Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)O[CH2:4][CH2:3][O:2]1.[Cl:7][C:8]1[C:13]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[N:20]([CH:24]([CH3:26])[CH3:25])[N:21]=[CH:22][N:23]=3)[N:18]=2)=[CH:12][N:11]=[C:10]([O:27][CH3:28])[CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([O:27][CH3:28])[N:11]=[CH:12][C:13]=1[C:14]1[N:15]([CH2:4][CH2:3][OH:2])[CH:16]=[C:17]([C:19]2[N:20]([CH:24]([CH3:25])[CH3:26])[N:21]=[CH:22][N:23]=2)[N:18]=1
Reactant: O=C1OCCO1
Reactant: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)c[nH]2)cn1
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)cn2CCO)cn1
Temperature: 130 °C
Yield: 75.6 %

Procedure:
To warmed ethylene carbonate (34 g) was added 4-chloro-5-[4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine (8.74 g, 27.4 mmol) and the mixture heated at 130° C. for 3 h. The cooled reaction mixture was diluted with DCM and loaded onto silica (150 g). The silica was washed with DCM then 5% methanol in DCM. Methanolic fractions were combined and concentrated in vacuo to give the title compound as a brown foam (7.52 g, 75%). LCMS RT=2.65, [M+H]+=363/365. 1H NMR 400 MHz (CDCl3) δ: 8.27 (1H, s), 8.02 (1H, s), 7.85 (1H, s), 6.93 (1H, s), 5.98-5.82 (1H, m), 4.00 (5H, m), 3.88 (2H, t, J=5.11 Hz), 1.51 (6H, d, J=6.62 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3C[C@@H](CO)[C@H](O)[C@@H]3O)[C:9]=2[N:10]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>CS(C)=O.CO>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A mixture of 2-amino-9-[(1S,2R,3S,4S)-2,3-dihydroxy-4-(hydroxymethyl)-cyclopentyl]-1,9-dihydro-6H-purin-6-one (60.0 g, 0.213 mol) and benzyl bromide (60.9 mL, 0.512 mol) in DMSO (300 mL) was stirred at room temperature for 18 h. Concentrated HCl aqueous solution (150 mL) was added to the reaction mixture and stirring was continued for 45 min. The resulting mixture was poured into MeOH (1800 ml). The solution was neutralized with 2 M NaOH solution. The resulting white precipitate was collected by filtration, washed with water, and dried under vacuum to afford the product (48 g, 93.3%). LCMS calculated for C12H12N5O (M+H): 242.1. found: 242.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:24]1N=N[C:26]2C=CC=N[C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:25]([NH:24][C:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH3:26]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a solution of (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (810 mg, 3.8 mmol) and HATU (1.40 g, 3.8 mmol) in DMF (7.5 mL) was added ethanamine (3.8 mL of 2 M, 7.5 mmol) followed by DIEA (1.0 g, 1.4 mL, 8.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed sequentially with 1M HCl, saturated NaHCO3 and brine solution. The organic layer was dried (Na2SO4) filtered and concentrated under reduced pressure to obtain tert-butyl (2R)-2-(ethylcarbamoyl)pyrrolidine-1-carboxylate (624 mg, 68%). LC/MS m/z 243.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][C:6]1[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[CH:9][N:10]=1.Cl>C(O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][C:6]1[NH:10][CH:9]=[CH:8][N:7]=1
Reactant: Fc1cccc(OCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1cccc(OCc2ncc[nH]2)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.1 %

Procedure:
To a stirred suspension of 2-(2,3-difluoro-phenoxymethyl)-1-trityl-1H-imidazole (230 mg) at room temperature in ethanol (2 ml) under an argon atmosphere was added 2 N HCl (3 ml). The mixture was heated to reflux and stirring was continued for 5 hours. The reaction mixture was cooled to room temperature and concentrated to leave an off-white solid. This was taken up in sat. aq. Na2CO3 and extracted with CH2Cl2/methanol 9:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:CH2Cl2→CH2Cl2/methanol 9:1) to give 2-(2,3-difluoro-phenoxymethyl)-1H-imidazole (108 mg) as an off-white solid. MS 210.9 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[C:4]([F:18])[CH:3]=1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:28]([O:29][CH3:30])=[O:31])=[C:4]([F:18])[CH:3]=1
Reactant: COC(=O)C1CCNC(c2ccc(Cl)cc2F)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
Methyl 2-(4-chloro-2-fluorophenyl)piperidine-4-carboxylate (7.45 g, 27.42 mmol) was dissolved into DCM (120 mL) then DIPEA (11.97 mL, 68.55 mmol) was added. Methyl carbonochloridate (3.02 mL, 38.39 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 3 h. The mixture was washed with 0.1 M HCl (2×100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated leaving dimethyl 2-(4-chloro-2-fluorophenyl)piperidine-1,4-dicarboxylate (7.77 g, 86%) as an orange oil. MS m/z 330 (M+H)+
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5](O)=[O:6].Cl.C[N:14](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>C(#N)C.O>[F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([NH2:14])=[O:6]
Reactant: CC(C)(CC(=O)O)C(F)(F)F
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(CC(N)=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Treat a 0° C. solution of 4,4,4-trifluoro-3,3-dimethylbutanoic acid [See: US2010/0240663] (17 g, 100 mmol) in acetonitrile (200 mL) with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 g, 120 mmol) and 1-hydroxybenzotriazole (16.2 g, 120 mmol), stir at 0° C. for 2 h, treat with concentrated ammonia in water (25 wt %, 15 mL), allow to warm to RT and stir overnight. Remove the organics under reduced pressure, dissolve the residue in EtOAc, and wash with saturated. NaHCO3, then brine, dry over MgSO4, and concentrate to dryness. Treat the material with pet ether, collect the solid via filtration and dry to afford the title compound (13 g, 77% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 6.93 (s, 1H), 2.19 (s, 2H), 1.18 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:35])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C@H:21]([OH:34])[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:23]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].C(O)(=O)C>C(O)C>[OH:34][C@H:21]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[CH:23]=1)[CH2:20][NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[C:4]([OH:35])=[O:3])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)/C=C/c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(/C=C/C(=O)O)cc3)CC2)ccc1O
Reaction time: 18 h
Yield: 94.6 %

Procedure:
A solution of 0.10 g (0.2 mmol) of (E)-3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-acrylic acid ethyl ester (which was obtained in Example 183) in ethanol (3 mL) was treated with 3 mL of 1 N NaOH. After 18 h at room temperature, the mixture was acidified with acetic acid. The resulting suspension was filtered and the precipitate was washed with water, and dried in vacuo to give 0.09 g of a tan solid; m.p. 220° C.; 1H NMR (DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.57-2.95 (m, 5H), 2.92 (t, 3H), 3.74-3.82 (m, 2H), 4.48-4.52 (m, 1H), 6.22 (s, 1H), 6.27 (s, 1H), 6.81-7.03 (m, 4H), 7.18 (d, 1H), 7.42-7.49 (m, 3H)); MS (ES) m/z: 476.0 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:33]1[S:42][CH2:41][C@H:40]2[C@:35]([C:43]3[S:44][CH:45]=[C:46](Br)[CH:47]=3)([CH2:36][CH2:37][O:38][CH2:39]2)[N:34]=1)C(=O)C1C=CC=CC=1)=O)(C)(C)C.C(OCC)(=O)C>CN(C=O)C.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>[F:1][C:2]1[C:7]([C:46]2[CH:47]=[C:43]([C@@:35]34[N:34]=[C:33]([NH2:24])[S:42][CH2:41][C@@H:40]3[CH2:39][O:38][CH2:37][CH2:36]4)[S:44][CH:45]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1)C1=N[C@@]2(c3cc(Br)cs3)CCOC[C@H]2CS1
Reactant: OB(O)c1cccnc1F
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: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)cs3)CCOC[C@H]2CS1
Temperature: 90 °C
Reaction time: 7 h
Yield: 36.1 %

Procedure:
2-Fluoropyridine-3-boronic acid (15.7 mg), tetrakis(triphenylphosphine)palladium (4.3 mg) and a 1 N sodium carbonate solution (112 μL) were added to a solution of (±)-N-tert-butoxycarbonyl-N-[(4aS*,8aS*)-8a-(4-bromo-thiophen-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azanaphthalen-2-yl]benzamide (20.0 mg) in DMF (1 mL). After replacement with nitrogen, the mixture was stirred at 90° C. for seven hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (4.7 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[O:30][CH3:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: COc1ccccc1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-methoxybenzoyl chloride: ESMS m/e: 514.1 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])[CH2:4][O:3]1.Cl>CC(=O)C>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[S:9]([O:8][CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])(=[O:10])=[O:11]
Reactant: CC1(C)OC[C@H](COS(=O)(=O)c2ccc3ccccc3c2)O1
Agent: Cl
Solvent: CC(C)=O
Product: O=S(=O)(OC[C@H](O)CO)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A mixture of 62 parts of (R)-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]2-naphthalenesulfonate, 400 parts of a hydrochloric acid solution 10% and 320 parts of 2-propanone was stirred for 2 hours at reflux temperature. After evaporation, the residue was taken up in trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 40 parts (73.7%) of (R)-(2,3-dihydroxypropyl) 2-naphthalenesulfonate as a residue (interm. 10).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:6][CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH3:5].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][NH:3][CH:4]([CH3:5])[CH2:6][CH2:7][C:8]1[C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12][C:13]=1[Cl:14]
Reactant: CON=C(C)CCc1c(Cl)cc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(C)CCc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
To a solution of 4-(2,4,6-trichloro-phenyl)-butan-2-one O-methyl-oxime (0.650 g, 2.33 mmol) in acetic acid, sodiumcyanoborohydride (0.293 g, 4.66 mmol) was added. The reaction mass was stirred at room temp for 6 hours. When the TLC confirmed the completion of the reaction, the acetic acid in the reaction mass was removed by azeotropic distillation. The residue was then basified with 10% NaOH solution and it was extracted with ethyl acetate (3×30 ml). The combined ethyl acetate layers were washed with water followed by brine solution and dried over sodium sulfate before concentration. Resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 3% ethyl acetate in hexane as eluent to give O-Methyl-N-[1-methyl-3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.6 g, 90%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: N#Cc1cccnc1-c1cccc(N)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C#N)c1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a suspension of 3-(3-cyanopyridin-2-yl)aniline (195 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (332 mg) and diisopropylethylamine (0.401 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (332 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from methanol. The precipitate was collected by filtration, washed with methanol and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-cyanopyridin-2-yl)phenyl)guanidine (383 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:29]([O-])=O)=[C:13]([CH:28]=2)[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[CH3:27])=[N:3]1.O.O.Cl[Sn]Cl>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:28]=[C:13]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][C:17]=3[CH3:27])[C:12]([NH2:29])=[CH:11][CH:10]=2)=[N:3]1
Reactant: Cc1cc(OC(F)(F)F)ccc1CNc1cc(OCc2ccn(C)n2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(OC(F)(F)F)ccc1CNc1cc(OCc2ccn(C)n2)ccc1N
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-((1-methyl-1H-pyrazol-3-yl)methoxy)-N-(2-methyl-4-(trifluoromethoxy)benzyl)-2-nitroaniline (187 mg, 0.43 mmol) in ethanol (30 mL) was added SnCl2.2H2O (482 mg, 2.21 mmol). The resulting mixture was heated at 90° Celsius. After overnight, the mixture was cooled to RT and diluted with saturated NaHCO3 (40 mL). The resulting mixture was extracted with DCM (3×50 mL). The combined organics were concentrated to dryness to provide the title compound, which was used without further purification. MS (ESI): mass calcd. for C20H21F3N4O2, 406.16; m/z found, 407 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([F:21])[CH:13]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([C:8]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:21])[CH:13]=2)[CH2:9][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(Oc2ccc(N)c(F)c2)CC1

Procedure:
In analogy to the procedure described in example 15.2, 1-(3-fluoro-4-nitro-phenoxy)-cyclopropanecarboxylic acid tert-butyl ester was hydrogenated in the presence of 10% palladium on charcoal in ethanol to give the title compound as brown solid. MS: m/e=268.2 [M+H+].
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Br:31]C(F)(F)C(F)(F)Br>CCCCC.CCOCC>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:14]1[Br:31])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)n1cc(CCOC2CCCCO2)c2ccccc21
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1c(Br)c(CCOC2CCCCO2)c2ccccc21
Temperature: 25 °C

Procedure:
tert-Butyllithium (28.1 ml of a 1.7 mol solution in pentane) was added slowly to a stirred solution of 1-tert-butoxycarbonyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (15.0 g) in dry ether at −78° C. under a dry nitrogen atmosphere. During the addition the temperature was maintained below −65° C. The reaction was stirred at −78° C. for 45 min at which time 1,2-dibromotetrafluoroethane (6.24 ml) was added. The reaction mixture was then allowed to warm to room temperature over 18 h, after which time it was quenched with water (100 ml) and extracted into ether (250 ml). The organic layer was separated, washed with water (250 ml) and brine (250 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure to give an orange oil. Purification by flash chromatography (SiO2; n-hexane/ethyl acetate 10:1) afforded the product as a pale yellow oil (7.12 g); 1H (250 MHz, CDCl3) δ1.50-2.00 (6H, br m), 1.61 (9H, s), 3.05 (2H, t, J=7.5 Hz), 3.43 (1H, m), 3.56 (1H, m), 3.74 (1H, m), 3.91 (1H, m), 4.61 (1H, t, J=2.5 Hz), 7.26 (2H, m), 7.54 (1H, d, J=5.0 Hz) and 8.07 (1H, d, J=5.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:20])=[C:5]([C:15](OCC)=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12].Cl.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:20])=[C:5]([C:15]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Ethyl 5-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (210 mg, 713 μmol, 1.0 eq) and glycine tert-butyl ester hydrochloride (143 mg, 855 μmol, 1.20 eq) were mixed in dioxane (5 mL) in a round bottom flask. DIPEA (186 μL, 1069 μmol, 1.5 eq) was added via syringe, and the reaction was stirred at 75° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude product was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired compound as a white solid (204 mg). MS m/e=380 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:10])[C:8]=1[CH3:9])#[CH:2].Br[C:12]1[C:13]([CH:19]=[O:20])=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[C:13]([C:12]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([F:10])[C:8]=2[CH3:9])=[CH:17][N:16]=1)[CH:19]=[O:20]
Reactant: C#Cc1cncc(F)c1C
Reactant: O=Cc1cc(Cl)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cncc1C#Cc1cnc(Cl)cc1C=O
Temperature: 60 °C
Yield: 77.7 %

Procedure:
A mixture of 3-ethynyl-5-fluoro-4-methyl-pyridine (240 mg, 1.78 mmol), 5-bromo-2-chloro-pyridine-4-carbaldehyde (392 mg, 1.78 mmol), N,N-diisopropylethylamine (0.62 mL, 3.55 mmol), dichlorobis(triphenylphosphine)palladium(II) (64 mg, 0.089 mmol), and cuprous iodide (17 mg, 0.089 mmol) in dioxane (5 mL) was heated at 60° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-70% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow solid (380 mg, 78%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([CH2:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:25]1)=[O:22])=[O:5]>C(O)=O>[Cl:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([CH2:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([OH:35])=[O:34])=[CH:25]1)=[O:22])=[O:5]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)s1
Solvent: O=CO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Cn2cc(C(=O)O)c3ccccc32)s1
Reaction time: 24 h
Yield: 40.5 %

Procedure:
tert-Butyl 1-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-yl)methylcarbamoylmethyl)indole-3-carboxylate (500 mg) was dissolved in formic acid (5 ml), and the solution was allowed to stand for one day. The reaction mixture was concentrated, and the obtained residue was crystallized from ethyl acetate to give 184 mg of 1-((4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-yl)methylcarbamoylmethyl)indole-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: NCCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and 2-phenylethylamine in DME. ES-MS m/e (%): 316 (M+H+, 100).