Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[OH-].[K+].CO.[K].Br[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25]>O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CC(Br)c1ccccc1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(Oc1ccc(Br)cc1C(=O)Nc1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 5-bromo-2-hydroxy-N-3-pyridinylbenzamide (may be prepared as described in Description 35; 300 mg, 1.02 mmol) was added to a solution of potassium hydroxide (57.4 mg, 1.02 mmol) in methanol (2 ml, 49.4 mmol). The mixture was then stirred at room temperature for 15 min and the solvent was removed in vacuo. To the potassium salt was added DMF (10 ml) and (1-bromoethyl)benzene (189 mg, 1.023 mmol), The reaction mixture was then heated under reflux for 2 h. The mixture was cooled, diluted with water (20 ml) and the precipitate was collected, and finally crystallized from ethyl acetate to yield the title compound. 63 mg.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([F:23])([F:22])[F:21])[N:12]=[C:11]([NH2:24])[N:10]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])#[N:26]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:11]1[N:10]=[C:9]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[C:28]([F:36])[CH:29]=2)[CH:14]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([F:23])([F:22])[F:21])[N:12]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(N2CCCC2C(F)(F)F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCCC3C(F)(F)F)nc(N)n2)cc1F
Temperature: 100 °C
Yield: 59.5 %

Procedure:
Potassium carbonate (129 mg, 0.934 mmol) and water (1.5 mL) were added to a stirring mixture of 4-chloro-6-[2-(trifluoromethyl)-1-pyrrolidinyl]-2-pyrimidinamine (83 mg, 0.311 mmol) and (4-cyano-3-fluorophenyl)boronic acid (61.6 mg, 0.374 mmol) in 1,4-dioxane (3 mL). After degassing, Pd(PPh3)4 (29 mg, 0.025 mmol) was added, and the vessel was seal and heated at 100° C. in an oil bath overnight. LCMS showed complete conversion. The mixture was diluted with EtOAc, and washed with water. The aqueous layer was back-extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4) filtered and evaporated. Purification by silica gel chromatography (Analogix RS-4 g) eluting with 5-20% EtOAc—CHCl3 afforded the title compound (65 mg) as a white foam. The sample contained some PH3P/Ph3PO by NMR, but was suitable for subsequent reactions. LC-MS (ES) m/z=352 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:7])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:26]([O:33][C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C@H:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42](O)=[O:43])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.O1CCOCC1>[CH2:26]([O:33][C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C@H:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42]([NH:1][C@@H:2]([C@H:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:7])[C:3]([OH:5])=[O:4])=[O:43])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(N[C@@H](Cc1c[nH]cn1)C(=O)O)C(N)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a mixture of 2S,3R)-2-amino-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (400 mg) and triethylamine (0.70 ml) in a mixture of water (10 ml) and dioxane (10 ml) was added (2S)-6-benzyloxycarbonylamino-2-t-butoxycarbonylaminohexanoic acid (894 mg) at 5° C. and the mixture was stirred in an ice-bath for 3 hours. The volatile solvent was evaporated in vacuo and the residue was adjusted to pH 4 with 1N hydrochloric acid. The mixture was subjected to a column of "Diaion HP-20" (80 ml). After the column was washed with water, the elution was carried out with a mixture of methanol and water (3:7-8:2) and the object fractions were collected and evaporated in vacuo. The residue was solidified with a mixture of methanol and ether to give (2S,3R)-2-[[(2S)-6-benzyloxycarbonylamino-2-t-butoxycarbonylaminohexanoyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (786 mg) as a white powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)C(O)=O)=[N:17][C:18]=1[C:19](=[O:27])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1N=CN([C:42](N2C=NC=C2)=[O:43])C=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CS(C)=O>[NH2:12][C:13]1[C:18]([C:19]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:27])=[N:17][C:16]([C:28]2[CH:36]=[CH:35][C:34]([C:42]([N:1]3[CH2:5][CH2:4][CH2:3][C@@H:2]3[CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[O:43])=[CH:30][CH:29]=2)=[CH:15][N:14]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(-c2cccc(C(=O)O)c2)nc1C(=O)Nc1ccccc1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)nc1C(=O)Nc1ccccc1
Temperature: 38 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
1-[[(2R)-pyrrolidin-2-yl]methyl]pyrrolidine (69.23 mg, 0.449 mmol) was weighed into a greenhouse tube and treated with a solution of 3-(5-amino-6-(phenylcarbamoyl)pyrazin-2-yl)benzoic acid (50 mg, 0.150 mmol), CDI (48.51 mg, 0.299 mmol) and DMAP (1.82 mg, 0.015 mmol) in DMSO (1 mL of a stock solution). DIPEA (78.2 uL, 0.449 mmol) was then added and the mixture stirred at 38° C. for 6 hours. The reaction mixture was filtered and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were freeze-dried to give the title compound as a solid (51.87 mg, 73% Yield). (ES+) 471
Reaction SMILES: [C:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:8]
Reactant: O=C(c1ccccc1)c1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1ccccc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of benzoylnaphthalene (5.00 g, 21.5 mmol) in methanol (30 mL) was added sodium borohydride (400 mg, 10.8 mmol) with ice-cooling and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure to provide 4.80 g of (2-naphthyl)phenylmethanol. To a solution of this compound (4.80 g, 20.5 mmol) in diisopropyl ether (30 mL) was added phosphorus tribromide (3.70 g, 13.7 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the solid residue was recrystallized from diisopropyl ether-hexane to provide 4.10 g of the title compound. Yield 64%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.Cl[CH2:24][O:25][CH3:26]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([O:13][CH2:24][O:25][CH3:26])([CH3:11])[CH3:12]
Reactant: Cc1cc(F)c(C(C)(C)O)c(Br)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(C)(C)c1c(F)cc(C)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
To a solution of 2-(2-bromo-6-fluoro-4-methylphenyl)propan-2-ol (12 g, 48.56 mmol) in DCM (120 mL) and diisopropylethylamine (6.9 g, 53.42 mmol) in DCM (120 mL) was added dropwise chloromethylmethylether (4.3 g, 53.42 mmol) at 0° C. under argon and the mixture was then stirred at rt for 15 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (20:1) to give 1-bromo-3-fluoro-2-(2-(methoxymethoxy)propan-2-yl)-5-methylbenzene (10 g, 70.73% yield) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.22 (s, 1H), 6.71-6.75 (m, 1H), 4.54 (s, 2H), 3.33 (s, 3H), 2.20 (s, 3H), 1.72 (d, J=5.2 Hz, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[CH3:28])=[O:8]>CO.CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[CH3:28])=[O:8]
Reactant: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(N)ccc2n1Cc1ccccc1
Reaction time: 24 h
Yield: 104.3 %

Procedure:
To a solution of 1-benzyl-2-methyl-5-nitro-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 45, 97 mg, 0.22 mmol) in MeOH (20 ml) and EtOAc (20 ml) was added Pd—C (10%, 47 mg, 0.045 mmol). The reaction was stirred under hydrogen for 24 h, filtered through Celite, washed with MeOH-EtOAc (1:1) to yield 5-amino-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 46) as a white solid (93 mg, 100%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14].[I:22]I>C1COCC1.C(OCC)(=O)C>[F:21][C:20]1[C:15]([C:13]#[N:14])=[N:16][CH:17]=[CH:18][C:19]=1[I:22]
Reactant: II
Reactant: N#Cc1ncccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: N#Cc1nccc(I)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
Diisopropylamine (50.9 mL, 360 mmol) was added to THF (1600 mL), and the mixture was cooled to 0° C. in an ice bath and then n-butyllithium (137.6 ml, 2.5 M in hexane) was added drop wise at 0° C., and stirred for another 30 minutes. The mixture was then cooled to −78° C., and a solution of 2-cyano-3-fluoropyridine (40 g, 328 mmol) in 300 mL of THF was added. After 25 minutes, a solution of I2 (83.2 g, 328 mmol) in THF (80 mL) was added and the reaction was stirred for 40 minutes at −78° C. The reaction was removed from the cooling bath and quenched with 400 mL sodium thiosulfate solution (10% aq.) followed by water (400 mL). The reaction mixture was diluted with ether (400 mL), and the layers were separated. The organic layer were washed with brine, dried over sodium sulfate, filtered and concentrated to a brown solid. The solid was purified with silica column chromatography eluted with 95:5 hexanes:ethyl acetate to give 3-fluoro-4-iodopicolinonitrile (25.6 g, 31.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25-8.26 (m, 1H) 8.35 (t, J=5.05 Hz, 1H). MS [M+H] found 249.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.[Cu]Br>[CH2:17]([NH:24][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1NCc1ccccc1
Temperature: 100 °C

Procedure:
Potassium carbonate (4.82 g, 34.9 mmol) was added to a mixture of 2-chloronicotinic acid (5.0 g, 31.7 mol), benzylamine (3.47 ml, 31.7 mmol) and copper (I) bromide (450 mg, 3.17 mmol) in N,N-dimethylformamide (50 ml), and the reaction heated at 100° C. for 2 hours, then cooled. The resulting solid was filtered off and the filtrate evaporated under reduced pressure. The residue was partitioned between 4N sodium hydroxide solution (25 ml) and dichloromethane (25 ml) and the layers separated. The organic solution was extracted with water (2×), and the combined aqueous solutions, neutralised using concentrated hydrochloric acid. The resulting solid was filtered off, washed with cold water and dried in vacuo at 50° C., to afford the title compound, 1.6 g.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:35](=[O:37])[CH3:36])=[CH:10][N:11]2[CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([F:22])[CH2:19][C@H:18]2[C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[F:33])=[O:16])=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.O>[C:35]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([CH2:4][C:3]([OH:38])=[O:2])=[CH:6][CH:7]=2)[N:11]([CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([F:22])[CH2:19][C@H:18]2[C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[F:33])=[O:16])[CH:10]=1)(=[O:37])[CH3:36]
Reactant: COC(=O)Cc1ccc2c(C(C)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(CC(=O)O)ccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of (3-acetyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yl)-acetic acid methyl ester Example 549 (200 mg, 0.366 mmol) in THF (5 mL) and water (0.5 mL) was added 1N NaOH (1.46 mL, 1.46 mmol) and the reaction was stirred at RT for 60 h. The mixture was partitioned between diethylether and water. The layers were separated and the aqueous phase was adjusted to pH=2 by addition of a 1N HCl solution to form a precipitate. The solid was filtered off, washed with water diethylether and dried in vacuo to afford the title compound as a solid. MS (LC/MS): 532 [M+H]+; tR (HPLC conditions k): 3.19 min.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CC[N:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])C.[OH:34]CC1CCNC1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:27]4[CH2:28][CH2:30][CH:33]([OH:34])[CH:31]4[CH3:32])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: OCC1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CCN(C(C)C)C(C)C
Product: CC1C(O)CCN1c1ccc2c(C(=O)NC[C@@]3(O)CCC[C@@H](C)C3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-(1-hydroxy-methyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.47 (s, 1H), 4.14 (s, 1H), 3.65 (m, 2H), 3.45 (m, 3H), 3.28 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 1H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 432 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=O)=[CH:5]2.[BH3-]C#N.[Na+].CCN(CC)CC.Cl.C(O[C:28]([C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[NH2:35])=[O:29])C.C([N:44]=[C:45]=[S:46])(=O)C1C=CC=CC=1>CO.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][N:35]1[C:34]3[CH:33]=[CH:32][NH:31][C:30]=3[C:28](=[O:29])[NH:44][C:45]1=[S:46])=[CH:5]2
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=C(N=C=S)c1ccccc1
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=S)n(Cc2cc3cc(Cl)ccc3[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
5-Chloro-1H-indole-2-carbaldehyde (0.15 g, 0.76 mmol), NaCNBH3 (0.040 g, 0.63 mmol) and Et3N (0.088 mL, 0.63 mmol) was added to a stirred solution of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.12 g, 0.63 mmol) in methanol (3 mL). The resulting mixture was stirred at r.t. overnight. The reaction mixture was heated to 50° C. Additional NaCNBH3 (0.5 equiv.) was added and the mixture was stirred at 50° C. for 3 h. A few drops of HOAc was added, and after 1 h the reaction mixture was cooled to r.t. and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2 mL) and methanol (2 mL). Benzoyl isothiocyanate (0.093 mL, 0.69 mmol) was added and after stirring at r.t. for 1 h the mixture was concentrated in vacuo. The residue was dissolved in ammonia (7N in methanol, 3 mL) and heated at 80° C. for 2 h. The precipitated product was filtered and washed through with methanol and diethyl ether, followed by purification by preparative HPLC, obtaining 0.063 g (30%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([O:21]CC3C=CC=CC=3)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([OH:21])=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Yield: 94 %

Procedure:
To a solution of benzyl 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylate (0.50 g) in ethanol (15 ml) was added a solution of potassium hydroxide (205 mg) in ethanol (10 ml) and the solution stirred at reflux for 15 h. Ethanol was removed under reduced pressure and water (15 ml) added. The solution was washed with ether and concentrated hydrochloric acid added to adjust the acidity to pH 1. The precipitated solid was filtered, washed with water and dried in vacuo at 50° C. to afford 2-(3-chlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid (366 mg).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].C([N:14]1[CH2:28][CH:17]2[C:18]3[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[CH:22][C:23]=3[C:24](=O)[CH:16]2[CH2:15]1)C1C=CC=CC=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCOCC>[CH3:27][O:26][C:20]1[CH:21]=[CH:22][C:23]2[CH:24]([CH2:1][CH3:2])[CH:16]3[CH2:15][NH:14][CH2:28][CH:17]3[C:18]=2[CH:19]=1
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: CCC1c2ccc(OC)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyltriphenylphosphonium bromide (0.6 g, 1.6 mmol) and potassium tert-butoxide (0.18 g, 1.6 mmol) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 1, Step C) (0.32 g, 1.1 mmol) in anhydrous ether (2.2 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (10 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% EtOAc-hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C21H23NO+H: 306, observed: 306.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[O:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>ClCCl.O>[O:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11])=[O:15]
Reactant: Nc1cccc2c1COC2=O
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc2c1COC2=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 4-aminoisobenzofuran-1(3H)-one (4.0 g, 26.8 mmol), 2-oxo-2-phenylacetic acid (4.1 g, 26.8 mmol), and HBTU (15.2 g, 40.2 mmol) in dichloromethane (240 mL) was added TEA (8 mL). The reaction mixture was stirred at room temperature overnight. The resulting mixture was added water and adjusted to pH=6-7 with 1% aq. HCl, and then was filtered. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was evaporated and the crude product was purified by gradient chromatography (silica gel, petroleum ether/ethyl acetate 6:1 to 3:1) to give the title compound (5.0 g, yield 66%). LC-MS (ESI) m/z: 282 (M+1)+.
Reaction SMILES: [OH:1][C:2]1([C:10]#[N:11])[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.C(N(CC)CC)C.[N:19]([C:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([CH3:33])=[CH2:32])[CH:26]=1)([CH3:24])[CH3:23])=[C:20]=[O:21]>C(#N)C.O1CCOCC1>[CH2:32]=[C:31]([C:27]1[CH:26]=[C:25]([C:22]([NH:19][C:20](=[O:21])[O:1][C:2]2([C:10]#[N:11])[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)([CH3:24])[CH3:23])[CH:30]=[CH:29][CH:28]=1)[CH3:33]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: N#CC1(O)CN2CCC1CC2
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=C(C)c1cccc(C(C)(C)NC(=O)OC2(C#N)CN3CCC2CC3)c1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 3-hydroxyquinuclidine-3-carbonitrile (38 mg, 0.25 mmol) in acetonitrile/dioxane (3 mL) at room temperature was added triethylamine (7.0 uL, 0.05 mmol). The reaction mixture was stirred for 15 min and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (49.0 uL, 0.248 mmol) was added dropwise. The reaction was stirred for a period of 18 h at 65° C. and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding carbamate as a clear oil (57 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.42-7.20 (s, 5H), 6.61 (s, 1H), 5.11 (s, 1H), 3.29 (d, J=12.0 Hz, 1H), 3.09 (d, J=12.0 Hz, 1H), 2.93 (d, J=4.0 Hz, 2H), 2.79-2.68 (m, 2H), 2.13 (s, 6H) 2.05-2.00 (m, 2H), 1.91 (s, 3H), 1.87 (s, 2H), 1.50-1.37 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 135.4, 128.7, 125.2, 124.5, 124.0, 122.0, 112.9, 61.2, 47.0, 46.2, 32.4, 31.8, 29.9, 29.4, 29.2, 26.6, 25.7, 23.7, 22.8, 22.2, 19.2 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.81 min; (M+1) 354.