Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:11][CH:12]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[OH-].[Na+]>O.C1COCC1>[CH:14]1([O:13][C:10]2[N:11]=[CH:12][C:7]([B:20]([OH:25])[OH:21])=[CH:8][CH:9]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(OC2CCCCC2)nc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc(OC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.2 %

Procedure:
n-Butyllithium (1.6 M in hexane) (20.5 mL) was dropwised to a mixture of 5-bromo-2-(cyclohexyloxy)pyridine (7.00 g) and THF (dry) (75 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 40 min. Triisopropyl borate (7.71 g) was dropwised to the mixture at −78° C. and the mixture was stirred at the same temperature for 5 min. Then the mixture was warmed up to room temperature and stirred for additional 30 min. The mixture was poured into 1N NaOH aq. (75 mL)/water (120 mL) and stirred for 1 hr. The organic layer was separated and the aqueous phase was washed with Et2O (100 mL×2) and neutralized by 1N HCl aq. The mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated in vacuo to give [6-(cyclohexyloxy)pyridin-3-yl]boronic acid (5.15 g) as pale yellow solid. Tetrakis(triphenylphosphine)palladium(0) (107 mg) was added to a suspension of 3-bromo-5-chloropyridin-2-amine (640 mg), [6-(cyclohexyloxy)pyridin-3-yl]boronic acid (750 mg) and sodium carbonate (654 mg) in DME (15 mL) and water (3 mL) and the mixture was stirred at 100° C. under nitrogen for 2.5 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (846 mg) as colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=[CH:6][C:5]=1[F:19].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CC(OC)(C)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[C:9]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[F:19]
Reactant: Clc1ncccn1
Reactant: COC(=O)c1c(F)cccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)c1c(F)cccc1-c1ncccn1
Temperature: 74 °C
Reaction time: 2.5 h
Yield: 38 %

Procedure:
To a 250 mL round-bottomed flask under nitrogen were added 2-fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (5.46 g, 19.5 mmol) in 2-methyl-THF (50 mL), 2-chloropyrimidine (2.68 g, 23.4 mmol), and sodium carbonate (6.2 g, 58.5 mmol) in water (17 mL). PdCl2(dppf)-dcm adduct (CAS#72287-26-4) (1.27 g, 1.56 mmol) was then added and the reaction mixture was warmed to 74° C. and stirred for 2.5 h. After cooling, the mixture was diluted with MTBE (50 mL) and water (80 mL). The layers were thoroughly mixed then separated. The aqueous layer was extracted with additional MTBE (100 mL). The combined organics were dried over magnesium sulfate, filtered, concentrated and then purified by flash chromatography (0-25% EA/hexanes) to provide the title compound (1.72 g, 72 wt %, 30% yield). 1H NMR (400 MHz, CDCl3): 8.79 (d, J=4.9 Hz, 2H), 8.15 (d, J=7.9 Hz, 1H), 7.51 (td, J=8.1, 5.6 Hz, 1H), 7.28-7.20 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [N:1]1([C:13]2([CH2:23][OH:24])[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)[C:5]2=[C:6]3[S:12][CH:11]=[CH:10][C:7]3=[N:8][CH:9]=[C:4]2[N:3]=[CH:2]1.Cl.O.[OH-].[Na+]>CC(C)=O>[OH:24][CH2:23][C:13]1([N:1]2[C:5]3=[C:6]4[S:12][CH:11]=[CH:10][C:7]4=[N:8][CH:9]=[C:4]3[N:3]=[CH:2]2)[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]1
Reactant: OCC1(n2cnc3cnc4ccsc4c32)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.9 %

Procedure:
A mixture of [8-(1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)-1,4-dioxaspiro[4.5]dec-8-yl]methanol (0.13 g, 0.38 mmol) and 3.0 M hydrogen chloride in water (2.0 mL, 6.0 mmol) in acetone (5 mL) was stirred at room temperature for 5 h and then at 60° C. for 1 h. After cooling, the mixture was made slightly basic by the addition of 2.0 N NaOH. The mixture was extracted with EtOAc (3×). The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel, eluted with 0-15% MeOH in dichloromethane to give 56 mg (49%) of the desired product. LCMS calculated for C15H16N3O2S (M+H)+: m/z=302.1. Found: 302.1.
Reaction SMILES: Br[CH2:2][C:3]([CH2:8]Br)([CH2:6]Br)[CH2:4][OH:5].[OH-].[K+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1>CCO>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:8][C:3]3([CH2:6][O:5][CH2:4]3)[CH2:2]2)(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: OCC(CBr)(CBr)CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CC3(COC3)C2)cc1
Yield: 63 %

Procedure:
To a solution of 3-bromo-2,2-bis(bromomethyl)propanol (127) (3.25 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol, in 10 mL water) in EtOH (20 mL) were added toluene-4-sulfonamide (3.76 g, 22 mmol). The reaction mixture was refluxed for 2 h, evaporated to remove EtOH then diluted with EAOAc (20 mL), washed with H2O (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered, evaporated to give the product to give 6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128) (1.6 g, 6.3 mmol, yield: 63%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[C:23]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:22][C:19]([CH:20]=O)=[C:18]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:17]=1>>[CH3:14][O:15][C:16]1[C:23]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:22][C:19](/[CH:20]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])=[C:18]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:17]=1
Reactant: COc1cc(OCCCN2CCOCC2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OCCCN2CCOCC2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 48 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) in a similar manner as described in Ex-22. Yellow solid, 48% yield, mp 193–196° C. 1H-NMR (DMSO-d6) δ 8.24 (m, 3H), 8.06 (s, 1H), 7.96 (d, 2H), 7.89 (d, 1H), 7.63 (d, 1H), 7.51 (m, 1H), 7.10 (dd, J=3, 4 Hz, 1H), 6.81 (s, 1H), 4.23 (t, 2H), 3.98 (s, 3H), 3.55 (t, 4H), 2.47 (m, 2H), 2.35 (t, 4H), 1.98 (q, 2H). MS m/z=542 ([M]+, 38%), 100 (100%). Anal. calculated for C27H30N2O6S2.3/5H2O: C, 58.59; H, 5.68; S, 11.59; found C, 58.59,H: 5.55, S, 11.40.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][C:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[CH:8]CC1C=CC=C(Br)C=1>C(O)(=O)C>[Br:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:7]([CH2:8][C:26]1[CH:25]=[CH:5][CH:4]=[C:3]([Br:2])[CH:27]=1)([CH2:6][C:5]1[CH:25]=[CH:26][CH:27]=[C:3]([Br:2])[CH:4]=1)[Br:1]
Reactant: Br
Reactant: Brc1cccc(CC=C(Cc2cccc(Br)c2)Cc2cccc(Br)c2)c1
Solvent: CC(=O)O
Product: Brc1cccc(CC(Br)(Cc2cccc(Br)c2)Cc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
500 ml of a 30% by weight solution of hydrogen bromide in glacial acetic acid were added dropwise to a solution of 140.7 g (270 mmol) of 1,1,2-tris(3-bromobenzyl)-ethene in 1000 ml of glacial acetic acid. After the mixture had been stirred at room temperature for 48 h, the colourless precipitate was filtered off with suction, washed twice with 200 ml of glacial acetic acid each time and subsequently dried under reduced pressure. The yield, with a purity of about 97%, was 157.2 g (261 mmol), corresponding to 96.7% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:9]([CH3:14])=[N:10][NH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:20]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:23]=[CH:22][CH:21]=1.O>COCCOCCOC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:12]([CH3:13])=[N:11][N:10]([C:28]3[N:27]=[C:26]([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][N:25]=4)[CH:31]=[CH:30][CH:29]=3)[C:9]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c(C)c1SCc1ccc(Cl)cc1
Reactant: Brc1cccc(-c2ccccn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1nn(-c2cccc(-c3ccccn3)n2)c(C)c1SCc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 42.6 %

Procedure:
To a solution of 4-(4-chloro-benzylsulfanyl)-3,5-dimethyl-1H-pyrazole (0.708 g, 2.80 mmol) in 2-methoxyethyl ether (7 mL) was added sodium hydride (0.123 g (60% dispersion), 3.08 mmol). After stirring for 5 minutes, 6-bromo-[2,2′]bipyridinyl (0.691 g, 2.94 mmol) was added, and the reaction mixture was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, and water (100 mL) was added. The suspension was extracted with ethyl acetate (50 mL×2), and the combined organic extracts washed with brine (100 mL). The organic phase was dried (magnesium sulfate), filtered, and concentrated to afford a tan solid. Flash chromatography over silica (methanol/methylene chloride) followed by recrystallization from aqueous methanol provided 0.485 g (43%) of the product as a white solid: 1H NMR (CDCl3) δ 8.70-8.68 (m, 1H), 8.34 (d, J=7.9 Hz, 1H), 8.29 (d, J=7.9 Hz, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.86 (dt, J=2.0, 7.9 Hz, 2H), 7.35-7.31 (m, 1H), 7.22 (d, J=8.3 Hz, 2H), 6.99 (d, J=8.3 Hz, 2H), 3.65 (s, 2H), 2.45 (s, 3H), 2.21 (s, 3H) ppm. 13C NMR (CDCl3) δ 155.7, 154.5, 153.8, 152.9, 149.5, 145.9, 139.7, 137.3, 137.2, 133.1, 130.7, 128.7, 124.2, 121.3, 118.5, 116.1, 110.0, 40.3, 13.6, 12.3 ppm.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1>C(Cl)Cl>[Br:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccsc1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1sccc1Br
Reaction time: 1 h
Yield: 30.6 %

Procedure:
Chlorosulfonic acid (20 ml, 300 mmol) was added to a solution of 3-bromothiophene (8.15 g, 50 mmol) in methylene chloride (50 ml) at -78° C. over a 20 min. period. After the completion of addition, the cold bath was removed and stirring continued at ambient temperature for 1 hr. The reaction mixture was carefully added, dropwise, to crushed ice (100 g). The mixture was extracted with methylene chloride (2×100 ml). The combined organic layers was dried over MgSO4 and evaporated. The crude product was purified by flash chromatography on silica gel using hexane as the eluent resulting in 3-bromothiophene-2-sulfonyl chloride (4 g, 30% yield) and 4-bromothiophene-2-sulfonyl chloride (200 mg, ≤1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[C:17]([CH2:18]3)=[N:16][N:15]([C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:14]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cn[nH]c1C2
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)n1cc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by acylation of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]-dodeca-2(6),3-diene using isobutyryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13](C)[C:12](=O)[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[C:10]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.CC(NC1N=C([Cl:46])C(C2C=CC(F)=CC=2)=C(C2C=CN=CC=2)N=1)(C1C=CC=CC=1)C>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([Cl:46])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[C:10]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(Nc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Reactant: Cc1cccc(-c2c(-c3ccnc(Cl)c3)nc(-c3ccnc(Cl)c3)n(C)c2=O)c1
Product: Cc1cccc(-c2c(Cl)nc(-c3ccnc(Cl)c3)nc2-c2ccnc(Cl)c2)c1

Procedure:
The title compound was synthesized from 2,6-bis(2-chloropyrid-4-yl)-3-methyl-5-(3-methylphenyl)-3H-pyrimidin-4-one in the same manner as 2-((1-methyl-1-phenylethyl)amino)-4-chloro-5-(4-fluorophenyl)-6-(4-pyridyl)pyrimidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>O1CCCC1.CO>[Cl:18][C:17]1[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=[C:13]([Cl:23])[C:12]=1[N:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.83 g) in tetrahydrofuran (20 ml) and methanol (20 ml) was added 4 N aqueous solution of sodium hydroxide (30 ml), and stirred at room temperature. After completion of the reaction, the solvent was evaporated, to the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (4.89 g) as a white solid. MS (ESI) m/z: 339, 341 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[N:3]=1.[NH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][CH2:22][NH:21][C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[N:3]=2)=[CH:25]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Cc1cccc(-c2nc(Cl)cc(-c3cccnc3)n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(-c2nc(NCCc3c[nH]c4ccccc34)cc(-c3cccnc3)n2)n1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-2-(6-methyl-pyridin-2-yl)-6-pyridin-3-yl-pyrimidine (Intermediate D) (1 eq, 50 mg), 3-(2-aminoethyl)indole (1.0 eq, 28.3 mg) and K2CO3 (1.0 eq, 24.4 mg) in NMP (1 ml) is heated using microwave radiation at 120° C. for 1 hour. After cooling to room temperature, the mixture is partitioned between EtOAc/water and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue is purified by flash chromatography on silica eluting with 0-5% MeOH in DCM and the appropriate fractions are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and the residue is dissolved in DCM and concentrated in vacuo once again. The resulting solid is dried under vacuum to afford the title compound [M+H]+=407.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12](=[O:15])(=[O:14])[NH2:13])[CH2:8][CH2:7][CH2:6]2.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12]([N:13]=[CH:18][N:19]([CH3:21])[CH3:20])(=[O:15])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1S(N)(=O)=O)CCC2
Reactant: COC(OC)N(C)C
Product: COc1cc2c(cc1S(=O)(=O)N=CN(C)C)CCC2

Procedure:
This compound is prepared analogously to Example 1 c from 5-methoxy-6-sulfamoylindane and dimethylformamide dimethylacetal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][NH:23]4)=[CH:19][C:18]=3[F:33])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][NH:23]4)=[CH:19][C:18]=3[F:33])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3cc4[nH]cc(CCC(=O)O)c4cc3F)no2)cc1Cl
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of ethyl 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D158) (250 mg) in isopropanol (20 mL) and water (4 mL) was added 0.8 mL of 20% NaOH aqueous solution. The mixture was then stirred overnight. Afterwards, the solution was adjusted to pH 3 by addition of concentrated HCl and evaporated in vacuo. The residue was treated with 8 mL DMF. The insolubles were filtered and the filtrate was purified by MDAP. The solvent was freeze dried to give 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E111) (80 mg). δH (DMSO-d6, 400 MHz): 1.32 (6H, d), 2.54 (2H, t), 2.88 (2H, t), 5.40 (1H, m), 7.37 (1H, s), 7.48 (1H, d), 8.05 (1H, d), 8.50 (1H, d), 8.87 (1H, d), 11.24 (1H, s), 12.05 (1H, s); δF (DMSO-d6, 376 MHz): −121.6; MS (ES): C21H18ClFN4O4 requires 444; found 445.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH:22]=[O:23])=[CH:7]2.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21])[C:8]([CH2:22][OH:23])=[CH:7]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F

Procedure:
Prepared according to Procedure B using 8-chloro-2-(2-trifluoromethylphenyl) quinoline-3-carbaldehyde (1.10 g, 3.28 mmol) and sodium borohydride (0.186 g, 4.91 mmol, 1.5 eq) in THF (15 mL). (8-chloro-2-(2-trifluoromethylphenyl)quinolin-3-yl)methanol was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.57 (1 H, s), 8.10 (1 H, dd, J=7.9, 1.2 Hz), 7.94 (2 H, t, J=6.4 Hz), 7.82 (1 H, t, J=7.6 Hz), 7.76 (1 H, t, J=7.6 Hz), 7.50-7.68 (4 H, m), 5.54 (1H, t, J=5.2 Hz), 4.45 (1 H, br d), 4.28 (1 H, br d) Mass Spectrum (ESI) m/e=338.0 and 340.0 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
A mixture of 3,4-difluorobenzaldehyde (2.00 g, 14.8 mmol), 6-chloropyridin-3-ol (1.82 g, 14.1 mmol) and potassium carbonate (2.14 g, 15.5 mmol) in N,N-dimethylformamide (DMF) (25 mL) was stirred at 110° C. for 12 h, diluted with ethyl acetate (50 mL), washed with water (50 mL×2). The organic part was separated, dried over anhydrous Na2SO4, filtered and concentrated. Purification via silica gel (3% ethyl acetate in petroleum ether) afforded the title product (2.8 g)
Reaction SMILES: [CH2:1](Br)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH2:12]([N:14]([CH2:26][CH3:27])[C:15](=[O:25])[C:16]1[CH:24]=[CH:23][C:21]([OH:22])=[C:18]([O:19][CH3:20])[CH:17]=1)[CH3:13]>>[CH2:1]([O:22][C:21]1[CH:23]=[CH:24][C:16]([C:15]([N:14]([CH2:26][CH3:27])[CH2:12][CH3:13])=[O:25])=[CH:17][C:18]=1[O:19][CH3:20])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CCN(CC)C(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)=CCC/C(C)=C/CBr
Product: CCN(CC)C(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)c(OC)c1

Procedure:
geranyl bromide was reacted with vanillic acid N,N-diethyl amide to obtain p-geranyloxy-m-methoxy-N,N-diethyl-benzamide (boiling point = 180°/0.05 mmHg);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:20])[C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]>N.CO.C1COCC1.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([N:9]([CH3:20])[C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)N(C)c2cccc(C#N)c2)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(C)c2cccc(CN)c2)cc1
Reaction time: 14 h

Procedure:
450 mg (1.7 mmol) N-(3-Cyano-phenyl)-4-methoxy-N-methyl-benzamide were dissolved in 10 ml NH3 in methanol (10%) and 10 ml THF. 500 mg Sponge nickel catalyst were added and the mixture was hydrogenated for 14 h at 5 bar pressure. The mixture was filtered and the filtrate was evaporated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:35]4[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=4)[C:29]#[N:30])[CH:3]=3)[O:8][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:28])[F:27])=[CH:20][CH:19]=3)[CH2:10]2)[N:12]=1
Reactant: CN1OC2(CC(c3ccc(OC(F)(F)F)cc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccc(OC(F)(F)F)cc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 2.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 0.11 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (32.4 mg, 0.22 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (1.39 mg, 5%). 1H-NMR (MeOD): 2.34 (t, 1H), 2.89 (d, 1H), 5.41 (t, 1H), 7.13 (d, 1H), 7.37 (t, 2H), 7.64 (m, 3H), 7.70 (d, 1H), 7.78 (t, 1H), 7.94 (t, 1H), 8.04 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>CO>[F:14][C:15]([F:22])([F:21])[C:16]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C[C@@H](N)C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C

Procedure:
To the mixture of D-alanine (20.00 g; 0.224 mol) and triethylamine (31.3 ml; 0.224 mol) in absolute methanol (100 ml), ethyl trifluoroacetate (33.4 ml; 0.280 mol) is added and stirred at room temperature to homogenise the mixture (approx. 1 day). The solution is concentrated on a rotavapor (35° C.; 16 mmHg) and then dissolved in the mixture THF/water (1:1; 140 ml). Acidic ion exchanger Dowex 50W-X8 (100 g) is added, stirred for 10 minutes, filtered and concentrated again on a rotavapor (35° C.; 16 mmHg). The residue is sublimed (80° C.; 0.05 mmHg). The pure product in the form of colourless crystals is obtained (33.50 g; 80.8%).