Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.Br[C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:4][N:5]([C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])[N:6]=1
Reactant: COC(=O)C(C)(C)Br
Reactant: CSc1nccc(-c2cn[nH]c2I)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)n1cc(-c2ccnc(SC)n2)c(I)n1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a mixture compound A (60 g, 0.19 mol) and methyl 2-bromo-2-methylpropanoate (102 g, 0.57 mol) in DMF (400 mL) was added freshly ground potassium carbonate (65 g, 0.47 mol) in one portion. The reaction mixture was stirred at 80° C. for 18 hours. LC-MS indicated the reaction was complete. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (1200 mL) and brine (300 mL). The aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography using 5-30% EtOAc in petroleum ether as eluent to give compound B-49-1 (62 g, 78%) as syrup, which solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1O.[O-2].[Pr+3].[O-2].[O-2].[Pr+3].[NH3:15].[H][H]>[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[NH2:15]
Reactant: [H][H]
Reactant: N
Reactant: Cc1cccc(C)c1O
Agent: [Pd]
Agent: [O-2]
Agent: [Pr+3]
Product: CC1CCCC(C)C1N
Temperature: 250 °C
Yield: 98.5 %

Procedure:
1,650 parts by weight of 2,6-dimethylphenol and 150 parts by weight of a pulverulent catalyst containing 10.0% by weight of palladium and 5.0% by weight of praseodymium oxide on aluminum oxide were introduced into a stirred autoclave having a capacity of 10,000 parts by volume. The autoclave was closed and 1,370 parts by weight of ammonia were forced in. The autoclave was then heated to 250° C. and hydrogen was introduced to bring the pressure to 300 bar. The autoclave was kept at the reaction temperature until constant pressure was achieved (about 10 hours). It was then allowed to cool and the mixture was filtered to give 1,691 parts by weight (98.5%) of 2,6-dimethylcyclohexylamine which, according to gas chromatography and NMR analysis, had the following isomer distribution:
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11]3)[CH2:3][CH2:2]1.Br[CH:27]([CH:30]=O)[CH:28]=[O:29].CN(C)C(=O)C>O>[CH:1]1([CH2:4][N:5]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]2[S:17][C:27]([CH2:28][OH:29])=[CH:30][N:16]=2)=[CH:11]3)[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH2:3][CH2:2]1
Reactant: O=CC(Br)C=O
Reactant: NC(=S)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(c1cccs1)N(CC1CC1)c1cccc2cc(-c3ncc(CO)s3)[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A mixture of 7-[(cyclopropylmethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (225 mg), bromomalonaldehyde (182 mg) and N,N-dimethylacetamide (3 mL) was stirred at 90° C. for 1 hr. Water was added and the obtained precipitate was washed with water, and then with hexane. The solid was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), and the mixture was cooled in an ice bath. Sodium borohydride (20 mg) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, and the residue was diluted with a mixture of tetrahydrofuran-ethyl acetate (1:1) and washed with saturated brine and aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate-hexane. The obtained solid was washed with a mixture of hexane-ether to give the title compound (100 mg, yield 50%) as crystals. melting point 174° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][N:6]1[C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=O)=[CH:9][N:8]=[C:7]1[SH:20].B.CSC.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][N:6]1[C:10]([CH2:11][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][N:8]=[C:7]1[SH:20]
Reactant: CN1CCN(C(=O)c2cnc(S)n2Cc2cc(F)cc(F)c2)CC1
Agent: B
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CSC
Product: CN1CCN(Cc2cnc(S)n2Cc2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(3,5-difluorobenzyl)-5-[(4-methyl-1-piperazinyl)carbonyl]-2-mercaptoimidazole (1.37 g, 3.89 mmole) in chloroform (15 ml) was added dropwise 1 molar borane-methyl sulfide (23.3 ml, 23.3 mmole) and the solution was stirred for 4 hours at 25° C. The reaction mixture was cooled in ice and methyl alcohol was added dropwise until gas evolution ceased. The solvent was removed by evaporation at reduced pressure, ten portions of methyl alcohol were added, the reaction mixture was heated at reflux for 5 minutes and the solvent was removed at reduced pressure. The crude product was dissolved in methylene chloride-methanol (9:1) and purified by flash slica chromatography. The product was purified by trituration with ethyl acetate and recrystallization from ethanol to give 1-(3,5-difluorobenzyl)-5-[(4-methyl-1-piperazinyl)methyl]-2-mercaptoimidazole as a solid, m.p.: 200°-201° C. (0.820 g, 62%).
Reaction SMILES: O.NN.[F:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[N:11]1C(=O)C2=CC=CC=C2C1=O.[ClH:22]>O1CCOCC1>[ClH:22].[F:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH2:11]
Reactant: O=C1N[C@H](CF)[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H]1C(=O)N[C@@H]1CF
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
14 ml of a solution of 1 ml of hydrazine hydrate in 50 ml of dioxane were added to a suspension of 1.24 g of the product of Step D in 1.2 ml of dioxane and the mixture was stirred at room temperature for 45 minutes and 5 ml of N hydrochloric acid were added thereto. The mixture was stirred for 15 hours and was evaporated to dryness. The residue was added to water and 2.3 ml of N hydrochloric acid with stirring and the mixture was filtered. Ethanol was added to the filtrate and the mixture was evaporated to dryness. Methanol was added to the residue followed by ethanol addition and the mixture was evaporated to dryness. The product was crystallized from methanol to obtain 0.391 g of cis 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride melting at ≃220° C. (decomposition).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:13](=[O:21])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:25][C:23]([NH:22][C@H:12]([C:13](=[O:21])[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:33])=[O:5])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1
Reaction time: 5 h
Yield: 120.2 %

Procedure:
To a solution of ester 51 (76 mg, 0.167 mmol) in CH2Cl2 (5 mL) was added TFA (0.5 mL) and the reaction solution stirred for 5 h. The solution was concentrated under reduced pressure to give crude 52 as a white solid (80 mg) which was used in the next step without purification. TLC Rf 0.32 (5% MeOH/CH2Cl2); 1H-NMR (400 MHz, DMSO-d6) δ 11.93 (br s, 1H), 9.99 (s, 1H), 7.58 (d, 2H), 7.55 (d, 1H), 7.35 (m, 4H), 7.29 (t, 2H), 7.03 (t, 1H), 5.02 (m, 2H), 4.11 (br dd, 1H), 2.17 (t, 2H), 1.59 (m, 2H), 1.48 (m, 2H), 1.22 (m, 4H).
Reaction SMILES: P(Cl)(Cl)Cl.[CH2:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][N+:8]=1[O-])[CH3:6].[OH-].[Na+]>C(Cl)Cl>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][N:8]=1)[CH3:6]
Reactant: CCc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCc1cc([N+](=O)[O-])ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of phosphorous trichloride (7.2 mL, 82 mmol) in CH2Cl2 was added to a cooled 0° C. solution of 2-ethyl-4-nitro-pyridine 1-oxide (3 g, 17.8 mmol) in CH2Cl2. The reaction was stirred for 2 hours and then warmed up to rt. After 3 hours the mixture was poured into ice, made basic with 15% NaOH and extracted with EtOAc. The organic extracts were dried over Na2SO4 and concentrated to a yellow oil that solidified on standing (2.56 g, 95%). 1H NMR (400 MHz, CDCl3): δ 1.40 (t, J=7.6 Hz, 3 H), 3.14 (d, J=7.6 Hz, 2 H), 8.04 (d, J=5.6 Hz, 1 H), 8.06 (s, 1 H), 8.92 (d, J=5.6 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C@H:22]([C:30](O)=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:35][C@H:36]([C:40]([OH:42])=O)[CH:37]([CH3:39])[CH3:38].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:68][C:69]1[S:73][C:72](=[S:74])[NH:71][N:70]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C@H:22]([C:30]([NH:35][C@H:36]([C:40]([NH:68][C:69]3[S:73][C:72](=[S:74])[NH:71][N:70]=3)=[O:42])[CH:37]([CH3:39])[CH3:38])=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1n[nH]c(=S)s1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1)C(=O)Nc1n[nH]c(=S)s1

Procedure:
(4-(4-t-Butylphenylsulfonylamino)benzoyl)-phenylalanine-valine, (0.48 grams) 1-hydroxybenzotriazole (0.15 grams), dicyclohexylcarbodiimide (0.17 grams) and 5-amino-1,3,4-thiadiazole-2-thione (0.5 grams) were reacted according to the procedure described in Example 1. The resulting product was recrystallized from ethanol/pentane to give a white solid. M.P. 140°-144° C. NMR spectrum (d6 -DMSO) 14.1 (s, 1H), 12.6,12.5 (s,s, 1H), 10.8 (s, 1H), 8.6-8.2, 7.8-7.4, 7.4-7.0 (m, 15 H, NM+aromatics), 4.8 (m, 1H), 4.35 (m, 1H), 3.5-2.8 (m, 2H), 2.05 (m, 1H), 1.2 (s, 9H), 0.85 (bs, 6H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:25]([CH2:27][NH2:28])[OH:26]>CN(P(N(C)C)(N(C)C)=O)C>[OH:26][CH2:25][CH2:27][NH-:28].[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Agent: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: [NH-]CCO
Reaction time: 2 h

Procedure:
2.72 g. of 2-(4-phenoxymethylphenoxy)-propionic acid is dissolved in 12 ml. of HMPA. At -10°, 0.77 ml. of thionyl chloride is added thereto, and the mixture is agitated for 2 hours at -5°. Thereafter, 2.5 ml. of ethanolamine is added and the reaction mixture is stirred overnight at 20°. The mixture is then poured on ice and worked up as usual, yielding the 2-hydroxyethylamide of 2-(4-phenoxymethylphenoxy)-propionic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C@@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC.[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][C@@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:13])=[O:12]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 15 h
Yield: 91.7 %

Procedure:
20 g of 2-naphthylsulphonyl chloride in 150 ml of ether are added to a solution of 7.3 g of (R)-phenylalanine in 120 ml of 1N sodium hydroxide solution. The reaction mixture is stirred for 15 hours and decanted. The aqueous phase is separated, washed with ether, acidified to pH 3 with HCl and extracted with ethyl acetate. The organic phase is dried and evaporated. The separated crystals are suspended in ether and filtered off. There are obtained 14.4 g of N-(2-naphthylsulfonyl)-3-phenyl-D-alanine, m.p. 146° C.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:37][CH3:38]>CN(C=O)C>[CH2:37]([O:1][C:2]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=[O:5])[CH3:38]
Reactant: CC(C)Oc1ccc(NC(=O)c2cc(S(=O)(=O)N3CCCCC3)ccc2O)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N2CCCCC2)cc1C(=O)Nc1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
The compound (30 mg) obtained in Example 151 was dissolved in DMF (0.50 mL), then potassium carbonate (30 mg) and iodoethane (0.030 mL) were added thereto in that order, and stirred at room temperature for 18 hours. This was purified through reversed-phase HPLC (0.1% TFA acetonitrile/H2O=from 10% to 95%, gradient) to give the entitled compound (25 mg, 78%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)cc1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-methoxyphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (41%).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][CH2:7][CH2:8][CH2:9][CH3:10].BrC1C2[C:15](=[CH:16][CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])C=2)[N:14]([Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:13]=1.C(I)C>C1COCC1>[C:32]([Si:29]([CH3:31])([CH3:30])[N:14]1[C:15]2[C:7](=[CH:6][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:8]([CH2:9][CH3:10])=[CH:13]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CCCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(Br)cn2[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cn([Si](C)(C)C(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A 1.5 M solution of tert-butyllithium in pentane (3.3 ml, 4.99 mmol) was added dropwise to a solution of 3-bromo-1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole (1 g, 2.3 mmol) in THF (6 ml) at −78° C. under an argon atmosphere. After 15 min ethyl iodide (0.37 ml, 4.5 mmol) was added at −78° C. The reaction mixture was stirred for 30 min at −78° C. and for 2 h at RT. After quenching with saturated aqueous NaHCO3 solution the reaction mixture was partitioned between ether and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 880 mg (2.26 mmol, 99%) 1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-3-ethyl-1H-indole.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>C(Cl)(Cl)Cl>[Br:1][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: BrBr
Reactant: COc1ccccc1C#N
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1C#N
Temperature: 25 °C
Yield: 71.4 %

Procedure:
Bromine (13.7 g, 86.0 mmol) in CHCl3 (20 mL) was added to a solution of 2-(methyloxy)benzonitrile (10.9 g, 81.9 mmol) in CHCl3 (50 mL). The mixture was refluxed for 29 h. The reaction was allowed to cool to room temperature, and washed with saturated sodium bisulfite (50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 5-bromo-2-(methyloxy)benzonitrile (12.4 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[Br:22][CH2:23][C:24]([N:8]([C@@H:9]([CH3:12])[CH2:10][OH:11])[CH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:25]
Reactant: COc1ccc(CN[C@@H](C)CO)cc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)CBr)[C@@H](C)CO)cc1
Temperature: -21 °C

Procedure:
Into a 20000 mL 4-necked, round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (S)-2-(4-methoxybenzylamino)propan-1-ol (300 g, 1.54 mol) in dichloromethane (12000 mL) and triethylamine (155.8 g, 1.54 mol). 2-Bromoacetyl bromide (310.8 g, 1.54 mol) was added dropwise, while cooling to a temperature of −17 to −25° C. and maintained at this temperature for 4 hours. The reaction mixture was warmed to room temperature and washed three times with 2000 mL of water, dried over MgSO4, filtered, and concentrated under vacuum to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[C:22]([Cl:24])[C:21]([F:25])=[C:20](Cl)[N:19]=1>C1COCC1.O>[Cl:17][C:18]1[N:19]=[C:20]([N:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[C:21]([F:25])=[C:22]([Cl:24])[N:23]=1
Reactant: CNCc1ccncc1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1ccncc1)c1nc(Cl)nc(Cl)c1F
Reaction time: 2.5 h
Yield: 49 %

Procedure:
Commercially available N-methyl-1-(4-pyridinyl)methanamine (0.305 g, 2.5 mmol) was dissolved in THF (5 mL). To this solution was added triethylamine (0.38 mL, 2.73 mmol), followed by 2,4,6-trichloro-5-fluoropyrimidine (0.5 g, 2.5 mmol), which was dissolved in THF (5 mL). The reaction was left to stir for 2.5 hours. The reaction mixture was diluted with water, then extracted with ether. The organics were dried (MgSO4) and concentrated. The resulting material was purified via filtration over silica gel with a solvent mixture of 5% MeOH in 95% DCM as the mobile phase to provide 2,6-dichloro-5-fluoro-N-methyl-N-(4-pyridinylmethyl)-4-pyrimidinamine as a brown oily solid (0.3516 g, 49%). LCMS: (M+H)+=287.0.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([CH:9]=O)=[CH:4][NH:3]1.CO.Cl.[NH2:14][OH:15].C([O-])(=O)C.[K+]>O>[OH:15][N:14]=[CH:9][C:5]1[C:6](=[O:8])[NH:7][C:2](=[O:1])[NH:3][CH:4]=1
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1[nH]cc(C=NO)c(=O)[nH]1
Yield: 84.4 %

Procedure:
A mixture of 2,4-dioxo-5(1H,3H)-pyrimidinecarbaldehyde (1.79 g, 12.8 mmol), methanol (35 mL) and water (35 mL) was heated at reflux and then a mixture of hydroxylamine hydrochloride (905 mg, 13 mmol), potassium acetate (1.28 g, 13 mmol) and water (15 mL) was added. The mixture was cooled and the solids were collected, washed with water and recrystallized from water/methanol to give 5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione (1.68 g, 10.8 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22]I>CN(C=O)C>[Cl:19][CH2:20][CH2:21][CH2:22][S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10]
Reactant: O=S(O)c1ccc(F)c(F)c1
Reactant: ClCCCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCl)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 28.3 mmol 3,4-difluoro-benzenesulfinic acid and 36.8 mmol triethylamine in 100 ml DMF was added 70.7 mmol 1-chloro-3-iodopropane and the mixture stirred at RT for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:22])=O>CN(C)C=O.ClCCCl>[ClH:22].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:1])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1

Procedure:
An acylating agent, in acid chloride form, was prepared by combining 26.3 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 36.5 g. of thionyl chloride and 1 drop of dimethylformamide in 200 ml. of 1,2-dichloroethane, and stirring the mixture under reflux for 2 hours under a nitrogen atmosphere. The mixture was then evaporated to dryness under vacuum to obtain the desired 4-(2-piperidinoethoxy)benzoyl chloride, hydrochloride, which was dissolved in 1 liter of 1,2-dichloroethane. To the solution was added 20 g. of 6-acetoxy-2-(4-acetoxyphenyl)benzo[b]thiophene and the mixture was stirred vigorously. To it was then added, over about 3 minutes, 73.4 g. of aluminum chloride. During the addition, the reaction mixture turned dark brown and hydrogen chloride evolved. The mixture was then stirred for one hour, and was poured over 1 liter of ice-water. The layers were separated, and the aqueous layer was extracted three times with 200 ml. portions of warm chloroform. The organic layers were combined and dried over magnesium sulfate, and were then filtered and evaporated under vacuum to obtain a brownish-yellow oil, which was not purified. The presence of the desired product was confirmed by thin layer chromatography (TLC) on silica gel, eluting with 9/1 chloroform/methanol, which showed that the major constituent ran at the same Rf as authentic 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:11]([CH2:14][NH:15][C:16]1[C:17]([I:32])=[C:18]([C:29](Cl)=[O:30])[C:19]([I:28])=[C:20]([NH:23][CH2:24][C:25](=[O:27])[CH3:26])[C:21]=1[I:22])(=[O:13])[CH3:12].CC([N:36](C)C)=O>>[C:11]([CH2:14][NH:15][C:16]1[C:17]([I:32])=[C:18]([C:29]([NH:36][CH:5]([CH2:4][CH2:3][CH3:2])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:30])[C:19]([I:28])=[C:20]([NH:23][CH2:24][C:25](=[O:27])[CH3:26])[C:21]=1[I:22])(=[O:13])[CH3:12]
Reactant: NCCCCCCC(=O)O
Reactant: CC(=O)N(C)C
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Cl)c1I
Product: CCCC(CCC(=O)O)NC(=O)c1c(I)c(NCC(C)=O)c(I)c(NCC(C)=O)c1I
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 7-aminoheptanoic acid (0.8 g, 5.5 mmol) in DMA (20 mL) was added MDTA-Cl (X) (2.8 g, 4.2 mmol) and the mixture stirred at 80° C. for 24 h. DMA was removed. To the residue water was added. The solid material was collected and recrystallized from EtOH to furnish the pure title compound XIIIc (1.02 g, 31%).