Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH2:40])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.C(OC([N:55]1[CH2:60][CH2:59][N:58]([C:61](=[O:68])[C:62]([C:65](O)=[O:66])([CH3:64])[CH3:63])[CH2:57][CH2:56]1)=O)C1C=CC=CC=1.C(OC(NCC(O)=O)=O)C1C=CC=CC=1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:65](=[O:66])[C:62]([CH3:63])([C:61]([N:58]4[CH2:59][CH2:60][NH:55][CH2:56][CH2:57]4)=[O:68])[CH3:64])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(C)(C(=O)O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(O)CNC(=O)OCc1ccccc1
Product: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCNCC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 13 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 1-benzyloxycarbonyl-4-[2-carboxy-2-(methyl)propionyl]piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-benzyloxycarbonylaminoacetic acid, respectively.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)=[CH:3][CH:4]=2)[NH:8]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2ccc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)cc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.5 %

Procedure:
6-bromoindolin-2-one (25.2 mg, 0.119 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (72.1 mg, 0.190 mmol), Fibercat palladium catalyst (Johnson-Matthey, 35.4 mg), and K2CO3 (2 M in water, 0.25 ml, 0.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with dichloromethane (3×10 ml) and EtOAc (6×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (7.1 mg, 16%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[OH:20].C([O-])([O-])=O.[Na+].[Na+].CC(O)=O>N1C=CC=CC=1.O>[OH:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccncc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C(Nc1ccncc1O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A solution of p-nitrobenzoyl chloride (4.8 g, 25.7 mmol) in pyridine (50 mL) was added to a solution of 4-amino-3-hydroxypyridine (2.5 g, 22.7 mmol) in pyridine (88 mL) at 10° C. and stirred at room temperature overnight. To the reaction mixture was added Na2CO3 (1.1 g, 10.4 mmol) in water (10 mL) and stirred for 1 hrs. 10% AcOH was added to neutralize the solution. The precipitate was collected by filtration, washed with 10% AcOH and dried to give N-(3-hydroxypyridin-4-yl)-4-nitrobenzamide as a yellow powder (2.27 g, yield: 52%). MS(ESI) calcd. for C12H9N3O4 (m/z): 259, found: 260 [M+H]+.
Reaction SMILES: Br[C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH3:26][CH:27]([C:29]1[CH:34]=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)[CH:30]=1)C.C(=O)([O-])[O-:61].[Cs+].[Cs+].CC(C)C#CO>C(#N)C.CC#N.CC#N.Cl[Pd]Cl.O>[OH:61][C:29]([CH3:34])([CH3:30])[C:27]#[C:26][C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: COc1cc2c(cc1Br)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: CC(C)C#CO
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1C#CC(C)(C)O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 85 °C
Reaction time: 2 h
Yield: 281.6 %

Procedure:
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 50 mg, 0.13 mmol), bis(acetonitrile)dichloropalladium (II) (1.64 mg, 0.05 eq.), XPhos (9.05 mg, 0.15 eq.), cesium carbonate (185 mg, 4.5 eq.) and 3-methyl-1-butyn-1-ol (18.6 μl, 1.5 eq.) were dissolved in acetonitrile and stirred at 85° C. for 2 hr. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by HPLC to obtain the title compound (brown solid, 21.3 mg, 42%).
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C)C=O.[CH3:9][O:10][C:11]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[C:26]([CH3:34])[C:12]=1[C:13]([C:15]1[C:16](Cl)=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])=[O:14].O>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[C:26]([CH3:34])[C:12]=1[C:13]([C:15]1[C:16]([S:2][CH3:1])=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])=[O:14]
Reactant: C[S-]
Reactant: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2Cl)c(OC)c1OC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2SC)c(OC)c1OC
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Sodium methanethiolate (0.32 g) was added to a dimethylformamide (15 ml) solution of 0.9 g of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-chloro-4-trifluoromethylpyridine (compound No. 11) at room temperature, followed by stirring for 1 hour. The mixture was poured into water (50 ml), and extraction with ethyl acetate was carried out. The ethyl acetate phase was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 0.54 g (yield 58%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-methylthio-4-trifluoromethylpyridine (compound No. 50; pale yellow oily substance), and its structure was confirmed by nuclear magnetic resonance spectrum.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([NH2:29])[CH2:6][C:7]1[CH:8]=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)C.[OH-].[Na+]>O1CCCC1>[NH2:29][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(N)Cc1cc(CP(=O)(OCC)OCC)cc(-c2ccc(Cl)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cc(CC(N)C(=O)O)cc(-c2ccc(Cl)cc2)c1)OCC

Procedure:
4.6 g (±)-α-amino-3-(4'-chloro-5-(diethoxyphosphinyl)methyl [1.1'-biphenyl]-3-yl) propanoic acid ethyl ester, 1 equivalent of 1N sodium hydroxide and 4 parts by volume of tetrahydrofuran are stirred at room temperature for about 15 hours. The tetrahydrofuran is evaporated in vacuo. The residue is extracted with toluene/diethyl ether (1:1). The pH of the aqueous layer is adjusted to 5, whereby the heading compound crystallizes, m.p. 195°-205° (decomp.).
Reaction SMILES: [CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH2:22][OH:23])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26]N(C=O)C.[H-].[Na+].CI>O>[CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH2:22][O:23][CH3:26])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc(CN2CCOC[C@@H]2CO)c2cc(C3CCCCC3)sc2n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC[C@H]1COCCN1Cc1nc(C)nc2sc(C3CCCCC3)cc12
Reaction time: 0.08 h

Procedure:
To a mixture of {(3S)-4-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]morpholin-3-yl}methanol (132 mg) and DMF was added NaH (60% oil, 15 mg) under ice-cooling, followed by stirring at the same temperature for 5 minutes, and then CH3I (17 μL) was added thereto, followed by stirring at the same temperature for 30 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, then dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-4-{[(3S)-3-(methoxymethyl)morpholin-4-yl]methyl}-2-methylthieno[2,3-d]pyrimidine (102 mg).
Reaction SMILES: CO[C:3]1[C:4](=O)[NH:5][CH:6]=[CH:7][CH:8]=1.Cl.Cl.[CH:12]1([NH:17][NH2:18])CCCC1.[O:19]1CCCC1>>[N:18]1[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]=2[C:12](=[O:19])[N:17]=1
Reactant: C1CCOC1
Reactant: COc1ccc[nH]c1=O
Reactant: NNC1CCCC1
Agent: Cl
Product: O=C1N=Nc2cccnc21
Temperature: 88 °C

Procedure:
treating said 3-methoxy-pyridinone compound of Formula (7.0.0) with cyclopentylhydrazine dihydrochioride; wherein a reaction mixture is established with tetrahydrofuran (THF) solvent and heating of said reaction mixture to 88° C., for 12 hours, while said reaction mixture is being swept by nitrogen in order to remove methanol, THF, and HCl; whereby there is produced a pyrazolopyridinone compound N-protected by p-methoxybenzyl, of Formula (8.0.0):
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH2:21][OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([CH:21]=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCC(CO)CCc1ccc(C#N)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCC(C=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
A solution of 4 g (13.18 mmol) of ethyl 8-(4-cyanophenyl)-6-hydroxymethyloctanoate from Example 85A in 100 ml of dichloromethane is mixed with 3.41 g (15.82 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 12 hours. After conversion is complete, the solvent is concentrated to dryness in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 2.74 g (9.09 mmol, 69% yield) of a colorless solid are obtained.
Reaction SMILES: C([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: NS(=O)(=O)c1nc2ccc(O)cc2s1

Procedure:
A stirred mixture of 6-ethoxy-2-benzothiazolesulfonamide (20g.) and aluminum chloride (40 g.) in heptane (500 ml) was heated at reflux for 4 hours and cooled. The heptane was decanted from the reaction mixture which was then treated with ice water (500 ml.). After 1/2 hour the crude product was filtered, dissolved in warm dilute sodium hydroxide, filtered and acidified with concentrated hydrochloric acid to give 7.5 g. of 6-hydroxy-2-benzothiazolesulfonamide which melts at 225°-228° C. after recrystallization from acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)ncc1Cl
Reactant: BrCC1CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Clc1cc(OCC2CCC2)c(Cl)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 49.9 %

Procedure:
To a solution of 2,5-dichloro-4-pyridinol (CAN 847664-65-7, 660 mg, 4.02 mmol) in THF (20 mL) and DMF (20 mL) was added with stirring sodium tert-butoxide (1.16 g, 12.1 mmol) and (bromomethyl)-cyclobutane (CAN 17247-58-4, 2.26 mL, 20.1 mmol). The resulting mixture was stirred at 80° C. for 20 h, cooled and concentrated. The residue was partitioned between water and ethyl acetate; the organic portions were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to give the title compound (466 mg, 50%) as white solid. LC-MS (UV peak area, m/z) 97.8%, 232.0293 (MH+).
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=O>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH2:17][CH2:18][N:20]([CH2:21][CH3:22])[CH2:23][CH3:24]
Reactant: CCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: B
Solvent: C1CCOC1
Product: CCN(CC)CCc1ccc([N+](=O)[O-])cc1Cl
Reaction time: 4 h

Procedure:
65.0 mL (65.0 mmol) of a 1M borane-THF solution is added dropwise at ambient temperature to a solution of 3.70 g (13.7 mmol) 2-(2-chloro-4-nitrophenyl)-N,N-diethylacetamide (VI.1.b) in 130 mL of THF and the mixture is stirred for 4 hours. Then the reaction mixture is evaporated down and the residue is combined with 15 mL of methanol and 15 mL of dilute hydrochloric acid. The mixture is then stirred for 15 minutes at 100° C., cooled, and diluted with water. Then the mixture is made alkaline with sodium carbonate solution and extracted twice with ethyl acetate. The combined organic phases are extracted twice with water and once with saturated saline solution and dried over sodium sulfate. The purification is carried out by column chromatography on Alox (neutral, activity II-III) with petroleum ether/ethyl acetate (4:1) as eluant. Yield: 2.10 g (60% of theory); Rf value: 0.65 (Alox, petroleum ether/ethyl acetate=3:1); C12H17ClN2O2.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(#N)C.O1CCOCC1.O>[F:29][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[C:20]([C:18]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[C:11]([NH:10][C:8]([C:6]3[N:7]=[C:3]([CH2:2][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[S:4][CH:5]=3)=[O:9])[CH:19]=2)[CH:28]=1
Reactant: C1CCNCC1
Reactant: O=C(Nc1cc(-c2cc(F)cc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1cc(-c2cc(F)cc3[nH]ccc23)cc2[nH]ncc12)c1csc(CN2CCCCC2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
To a suspension of 2-(chloromethyl)-N-[6-(6-fluoro-1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.088 mmol) in acetonitrile (2 ml) was added piperidine (0.02 ml, 0.18 mmol) and the mixture was heated to 80° C. for 2 hours. Further piperidine (0.02 ml, 0.18 mmol) was added and heating was continued at 80° C. for 30 mins. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in MeOH and 2M aqueous NaOH (5 ml, 1:1, v.v) and stirred at room temperature for 1 hour, then neutralised with 2M aqueous HCl to ˜pH=5 and extracted with DCM (3×5 ml). The extracts were combined and the solvent removed under a stream of nitrogen. The residue was taken up again in MeOH and 2M aqueous NaOH (5 ml, 1:1, v/v) and stirred at room temperature for 3 hours. The mixture was neutralised with 2M aqueous HCl to ˜pH=7 and the MeOH was blown off under a stream of nitrogen. A precipitate was observed which was collected by filtration, then dissolved in 1 ml DMSO/MeOH (1:1) and purified by MDAP (Method B). The product-containing fractions were blown down under a stream of nitrogen to give a clear oil which was dissolved in dioxane/water (2 ml, 1:1, v/v) and freeze dried to give the title compound as a white solid (10 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:31])([CH3:30])[C@@H:14]([O:22]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:30])([CH3:31])[C@@H:14]([OH:22])[C:15]([O:17][CH2:18][CH:19]([CH3:20])[CH3:21])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCC(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCC(C)C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of 2-methylpropyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate acid (30c) (0.43 g, 0.94 mmol) and 400 mg of 10 wt-% palladium on activated carbon in 10 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC and lyophilization of the solvents, 200 mg (58% yield) of the title compound (30) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=0.96-1.00 (m, 9H), 1.16 (s, 3H), 1.96-2.05 (m, 4H), 2.05-2.14 (m, 2H), 3.13-3.26 (m, 2H), 3.27 (d, J=6.4 Hz, 1H), 3.33-3.49 (m, 2H), 3.97 (d, J=8.8 Hz, 1H), 3.98 (d, J=6.4 Hz, 1H), 3.99-4.03 (m, 1H), 4.03-4.07 (m, 1H), 4.18 (d, J=8.8 Hz, 1H), 5.88-5.94 (br. m, 1H) ppm. MS (ESI) m/z: 368.16 (M+H)+, 366.19 (M−H)−. The analytical data was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)=[C:4]([F:18])[CH:3]=1.[NH2:19][C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:22](Cl)[N:21]=1>>[NH2:19][C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:22]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[CH:10]4)=[C:4]([F:18])[CH:3]=2)[N:21]=1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Product: COC(=O)c1cc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)nc(N)n1

Procedure:
Analogously to example 53, the title compound is synthesized from 1.01 g (4.05 mmol) of 5-(4-amino-2-fluorophenoxy)-1H-indazole (from example XII) and 0.84 g (4.06 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]=1[CH:11]=O)=[O:5])[CH3:2].O.[NH2:28][NH2:29]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:10]=1[CH:11]=[N:28][NH2:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=O
Reactant: NN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=NN
Temperature: 25 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-formyl-1H-imidazole-4-carboxylic acid ethyl ester (I-2e, 102 mg, 0.26 mmol), aqueous hydrazine hydrate (50% solution, 0.6 mmol) and glacial acetic acid (1 drop) was heated under reflux in toluene (3 ml) for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between CH2Cl2 and sat'd aq. NaHCO3. The organic solution was dried and concentrated in vacuo. Purification using 2 mm chromatotron plates and a solvent gradient of 1:1 EtOAc/hexanes to 100% EtOAc provided the desired product I-2f (Rf=0.8, 100% EtOAc, 62 mg): +APCI MS (M+1) 403.1; 1H NMR (CD2Cl2) δ 1.40 (3H, t), 4.37 (2H, q), 5.60 (2H, br s), 7.10–7.14 (2H, m), 7.21–7.25 (3H, m), 7.29–7.33 (3H, m), 8.40 (1H, s).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:22]2[CH2:24][CH:23]2[C:25]#[N:26])(O)[CH3:20])=[CH:15][CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38][CH3:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:22]2[CH2:24][CH:23]2[C:25]#[N:26])([C:31]2[C:30]3[C:34](=[C:35]([CH2:37][S:38][CH3:39])[CH:36]=[C:28]([F:27])[CH:29]=3)[NH:33][CH:32]=2)[CH3:20])=[CH:15][CH:14]=1
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1C#N
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cc(F)cc2c(C(C)(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12

Procedure:
367 mg (1.66 mmol) of indium(III) chloride and 0.12 ml (1.58 mmol) of trifluoroacetic acid were added to 350 mg (1.58 mmol) of the compound from Example 75A and 308 mg (1.58 mmol) of the compound from Example 11A in 9 ml of dichloromethane at RT, and the mixture was heated under reflux for 15 min. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 32.5 mg (5% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:15]=[C:16]=[O:17])=[C:4]([F:18])[CH:3]=1.C[Si]([N:23]=[N+:24]=[N-:25])(C)C>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][C:5]([N:15]2[C:16](=[O:17])[NH:25][N:24]=[N:23]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C=Nc1cc(Oc2ncccn2)c(Cl)cc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: O=c1[nH]nnn1-c1cc(Oc2ncccn2)c(Cl)cc1F

Procedure:
4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenylisocyanate (0.96 g) and trimethylsilyl azide (5 ml) were heated at reflux overnight under nitrogen. The reaction mixture was processed and the resulting oil chromatographed on silica gel eluting with ethyl acetate:methylene chloride, 1:4, to give a yellow semi-solid (0.54 g). 1H NMR (CDCl3, TMS): 7.16(1H, dd, J=4.8 Hz), 7.49(1H, d, J=9.3 Hz), 7.64(1H, d, J=6.8 Hz), 8.59(2H, d, J=4.8 Hz).