Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]O.C(N(CC)CC)C.CS([Cl:23])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][Cl:23]
Reactant: COc1ccc(CO)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CCl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
To a solution of 3-chloro-4-methoxybenzyl alcohol (1.1 g, 6 mmol) in tetrahydrofuran (5 mL) were added under ice-cooling triethylamine (1.67 mL, 12 mmol) and methanesulfonyl chloride (0.51 ml, 6 mmol) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (700 mg, 61%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH2:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31].[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)[C:42]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:44])=[CH:37][CH:36]=1)(=[O:33])=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: Nc1nccs1
Reactant: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.9 %

Procedure:
A solution of triphenylphosphine (99 mg, 0.37 mmol) and N-bromosuccinimide (76 mg, 0.42 mmol) in methylene chloride (1.26 mL) cooled to 0° C. was treated with 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid (85 mg, 0.25 mmol) in methylene chloride. The reaction mixture was stirred at 25° C. for 45 min. At this time, the reaction was treated with 2-aminothiazole (33 mg, 0.32 mmol) and pyridine (0.03 mL, 0.37 mmol). The reaction was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. At this time, the reaction was diluted with water (50 mL) and extracted with chloroform (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 50/50 hexanes/ethyl acetate) afforded 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide (69.3 mg, 65.6%) as an off-white solid: mp 163-165° C.; EI-HRMS m/e calcd for C21H28N2O3S2 (M+) 420.1541 found 420.1535.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:10]=1)=O)C.[C-:28]#[N:29].[Na+].CN>>[CH3:28][NH:29][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:10]=1)=[O:3]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2o1
Agent: CN
Agent: [Na+]
Product: CNC(=O)c1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2o1

Procedure:
tert-Butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (6.17 g, 16.5 mmol) and sodium cyanide (0.081 g, 1.6 mmol) were stirred overnight at rt in methyl amine (8 M in ethanol) (62 mL, 490 mmol). The solvent was removed by rotary evaporation, the residue was dissolved in dichloromethane and transferred to a separatory funnel. The mixture was washed with 2 M sodium hydroxide and water. The organic phase was separated, dried over potassium carbonate, filtered and the solvent was removed by rotary evaporation to give the title compound. Yield: 5.8 g, 98%. The crude product was used in the subsequent step iii) without further purification. 1H NMR (500 MHz, CDCl3) δ ppm 1.51 (s, 9H) 3.06 (d, 3H) 3.15-3.23 (m, 4H) 3.61-3.70 (m, 4H) 6.59-6.66 (m, 1H) 6.71 (d, 1H) 7.13 (d, 1H) 7.29-7.35 (m, 1H) 7.51 (d, 1H).
Reaction SMILES: [C:1]([CH2:5]P(=O)(OCC)OCC)([O:3][CH3:4])=[O:2].CN(C)C=O.[H-].[Na+].[CH3:21][C:22]([CH2:30][CH3:31])=[CH:23][CH2:24][CH2:25][CH2:26][C:27](=O)[CH3:28]>O>[CH3:28][C:27]([CH2:26][CH2:25][CH2:24][CH:23]=[C:22]([CH3:21])[CH2:30][CH3:31])=[CH:5][C:1]([O:3][CH3:4])=[O:2]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CCC(C)=CCCCC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)=CCCCC(C)=CC(=O)OC

Procedure:
A mixture of 11.2 g. of diethyl carbomethoxymethylphosphonate in 100 ml. of dimethylformamide is treated with 2.4 g. of sodium hydride. The mixture is stirred until the evolution of gas ceases and then 10 g. of 7-methyl-6-nonen-2-one is added slowly with stirring, maintaining temperature below 30°. The mixture is stirred for about one hour, then diluted with water and then extracted with ether. The ethereal phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield methyl 3,8-dimethyldeca-2,7-dienoate as a mixture of isomers (trans,cis; trans,trans; cis,cis and cis,trans) which are separated by chromatography.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:33])[CH:29]=2)[N:24]=1>>[F:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([CH2:22][N:18]1[CH2:19][CH:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:16][C:17]1=[O:20])[CH:32]=[CH:31]2
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Reactant: Fc1ccc2nc(CCl)ccc2c1
Product: COc1ccc(C2CC(=O)N(Cc3ccc4cc(F)ccc4n3)C2)cc1OC1CCCC1

Procedure:
Reaction of 4-[3-(cyclopentyloxy)-4-methoxyphenyl]pyrrolidinone with 2-chloromethyl-6-fluoroquinoline, analogous to the procedure of Example 29, yielded the title compound. M.P.: 65°-68° C. High Resolution Mass Spectra: Calc'd: 434.1983. Found: 434.2005.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[NH2:15])=[O:5])[CH3:2].[N:16]#[C:17][NH2:18].[ClH:19]>O1CCOCC1>[ClH:19].[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[NH:15][C:17]([NH2:18])=[NH:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)[nH]c2ccccc12
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(NC(=N)N)[nH]c2ccccc12
Yield: 38 %

Procedure:
A suspension of 2 aminoindole-3-carboxylic acid ethyl ester (2.04 g, 10.0 mmol), cyanamide (534 mg, 12.7 mmol), and concentrated hydrochloric acid (1 mL) in dioxane (91 mL), are heated under reflux for 48 hr. After the reaction mixture has cooled to 25 C. it is filtered and the solids washed well with dry diethyl ether, and then air dried to give 2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride (1.08 g, 38%) 2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride as an off-white solid, mp >250 C.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].C.C(OC)(C)(C)C>C1C=CC=CC=1>[Cl:12][CH2:13][C:14]([N:6]1[CH2:7][C@@H:3]([OH:2])[CH2:4][C@@H:5]1[C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H]1C[C@H](O)CN1
Agent: Cl
Solvent: c1ccccc1
Solvent: COC(C)(C)C
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)CCl
Reaction time: 0.5 h

Procedure:
To a suspension of Example 17A (100 g, 0.55 mol, 1 equivalent) in benzene (2.5 L), chloroacetyl chloride (62.4 g, 0.50 mol, 1 equivalent) was added dropwise at 20-25° C. The reaction mixture was refluxed for 3 hours. Then charcoal (2 g) was added, and the mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to get a solid. To this crude material, methyl tert-butyl ether (500 mL) was added and stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.06-2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=11.1 Hz), 3.76 (s, 3H), 3.76-3.86 (m, 2H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:26]/[O:27][CH2:28][C:29]([O:31]CC2C=CC([N+]([O-])=O)=CC=2)=[O:30])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[N:14]([S:21]([O-:24])(=[O:23])=[O:22])[C:13]2=[O:25])=[O:10])[N:7]=1>CO.[Pd]>[Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:26]/[O:27][CH2:28][C:29]([OH:31])=[O:30])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[N:14]([S:21]([O-:24])(=[O:22])=[O:23])[C:13]2=[O:25])=[O:10])[N:7]=1
Reactant: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Yield: 54.8 %

Procedure:
270 mg (0.43 mmol) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2[[(p-nitrobenzyloxycarbonyl)methoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 30 ml of methanol and the solution is hydrogenated over 150 mg of 5% palladium-on-silica gel. The catalyst is filtered off and the solvent is evaporated. The residue is taken up in 2.5 ml of water and washed twice with ethyl acetate. The aqueous phase is chromatographed (reverse-phase using water as the eluting agent). There are obtained 115 mg (54%) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25].C(O)(=O)C.CC([O-])=O.[Na+]>CCOC(C)=O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH:16]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:13]=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:25])([F:27])[F:26]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C=O)ccc1-c1ccccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1-c1ccccc1C(F)(F)F
Temperature: 95 °C
Reaction time: 14 h

Procedure:
To a flask was added rhodanine (37 mg, 275 μmol), 2-Methoxy-2′-trifluoromethyl-biphenyl-4-carboxaldehyde (70 mg, 250 μmol), acetic acid (4 mL) and NaOAc (60 mg, 3 equiv). The reaction solution was allowed to stir at 95° C. under N2 for 14 h. Additional NaOAc (60 mg, 3 equiv) was added to the solution and stirred at 100° C. for an additional 24 h. The reaction solution was diluted with EtOAc (100 mL), washed with water (50 mL×3), washed with aq NaHCO3 (50 mL×3), dried and concentrated. The crude material was chromatographed (SiO2, Hex:EtOAc 100:0 to 70:30) to yield the intermediate compound. (79 mg, 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(F)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-fluorobenzyl bromide
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[C:16]([O:20][C:21](=[O:30])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>>[C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([NH:22][C:21](=[O:30])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:24][CH2:25]1)=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (480 mg, 2.0 mmol) was reacted with tert-butyl(trans-4-aminocyclohexyl)carbamate (430 mg, 2.0 mmol) to afford the desired product (600 mg, 71%) as a light orange solid: 1H NMR (500 MHz, CDCl3) δ 10.91 (br s, 1H), 8.96 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 5.10-4.99 (m, 1H), 4.48 (br s, 1H), 3.55 (br s, 1H), 2.69 (s, 3H), 2.34-2.25 (m, 2H), 2.19-2.10 (m, 2H), 1.56-1.45 (m, 2H), 1.47 (s, 9H), 1.44-1.33 (m, 2H);
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O)[CH3:11].C([BH3-])#N.[Na+]>C(O)C>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH2:16][C:15]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=1)[CH3:3]
Reactant: CCOC(=O)CCN
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCNCc1ccc(OC)c(OCC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.1 %

Procedure:
A mixture of β-alanine ethyl ester hydrochloride (1.6 g), 3-ethoxy-4-methoxybenzaldehyde (1.8 g), sodium cyanoborohydride (0.42 g) and powdered 3Å molecular seives (2.5 g) in ethanol (25 ml) was stirred at ambient temperature for 24 hours. A further aliquot of sodium cyanoborohydride (0.42 g) was added and stirring was continued for a further 24 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was treated with ethyl acetate (100 ml) and the solution was washed with 10% aqueous potassium carbonate (50 ml), then twice with water (25 ml), then with brine (25 ml), then dried over magnesium sulphate and then evaporated. The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5, v/v) to give the title compound as a colourless oil (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:22]=[N+:23]=[O:24].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:7]=1[N+:23]([O-:24])=[O:22]
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)cc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
276 mg (1.45 mmol) of ethyl 3-(4-chlorophenyl)-3-methylbutanoate were dissolved in 10 ml of dichloromethane, and the mixture was cooled to 0° C. A little at a time, 278 mg (1.38 mmol) of nitronium tetrafluoroborate were then added, and the mixture was stirred at a temperature between 0° C. and 10° C. for 4 h. 10 ml of water and 10 ml of dichloromethane were then added, and the phases were separated. The organic phase was dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 223 mg of the title compound (68% of theory).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][CH2:11]Cl)=[N:7][CH:8]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.C(O)(C)C>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][N:7]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Cc1ccc(C=CCCl)nc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)nc1
Yield: 22 %

Procedure:
Prepared from 3-(5-methyl-2-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 22% of theory, Melting point: 172°-175° C. (isopropanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].CCN(CC)CC.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:13]([Si:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:1][CH2:2][CH2:3][C:4]#[N:5])([CH3:16])([CH3:14])[CH3:15]
Reactant: N#CCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in 30 mL of dry DCM at room temperature was added NEt3 (30.3 g, 0.3 mol), followed by tert-butyldiphenyl-silylchloride (27.5 g, 0.1 mol). A lot of white solid appeared. After stirring at room temperature overnight, the reaction mixture was quenched with Sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, hexane/EtOAc=100:2 to 100:5 to 100:10) gave the title compound as a white solid. B. Preparation 3-(tert-butyldiphenylsilyloxy)propanamidine. To a suspension of NH4Cl (5.35 g, 0.1 mol) in 60 mL of dry benzend at 0 C was slowly added 50 mL of 2 M solution of trimethylaluminum in toluene. After the addition was complete, the reaction mixture was allowed to warm up to room temperature and was stirred for 2 h until gas evolution had ceased. A solution of the above nitrile in 20 mL of dry benzene was added to the aluminum amide reagent and the resulting mixture was heated up to 80 C for 20 h. The reaction mixture was slowly cooled to room temperature and then carefully poured into a slurry of 300 mL of DCM and 200 g of silica gel. It was then filtered and washed thoroughly with MeOH/DCM (1:2). After concentration, flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:20 to 100:30 to EtOAc/2 m NH3 in MeOH=100:30) gave the product as a white solid. C. Preparation of 3-(tert-butyldiphenylsilyloxy)propanamidine2-(2-(tert-butyldiphenylsilyloxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)=[CH:10][N:9]=1.[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35](O)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40].C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>C(Cl)Cl>[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35]([NH:20][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:11]4[CH:10]=[N:9][C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@H:3]5[C:2]([F:1])([F:21])[F:22])=[N:13][CH:12]=4)[N:19]=3)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40]
Reactant: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Reactant: Nc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](C(=O)Nc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1)n1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 3, 5.44 g, 17.59 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propanoic acid (Intermediate 8, 5.10 g, 20.23 mmol, ee: 99%), CH2Cl2 (58.6 mL) and the resulting mixture was stirred at 25° C. for 5 minutes. To the resulting yellow heterogeneous mixture was added HOAt (2.394 g, 17.59 mmol) and DCC (6.90 g, 33.4 mmol). The reaction mixture was cooled to 0° C. and pyridine (2.85 mL, 35.2 mmol) was added slowly around the edges of the flask. The reaction mixture was kept at 0° C. for 5 minutes before it was removed from the ice bath, and was then stirred at 25° C. for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite® to remove urea byproduct. The filtrate was then quickly concentrated to an oil, taken up in minimal CH2Cl2 and added dropwise to stirring hexanes to precipitate out crude (S,S)-product which was dried overnight. The product was recrystallized from CH2Cl2:MeOH (4:1) to obtain the title product (4.78 g, 8.79 mmol, 50%, de>99%); 1H NMR; 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.12 (s, 2H), 8.34 (s, 1H), 7.88 (dt, J=15.7, 8.1 Hz, 2H), 7.68 (d, J=8.2 Hz, 1H), 5.84 (d, J=6.7 Hz, 1H), 5.11 (p, J=7.4, 7.0 Hz, 1H), 3.83-3.61 (m, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.33-1.96 (m, 4H), 1.87 (d, J=7.3 Hz, 3H); m/z [M+H]+=544.20.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+]>O.CCOCC>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCCCc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCCCCCc1ncccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-pyrimidinehexanol (1.18 g), 1,6-dibromohexane (4 ml), 50% sodium hydroxide (4 ml) and TAB (100 mg) was vigorously stirred at room temperature for 17 h, then diluted with water (40 ml) and ether (50 ml). The organic phase was dried and evaporated in vacuo to an oil which was purified by FCC. Elution with hexane followed by hexane-ether (1:1) gave the title compound as a colourless oil (670 mg), t.l.c. (ether) Rf 0.24
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23]([OH:25])=O)[C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27]>>[CH2:26]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:23](=[O:25])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:27]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cn1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:17]([NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[N:9][CH:10]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC(C)(C)C)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3.5 ml (40 mMol) Oxalylchloride and 57.4 □l (0.74 mMol) DMF were added to a suspension of 5.0 g (36.5 mMol) 6-methyl-nicotinic acid in 25 ml toluene and the system was heated to 40° C. for one hour. After diluting with 20 ml toluene and cooling to 0° C., 11.5 ml (109 mMol) tert.-butylamine were slowly added. After 30 minutes stirring at room temperature, 25 ml aqueous NaOH 2N were added and stirring pursued for 30 minutes. The phases were separated and the aqueous phase was extracted with toluene. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (eluent: ethyl acetate/n-heptan 1:1) to yield 5.4 g (77%) N-tert.-butyl-6-methyl-nicotinamide as a light beige solid of m.p. =103.5-104.8° C.