Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]([C:19](O)=[O:20])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:28])[CH:15]=2)[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:33])=O>C1COCC1.CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18]([C:19]([Cl:33])=[O:20])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:28])[CH:15]=2)[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1OCc1ccccc1

Procedure:
2-Benzyloxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (240 mg) was dissolved in THF (4.8 ml), and oxalyl chloride (100 μl) and DMF (1 drop) were added at 0° C. with stirring. The mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times to give 2-benzyloxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][CH2:12][NH2:13].[BH4-].[Na+]>CO>[CH2:6]([NH:13][CH2:12][CH2:11][CH2:10][N:9]([CH3:14])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CN(C)CCCN
Reactant: CCCCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCNCCCN(C)C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of n-capronaldehyde (3.79 g, 37.8 mmol) and N,N-dimethylpropane-1,3-diamine (5 mL, 39.7 mmol) in anhydrous methanol (140 mL) was stirred at room temperature for 3 hours. To this solution was added slowly sodium borohydride (2.15 g, 56.8 mmol) over 5 minutes. The solution was stirred for 30 minutes then quenched with 1M NaOH (75 mL), diluted with water (125 mL) and extracted with ethyl acetate (3×150 mL). The combined ethyl acetate extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (gradient: 100% DCM to 10% MeOH in DCM with 1% NH4OH) to afford the title compound as a pale yellow oil (3.79 g, 54%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([F:44])=[C:23]([C@:25]34[CH2:33][C@H:32]([O:34][CH3:35])[CH2:31][C@H:30]3[CH2:29][S:28][C:27]([NH:36]C(=O)OC(C)(C)C)=[N:26]4)[CH:24]=2)=[O:17])=[N:14][CH:15]=1)#[N:9].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:36][C:27]1[S:28][CH2:29][C@@H:30]2[CH2:31][C@@H:32]([O:34][CH3:35])[CH2:33][C@:25]2([C:23]2[CH:24]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[CH:11][C:10]([C:8]#[N:9])=[CH:15][N:14]=3)=[O:17])[CH:20]=[CH:21][C:22]=2[F:44])[N:26]=1
Reactant: CO[C@@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1C[C@H]2CSC(N)=N[C@@]2(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl ((4aR*,6R*,7aS*)-7a-{5-[(5-cyanopyridine-2-carbonyl)amino]-2-fluorophenyl}-6-methoxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)carbamate (29 mg) in dichloromethane (2 mL), and the reaction solution was stirred at room temperature for one hour. The reaction solution was poured into a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH2:23])[CH:17]=1.C(N(CC)CC)C>C1COCC1>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=1[NH:23][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(Br)ccc2O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A solution of 4-methoxy-3-nitro-benzoyl chloride (7.12 g, 33.0 mmol) in THF (50 ml) was added dropwise with stirring to a solution of 4-bromo-2-aminophenol (6.20 g, 33.0 mmol) in THF (50 ml) containing triethylamine (6.82 ml, 66.0 mmol). After addition was complete the reaction was stirred at room temperature overnight. The reaction mixture was concentrated to approximately half the original volume and the precipitate collected by filtration. The solid was washed with methanol and ether and dried under vacuum to give the subtitle compound as a brown solid (5.24 g, 42%). 1H NMR (DMSO) δ 8.58(d, 1H), 8.36(dd, 1H), 7.55(d, 1H), 6.96(m, 2H), 6.68(dd, 1H), 4.05(s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH2:3][CH2:2]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[O:16]=[C:7]1[C:4]2([CH2:3][CH2:2][N:1]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:6][CH2:5]2)[CH2:15][CH2:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: O=C1c2ccccc2CCC12CCNCC2
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CN1CCC2(CCc3ccccc3C2=O)CC1
Temperature: 25 °C

Procedure:
A solution of 3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidin]-1-one (72 mg, 0.286 mmol), ethyl bromoacetate (62.1 mg, 0.37 mmol) and triethylamine (0.20 mL, 1.43 mmol) in acetonitrile (5 ml) was heated at 80° C. for 3 h. The reaction was cooled to 25° C. and diluted with 20 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (gradient of 85:15 to 60:40 heptane/ethyl acetate over 20 min) to give the title compound as a white solid. MS calculated for C18H24NO3 302.4. found (ESI) m/z 302.5 (M+H)+, retention time 0.81 min.
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1.CN([CH:21]=[O:22])C>C1COCC1>[Br:8][C:9]1[C:10]([CH:21]=[O:22])=[C:11]([F:17])[C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1F
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a solution of diisopropylamine (11 mL) in anhydrous THF (50 mL) was cooled to 0° C. and was added 1.6 M n-butyl lithium/hexanes (47 mL) dropwise under nitrogen atmosphere. The mixture was stirred for 10 min at 0° C. and was then cooled to −78° C. with an acetone dry ice bath. A solution of 4-bromo-2-fluoro-1-methoxybenzene (7.9 mL, 61 mmol) in anhydrous THF (50 mL) was added dropwise. The mixture was then allowed to stir for 30 min at −78° C. DMF (7.5 mL) was added dropwise at −78° C. The reaction was stirred for 1 h at room temperature. Half of the solvent from the solution was removed under reduced pressure and the solution was extracted using ethyl acetate, water (300 mL), and 1 M HCl (65 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was crystallized by washing with hexanes. The solid was collected by filtration and dried under reduced pressure to give 6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:21])([F:20])[F:1])=[CH:10][CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=c1[nH]cnc2cc(-c3ccccc3C(F)(F)F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1ccc2c(Cl)ncnc2c1

Procedure:
Reflux a solution of 7-(2-Trifluoromethyl-phenyl)-3H-quinazolin-4-one (1.12 g, 0.0039 mol) in POCl3 for 16 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between saturated aqueous NaHCO3 and EtOAc. Wash the EtOAc layer once with additional NaHCO3, dry it (Na2SO4), and concentrate under reduced pressure to obtain the crude product as a solid. Filter the residue through a 2 inch pad of silica gel (50% EtOAc/Hexanes) and concentrate under reduce pressure to give 4-chloro-7-(2-trifluoromethyl-phenyl)-quinazoline as a pale yellow-brown solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1([C:10]2[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=2)[CH:9]=[CH:8][N:7]=[CH:6]1>CN(C=O)C>[Cl:3][CH2:16][C:12]1[CH:11]=[C:10]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-n2ccnc2)c1
Solvent: CN(C)C=O
Product: ClCc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Thionyl chloride (4.0 ml, 54.0 mmol) was added to a solution of (3-imidazol-1-yl-phenyl)-methanol (3.17 g, 17.0 mmol) in DMF (50 ml) and the reaction stirred at room temperature for 40 h. The solvent was evaporated, the residue diluted with DCM and washed with water, neutralised with aqueous sodium bicarbonate (pH 9-10) and then extracted with DCM (3×). The organic phase was dried over sodium sulfate, filtered and concentrated to give 1-(3-chloromethyl-phenyl)-1H-imidazole as an orange oil (5.3 g, crude contaminated with DMF).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@H:15]2[CH2:17][C@@H:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](N)=[O:33])[CH2:27][CH2:26]1.[CH3:35]N1C(=O)CCC1>CS(C)=O.CO>[C:32]([NH:31][CH:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([C@H:15]3[CH2:17][C@@H:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:35]
Reactant: NC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)[C@H]3C[C@@H]3c3ccccc3)cc(Cl)n2n1
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: CC(=O)NC1CCN(c2cc(NC(=O)[C@H]3C[C@@H]3c3ccccc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
The title compound was prepared by combining (1R,2R)—N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8E, 0.08 g, 0.245 mmol) and the 1-(piperidin-4-yl)urea hydrochloride (0.088 g, 0.490 mmol) in NMP (0.816 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by 40-60% preparatory HPLC (ACN/MeOH)/H2O+0.01% TFA). Lyophilization of the combined fractions gave 63 mg (59%) of the titled compound as a yellow solid. 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 7.24-7.35 (m, 3H), 7.14-7.24 (m, 3H), 6.08 (s, 3H), 4.24 (d, J=13.1 Hz, 2H), 3.66 (br. s., 2H), 3.17 (dd, J=23.7, 12.1 Hz, 2H), 2.39-2.47 (m, 1H), 2.26-2.38 (m, 4H), 1.90 (d, J=13.1 Hz, 2H), 1.34-1.59 (m, 4H); ESI-MS: m/z 433.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+].C(=O)(ON1C(=O)CCC1=O)OCC1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2>O1CCOCC1.CCOC(C)=O>[CH:41]1[C:40]2[CH:4]([CH2:1][O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[C:10]([OH:12])=[O:11])=[O:7])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)c(Cl)c1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccc(F)c(Cl)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The (S)-2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid (183.0 mg, 0.576 mmol) was suspended in a 4M hydrochloric acid (1440 μl, 5.76 mmol) solution in dioxane at room temperature for 2 h. After solvent evaporation, the crude product was cooled to 0° C. using an ice bath before being dissolved in MeCN (288 μl) and a 2.0M aqueous solution of Na2CO3 (288 μl, 0.576 mmol). (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (194 mg, 0.576 mmol) was added to the solution and the reaction mixture was allowed to stir for 30 min. The mixture was diluted in 5.0 mL of EtOAc and the aqueous phase was neutralized with a few drops of an aqueous 1N HCl solution. The organic solvents were evaporated and the crude product was then partitioned between a saturated aqueous NH4Cl solution and EtOAc. The crude product was extracted with EtOAc. The organic fractions were combined and dried over anhydrous sodium sulfate. After filtration and concentration, a yellow crystalline solid was obtained. Purification by silica gel chromatography using 100% hexanes to 30% EtOAc/Hexanes yielded the desired product as a white crystalline solid. A second purification on silica gel was performed using 100% DCM to 20% MeOH/DCM as eluant. The desired product, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid, was obtained as a white solid (0.111 g, 44%). 1H NMR (400 MHz, methanol-d4) δ 7.79 (d, J=7.5 Hz, 2H), 7.60 (t, J=6.8 Hz, 2H), 7.47-7.23 (m, 5H), 7.25-7.14 (m, 1H), 7.13 (d, J=9.0 Hz, 1H), 4.52-4.11 (m, 4H), 3.19 (dd, J=14.3, 4.6 Hz, 1H), 2.92 (dd, J=13.9, 9.7 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].O(C)[Na].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]#[N:15])[CH:8]=1>>[OH:3]/[N:2]=[C:14](\[NH2:15])/[CH2:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCc1cccnc1
Reactant: NO
Agent: CO[Na]
Agent: Cl
Product: N/C(Cc1cccnc1)=N\O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (0.87 g, 0.0125 mmol) was added to 0.5M NaOCH3 (25 mL, 0.0125 mmol) and stirred at ambient temperature for 30 min. The reaction mixture was filtered and the filtrate was combined with pyridin-3-ylacetonitrile (1.18 g, 0.010 mmol). The resultant mixture was heated at reflux for 2 h, stirred at ambient temperature overnight and concentrated to give crude (1Z)-N′-hydroxy-2-pyridin-3-ylethanimidamide which was used immediately without purification. ES-LCMS m/z 152.18 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:37])[N:32]([CH2:34][CH2:35][OH:36])[CH3:33])=[CH:27][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[OH:36][CH2:35][CH2:34][N:32]([CH3:33])[C:31](=[O:37])[C:28]1[CH:27]=[CH:26][C:25]([C:14](=[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)=[CH:30][CH:29]=1
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc3cccnc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CCO)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Compound 1B (4.7 g, 9.3 mmol) was treated with 4N HCl in dioxane (30 mL). 10 min. later, the mixture was decanted, and the solid was stirred in ether (40 mL) for 2 h. The ether was then decanted and the remaining yellow solid dried under high vacuum to yield 3.7 g 1C (100%). 1H NMR (300.132 MHz, DMSO, 90° C.) δ 8.98 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.96 (d, J=6.6 Hz, 1H), 7.69-7.57 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 3.53 (t, J=5.8 Hz, 2H), 3.36 (t, J=5.7 Hz, 2H), 3.23 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz, 2H), 2.92 (s, 3H), 2.63 (t, J=6.0 Hz, 2H), 2.15 (t, J=6.0 Hz, 2H). TOF MS ES+402.17.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[S:7].[CH3:8][I:9]>CC(C)=O>[IH:9].[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[S:7][CH3:8]
Reactant: CI
Reactant: CN1CCNC1=S
Solvent: CC(C)=O
Product: CSC1=NCCN1C
Product: I
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
The title compound was prepared according to: Kister, J.; Assef, G.; Dou, H. J.-M.; Metzger, J. Tetrahedron 1976, 32, 1395. Thus, a solution of N-methylethylenediamine (10.8 g, 146 mmol) in EtOH—H2O (1:1, 90 mL) was preheated to 60° C. and CS2 (9.0 mL, 150 mmol) was added dropwise. The resulting mixture was heated at 60° C. for 3 h and then conc. HCl (4.7 mL) was slowly added. The temperature was raised to 90° C. and stirring was continued for 6 h. After the cooled mixture had been stored at −20° C., it was filtered and the resulting solid dried in vacuo to afford 1-methylimidazolidine-2-thione (8.43 g, 50%) as a beige solid. 1H NMR (400 MHz, CDCl3) δ 5.15 (s, br, 1H), 3.67-3.70 (m, 2H), 3.53-3.58 (m, 2H), 3.11 (s, 3H). To a suspension of 1-methylimidazolidine-2-thione (5.17 g, 44.5 mmol) in acetone (50 mL) was added MeI (2.9 mL, 46.6 mmol). The solution was allowed to stir at room temperature for 4 h and the resulting solid was quickly filtered and then dried in vacuo to give 1-methyl-2-(methylthio)-4,5-dihydro-1H-imidazole hydroiodide (8.79 g, 77%) as beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5](C(O)=O)=[CH:4][C:3]=1[Cl:15].[C:16](#[N:18])[CH3:17]>>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:15].[NH:18]1[C-:16]=[CH:17][N:1]=[CH:2]1
Reactant: CC#N
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1OCCO2
Product: Nc1c(Cl)ccc2c1OCCO2
Product: [c-]1cnc[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 8-amino-7-chloro-1,4-benzodioxan-5-carboxylic acid (prepared from the corresponding 7-H acid (prepared as in GB 1571278) by chlorination of the protected form) (1.10 g) in acetonitrile was added biscarbonyldiimidazole (0.77 g). The reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to afford crude 8-amino-7-chloro-1,4-benzodioxan-5-imidazolide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:33]
Reactant: COc1cc(C(=O)O)cc(OC/C=C(\C)CCC=C(C)C)c1OC
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC)c(OC/C=C(\C)CCC=C(C)C)c1
Yield: 58.3 %

Procedure:
In a manner identical to Example 15, 3,4-dimethoxy-5-geranyloxy benzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.31 g), thereby yielding 0.62 g(58%) of the aimed compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[N:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1
Reactant: COCOc1ccc(O)nc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(OCOC)cn1
Temperature: 60 °C
Yield: 26.9 %

Procedure:
To a mixture of 5-(methoxymethoxy)pyridin-2-ol (1.35 g, 8.71 mmol, 1 eq.) and K2CO3 (6.01 g, 43.6 mmol, 5.0 eq.) in DMF (30.0 mL) was added 1-bromo-2-methoxyethane (3.61 g, 26.1 mmol, 3 eq.). The mixture was heated at 60° C. for 2 h, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (500 mg, 27%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=3.0 Hz, 1H), 7.35 (ddd, J=8.9, 3.0, 1.0 Hz, 1H), 6.76 (dd, J=8.9, 1.0 Hz, 1H), 5.11 (s, 2H), 4.48-4.40 (m, 2H), 3.79-3.71 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H). MS (ESI) m/z 214.1 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:10]([OH:14])[C:11]([NH2:13])=[O:12])=O)(C)(C)C.O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(OCC)C>C(#N)C>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[NH2:8][CH:9]([CH2:15][C:16]([F:17])([F:18])[F:19])[CH:10]([OH:14])[C:11]([NH2:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(O)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: NC(=O)C(O)C(N)CC(F)(F)F

Procedure:
A solution of 580 mg (2.03 mmol) of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxyvaleramide and 1.16 g (6.11 mmol) of 4-toluenesulphonic acid monohydrate in 10 ml of acetonitrile was stirred until the reaction had finished according to thin-layer chromatography. 10 ml of diethyl ether were added and the 3(RS)-amino-5,5,5-trifluoro-2(RS)-hydroxyvaleramide p-toluenesulphonate (1:1) which formed was removed by filtration and added to a solution of 1.06 g (1.156 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine (prepared as described in Example 1), 321 mg (2.79 mmol) of N-ethylmorpholine, 268 mg (1.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 190 mg (1.4 mmol) of 1-hydroxy-7-azabenzotriazole in 20 ml of dichloromethane. The mixture was stirred at room temperature until the reaction had finished according to thin-layer chromatography. The solution was washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The residue was triturated with diethyl ether/petroleum ether (1:1) and the solid was removed by filtration to give 0.7 g of 3(RS)-[[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2(RS)-hydroxyvaleramide as a white solid, MS: m/e 1086.6 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH3:16])=[O:5].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][Br:24])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc(Cl)cc(C)c2n1C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of 0.30 g (0.9 mmol) of 5-chloro-7-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in CCl4 (10 ml), 016 g N-bromosuccinimide (NBS) and 11 mg of benzoyl peroxide were added. The reaction mixture was heated at reflux for one hour and cooled down to RT. The succinimide was filtered off and the solvent removed under reduced pressure to afford 0.35 g (95%) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester as a light brown solid. This product was directly used in the next step (unstable).