concentrated to give 27.0 g of the title compound which was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([NH:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: NCCN1CCOCC1
Product: Clc1nc(N2CCOCC2)c2sc(NCCN3CCOCC3)nc2n1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 2-morpholinoethanamine via General Procedure C to give crude 5-chloro-7-morpholino-N-(2-morpholinoethyl)thiazolo[4,5-d]pyrimidin-2-amine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure C again to give 136 after purification by reverse HPLC. MS (Q1) 444 (M+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)OCCOCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCOCCOc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
10 g of 4-benzyloxyphenol in 120 ml of dimethylformamide were treated with 2.4 g of a 50% sodium hydride dispersion in mineral oil and the mixture was stirred for 5 minutes. 12.2 g of 2-(2-phenylethoxy)ethyl methanesulfonate [prepared as described in Example 1(a)] were added and the mixture was heated at 60° C. for 0.5 hour with stirring. The mixture was evaporated to dryness and the residue was partitioned between 2N sodium hydroxide and ethyl acetate. The organic phase was separated, washed well with water, dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from methylcyclohexane to give 16.1 g (93%) of 1-benzyloxy-4-(2-phenethyloxyethoxy)benzene of melting point 46°-49° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]4[CH:33]=[N:34][CH:35]=[CH:36][C:31]=4[N:30]=[CH:29]3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([SH:45])[CH:42]=[CH:43][CH:44]=1>CN(C)C=O.O1CCCC1>[N:30]1[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[N:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:14]3[C:13]([S:45][C:41]4[CH:42]=[CH:43][CH:44]=[C:39]([O:38][CH3:37])[CH:40]=4)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:16][C:15]=3[CH:23]=2)[CH:29]=1
Reactant: COc1cccc(S)c1
Reactant: CCOC(=O)c1sc2cc(Cn3cnc4ccncc43)ccc2c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2cc(Cn3cnc4ccncc43)ccc2c1Sc1cccc(OC)c1
Temperature: 60 °C
Yield: 81.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--0.07 ml, 0.48 mmol) was added to a mixture of ethyl 3-(chloro)-6-(3H-imidazo[4,5-c]pyridin-3-ylmethyl)benzo[b]thiophene-2 carboxylate (Preparation 12, 150 mg, 0.4 mmol) and 3-methoxybenzenethiol (0.07 ml, 0.6 mmol) in a mixture of dimethylformamide (1 ml) and tetrahydrofuran (1 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 6 hours and then partitioned between ethyl acetate and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was triturated with diethyl ether and hexane mixture to give the title compound as a colourless solid (155 mg).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:36])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[C:25]2[CH:24]=[C:23]([CH:31]=[CH:32][C:33](Cl)=[O:34])[CH:22]=[CH:21][C:20]1=2>>[CH3:18][C:19]1([CH3:36])[CH2:28][CH2:27][C:26]([CH3:29])([CH3:30])[C:25]2[CH:24]=[C:23]([CH:31]=[CH:32][C:33]([O:1][C:2]3[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:7])=[CH:4][CH:3]=3)=[O:34])[CH:22]=[CH:21][C:20]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21

Procedure:
In a similar manner to that of Example 1 (d), by reaction of 2.3 g (10 mmol) of benzyl 4-hydroxy-benzoate with 2.8 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyl chloride, 1.7 g (37%) of the expected benzyl ester, with a melting point 97-9° C., are obtained.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]3)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1>CC(O)C>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][N:22]=[C:21]2[N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[C:10]([S:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:9])=[O:8])[CH:11]=[CH:12][CH:13]=2)[CH2:18]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=S(=O)(c1cccc2c1CNCC2)N1CCOCC1
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cccc(S(=O)(=O)N5CCOCC5)c4C3)c2cc1OC
Yield: 84.9 %

Procedure:
8-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydroisoquinoline (15.7 g, 55.6 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (12.5 g, 55.6 mmol) were refluxed overnight in 2-propanol (400 mL). The solvent was removed under vacuum and the resultant solid was partitioned between aqueous ammonia and CH2Cl2. The mixture was extracted three times with CH2Cl2 and the combined extracts were dried and concentrated. Flash chromatography (0.1:3:97 NH4OH/MeOH/CH2Cl2) followed by recrystallization of the product fractions from EtOH provided, in two crops, 22.2 g (85%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=2[CH3:1])[CH2:13][CH2:12]1
Reactant: Cc1cccc(C=O)c1C
Reactant: NC1CC1
Product: Cc1cccc(CNC2CC2)c1C

Procedure:
Synthesized according to typical procedure J from 2,3-dimethylbenzaldehyde and cyclopropylamine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:28])[CH:10]2[NH:14][C:15](=[O:27])[CH:16]([C:22]([O:24]CC)=[O:23])[N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)[C:7]=1[C:29]([OH:31])=[O:30])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:28])[CH:10]2[NH:14][C:15](=[O:27])[CH:16]([C:22]([OH:24])=[O:23])[N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)[C:7]=1[C:29]([OH:31])=[O:30])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CSC12)n1cccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)n3cccc3)C2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(Acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid is added to trifluoroacetic acid (TFA) maintained at 0° C. This mixture is stirred for about 30 minutes, warmed to about 20° C. for about 30 minutes and then warmed (maximum of 25° C.) under vacuum to remove the TFA. The acid is taken up in ethyl acetate. The ethyl acetate is washed with water, dried over magnesium sulfate, filtered and partially concentrated. The title compound was recovered from the solvent by filtration.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:11]1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:11]1
Reactant: CC(=O)OC[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
HCl 4M in dioxane (5 mL) was added at RT to a solution of racemic trans acetic acid 3-tert-butoxycarbonylamino-cyclohexylmethyl ester (theoretically 7.37 mmol) in 10 mL of DCM. The resulting mixture was stirred at RT for 4 hours before being evaporated to give 1.5 g of racemic trans acetic acid-3-amino-cyclohexylmethyl ester hydrochloride (>95% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])[CH2:6][CH3:7].[I-].C[N+](C)(C)[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=2[CH3:34])[N:27]([CH3:36])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=3[CH3:34])[N:27]([CH3:36])[CH:26]=2)[C:9]1=[O:19])[CH2:6][CH3:7]
Reactant: Cc1cc(C)c2c(C[N+](C)(C)C)cn(C)c2c1
Reactant: CC[C@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Temperature: 65 °C
Yield: 35.3 %

Procedure:
A mixture of 1.75 g of (R)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester, 2.5 g of trimethyl-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-ammonium iodide and 1.7 g of potassium carbonate in 50 mL of N,N-dimethylformamide is heated at 65° C. for 3 h. The resulting mixture is diluted with water and the product is extracted with ethyl acetate. The organic layer is washed with brine, dried (sodium sulfate) filtered and concentrated. The residue is purified by flash chromatography on silica gel to give 1.0 g (35%) of (R)-3-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester.
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[SH:12])C.C[O-].[Na+].[CH3:17][O:18][C:19](=[O:28])[C:20]([NH:23][C:24](=[O:27])[CH2:25]Cl)([CH3:22])[CH3:21]>CO>[CH3:17][O:18][C:19](=[O:28])[C:20]([NH:23][C:24]([C:25]1[S:12][C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[C:4]=1[OH:13])=[O:27])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cc(F)ccc1S
Reactant: COC(=O)C(C)(C)NC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1sc2ccc(F)cc2c1O
Yield: 70.7 %

Procedure:
To a solution of 1.00 g 5-fluoro-2-mercaptobenzoic acid ethyl ester in 10 ml methanol 0.81 g of sodium methoxide were added portionwise, followed by addition of 0.97 g 2-(2-chloro-acetylamino)-2-methyl-propionic acid methyl ester. After refluxing the reaction under argon-atmosphere for 0.5 h the resulting mixture was filtrated, 20 ml water and 1.25 ml of acetic acid were added and the precipitated product was collected by filtration, washed with water, dissolved in ethyl acetate and THF, dried over sodium sulphate, filtrated and concentrated in vacuo. The resulting crude product was crystallized from diethylether to yield 1.10 g 2-[(5-fluoro-3-hydroxy-benzo[b]thio-phene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:28]([O-])=O)=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:14]=2)[CH:9]1[CH2:31][C:32]1[CH:37]=[C:36]([Br:38])[C:35]([O:39][CH3:40])=[C:34]([Br:41])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(OCC)(=O)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH2:28])=[C:13]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:14]=2)[CH:9]1[CH2:31][C:32]1[CH:33]=[C:34]([Br:41])[C:35]([O:39][CH3:40])=[C:36]([Br:38])[CH:37]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(COc2cc3c(cc2[N+](=O)[O-])C(Cc2cc(Br)c(OC)c(Br)c2)N(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COc2cc3c(cc2N)C(Cc2cc(Br)c(OC)c(Br)c2)N(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3,5-dibromo-4-methoxybenzyl)-6-(4-methoxy-benzyloxy)-7-nitro-1,2,3,4-tetrahydro-isoquinoline-2-carboxylic acid tert-butyl ester (8.31 g, 0.012 mol) in 120 mL of ethyl acetate and 12 mL of pyridine was added powder tin (II) chloride dihydrate (27.08 g, 0.12 mol). The reaction mixture was stirred for 5 h at 55° C., cooled and filtered. The filtrate was washed 2 times with 1N NaOH. Water phase was extracted with chloroform. The extracts and ethyl acetate solution were combined, dried over Na2SO4 and concentrated. The product was purified by column chromatography (silica gel, ethyl acetate-hexanes mixture (1:4)), evaporated with ethyl ether and dried in vacuum. Yield 4.864 g (61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl.O>[CH2:12]([NH:11][C:7]1[N:6]([CH2:5][C:4]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:2]([Cl:1])[CH:3]=2)[CH:10]=[CH:9][N:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Nc1nccn1Cc1cc(Cl)cc(Cl)c1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1cc(Cl)cc(Cn2ccnc2NCc2ccccc2)c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
N-[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-yl]-benzamide, was dissolved in anhydrous THF and 1M LiAlH4 was added to the reaction solution at room temperature. The reaction mixture was then heated to 70° C. and stirred for 10 min. The mixture was then diluted with CH2Cl2 and water was slowly added until H2 formation stopped. The reaction mixture was passed through a cartridge packed with anhydrous Na2SO4. The filtrated was concentrated and purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH to afford the title compound (5 mg, 7%); MS m/z 332 [C17H15Cl2N3+H]+.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([NH:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])=[CH:14][C:13]=1[Cl:29])=O)C1C=CC=CC=1>O1CCCC1.[Pd]>[NH2:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([NH:18][CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[O:17])=[CH:14][C:13]=1[Cl:29]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(NC(=O)OCc2ccccc2)c(Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
t-Butyl N-(4-benzyloxycarbonylamino-3-chlorobenzoyl)glycinate (0.80 g) was dissolved in tetrahydrofuran (30 ml) and then admixed with 10% Pd/C (50% water, 160 mg) and then stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The catalyst was filtered off and the filtrate was diluted with ethyl acetate and washed three times with water and twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:1). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of diisopropyl ether and hexane to yield t-butyl N-(4-amino-3-chlorobenzoyl)glycinate (0.49 g) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[N:11]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([OH:17])[C:13]([N+:18]([O-:20])=[O:19])=[C:14]([OH:16])[N:15]=1
Reactant: COc1ccc(F)c(-c2nc(O)cc(O)n2)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(F)c(-c2nc(O)c([N+](=O)[O-])c(O)n2)c1
Temperature: 50 °C

Procedure:
To a suspension of 2-(2-Fluoro-5-methoxyphenyl)-4.6-dihydroxy-pyrimidine (12 g) in 35 mL of acetic acid is added 12 mL of 90% nitric acid and the mixture is heated at 50° C. for 45 min. The reaction mixture is diluted with 150 mL of water and the product is collected, washed with water and ethanol and oven dried to afford 2-(2-Fluoro-5-methoxyphenyl)-5-nitro-4.6-dihydroxy-pyrimidine as a pink solid.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][O:7][CH2:8][C@H:9]1[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][N:11](C(OC(C)(C)C)=O)[C@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:39].O1CCOCC1>O1CCOCC1>[ClH:39].[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)[CH2:6][O:7][CH2:8][C@H:9]1[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][NH:11][C@H:10]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)[C@@H](c2ccccc2)[C@H]1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)CN[C@@H](c2ccccc2)[C@H]1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl (2S,3S)-3-(3,5-bis(trifluoromethyl)benzyloxymethyl)-4-methyl-5-oxo-2-phenylpiperizine-1-carboxylate (6.5 g, 11.9 mmol) in 1,4-dioxane (100 mL) was added 4 mol/L HCl-1,4-dioxane (15 mL, 59.5 mmol). After stirring at room temperature for 2 hours, the solvent was removed by evaporation under reduced pressure to give (5S,6S)-6-(3,5-bis(trifluoromethyl)benzyloxymethyl)-1-methyl-5-phenylpiperazin-2-one hydrochloride (Compound 24) (5.5 g, 96%).