Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH:17]=1)[CH:15]=[O:16]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:12]1[C:13]([OH:18])=[C:14]([CH:17]=[C:10]([F:9])[CH:11]=1)[CH:15]=[O:16]
Reactant: O=Cc1cc(F)ccc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(F)cc(Br)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
N-bromosuccinimide (1.51 g, 8.52 mmol) was added to a magnetically stirred solution of 5-fluoro-2-hydroxybenzaldehyde (1 g, 7.1 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 5 hour. The mixture was diluted with ethyl acetate and the organic layer was washed with 5% citric acid, brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product was purified from the residue by chromatography over silica gel employing 50% ethyl acetate/hexanes to give 3-bromo-5-fluoro-2-hydroxybenzaldehyde (1.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][CH2:18][CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:15][CH2:16]1)=[O:21])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CC[C@H]1CC[C@H](CCCO)CC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.35 g (11.20 mmol) trans-{2-[4-(3-hydroxy-propyl)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester and 1.54 ml (13.4 mmol) of methanesulfonyl chloride in 35 ml dichloromethane was added under ice-cooling within 5 minutes a solution of 1.87 ml (13.4 mmol) triethylamine in 5 ml of dichloromethane. The reaction mixture was then stirred for 1 hour at room temperature. It was subsequently partitioned between ether, water and 1N hydrogen chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure giving 4.06 g (96.1%) almost pure trans-methanesulfonic acid 3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-propyl ester as colorless viscous oil, MS: 395 (MNH4+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][C:36]1[CH:37]=[C:38](CO)[CH:39]=[CH:40][CH:41]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:35])[CH:41]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4cccc(C)c4)cc3)c2cc1OC
Yield: 97.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-methylphenyl)methanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (146 mg, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=O)[CH2:19][CH2:18]2)[CH:3]=1.Cl[C:31]1C=C(Cl)C2C(=CC=C(C)C=2)N=1.S1(=O)C2C=CC=CC=2CNCC1.NC1(CNC2C3C(=CC=C(C)C=3)N=C(N3CC4C=CC=CC=4S(=O)CC3)C=2)COC1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:31])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Agent: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCC3(N)COC3)c2c1
Agent: O=S1CCNCc2ccccc21
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1

Procedure:
The title compound was prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 in Scheme 6 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. N-[(3-Aminooxetan-3-yl)methyl]-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].[Cl-].[Na+]>O1CCCC1>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: CN(C)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(OC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 166.1 %

Procedure:
Tetrahydrofuran (100 ml) was added to sodium hydride (1.94 g, 45 mmol) under an atmosphere of nitrogen. To the suspension was added a tetrahydrofuran solution of 1-(3-hydroxyphenyl)ethanone (5.05 g, 37 mmol) in an ice bath. After stirring the mixture for 15 minutes dimethylcarbamyl chloride (1.7 ml, 19 mmol) was added dropwise into the mixture and the resulting mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium chloride solution was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column to afford the desired compound (6.54 g).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][CH2:29][CH:30]2[NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:44])[CH:40]=3)[N:35]=2)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][CH2:29][CH:30]2[NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:44][C:1]([NH:22][CH:19]4[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]4)=[O:12])[CH:40]=3)[N:35]=2)=[CH:26][CH:25]=1
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1
Product: CC(C)N1CCC(NC(=O)Nc2ccc3nc(NC4CCc5ccc(F)cc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no: 127285-08-9) and rac-N2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=462.5 (M+H+).
Reaction SMILES: [C:1]([CH:3]=[CH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11]C(=O)OC(C)(C)C)[CH2:6]1)#[N:2].[ClH:19].O1CCOCC1>C(Cl)Cl>[ClH:19].[NH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([CH:4]=[CH:3][C:1]#[N:2])[CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C=CC#N)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CC=CC1CCCC(N)C1

Procedure:
tert-Butyl {3-[2-cyanovinyl]cyclohexyl}carbamate was treated with 4.0 M hydrogen chloride in dioxane (1.6 mL, 6.6 mmol) in methylene chloride (2 mL) at room temperature for 2 h. The mixture was stripped to dryness to give the desired product as a mixture of cis- and trans-isomers. LCMS calculated for C9H15N2 (M+H)+: m/z=151.1. Found: 151.1.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].Cl.[NH:23]1[C:27]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][C:31]3=[O:43])=[N:26][N:25]=[N:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:8]2=[N:9][C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:12]([C:13]([N:36]3[CH2:37][CH2:38][C:33]4([CH2:32][C:31](=[O:43])[C:30]5[C:40](=[CH:41][CH:42]=[C:28]([C:27]6[NH:26][N:25]=[N:24][N:23]=6)[CH:29]=5)[O:39]4)[CH2:34][CH2:35]3)=[O:15])=[C:7]2[CH:6]=[N:5]1)[CH3:1]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccccc3)nc21
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncc2c(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5nnn[nH]5)ccc3O4)cc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (0.2 mL) was added to a DMF suspension (2 mL) of 1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride, EDCI and HOBT.H2O, heated at 80° C. and stirred for 2 hours. This was cooled to room temperature, iced water was added thereto, and its pH was adjusted to 2.5 with 1 N HCl solution added thereto. The resulting crystal was taken out through filtration, washed with water, washed with Et2O, and dried in vacuum at 70° C. to obtain the title compound as a pale brown powder. 1H-NMR (400 MHz, DMSO-d6) δ: 8.34 (1H, d, J=2.2 Hz), 8.26-8.21 (2H, m), 8.19 (1H, s), 8.19 (1H, dd, J=8.4, 2.6 Hz), 7.82 (1H, s), 7.58-7.47 (3H, m), 7.20 (1H, d, J=8.4 Hz), 5.33 (1H, sept, J=6.8 Hz), 4.45-4.30 (1H, m), 3.70-3.00 (3H, m), 2.95 (2H, s), 2.20-1.70 (4H, m), 1.55 (6H, d, J=6.8 Hz). MS [M+H]+=549.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][NH2:15].CCO.O>C(Cl)Cl>[CH3:14][NH:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: CN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCOC(=S)c1cnc(C)nc1NC
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 20 g, 86 mmol) in 250 mL of DCM at 0° C. was slowly added a solution of methylamine in EtOH (33%, 35 mL 281 nmol). After stirring for 30 minutes, water (150 mL) was added and the phases were separated. The organic phase was dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure to give 19 g of the ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: Br[CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:23][C:24]([NH2:26])=[S:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:23]=[C:24]([NH2:26])[S:25][C:2]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(Br)Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc(N)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 79.1 %

Procedure:
To a 50 ml eggplant-shaped flask were added 0.45 g (1.24 mmol) 2-bromo-1-(4-methoxy-phenyl)-3-(4-nitro-phenyl)-propan-1-one prepared in the step 4 and 15 ml anhydrous ethanol, added 94 mg (1.24 mmol) thiourea and 101 mg (1.24 mmol) anhydrous sodium acetate under stirring. The resulting mixture was refluxed for 3 hours, distilled under a reduced pressure to remove the solvent, added 20 ml ethyl acetate and 20 ml 5% NaHCO3 aqueous solution, the organic layer was separated, washed with saturated brine until neutrality, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was recrystallized with ethyl acetate to obtain a 0.34 product in a yield of 79.1%, mp: 209-210 └(Dec.). 1H-NMR (DMSO-d6, 400 MHz) δ: 3.34 (3H, s, OCH3), 4.20 (2H, s, CH2), 6.93 (2H, s, NH2), 6.95 (2H, d, J=8.72 Hz, ArH), 7.43˜7.46 (4H, m, ArH), 8.19 (2H, d, J=8.72 Hz, ArH); EI-MS m/e (%): 341.2 (M+, 100), 219.1 (14); HREI-MS Calcd. for C17H15N3O3S: 341.0834. found: 341.0834. Anal. Calcd. for C17H15N3O3S: C, 59.81; H, 4.43; N, 12.31. found: C, 59.76; H, 4.36; N, 12.05.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])[CH3:3].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.N>O1CCCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH2:21])=[O:9])([CH3:4])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Temperature: 26 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
In a 22 L Morton flask, 749 g (3.0 mol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, 533 g (3.3 mol) carbonyldiimidazole and tetrahydrofuran (THF) were combined and heated slowly to reflux and allowed to reflux for 2.5 hours. The reaction mixture was cooled to 26° C. and concentrated aqueous ammonia was added. Stirring was continued for 2 hours and the reaction mixture was allowed to stand overnight. The contents were transferred to a flask and rinsed with tetrahydrofuran (250 mL). The mixture was stirred, layers were separated, and the aqueous layer was saved. The organic layer was washed with brine (2.5 L) followed by brine/deionized (DI) water (1 L/1.5 L). The organic layer was washed with 9.7 M hydrochloric acid (HCl)/deionized water (0.25 L/2.25 L), followed by 9.7 M hydrochloric acid/deionized water (0.5 L/2.8 L), and 9.7 M hydrochloric acid/deionized water/brine (0.5 L/1.5 L/1.5 L). The organic layer was set aside while the combined aqueous layers were washed with tetrahydrofuran. The combined organic layers were washed with brine, dried with sodium sulfate (855 g) and filtered. The filtrate was evaporated to 1011 g of a wet (water), white solid. Methylene chloride was added and removed in vacuo. This procedure was repeated with ethyl acetate (6 L, then 2 L) to produce a solid residue (779 g). The residue was slurried in ethyl acetate and heptane, filtered, and dried in a vacuum oven to yield the desired amide (736 g, 98.7%) as a white solid.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][C:8]3=O)=[CH:3][CH:2]=1.[CH3:15][Li].[BH4-].[Na+].[ClH:19]>CCOCC.CO>[ClH:19].[CH3:15][CH:8]1[NH:9][CH2:10][CH:11]2[C:7]1([C:4]1[CH:5]=[CH:6][C:1]([CH3:14])=[CH:2][CH:3]=1)[CH2:12]2
Reactant: [Li]C
Reactant: Cc1ccc(C23CC2CNC3=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(C23CC2CNC3C)cc1

Procedure:
Using the method of M. Takeda, et al., Chem. Pharm. Bull., 24, 2312 (1976), 1-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one is reacted with methyllithium followed by sodium borohydride. Excess reagents are decomposed with methanol, followed by 1N hydrochloric acid, and then 1N sodium hydroxide and then evaporation of the solution gives a residue which is dissolved in ether. This solution is dried over sodium sulfate and filtered, and to the filtrate is added dry hydrogen chloride. Filtration of this suspension gives 2-methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH2:14]([S:21][C:22](=[O:35])[CH2:23][C@H:24]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[C:25]([OH:27])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CS(C)=O>[CH2:14]([S:21][C:22](=[O:35])[CH2:23][C@H:24]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[C:25]([O:27][CH2:2][C:3]#[N:4])=[O:26])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
2-Bromoacetonitrile (4.35 ml, 62.4 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.651 ml, 3.74 mmol) were added to a solution of (S)-4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-ID) (1.00 g, 3.12 mmol) in DMSO (4.35 ml), and the mixture was stirred at room temperature for 40 minutes. A saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→40/60) to afford (S)-cyanomethyl 4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-ID) (885.2 mg, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)C=O.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: ClCCCN1CCOCC1
Reactant: COc1ccc(O)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN2CCOCC2)c(C=O)c1
Temperature: 70 °C

Procedure:
A stirred solution of 25 g of 2-hydroxy-5-methoxybenzaldehyde in 125 ml. of dimethylformamide is treated portionwise with 8.2 g of 50% sodium hydride (oil dispersion). The temperature is kept below 35° C. by means of an ice-water bath. When the addition is complete, the mixture is warmed to 70° C. and cooled to 25° C. This is followed by the addition of a solution of 36 g. of N-(3-chloropropyl)morpholine in 65 ml. of toluene. The mixture is stirred and heated at 100°-105° C. for 4 hours, cooled, poured into 300 ml. of ice-water and extracted with three 150 ml. portions of ether. The combined ether layers are then extracted with 40 ml. of cold 1:1 hydrochloric acid, followed by 20 ml. of water. The aqueous phases are combined, layered over with 150 ml. of ether, stirred and basified with 40 g. of potassium carbonate. The layers are separated and the aqueous phase is extracted with three 100 ml. portions of ether. The combined ether layers are dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is distilled to give 34 g. of the title compound, boiling point 180°-185° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].C(OC([N:36]1[CH2:40][CH2:39][CH2:38][C@@:37]1([CH3:44])[C:41](O)=[O:42])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>O1CCOCC1.CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:41]([C@:37]4([CH3:44])[CH2:38][CH2:39][CH2:40][NH:36]4)=[O:42])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)[C@]4(C)CCCN4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (150 mg, 0.36 mmol), (S)-2-Methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (98 mg, 0.43 mmol), TBTU (171 mg, 0.533 mmol), DIPEA (0.30 mL, 2.0 mmol) and DMF (10 mL) was stirred at 50° C. for 3 h. Reaction mixture was concentrated in vacuo, and the residue was taken up with DCM, washed with H2O, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography using 1→4% NH3 in MeOH in DCM afforded an oil that was dissolved in 1,4-dioxane (2.0 mL). 4 M HCl in 1,4-Dioxane (0.9 mL) was added to the solution and the reaction mixture was stirred at 40° C. for 1 h and at 60° C. for 3 h. Purification of the crude material by prep TLC (eluting with NH3/MeOH/DCM) afforded the title compound as a light yellow solid. The compound was dissolved in DCM and 2 M of HCl in Et2O (4 mL) was added to the reaction mixture. The reaction mixture was concentrated in vacuo to afford the title compound as HCl salt. 1H NMR (400 MHz, CD3OD): δ=1.46 (s, 3H), 1.66-1.84 (m, 2H), 1.88 (d, J=6.8 Hz, 3H), 2.20 (br. s., 2H), 2.55 (br. s., 2H), 2.73-3.00 (m, 2H), 3.68-3.98 (m, 2H), 4.30 (br. s., 2H), 6.30 (br. s., 1H), 6.49 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=8.8, 4.8 Hz, 1H), 7.65 (s, 1H), 8.20 (s, 1H). MS (ES+): m/z 533.08/535.09 (100/69) [MH+]. HPLC: tR=2.45 min.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:19]([C:21]1[N:22]([CH2:34][C:35]#[CH:36])[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:20]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:19]([C:21]1[N:22]([CH2:34][C:35]#[C:36][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:20]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (66 mg, 0.03 eq.), 3-iodobenzotrifluoride (336 μL, 1.1 eq.), triethylamine (889 μL, 3.0 eq.), and copper (I) iodide (24.3 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (500 mg, 2.13 mmol, 1.0 eq.) in DMF (10.6 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2/98 methanol/chloroform) to provide 0.73 g of 2-ethyl-1-[3-(3-trifluoromethylphenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline as a light tan solid.