Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:16])[CH2:12]1.C(N(CC)CC)C>O1CCOCC1>[F:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]2[CH2:12][N:13]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([N:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:27]4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[O:16])[CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: NCC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reactant: Fc1cccc(F)n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(CNc2cccc(F)n2)C1
Temperature: 80 °C

Procedure:
Add 2,6-difluoropyridine (55 μL, 70 mg, 0.61 mmol, 2.0 equiv) to a solution of (3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone (134 mg, 0.301 mmol, 1 equiv) and triethylamine (120 μL, 87 mg, 0.86 mmol, 2.9 equiv) in 1,4-dioxane (3 mL) and heat at 80° C. for 16 h. Mass spec shows no desired product. Add more triethylamine (120 μL) and 2,6-difluoropyridine (110 μL). After 32 h at 80° C., LC/MS shows a small amount of desired product. Add more triethylamine (200 μL) and 2,6-difluoropyridine (110 μL). After 38 h, add more triethylamine (200 μL) and 2,6-difluoropyridine (110 μL). After 100 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (50-65% EtOAc/hex) to yield 65 mg (40%) of [3-[(6-fluoro-pyridin-2-ylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a white foam. MS (m/e): 541.02 (M+1); 539.17 (M−1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH4+:25].[OH-]>O1CCOCC1.O>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:25])[N:8]=1
Reactant: [NH4+]
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(N)n1
Yield: 91 %

Procedure:
4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (1 g, 2.4 mmol) was combined with aqueous 28% NH4OH solution (8 mL) in 1,4-dioxane (8 mL) and the resulting mixture was split evenly between two reaction vials. Each was irradiated in a microwave reactor for 40 minutes at 130° C. TLC analysis indicated complete reaction. The combined reactions were then diluted with water (100 mL) followed by extraction with EtOAc (100 mL). The EtOAc layer was washed with brine then dried (Na2SO4), and concentrated. Purification of the resulting residue by flash chromatography on silica gel using an EtOAc-hexanes gradient (0 to 60%) provided 0.87 g of (2.1 mmol, 91%) of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine as a white solid: LCMS (m/z): 410.0 (MH+), tR=0.81 minute.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=[S:21])C>C(O)(=O)C>[N:1]1([C:6]2[CH:7]=[C:8]([C:9](=[S:21])[NH2:10])[CH:11]=[CH:12][C:13]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(O)=S
Reactant: CC(C)COc1ccc(C#N)cc1-n1ccnc1
Solvent: CC(=O)O
Product: CC(C)COc1ccc(C(N)=S)cc1-n1ccnc1
Temperature: 50 °C

Procedure:
A reaction mixture prepared by suspending the crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile obtained above in a mixture of 0.2 mL of acetic acid and 0.5 mL of thioacetic acid was heated at 50° C. for 14 hours under a nitrogen atmosphere. Concentration under reduced pressure was prepared to obtain a crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzene-1-carbothioamide.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:12]([C:14]2[CH:24]=[CH:23][C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)[OH:13])=[N:8][C:9]=1[O:10][CH3:11].O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:12]([C:14]2[CH:24]=[CH:23][C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=[O:13])=[N:8][C:9]=1[O:10][CH3:11]
Reactant: COc1nc(C(O)c2ccc3c(c2)OCCN3C)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C(=O)c2ccc3c(c2)OCCN3C)ccc1Cl
Temperature: 25 °C
Yield: 77 %

Procedure:
Sodium hydride (purity: 63%, 75 mg) was added to a solution of (5-chloro-6-methoxypyridin-2-yl)(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanol (302 mg) in tetrahydrofuran (2 mL) under ice-cooling, and the mixture was stirred with warming to room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to give the title compound as a yellow solid (231 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:24][CH2:23][C:22]([F:26])([F:25])[F:21])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Reactant: NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2NCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A mixture of 5,7-dichloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine (3.19 g, 10 mmol), 2,2,2-trifluoroethylamine (3.0 g, 30 mmol), and triethylamine (3.0 g, 30 mmol) in 30 mL of N,N-dimethylformamide is stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture is diluted with ethyl acetate. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is filtered through hydrous magnesium silicate. Concentration provides 5-chloro-6-(2,4,6-trifluorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a light yellow solid (3.70 g). MS: m/z 381.9 (M+H).
Reaction SMILES: Cl.[O:2]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:17]>CCOCC>[O:2]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(Oc2ccccc2)c1
Reactant: O
Agent: Cl
Solvent: CCOCC
Product: O=Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Hydrogen chloride was introduced until saturation into a solution of 37.9 g of anhydrous stannous chloride (0.2 mole) in 200 ml of anhydrous ether. To the resulting solution, was added 19.5 g of 3-phenoxybenzonitrile (0.1 mole) and the mixture was stirred for 10 hours at room temperature. After addition of 200 ml of water and thorough stirring, the insoluble matter was removed by filtration. The filtrate was separated and the ether layer was further washed three times with 50 ml of water. After removal of the ether by distillation, the residue was distilled to obtain 8.5 g of crude 3-phenoxybenzaldehyde boiling at 100° to 115° C./0.45 mmHg which contained 71.4% of 3-phenoxybenzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C#Cc1cccc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1cccc(OC)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 90 %

Procedure:
The title compound was synthesized from (3-methoxy-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in a 90% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.45-6.68 (m, 9H), 6.49 (m, 2H), 6.23 (s, 1H), 4.37 (m, 2H), 4.13 (q, 2H, J=7.2 Hz), 3.76 (t, 2H, J=5.2 Hz), 3.68 (s, 2.1H), 3.58 (s, 0.9H), 3.20 (m, 2H), 2.73 (t, 2H, J=6.8 Hz), 1.90 (m, 2H), 1.51 (s, 9H), 1.26 (t, 2.1H, J=7.2 Hz), 1.13 (t, 0.9H, J=7.2 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H32N3O4 498.2 (M-Boc+1); found 498.4.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][C:34]([OH:36])=[O:35].[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:38].[Na+]>C(#N)C>[CH2:37]([O:35][C:34](=[O:36])[CH2:33][NH:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:38]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Reactant: N#Cc1c(Cc2ccc(N)c(OCc3ccccc3)c2)cccc1OCc1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(Cc2cccc(OCc3ccccc3)c2C#N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl glyoxlate is added to a solution of 2-(4-amino-3-benzyloxybenzyl)-6-benzyloxybenzonitrile (0.281 g, 0.668 mmol), ACN (3 mL) and AcOH (1.5 mL) under N2. The mixture is stirred at ambient temperature for 2 h. The reaction is cooled in an ice bath and a slurry of sodium triacetoxyborohydride (0.284 g, 1.34 mmol) and ACN (1.5 mL) is added dropwise. Upon consumption of the starting material by LC/MS, the reaction is concentrated and the residue quenched with saturated NaHCO3 (2×10 mL). The mixture is extracted with DCM (40 mL) and the organics dried over Na2CO3. Evaporation affords [2-benzyloxy-4-(3-benzyloxy-2-cyanobenzyl)-phenylamino]-acetic acid ethyl ester as a green oil: MS (M+H)+=507.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]([O:37][CH3:38])=[O:36])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]([O:37][CH3:38])=[O:36])([CH3:34])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 97 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 104b (0.7 g, 1.23 mmol) was reacted trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.75 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C(#N)C>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[O:18])=[CH:22][CH:23]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccncc1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 60 °C

Procedure:
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.324 mmol) was added to a solution of 4-aminopyridine (0.036 g, 0.387 mmol) and pyridine (0.078 mL, 0.969 mmol) in acetonitrile (10 mL). The reaction mixture was heated at 60° C. for 12 h, concentrated and the crude product was purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid pyridine-4-ylamide. LCMS m/z=366.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:37][N:38]1[CH2:43][CH2:42]N[CH2:40][CH2:39]1>C1COCC1>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([N:18]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)N3CCN(C)CC3)cc21
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 1-methyl-piperazine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-3 as an oil in 95% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:21]1
Reactant: COc1ccc2c(c1CN1CCOCC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCOCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
A solution of 6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0877 g, 0.600 mmol) and piperidine (0.00425 g, 0.0500 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol), and the resulting crude product was crystallized from ethyl acetate. The precipitated solid was collected by filtration, and then suspended in acetonitrile and thereby washed to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0238 g). Further, the filtrate was concentrated, and the resulting residue was purified again by silica gel column chromatography (chloroform/methanol) to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0254 g) (0.0492 g, 25% in total).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:25]=[CH:24]3)[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]1.[Cl:34][C:35]1[CH:36]=[N+:37]([O-:60])[CH:38]=[C:39]([Cl:59])[C:40]=1[CH2:41][C@@H:42]([C:44]1[CH:49]=[CH:48][C:47]([O:50][CH:51]([F:53])[F:52])=[C:46]([O:54][CH2:55][CH:56]2[CH2:58][CH2:57]2)[CH:45]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[ClH:34].[Cl:34][C:35]1[CH:36]=[N+:37]([O-:60])[CH:38]=[C:39]([Cl:59])[C:40]=1[CH2:41][C@@H:42]([C:44]1[CH:49]=[CH:48][C:47]([O:50][CH:51]([F:53])[F:52])=[C:46]([O:54][CH2:55][CH:56]2[CH2:58][CH2:57]2)[CH:45]=1)[O:32][C:31](=[O:33])[CH2:30][N:26]1[C:27]2[C:23](=[CH:22][C:21]([N:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][O:8][CH2:9][CH2:10]3)[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(ccn2CC(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(ccn2CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of crude 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetic acid 2,2,2-trifluoroacetate (150 mg, 0.303 mmol) in DCM, (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (165 mg, 0.393 mmol), EDC (226 mg, 1.180 mmol) and DMAP (24.02 mg, 0.197 mmol) were added, and the resulting mixture was stirred overnight at room temperature. The solvent was removed, and the residue was purified by flash chromatography on silica gel (DCM/MeOH 95/5). The obtained compound was treated with 4N HCl in dioxane (30 ml) affording after evaporation of the volatiles (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide hydrochloride (76.3 mg, 0.093 mmol, 32% yield, MS/ESI+ 783.47 [MH]+, [αD]=−17.52, c=0.25 in DCM). 1H NMR (300 MHz, DMSO-d6+Na2CO3) δ ppm 8.50 (s, 2H), 7.34 (d, 1H), 7.07-7.23 (m, 5H), 6.89 (dd, 1H), 7.06 (t, 1H), 6.55 (d, 1H), 6.02 (dd, 1H), 5.25 (d, 1H), 5.10 (d, 1H), 3.91 (d, 2H), 3.77-3.85 (m, 2H), 3.46-3.52 (m, 4H), 3.39-3.47 (m, 1H), 3.16-3.25 (m, 1H), 3.09 (s, 3H), 2.30-2.36 (m, 2H), 2.24-2.31 (m, 4H), 1.10-1.24 (m, 1H), 0.52-0.67 (m, 2H), 0.23-0.47 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.P(Cl)(Cl)[Cl:12]>C(Cl)(Cl)Cl>[Cl:12][C:7]1[CH2:9][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:5])[CH:6]=1
Reactant: ClP(Cl)Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)C=C(Cl)C1
Temperature: 0 °C
Yield: 40 %

Procedure:
To 200 ml of a chloroform solution containing 100 g (0.71 mol) of dimedone was added 21 ml of phosphorus trichloride and the mixture was refluxed by heating for 3 hours. To the reaction solution was added ice water to terminate the reaction, the chloroform was distilled off under reduced pressure and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by distillation under reduced pressure to obtain 45 g of 3 -chloro-5,5-dimethyl-2-cyclohexene-1-one. Yield: 40%, Boiling Point: 95° C. at 18 mmHg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:22])[C:10]([C:13]2[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]([Cl:21])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH:3]=1.C(Cl)Cl>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:22])[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([Cl:21])[CH:14]=2)([CH3:11])[CH3:12])=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH:3]=1
Reactant: COc1cc(Cl)cc(C(C)(C)C(=O)N(C)c2cnc(Cl)cc2-c2ccccc2Cl)c1
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(O)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reaction time: 6 h
Yield: 65.7 %

Procedure:
To a solution of 1.10 g (2.37 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramide in 20 ml CH2Cl2 4.74 ml (4.74 mmol) BBr3 (1 M in CH2Cl2) was added at 0° C. The reaction mixture was allowed to reach ambient temperature and stirred for 6 h After addition of 50 ml water the mixture was extracted three times with 60 ml CH2Cl2. The combined organic solvents were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) to give 0.70 g (65%) of the title compound as a white foam.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:48])[CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([NH:21][C@H:22]([B:35]2[O:43]C3C(C)(C4CC(C3)C4(C)C)[O:36]2)[CH2:23][C:24]2[C:25](OC)=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([OH:29])=[O:28])=[O:20])[CH2:14][CH2:13]1)=O)(C)(C)C.Cl>>[NH2:8][C@@H:9]([CH3:48])[CH2:10][NH:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]([NH:21][C@H:22]2[CH2:23][C:24]3[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]=3[O:36][B:35]2[OH:43])=[O:20])[CH2:16][CH2:17]1
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](NC[C@H](C)NC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: Cl
Product: C[C@H](N)CN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
To 3-((2R)-2-(2-(trans-4-((S)-2-(tert-butoxycarbonylamino)propylamino)cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoic acid from Step 2 in a flask was added 3N aqueous HCl and the reaction mixture was stirred at refluxing for 1 hr. The product was purified using reverse phase HPLC and dried using lyophilization. ESI-MS m/z 409 (MH)+.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCCCCCC.C(OCC)(=O)C>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(=O)N(CCCCCCO[Si](C)(C)C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N(CCCCCCO)C(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 2g of 16e in 20 ml of THF was treated with 11 ml of 1M tetra-n-butyl ammonium fluoride in THF at 55° C. After stirring for 1 hr the mixture was concentrated, diluted with 50 ml of 5% aq. NH4Cl and 10 ml of sat. NaCl and extracted with ethyl acetate. The organic layer was concentrated to give an oil. This was passed trough a silica pad using a gradient of heptane/ethyl acetate as eluent, to provide 1.5 g of 16f as a colorless oil, which was used without further purification in the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.Br[CH2:26][CH2:27][CH2:28][Cl:29].C(OCC)C>CN(C)C=O>[Cl:29][CH2:28][CH2:27][CH2:26][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:17][CH2:18][CH2:19][O:20]3)[CH2:15][CH2:14]2)=[CH:23][CH:24]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(CC2CCC3(CC2)OCCO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(CC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of potassium carbonate 3.92 g) in a solution of 8-(4-hydroxybenzyl)-1,4-dioxaspiro[4.5]decane (1.41 g) and 1-bromo-3-chloropropane (2.81 mL) in N,N-dimethylformamide (35 mL) is stirred for 20 h at room temperature. Diethyl oxide (210 mL) is added and the suspension is filtered. The filtrate is washed with water (twice 50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 1.635 g of 8-[4-(3-chloropropoxy)benzyl]-1,4-dioxaspiro[4.5]-decane used without further purification.