Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(O)[C:20]2[CH:19]=[C:18]([Br:21])[CH:17]=[CH:16][C:15]=2[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(O)[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.[I-].[K+].O.[PH2](=O)[O-].[Na+].[PH2](=O)O>C(O)(=O)C>[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[C:13]([C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:15]3[C:20]=1[CH:19]=[C:18]([Br:21])[CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: OC1(c2ccccc2-c2ccccc2)c2ccccc2C(O)(c2ccccc2-c2ccccc2)c2cc(Br)ccc21
Agent: O=[PH2]O
Agent: O=[PH2][O-]
Agent: [I-]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2c(-c3ccccc3-c3ccccc3)c3ccccc3c(-c3ccccc3-c3ccccc3)c2c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
18.32 g (30.66 mmol) of the obtained 9,10-di(2-biphenylyl)-2-bromo-9,10-dihydroanthracene-9,10-diol, 9.16 g (55.19 mmol) of potassium iodide, 17.55 g (165.56 mmol) of sodium phosphinate monohydrate, and 150 mL of glacial acetic acid were put into a three-neck flask, and the mixture was stirred for 5 hours at 120° C. Thereafter, 100 mL of 50% phosphinic acid was added to the mixture, followed by stirring for 1 hour at 120° C. After the reaction, the solution was washed with water, and the precipitate was filtered, recrystallized with chloroform and hexane, obtaining 11.4 g of 9,10-di(2-biphenylyl)-2-bromoanthracene as a light yellow solid in 66% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]1([CH3:21])C=CC=C[CH:16]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>[Cl:1][C:2]1[CH:7]=[C:6]([CH:21]2[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Product: Clc1cc(C2CC2)ncn1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4,6-dichloropyrimidine (200 mg, 1.342 mmol) in toluene (5.00 mL) in a 2 mL microwave vial was added potassium cyclopropyl(trifluoro)borate (219 mg, 1.477 mmol) (Frontier Scientific Inc.), di(1-adamantyl)-n-butylphosphine (14.44 mg, 0.040 mmol), palladium(II) acetate (6.03 mg, 0.027 mmol) and cesium carbonate (1312 mg, 4.03 mmol) and stirred under argon at 100° C. for 24 hrs in a microwave reactor. The reaction mixture was washed with water (50 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were collected, dried (MgSO4) and evaporated to dryness in vacuo to afford a crude residue. Crude residues were then purified on Biotage Isolera Four (25 g pre-packed cartridge) eluting with 0-15% ethyl acetate-isohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (80 mg).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@:27]1([CH3:60])[CH2:36][C@@H:35]2[N:30]([C:31](=[O:52])/[C:32](=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)/[CH2:33][CH2:34]2)[C@H:29]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)[CH2:28]1)(C(C)(C)C)(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[F:59][C:56]1[CH:57]=[CH:58][C:53]([C@@H:29]2[CH2:28][C@@:27]([OH:26])([CH3:60])[CH2:36][C@@H:35]3[N:30]2[C:31](=[O:52])/[C:32](=[CH:37]/[C:38]2[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=2)/[CH2:33][CH2:34]3)=[CH:54][CH:55]=1
Reactant: COc1cc(/C=C2\CC[C@@H]3C[C@@](C)(O[Si](C)(C)C(C)(C)C)C[C@@H](c4ccc(F)cc4)N3C2=O)ccc1-n1cnc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@@H]3C[C@@](C)(O)C[C@@H](c4ccc(F)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
TBAF (1.0 M solution in THF, 404 μL) was added to a solution of (E)-(6S*,8R*,9aR*)-8-(tert-butyldimethylsilanyloxy)-6-(4-fluorophenyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-8-methyloctahydroquinolizin-4-one (102 mg) in THF (2.0 mL), and the reaction solution was stirred at room temperature overnight. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 66.4 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:47])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][C@@H:24]2[C@@H:28]([S:29][CH2:30][C:31]([OH:38])([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:27]([O:39]C3CCCCO3)[CH2:26][CH:25]2[OH:46])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1C=CC(OC(=O)C([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CCC)=CC=1)(=O)C1C=CC=CC=1.[H-].[Na+].C(O)(=O)C>O.C1COCC1>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:47])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][C@@H:24]2[C@@H:28]([S:29][CH2:30][C:31]([OH:38])([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:27]([OH:39])[CH2:26][CH:25]2[OH:46])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(C)(O)CS[C@H]1C(OC2CCCCO2)CC(O)[C@@H]1CC=CCCCC(=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Agent: CCCC(C(=O)Oc1ccc(NC(=O)c2ccccc2)cc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(C)(O)CS[C@H]1C(O)CC(O)[C@@H]1CC=CCCCC(=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
0.25 g. of 9,15-dihydroxy-15-methyl-11-tetrahydropyranyloxy-13-thia-5-prostenoic acid p-benzoylaminophenyl ester (obtainable by the reaction of 2-(2-hydroxy-2-methylheptylthio)-5-hydroxy-3-tetrahydropyranyloxy-acetaldehyde lactol with triphenylphosphoniopentanoic acid p-benzoylaminophenyl ester in the presence of 2 moles of NaH) is stirred for 5 hours at 45° C. in 7 ml. of a mixture of acetic acid, THF and water (3:1:1). The solvent is distilled off, and after chromatographic purification of the residue (silica gel/ethyl acetate), 9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid p-benzoylaminophenyl ester is obtained.
Reaction SMILES: [C:1]1([C:7](=[O:19])[C:8]([O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([Mg]Br)#[CH:21].[Mg].C(Br)C.C#C.[Cl-].[NH4+]>O.C1COCC1>[C:20]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:19])[C:8]([O:10][CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:9])#[CH:21]
Reactant: C#C[Mg]Br
Reactant: O=C(OC1CN2CCC1CC2)C(=O)c1ccccc1
Agent: C#C
Agent: [Cl-]
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)(C(=O)OC1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
The above ester (13.0 g., 0.5 mole) was dissolved in 500 ml. of THF, cooled to 5° in an ice bath and treated, dropwise with a THF solution of ethynylmagnesium bromide prepared by known procedures from magnesium (1.3 g., 0.055 g. atom), ethyl bromide (5.5 g., 0.05 mole) and excess acetylene. The reaction mixture was stirred at room temperature for 23 hours, and then poured onto 100 ml. of cold water containing 20 g. of ammonium chloride. The mixture was extracted with ether and then with chloroform. The organic extracts were combined, dried and subsequently stripped of volatile components in vacuo to yield 12.0 g. of oil. The product (3.6 g., 25%) was precipitated from the oil by the addition of ether, and melted at 154°-156° C. after recrystallization from hexane. N.m.r. spectroscopy verified the structural assignments.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:3]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[C:28]([Si:25]([CH3:27])([CH3:26])[O:18][C:16]([CH3:19])([CH3:17])[CH2:15][O:14][C:4]1[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=[C:2]([NH2:1])[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(O)COc1cc(N)nc(N2CCOCC2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(COc1cc(N)nc(N2CCOCC2)n1)O[Si](C)(C)C(C)(C)C
Reaction time: 72 h
Yield: 34.4 %

Procedure:
1-(6-amino-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol (1.03 g; 3.8 mmol) and imidazole (500 mg; 8 mmol) were-dissolved in dimethyl formamide (16 mL). To this solution was added tert-butyldimethylsilyl chloride (1.2 g; 8 mmol), and it was stirred for 72 hours. The solution was poured into ethyl acetate (100 mL) which was then washed with water (3×200 mL). The organic layer was separated, dried over magnesium sulfate, and purified by column chromatography to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-2-methyl-propoxy]-2-morpholin-4-yl-pyrimidin-4-ylamine (500 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4](I)[CH:3]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16](B(O)O)[CH:17]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH:3]=1
Reactant: Cc1ccc(F)cc1B(O)O
Reactant: CNc1cnc(Cl)cc1I
Product: CNc1cnc(Cl)cc1-c1cc(F)ccc1C

Procedure:
The title compound was prepared in analogy to example 72, from 6-chloro-4-iodo-N-methylpyridin-3-amine (prepared according to WO2006013050) and 5-fluoro-2-methylphenylboronic acid after heating at reflux for 21 hours. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (85%). MS (ESI): m/z=251.08 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13]C(C#N)=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:4]=[CH:5][N:6]=1.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:21]([C:20]([OH:23])=[O:22])=[CH:9][C:8]=2[C:15]([F:18])([F:16])[F:17])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(C#N)cc1C(F)(F)F
Reactant: CC(=O)O
Agent: Cl
Product: Cc1nccn1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzonitrile (1.01 g, 4 mmol), 6 mL of acetic acid and 3 mL of 12M hydrochloric acid (37%) is shaken for 16 hours at 95° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The resulting residue is evaporated twice with toluene, dissolved in water and the pH is adjusted to ˜5-6 by dropwise addition of 1M sodium hydroxide solution. The aqueous phase is extracted twice with n-butanol and the organic phase evaporated to yield the title compound as a beige solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:27]1([C@@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([CH2:8][C:9]([NH:35][C@H:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[O:11])[CH2:6][CH2:7]1
Reactant: O=C(O)CC1CCC(=O)CC1
Reactant: C[C@H](N)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)CC1CCC(=O)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 143.2 %

Procedure:
A solution of 4-oxocyclohexaneacetic acid (28.39 g) (Example H) and triethylamine (30.4 ml) in 800 ml of dichloromethane at -10° C. is treated dropwise with isobutyl chloroformate (26.0 ml). The reaction mixture is stirred at this temperature for 15 minutes and 1(S)-phenylethylamine (26.51 g) is added via syringe. After 30 minutes at -10° C., the mixture is stirred at room temperature for another 30 minutes. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (1000 ml) and 1 N hydrochloric acid solution (400 ml). The organic extract is washed with 1 N sodium hydroxide solution and brine, dried (magnesium sulfate), and concentrated in vacuo to leave 67.5 g of crude (S)-4-oxo-N-(1-phenylethyl)cyclohexaneacetamide as a white solid; mp 110°-151° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([I:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])C.[OH-].[Na+].Cl.O>O1CCOCC1>[Cl:12][C:10]1[CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]2[C:15]([I:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 73.6 %

Procedure:
To a solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (25 g, 57 mmol) in 1,4-dioxane (200 mL) was added an aqueous sodium hyroxide solution (1M, 180 mL). The reaction mixture was stirred at room temperature for 7 hours and then an aqueous HCl solution (1M, 200 mL) was carefully added. Water (140 mL) was added, and after 5 minutes of stirring the precipitate was filtered, washed with water, cyclohexane and then dried to afford the title compound as a yellow solid (17.1 g, 73%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].Cl.[NH2:17][CH2:18][C:19]([NH:21][C@H:22]([C:31]([NH2:33])=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)=[O:20].C(Cl)CCl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:33][C:31](=[O:32])[C@@H:22]([NH:21][C:19](=[O:20])[CH2:18][NH:17][C:10](=[O:12])[CH:9]([NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[CH:13]([CH3:15])[CH3:14])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1
Reactant: CC(C)[C@H](Nc1ncc(C=O)s1)C(=O)O
Reactant: NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(Nc1ncc(C=O)s1)C(=O)NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Yield: 114.6 %

Procedure:
Following the procedure described in Example 4, except using the material from Example 20 (77 mg, 0.169 mmol), glycyl-L-tyrosinamide hydrochloride (159.5 mg, 0.583 mmol), EDC (190.3 mg, 0.993 mmol), 1-hydroxy-7-azabenzotriazole (29 mg, 0.213 mmol), anhydrous DMF (4 mL) and N-methylmorpholine (350 μL, 3.18 mmol), 86.7 mg (41%) of the title compound is obtained as an orange solid as a TFA salt. Purification is done by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 15% Solvent B to 85% Solvent B over 11 min, ret, T=6.82-6.69 min. LC/MS (Condition A): ret. T=2.11-2.18 min, (M+H)+ 448.18.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cccs2)nc1

Procedure:
A solution of 2.0 g of (methyl 6-hydroxypyridine-3-carboxylate, o-triflate) and 5.23 g of 2-(tributylstannyl)thiophene in 50 ml of dry toluene is stirred under nitrogen at reflux for 16 hours in the presence of tetrakis(triphenylphosphine)palladium(O). The reaction mixture is diluted with 50 ml of chloroform and filtered through a pad of diatomaceous earth. The filtrate is evaporated in vacuo to a residue which is extracted and decanted (2×100 ml) with 1:1 ether:petroleum ether. The combined extracts are evaporated in vacuo to give 1.6 g of the desired product as a residue.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH:21]=2)[N:17]=[C:16]2[N:33]([CH:36]([CH3:38])[CH3:37])[N:34]=[CH:35][C:15]=12)=[O:13]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.8 g, 5.4 mmol) in DCM (15 mL), TFA (13 mL) was added at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and residue neutralized with saturated NaHCO3 solution Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure, finally the residue was washed with diethyl ether to provide the desired intermediate (1.5 g, 66.4%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:34][C@H]1CC[C@H](O)[C@@H](C2N(COCCOC)N=CC=2)C1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>CN(C1C=CN=CC=1)C.ClC(Cl)C.O>[C:27]([O:15][C@H:13]1[CH2:14][C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11][C@@H:12]1[C:16]1[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[CH:18][CH:17]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COCCOCn1nccc1[C@H]1CC[C@@H](OCc2ccccc2)C[C@@H]1O
Reactant: COCCOCn1nccc1[C@H]1C[C@@H](OCc2ccccc2)CC[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COCCOCn1nccc1[C@H]1CC[C@@H](OCc2ccccc2)C[C@@H]1OC(=O)c1ccccc1
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of the mixture (2.99 g, 8.30 mmol) of (1S*,2R*,5R*)-5-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol and (1S*,2R*,4S*)-4-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol prepared in Example 155b, triethylamine (4.62 mL, 33.2 mmol), 4-(N,N-dimethylamino)pyridine (203 mg, 1.66 mmol) in dichloroethane (30 mL), and benzoyl chloride (1.93 mL, 16.6 mmol) was added, and the reaction solution was stirred for 5 hours under heated reflux. To the reaction solution, water (100 mL) was added, and an organic layer was extracted and then dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (hexane/ethyl acetate=1:9) to yield the title compound (2.72 g, 71%) as a mixture (2.72 g, 71%) with (1R*,2R*,4S*)-4-(benzyloxy)-2-[(1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexyl benzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1.[C:20]([C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C.O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 1.58 h
Yield: 26.4 %

Procedure:
To a solution of (4-(pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (510 mg, 1.84 mmol) described in Manufacturing Example 2-1-5 and 3-ethynyl-pyridin-2-ylamine (150 mg, 1.27 mmol) described in Manufacturing Example 1-2-3 in tetrahydrofuran (5 mL) was added triethylamine (708 μL, 5.08 mmol) at room temperature, which was stirred for 95 minutes at room temperature. Water was added at room temperature to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (120 mg, 26%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[N:5](C(=O)C(F)(F)F)[CH2:4]1.C(Cl)Cl.[CH2:32]([CH2:34][NH2:35])[OH:33].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CO.O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:35][CH2:34][CH2:32][OH:33])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: NCCO
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(c3ccc(S(=O)(=O)NCCO)cc13)C(CCl)CN2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
(Scheme C). A solution of 116 (456 mg, 1.00 mmol) in TV (5 mL) and CH2Cl2 (5 mL) was treated at 0° C. with a solution of ethanolamine (134 mg, 2.19 mmol) in THF (0.5 mL). The mixture was stirred at 0° C. for 5 min, then warmed to room temperature for 10 min and treated with a solution of Cs2CO3 (980 mg, 3 mmol) in MeOH (20 mL). After stirring at room temperature for a further 10 min, the mixture was diluted with water and extracted with EtOAc (×2). The combined organic layers were washed with water (×2), dried, filtered through a short column of silica gel, and then concentrated to a small volume and diluted with i-Pr2O/hexane to give 1-(chloromethyl)-N-(2-hydroxyethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-7-sulfonamide (121) (346 mg, 90%): mp 173-174° C.; 1H NMR [(CD3)2SO] δ 8.57 (d, J=1.6 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 7.80 (dd, J=8.9, 1.7 Hz, 1H), 7.77 (s, 1H), 7.69 (br s, 1H), 6.73 (s, 1H), 4.64 (t, J=5.6 Hz, 1H), 4.29-4.19 (m, 1H), 3.95-3.84 (m, 2H), 3.80 (dd, J=11.0, 8.4 Hz, 1H), 3.74 (dd, J=10.4, 3.3 Hz, 1H), 3.35 (after D2O exchange, t, J=6.3 Hz, 2H), 2.81 (t, J=6.3 Hz, 2H). Anal. (C15H16C11N3O5S) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[O:15]([CH2:22][C:23](=O)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:23]([CH3:24])[CH2:22][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)COc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)COc1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-phenoxy-propan-2-one.