Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][N:7]([CH3:12])[S:8](Cl)(=[O:10])=[O:9]>>[CH3:6][N:7]([CH3:12])[S:8]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)n1ccnc1

Procedure:
Imidazole was treated with dimethyl amino sulfonyl chloride providing 1-(dimethylaminosulfonyl)-imidazole, which was subsequently treated with n-butyl lithium and t-butyldimethylsilyl chloride to afford 1-(dimethylaminosulfonyl)-2-(t-butyldimethylsilyl)-imidazol e. This material was treated with n-butyllithium and tri-n-butyltin chloride to afford the target compound.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([CH2:6][CH:7]([Cl:10])[C:8]#[N:9])[C:3](Cl)=[O:4].[ClH:12]>>[Cl:1][C:2]1([Cl:11])[CH2:6][C:7]([Cl:10])=[C:8]([Cl:12])[NH:9][C:3]1=[O:4]
Reactant: N#CC(Cl)CC(Cl)(Cl)C(=O)Cl
Reactant: Cl
Product: O=C1NC(Cl)=C(Cl)CC1(Cl)Cl

Procedure:
The cyclization reaction may be conveniently conducted in a batch reaction or in a continuous fashion in a coil reactor. In a typical reaction, 2,2,4-trichloro-4-cyanobutanoyl chloride is diluted with the desired solvent in a closed pressure vessel, and the vessel is pressurized with anhydrous HCl to the desired pressure. The reaction mixture is stirred at the appropriate temperature until the reaction is completed, usually from about one to about three hours. The reaction vessel is vented and the product, 3,3,5,6-tetrachloro-3,4-dihydropyridin-2-one, can be isolated by conventional procedures. For example, evaporation of the solvent provides a crude solid product which can be slurried with an aliphatic hydrocarbon, such as hexane, and which can then be isolated by filtration. Product so obtained is sufficiently pure after drying to be used in the subsequent aromatization. Alternatively, the crude reaction mixture can be used directly, immediately after venting and removal of the HCl.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: C1COCCN1
Product: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-bromo-3-(trifluoromethyl)-benzonitrile and morpholine (Fluka, Buchs, Switzerland), with a reaction temperature of 95° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[ClH:35]>O1CCOCC1>[ClH:35].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH2:26][NH2:27])[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Agent: Cl
Solvent: C1COCCO1
Product: NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of tert-butyl 2-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)ethylcarbamate (260 mg; 0.54 mmol) in dioxane (5 mL) was added conc. aqueous HCl (5 mL; 36%). The reaction mixture was stirred for 1 hours and concentrated to afford 260 mg (68%) of the title compound as a yellow solid, which was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
4-(4-chlorophenoxy)benzaldehyde (0.119 g, 0.510 mmol) and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.126 g, 0.510 mmol) were mixed in 1,2-dichloroethane (5 mL) and then treated with sodium triacetoxyborohydride (0.424 g, 2.00 mmol) and HOAc (0.03 mL, 0.5 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated NaHCO3 aqueous solution and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo, and purified by preparative TLC using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (53 mg, 23%). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.34-7.19 (m, 7H), 6.98-6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J=11.8 Hz), 2.58-2.44 (m, 2H), 2.10-1.98 (m, 2H), 1.83-1.76 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:24](=[NH:25])[N:23]([CH3:26])[C:12]2[N:13]=[C:14]([O:17]CCOCC)[N:15]=[CH:16][C:11]=2[CH:10]=1>Cl>[ClH:1].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:24](=[NH:25])[N:23]([CH3:26])[C:12]2[N:13]=[C:14]([OH:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCOCCOc1ncc2cc(-c3c(Cl)cccc3Cl)c(=N)n(C)c2n1
Agent: Cl
Product: Cn1c(=N)c(-c2c(Cl)cccc2Cl)cc2cnc(O)nc21

Procedure:
A solution of 78.0 mg (0.20 mmol) of the ethoxyethyl ether from Example 22 in 1.0 mL of 6N hydrochloric acid was heated at reflux for 5 minutes. The solvent was removed by evaporation under reduced pressure. The remaining solid hydrochloride salt was recrystallized from ethanol-ethyl acetate to afford crystalline 6-(2,6-dichlorophenyl)-2-hydroxy-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-ylideneamine, hydrochloride; mp 255°-260° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I-].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[O:41]1[C:45]2=[CH:46][N:47]=[CH:48][CH:49]=[C:44]2[CH:43]=[C:42]1[CH:50]=O>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([CH:21]=[CH:50][C:42]2[O:41][C:45]3=[CH:46][N:47]=[CH:48][CH:49]=[C:44]3[CH:43]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1cc2ccncc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=Cc2cc3ccncc3o2)CC1
Reaction time: 64 h

Procedure:
K2CO3 (122 mg, 0.88 mmol) and 18C6 (catalytic amount) were added to a stirred solution of (1-tert-butoxycarbonylpiperidin-4-ylmethyl)triphenylphosphonium iodide (491 mg, 0.88 mmol) and furo[2,3-c]pyridine-2-carbaldehyde (65 mg, 0.44 mmol) in anhydrous CH2Cl2 (10 mL). After 64 h, the reaction mixture was partitioned between CH2Cl2 (50 mL) and H2O (20 mL). The aqueous phase was further extracted with CH2Cl2 (2×20 mL), then the combined organic extracts were washed with H2O (20 mL) and brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 7:3) afforded 4-(2-furo[2,3-c]pyridin-2-ylvinyl)piperidine-1-carboxylic acid tert-butyl ester: m/z (ES+)=329.2 [M+H]+. This alkene (30 mg, 91 μmol) was hydrogenated, as described above in Example 18, to yield the title compound: RT=2.86 min; m/z (ES+)=331.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.O>C(OCC)C>[F:1][C:2]1[N:3]=[CH:4][C:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(C2CCNCC2)cn1
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
A solution of 2-fluoro-5-bromopyridine (7.69 g) in diethyl ether (160 ml) was cooled to −78° C., and into which n-butyl lithium (1,56M-hexane solution, 30 ml) was added dropwise at a temperature not higher than −70° C. After 15 minutes' stirring, tert-butyl 4-oxo-1-piperidinecarboxylate (8.7 g) was added. Temperature of the reaction liquid was raised to −35° C. and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure and isopropyl ether was added to the resulting residue. Whereupon precipitated crystals were recovered by filtration to provide the title compound (4.15 g). The filtrate was purified on column chromatography (hexane/ethyl acetate=3/1-2/1) to provide tert-butyl 4-(6-fluoro-3-pyridinyl)-4-hydroxy-tetrahydro-1(2H)-pyridinecarboxylate (1.25 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][C:15]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)C=Cc1nc(-c2ccc(F)cc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)C=Cc1nc(-c2ccc(F)cc2)cs1)C(C)C

Procedure:
98 mg (0.39 mmol) of 3-[4-(4-fluoro-phenyl)-thiazol-2-yl]-acrylic acid, 79.6 mg (0.78 mmol) of diisopropylamine, 119.35 mg (1.17 mmol) of triethylamine and 164.5 mg (0.43 mmol) of HATU in 5 ml of DMF were stirred at room temperature for 2 h. The reaction mixture was concentrated, and water and ethyl acetate were added. The organic phase was separated, washed and evaporated. The residue was purified by chromatography (RP18). Yield: 39 mg.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: C1CCNC1
Reactant: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1nc(-c2ccc(F)cc2)cs1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 38.7 mg (0.54 mmol) of pyrrolidine. Yield: 6 mg.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:2]1[S:1][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:17]
Reactant: O=C1NCCCc2ccsc21
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCl)c1cc2c(s1)C(=O)NCCC2
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 2.5 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride under cooling. The mixture was stirred for 30 minutes, refluxed under heating and poured into water, and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was crystallized from ethyl acetate-isopropyl ether to give 1.2 g of 2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as white crystals, m.p. 163°-165° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:16]3[C:17]([C:21]([O:23]C)=[O:22])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH2:2]2.O.[OH-].[Li+:27].O>O1CCCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:16]3[C:17]([C:21]([O-:23])=[O:22])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH2:2]2.[Li+:27]
Reactant: COC(=O)c1cccc2ncn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2ncn(CCN[C@@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g, 0.7 mmol) from Step F above, lithium hydroxide monohydrate (0.1 g, 2.1 mmol), water (5 mL), and tetrahydrofuran (5 mL) was heated at reflux for 5 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g): MS (ESI+) m/z 315 (M+H).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][C@H:57]([C@H:59]2[CH2:63][O:62][C:61]3([CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]3)[O:60]2)[CH3:58])[N:53]=[C:52]([S:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[C:73]([F:77])[C:72]=2[F:78])[N:51]=1.[Cl-].[NH4+]>O1CCOCC1.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]>[F:78][C:72]1[C:73]([F:77])=[CH:74][CH:75]=[CH:76][C:71]=1[CH2:70][S:69][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][C@H:57]([C@H:59]2[CH2:63][O:62][C:61]3([CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]3)[O:60]2)[CH3:58])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: C[C@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC2(CCCCC2)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC2(CCCCC2)O1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.131 g), tris(dibenzylideneacetone)-dipalladium (0) (22 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (11 mg), cesium carbonate (0.117 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-{(1S)-1-[(2R)-1,4-dioxaspiro[4.5]dec-2-yl]ethoxy}pyrimidine (the product of step i) (0.100 g) in anhydrous dioxane (5 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 15 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 1:19 to 3:7 mixture of EtOAc and iso-hexane as eluent and then by reverse phase HPLC (gradient 25-95% acetonitrile in 0.1% ammonium acetate) to give the subtitle compound as a colourless gum. Yield: 43 mg
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>CN(C=O)C.C1COCC1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5[S:32]([CH3:31])(=[O:34])=[O:33])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1S(C)(=O)=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1:9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 min under N2, the suspension was cooled down to −15° C. and a solution of methanesulfonyl chloride (1.1 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 30 min at −15° C. then for 6 h at room temperature. Water (0.5 mL) was added at 0° C., solvent was removed, and the residue was diluted with MeOH, filtrated and purified by preparative HPLC to give 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-(methyl sulfonyl)-1H-indol-5-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO) δ 11.6 (s, 1H), 8.7 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.33 (dd, J1=1.9 Hz, J2=8.7 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 6.95 (dd, J1=1.7 Hz, J2=8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.02 (s, 2H), 3.07 (s, 3H), 1.56-1.40 (m, 9H), 1.41 (dd, J1=4.0 Hz, J2=6.7 Hz, 2H), 1.03 (dd, J1=4.0 Hz, J2=6.7 Hz, 2H). MS (ESI) m/e (M+H+) 455.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][N:28]1[CH:32]=[N:31][N:30]=[CH:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][N:28]2[CH:32]=[N:31][N:30]=[CH:29]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nn1cnnc1
Product: O=C(Nn1cnnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 4-amino-1,2,4-triazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(4H-1,2,4-triazol-4-yl)terephthalamide. MS (Q1) 453 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(OC)c1N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(OC)c1N
Reaction time: 17 h
Yield: 73.4 %

Procedure:
To a solution of methyl 2-amino-3-methoxybenzoate (13.0 g, 71.8 mmol) in DMF (30 mL) was added NBS (14.38 g, 80.8 mmol) at room temperature and the resulting reaction mixture was stirred for 17 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 2% to 5% EtOAc in hexanes) to afford methyl 2-amino-5-bromo-3-methoxybenzoate (13.7 g, 73%). 1H NMR consistent.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CN(C)C=O.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[F:32].C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl>[Br:1][C:2]1[C:3]([O:16][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=2[F:32])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(Br)c(Oc3ccc([N+](=O)[O-])cc3F)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A 50-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen and charged with 1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (350 mg, 1.23 mmol), N,N-dimethylformamide (10 mL), 1,2-difluoro-4-nitrobenzene (415 mg, 2.61 mmol) and cesium carbonate (1.3 g, 3.99 mmol). The resulting mixture stirred for 3 h at 110° C. After cooling to room temperature, the reaction mixture was poured into dichloromethane (50 mL), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford 1-[(2S)-6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (450 mg, 86%) of as yellow oil. MS (ESI, neg. ion) m/z 421, 423[M−H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[CH2:27][S:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[CH2:27][S:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH:6]=1
Reactant: COC(=O)Cc1ccc(C#C[Si](C)(C)C)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1ccc(CC(=O)OC)cc1Oc1ccc([N+](=O)[O-])cc1CSCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trimethylsilanylethynyl-phenyl}-acetic acid methyl ester (0.410 g, 0.8 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (1M in THF; 1.2 mL, 1.2 mmol), and the reaction was stirred for 30 minutes at room temperature. Once no starting material was seen by analytical tlc, the mixture was worked-up with EtOAc and H2O, and the residue was purified by silica gel chromatography to give {4-Ethynyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[NH2:20][CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1>CO>[CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][NH:20][CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: NC1CCCc2cccnc21
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(CNC2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a stirred solution of 1-(2-trimethylsilylethoxymethyl)-2-formyl-benzimidazole (4.26 g, 15.4 mmol) in dry MeOH (50 mL) was added a solution of 8-amino-5,6,7,8-tetrahydroquinoline (2.20 g, 14.8 mmol) in dry MeOH (20 mL) and the mixture stirred for 2 h at room temperature under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and the resultant residue analyzed by 1H NMR to confirm imine formation. The residue was re-dissolved in dry MeOH (80 mL) and to the resultant solution was added sodium borohydridc (1.17 g, 30.8 mmol). The mixture was stirred for 5 h, concentrated in vacuo and diluted with CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (125 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (2×75 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude material through a plug of silica gel (CH2Cl2/MeOH 96:4) afforded the desired amine (5.91 g, 98%) as an orange oil. 1H NMR (CDCl3) δ −0.07 (s, 9H), 0.90 (t, 2H, J=9 Hz), 1.72-1.83 (m, 2H), 1.95-2.01 (m, 1H), 2.76-2.85 (m, 2H), 3.54 (t, 2H, J=9 Hz), 4.33 (m, 2H), 5.68 (d, 1H, J=12 Hz), 5.75 (d, 1H, J=12 Hz), 7.05-7.09 (m, 1H), 7.25-7.30 (m, 2H), 7.38 (d, 1H, J=9 Hz), 7.44-7.46 (m, 1H), 7.71-7.73 (m, 1H), 8.36-8.38 (m, 1H).