Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[CH2:14]2)=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1>Cl.O1CCOCC1>[NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:20]([NH:19][CH2:18][C@H:15]2[CH2:16][CH2:17][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=3[O:30][CH3:31])[CH2:14]2)=[O:22])=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCCCCN1CC[C@H](CNC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCCN1CC[C@H](CNC(=O)c2cc(Cl)c(N)cc2OC)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
4-Amino-N-(4-((3R)-3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)butyl)-5-chloro-2-methoxybenzamide (2.28 g) was dissolved in 4N hydrochloric acid-dioxane solution (10 ml) and the mixture was stood at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. Dimethylformamide (30 ml) was added to the residue and the mixture was neutralized with triethylamine (2.23 ml). 4-Amino-5-chloro-2-methoxybenzoic acid (1.07 g) and 1-hydroxybenzotriazole (0.79 g) were added thereto, and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.12 g) was added, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.60 g of 4-amino-N-((3R)-1-(4-(4-amino-5-chloro-2-methoxybenzoyl-amino)butyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.CS(O)(=O)=O.[NH:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]1[CH2:62][NH2:63]>>[NH:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]1[CH2:62][NH:63][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:43]
Reactant: NCc1cc2ccccc2[nH]1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: CS(=O)(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc2ccccc2[nH]1
Yield: 75 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1H-indol-2-yl)methanamine methanesulfonate, the title compound was obtained as an off-white solid in 75% yield: 1H NMR (300 MHz, CDCl3) δ 9.18 (br s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.30-7.22 (m, 2H), 7.19-6.98 (m, 4H), 6.36 (s, 1H), 6.28 (t, J=5.9 Hz, 1H), 6.10 (s, 1H), 4.62 (d, J=5.9 Hz, 2H), 4.42 (s, 2H), 3.81-3.73 (m, 2H), 3.45-3.38 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 463.2 (M+1), 485.2 (M+23).
Reaction SMILES: Br[CH:2]([CH:13]([CH3:16])[CH2:14]Br)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:6]([O:5][C:3]([C@H:2]1[C@@H:13]([CH3:16])[CH2:14][N:17]1[CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(CBr)C(Br)C(=O)OCc1ccccc1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C[C@H]1CN(C(c2ccccc2)c2ccccc2)[C@H]1C(=O)OCc1ccccc1

Procedure:
A stirred mixture of 23.94 g of 3D, 37.6 g of aminodiphenylmethane and 170 ml of acetonitrile was refluxed for 40 hours. The mixture was cooled, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in the minimum amount of methylene chloride, the solution was filtered through a short column of silica gel, using a 2:1 v:v mixture of hexane and ether as eluent. The solvents were evaporated. The residue was subjected to high pressure liquid chromatography (HPLC) twice, using an 8:1 v:v mixture of hexane and ether as eluent. The less polar portions thus obtained were combined, the solvents were evaporated and the residue crystallized from methylene chloride/hexane to give N-diphenylmethyl-cis-3-methyl-2-azetidinecarboxylic acid benzyl ester (3E), as a colorless solid, 112°-113.5° C.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:24](=[CH:25][CH:26]=1)[O:23][C:11]1([CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]1)[CH2:10][C:9]2=[O:27].Cl>CC(O)=O>[CH2:16]([N:13]1[CH2:14][CH2:15][C:11]2([CH2:10][C:9](=[O:27])[C:8]3[C:24](=[CH:25][CH:26]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=3)[O:23]2)[CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Yield: 99.1 %

Procedure:
(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (472 mg, 1.25 mmol) was hydrolyzed with aqueous 20% HCl solution and AcOH following the procedure described in Example 1, Step A, giving (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (450 mg) as a white solid (hydrochloride salt).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]([C:23]#[N:24])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:5][CH2:4]1)#N.Cl>C(O)(=O)C.O>[C:23]([C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)#[N:24]
Reactant: N#CN1CCC(C#N)(c2ccccc2Sc2ccc(F)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2Sc2ccc(F)cc2)CCNCC1

Procedure:
A solution of 2.0 g of 1,4-dicyano-4-[2-(4-fluorophenylthio)phenyl]piperidine, Example 29, in 12 ml of glacial acetic acid and 21 ml of 3 N hydrochloric acid is stirred at 110°-120° C. for 18 hours. Thereafter, the solution is diluted with 50 ml of water and the diluted solution is rotary evaporated twice to near dryness. The residual material is diluted in 100 ml of water and 2 ml of 58% ammonium hydroxide, giving a milky solution at pH 9. This aqueous suspension is extracted thrice with 150 ml portions of a benzene-ether (1:1) mixture. The combined extracts are washed, first with 50 ml of water and then with 25 ml saturated sodium chloride solution, and dried. The residual material is recrystallized from a benzene-hexane mixture to provide 4-cyano-4-[2-(4-fluorophenylthio)phenyl]piperidine.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH3:41])[CH:34]=[C:35]([O:39]C)[C:36]=1[O:37][CH3:38]>ClCCCl>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:34]1[C:35]([OH:39])=[C:36]([O:37][CH3:38])[C:31]([O:30][CH3:29])=[CH:32][C:33]=1[CH3:41])=[O:23]
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a solution of 18-acetoxy-n-octadecanoyl chloride (11 g) in 1,2-dichloroethane (50 ml) is added aluminum chloride (7 g) and the mixture is stirred at room temperature for 2 hours. This reaction mixture is cooled to 5° C. and a solution of 3,4,5-trimethoxytoluene (6.2 g) in 1,2-dichloroethane (20 ml) is added. The mixture is stirred at room temperature for 72 hours. Then, this reaction mixture is heated to 50° C.-60° C. and stirred for 30 minutes. After cooling, ice-water is added to the reaction mixture and the product is extracted with dichloromethane. The dichloromethane layer is washed with water and the solvent is distilled off to recover an oil (12.1 g). This oil is dissolved in methanol (150 ml) followed by addition of sodium hydroxide (5.2 g). The mixture is stirred at room temperature for 2 hours, at the end of which time it is neutralized with 5N--HCl and the solvent is distilled off. The resultant crude crystals are rinsed with water and recrystallized from dichloromethane-ether (1:1). The above procedure yields 6-(18-hydroxy-1-oxooctadecyl)-2,3-dimethoxy-5-methylphenol (6.4 g) as colorless needles, m.p. 101° C.
Reaction SMILES: [F:1][C:2]1[C:28]([I:29])=[CH:27][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13]CC)=O)[N:8]([CH2:16][C:17]4[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=4)[C:7]=3[CH:23]3[CH2:26][CH:25]([C:4]=2[CH:3]=1)[CH2:24]3.[NH3:30]>>[F:1][C:2]1[C:28]([I:29])=[CH:27][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:30])=[O:13])[N:8]([CH2:16][C:17]4[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=4)[C:7]=3[CH:23]3[CH2:26][CH:25]([C:4]=2[CH:3]=1)[CH2:24]3
Reactant: CCOC(=O)c1nc2c(n1Cc1ccnn1C)C1CC(C1)c1cc(F)c(I)cc1-2
Reactant: N
Product: Cn1nccc1Cn1c(C(N)=O)nc2c1C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 44 °C
Yield: 93 %

Procedure:
A pressure tube containing a solution of ethyl 8-fluoro-9-iodo-3((1-methyl-1H-pyrazol-5-yl)methyl)-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (77 mg, 0.15 mmol) in methanolic ammonia (5 mL of 7.0M ammonia in methanol) was warmed to 44° C. for 48 hr. Evaporation of the reaction mixture furnished the title compound (67 mg, 0.14 mmol, 93%) as a colorless solid: 1H NMR (500 MHz, d4-methanol) δ 1.65 (d, J=11.35 Hz, 2H), 2.93-3.02 (m, 2H), 3.47-3.53 (m, 1H), 3.64 (td, J=8.04, 4.10 Hz, 1H), 3.89 (s, 3H), 5.61 (d, J=1.89 Hz, 1H), 5.88 (s, 2H), 6.93 (d, J=8.83 Hz, 1H), 7.30 (d, J=1.89 Hz, 1H), 8.79 (d, J=6.94 Hz, 1H); M+H=478.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[N:18]([C@H:21]1[CH2:23][C@@H:22]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:19]=[O:20]>C(Cl)Cl>[C:24]1([C@H:22]2[CH2:23][C@@H:21]2[NH:18][C:19]([N:4]2[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C@H:3]2[C:7]([O:9][CH3:10])=[O:8])=[O:20])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=N[C@H]1C[C@@H]1c1ccccc1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)N[C@H]1C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-tert-butyl 3-methyl (3S)-1,3-piperazinedicarboxylate (AA3) in DCM (0.17 M) was added to a stirred solution of [(1R,2S)-2-isocyanatocyclopropyl]benzene (1.0 eq.) in DCM (0.17 M) and the mixture was stirred at RT for 1 h. Solvents were evaporated under reduced pressure to give the title compound that was used as such in next step. MS (ES+) C21H29N3O5 requires 403, found: 404 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:9]Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][CH:12]1[CH2:16][CH2:15][CH:14]([CH3:17])[C:13]1=[O:18].N1CCCC1.O>C(#N)C>[CH3:11][C:12]12[C:13](=[O:18])[C:14]([CH3:17])([CH2:15][CH2:16]1)[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2]2
Reactant: CC1CCC(C)C1=O
Reactant: BrCc1ccccc1CBr
Solvent: O
Solvent: CC#N
Solvent: C1CCNC1
Product: CC12CCC(C)(Cc3ccccc3C1)C2=O

Procedure:
α,α'-Dibromoxylene (30.3 g., 0.115 Mole) is dissolved in dry acetonitrile (250 ml.) and then, under nitrogen, the pyrrolidine enamine of 2,5-dimethylcyclopentanone (prepared from 2,5-dimethylcyclopentanone and pyrrolidine via the method of Stork) is added dropwise over one-half hour. The mixture is refluxed 2 days, cooled, water (100 ml.) is added; and the mixture is refluxed 1 hour, cooled, concentrated in vacuo, then extracted with ether (3×75 ml.). The combined extracts are washed with 10% HCl (50 ml.), brine (50 ml.), then dried and evaporated to yield 16 g. of solid, which recrystallized from dichloroethane-hexane gives pure title compound (9.7 g.). The mother liquors are chromatographed on silica gel (100 g.), eluting with ether-hexane (1:4) to give 5.8 g. more title compound, which yields 4.9 g. pure on crystallization from ether-hexane (64% total yield), m.p. 134°-135° C.
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=1)[C:35]([OH:37])=O>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=1)[C:35]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:5])=[O:37]
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 2-chloro-6-trifluoromethyl-isonicotinic acid (prepared in analogy to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) after a reaction time of 18 hours. The compound was purified by two silica gel chromatographies on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless solid (26%). MS (ESI): m/z=440.08 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)CCl>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:17](=[O:19])[CH3:18])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
In a 5 L 4-neck round bottom flask, EDC (2 L) was added to the 4,4-dimethylthiochroman from the previous step. The contents were stirred and cooled to a temperature of about −10° C. Aluminum chloride (252 g) was slowly added to the reaction mixture. Acetyl chloride (152.7 g) was added at a temperature ranging from about −10° C. to about −5° C. over about 1.5 hours. After the addition, the reaction mixture was maintained at a temperature ranging from about −5° C. to about 0° C. for about 2 hours. The reaction was monitored by TLC. [If the reaction is incomplete as determined by TLC, bring the reaction mixture to a temperature ranging from about 25° C. to about 35° C. under stirring for about 4 hours.] The reaction mixture was quenched with ice (4.87 kg) and hydrochloric acid (1.63 L), and the reaction mass was stirred for about 30 minutes. EDC (2.5 L) was added to the reaction mass. The layers were separated. The aqueous layer was extracted with MDC (2×2 L). The organic layers were combined and washed with 5% sodium bicarbonate solution (2×2 L) and water (2×2 L) until the pH is about 7. This was followed by a washing with brine (1.5 L). The EDC and MDC layer were distilled out under reduced pressure until the moisture content was less than about 0.1%. There was a residual volume of about 3 L.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1B(O)O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.[Pd].[Pd].C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([C:11]2[N:10]([CH3:9])[C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=[N:4][CH:3]=1
Reactant: Nc1cncc(Br)c1
Reactant: Cn1c(B(O)O)cc2ccccc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1c(-c2cncc(N)c2)cc2ccccc21
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A flask is charged with 3-amino-5-bromopyridine (0.173 g, 0.950 mmol), N-methyl-indole boronic acid (0.262 g, 1.425 mmol), s-Phos (0.030 g, 0.071 mmol), finely crushed potassium phosphate (0.407 g, 1.900 mmol) and toluene (4 mL). After degassing for 30 min, Pd2dba3 (0.018 g, 0.019 mmol) is added, the flask is flushed with nitrogen and the mixture is heated to 85° C. After 3 h, the mixture is allowed to cool to r.t., diluted with ethyl acetate and filtered through a plug of silica gel (elution with ethyl acetate). The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:7 to 0:1) to give 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3H), 5.49 (s, 2H), 6.56 (s, 1H), 7.05-7.09 (m, 1H), 7.09-7.10 (m, 1H), 7.17-7.21 (m, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H). MS (ESI) m/z 224 (M+H)+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[C:15]([NH2:18])=[N:16][CH:17]=1>>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[C:15]([NH:18][CH:5]=[O:7])=[N:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Solvent: O=CO
Product: O=CNc1ncc(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of acetic anhydride (49 mL, 0.5 mol) and formic acid (19 mL, 0.5 mol) was heated at 60° C. for 3 h. 5-Fluoro-3-nitropyridin-2-amine was added and the mixture was stirred at 60° C. for 1 h. The mixture was concentrated under reduced pressure and the residue was stirred vigorously in diethyl ether (200 mL) for 30 minutes. The solid was collected by filtration to afford N-(5-fluoro-3-nitropyridin-2-yl)formamide (4.5 g, 96%) as an orange solid which did not require further purification. LCMS (ESI) m/z 186 (M+H)+.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[C:18](=[O:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)C(=O)C1
Temperature: 119 °C
Yield: 86.6 %

Procedure:
A suspension of p-iodo-aniline (918 mg, 4.8 mmol), 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (960 mg, 4.2 mmol) (1R,2R)-cyclohexane-1,2-diamine (0.05 mL, 0.42 mmol), copper (I) iodide (14.9 mg, 0.0042 mmol) and K2CO3 (1.19 g, 2.04 mmol) in dioxane (4 mL), is purged with nitrogen for 5 min in a reaction tube. The tube is sealed and the reaction mixture is heated at 119° C. for 15 hours. After cooling to room temperature, the reaction mixture is filtered through a silica cartridge washing with ethyl acetate (40 mL). The filtrate is concentrated in vacuo to afford the title compound as a brown liquid (1.06 g, 87%). LCMS: Rt 0.88 min (91%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][N:19]=[C:20]=[S:21]>C1(C)C=CC=CC=1>[CH3:18][NH:19][C:20]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[S:21]
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: CN=C=S
Solvent: Cc1ccccc1
Product: CNC(=S)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 10 mmol) in hot toluene (80 mL), methyl isothiocyanate (0.73 g, 10 mmol) was added and the reaction mixture was heated overnight at reflux. The mixture was cooled to room temperature, the resulting precipitate was filtered to afford 1-methyl-3-[3-(quinoxalin-2-yl)phenyl]thiourea (2.0 g, 68% yield). LCMS calculated for C16H14N4S (M+H): 295.38. found 295. 1H-NMR (DMSO-d6, 250 Mhz) δH: 9.85 (1H, br. s), 9.55 (1H, s), 8.40-8.30 (1H, m), 8.20-8.00 (3H, m), 7.98-7.80 (3H, m), 7.70-7.60 (1H, m), 7.60-7.45 (1H, m).
Reaction SMILES: F[C:2]1C=CC(CCC2C(C(O)=O)=NC(OC(C3C=CC(F)=CC=3)CC3N(C)C=NC=3)=CC=2)=C[CH:3]=1.[F:35][C:36]1[CH:80]=[CH:79][C:39]([CH2:40][CH2:41][C:42]2[C:43]([C:64]([NH:66][C@@H:67]([CH2:75][CH2:76][S:77][CH3:78])[C:68]([O:70][C:71](C)([CH3:73])[CH3:72])=[O:69])=[O:65])=[N:44][C:45]([O:48][CH:49]([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)[CH2:50][C:51]3[N:55]([CH3:56])[CH:54]=[N:53][CH:52]=3)=[CH:46][CH:47]=2)=[CH:38][CH:37]=1.C1(OC(=O)[C@H](CCSC)N)CCCC1.C(OC(=O)[C@H](CCSC)N)(C)(C)C>>[F:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:40][CH2:41][C:42]2[C:43]([C:64]([NH:66][C@@H:67]([CH2:75][CH2:76][S:77][CH3:78])[C:68]([O:70][CH:71]3[CH2:72][CH2:3][CH2:2][CH2:73]3)=[O:69])=[O:65])=[N:44][C:45]([O:48][CH:49]([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)[CH2:50][C:51]3[N:55]([CH3:56])[CH:54]=[N:53][CH:52]=3)=[CH:46][CH:47]=2)=[CH:79][CH:80]=1
Reactant: CSCC[C@H](NC(=O)c1nc(OC(Cc2cncn2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)n1)c1ccc(F)cc1
Agent: CSCC[C@H](N)C(=O)OC(C)(C)C
Agent: CSCC[C@H](N)C(=O)OC1CCCC1
Product: CSCC[C@H](NC(=O)c1nc(OC(Cc2cncn2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)OC1CCCC1

Procedure:
The title compound was prepared from 3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylic acid by a similar route to that described for the preparation of tert-butyl (2S)-2-{3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyrid-2-oylamino}-4-methylsulfanylbutyrate but using L-methionine cyclopentyl ester rather than L-methionine-tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.O.CS(C)=O.[Pd](Cl)Cl.C([O-])(=O)C.[Na+]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 88.9 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of glycol and 10 ml of water were heated to 120° C. At 80° C., 19.3 mg of palladium chloride, 17.9 mg of sodium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO were added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.7 g of 2-cyano-4'-methylbiphenyl.