Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]=[C:31]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=4[Cl:1])[C:6]=3[CH:14]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)CC1
Yield: 35 %

Procedure:
1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as in General Procedure 4A to give the title compound as a beige solid (35% yield). M.p. 92-95° C., LCMS: m/z=477.28 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 2.32-2.38 (m, 2H), 3.39-3.46 (m, 2H), 3.52-3.59 (m, 2H), 3.60-3.65 (m, 2H), 3.95-3.99 (m, 2H), 4.43 (s, 2H), 5.18 (s, 1H), 5.69-5.72 (m, 1H), 6.43 (s, 1H), 7.17-7.20 (m, 1H), 7.23 (s, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.50 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21]Br)=[O:5])[CH3:2].[CH2:23]([O:25][C:26](=[O:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:24].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
A mixture of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.05 g, 2.67 mmol), tert-butoxycarbonylamino-acetic acid ethyl ester (540 mg, 2.66 mmol) and sodium hydride (60% in mineral oil, 128 mg, 3.2 mmol) in anhydrous dimethylformamide (10 mL) was stirred at 0° C. for two hours and room temperature for half an hour before it was quenched with brine. The mixture was filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (319 mg): MS: (+) m/z 538.9 (M+Na+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([CH3:14])([CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[N:6]1>[C].[Pd].C(O)C.C(OCC)(=O)C>[CH3:1][N:2]([CH3:15])[C:3]([CH3:13])([CH3:14])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1
Reactant: CN(C)C(C)(C)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C(C)(C)Cn1ccc(N)n1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
N,N,2-trimethyl-1-(3-nitro-1H-pyrazol-1-yl)propan-2-amine (70.6 mg) was dissolved in a mixed solution (ethanol-ethyl acetate, 4:1, 5 mL). Then, 10% palladium-carbon (7 mg) was added to the prepared solution, and the solution was subjected to catalytic reduction at 101 kPa for about 2 hours. The reaction mixture was filtrated through Celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel NH, ethyl acetate:hexane=1:1) to give the title compound as a yellow oil (56.8 mg, yield: 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]([CH2:8][O:9]CC1C=CC=CC=1)=[O:7])[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]([CH2:8][OH:9])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CCOC(=O)CC(=O)CO
Reaction time: 2 h
Yield: 102 %

Procedure:
21.24 g of the 4-benzyloxyacetoacetic ethyl ester dissolved in acetic ester (100 ml) was inserted into a 200 ml steel autoclave provided with a magnetic stirrer and was hydrogenolized in the presence of 1.05 g Pd 5 percent on coal with hydrogen with a pressure of 5 atm. After the reaction was completed, which amounted to a period of about 2 hours, and after a 2 hour post-reaction time, the catalyst was filtered out. The filtrate was evaporated on a vacuum rotation evaporator at 35° C. The residue was dried in the high vacuum. 13.4 g of 4-hydroxyacetoacetic ethyl ester in the form of a slightly yellowish oil resulted.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccc(C=O)cc2)c1
Temperature: 90 °C
Yield: 100 %

Procedure:
To a solution of p-fluorobenzaldehyde (1.6 mmol, 0.2 g) in dimethylformamide (8 mLs) was added 3-methoxyphenol (3.52 mmol, 0.437 g) and cesium carbonate (3.52 mmol, 1.15 g). The reaction was heated to 90° C. for 3 hours at which time it was cooled to room temperature and filtered through a fritted funnel. The reaction mixture was diluted with 125 mL of ethyl acetate and extracted with eight 15 mL portions of water and one 10 mL portion of brine. The organic layer was dried with magnesium sulfate and evaporated to dryness. The crude oil was purified by flash chromatography to recover 0.365 g (1.6 mmol) of the title product. 1H NMR (300 MHz, CDCl3) δ 9.92 (s, 1H), 7.84 (d, J=8.7, 2H), 7.29 (dd, J=5.7, 13.9, 1H), 7.07 (d, J=8.7, 2H), 6.76 (d, J=8.3, 1H), 6.72-6.57 (m, 2H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 190.99, 163.25, 161.38, 156.42, 132.15, 130.76, 117.91, 112.63, 110.81, 106.59, 55.66.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.Cl.[OH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>C(OCC)(=O)C>[ClH:1].[Cl:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][NH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:2]([N:29]2[CH2:30][CH2:31][CH2:32][C@@H:27]([OH:26])[CH2:28]2)=[N:3][N:4]=1
Reactant: O[C@@H]1CCCNC1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nnc(N3CCC[C@@H](O)C3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
A mixture of 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 1.92 g (R)-(+)-3-hydroxypiperidine hydrochloride, 1.80 g diisopropyl ethylamine and 12 ml 1-methyl-2-pyrrolidone was stirred at 170° C. for 1 hr and 15 min. After cooling, ethyl acetate was added to the reaction solution which was then washed with water and brine. It was dried over anhydrous sodium sulfate, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography. The resulting free compound was suspended in acetic acid/ethanol/water, 1 N aqueous hydrochloric acid was added thereto, and it was dissolved by heating. After cooling, the resulting crystals were collected by filtration to give 860 mg of the title compound as a yellow powder.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[Cl:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:44][C:43]1[CH:42]=[CH:41][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[N:34]=3)[CH:31]=2)=[CH:23][C:22]=1[NH:21][C:8]([C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=1)=[O:10]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Reactant: CCn1nc(C)cc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Yield: 40.9 %

Procedure:
In the same manner as in Example 55 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (56.2 mg, 0.365 mmol), tetrahydrofuran (5 mL), thionyl chloride (63.3 μL, 0.730 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (114 mg, 0.332 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (65.2 mg, 41%) was obtained as a white solid.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:32][CH3:33])=[C:19]([CH2:20][N:21]4C(=O)C5C(=CC=CC=5)C4=O)[C:12]=3[O:11][C:10]=2[C:34]=1[CH2:35][C:36]#[N:37].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:21][CH2:20][C:19]1[C:12]2[O:11][C:10]3[C:34]([CH2:35][C:36]#[N:37])=[C:6]([O:5][CH3:4])[CH:7]=[CH:8][C:9]=3[N:14]([CH3:15])[C:13]=2[CH:16]=[CH:17][C:18]=1[O:32][CH3:33]
Reactant: COc1ccc2c(c1CC#N)Oc1c(ccc(OC)c1CN1C(=O)c3ccccc3C1=O)N2C
Agent: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC#N)N2C
Yield: 90 %

Procedure:
2.0 ml of ethanolic hydrazine hydrate solution (1M) were added at room temperature to a suspension of 280 mg of [3,7-dimethoxy-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylmethyl)-10-methyl-10H-dibenz[b,e][1,4]-oxazin-4-yl]-acetonitrile. The reaction mixture was heated to 85° for 4 hours, the cooled and poured into methylene chloride and 10% sodium carbonate solution. The aqueous phase was extracted with ethylene chloride and the combined organic fractions were dried over magnesium chloride and concentrated. The residue was dried in a high vacuum and, after recrystallization from tert.-butyl methyl ether/methanol, 180 mg (90.1%) of 6-aminomethyl-3,7-dimethoxy-10-methyl-10H-dibenzo[b,e][1,4]oxazine-4-acetonitrile were obtained as a beige solid of m.p. 167°-169° (dec.).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=3[F:17])[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)[CH2:3][CH2:2]1.C([O:26][C:27](=O)[CH2:28][C:29]([CH3:31])=[O:30])(C)(C)C>C1(C)C(C)=CC=CC=1>[CH:1]1([C:4]2[N:8]([C:9]3[C:10]([F:17])=[CH:11][C:12]([NH:13][C:27](=[O:26])[CH2:28][C:29](=[O:30])[CH3:31])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:18]([F:20])([F:19])[F:21])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Temperature: 145 °C
Yield: 78.2 %

Procedure:
Intermediate 35 (1 g, 3.3 mmol) and t-Butylacetoacetate (782 mg, 4.94 mmol) were dissolved in xylene (3 ml) and heated to 145° C. for 90 mins Reaction mixture was cooled to rt to obtain a solid. Solid that formed was filtered, washed with petether and dried to obtain N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3,5-difluorophenyl}-3-oxobutanamide (1.0 g).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:38](=[O:39])[C:37]3[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:42][CH:41]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c(-c2ccccc2)cn1S(=O)(=O)c1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
4-Phenyl-1-(indoline-5 -sulfonyl)-2-imidazolone (300 mg, 0.88 mmol) prepared in Preparation 3 was suspended in 10 m of dichloromethane. Then, pyridine (85 μ, 1.05 mmol) and 4-nitrobenzoyl chloride (163 mg, 0.88 mmol) were added thereto one after another. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 hours while the reaction being monitored by TLC. After the reaction was completed, the whole mixture was diluted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, concentrated, and finally purified by silica gel column chromatography (eluent: dichloromethane/methanol=15/1, v/v) to afford 400 mg of the title compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][N:14]2[C:18]([C:19](OCC)=[O:20])=[CH:17][C:16]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15]2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1.C(Cl)Cl>[OH:10][CH2:11][C@@H:12]1[CH2:13][N:14]2[N:15]=[C:16]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=[C:18]2[C:19](=[O:20])[NH:8]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1N[C@H](CO)Cn2nc(COc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
(S)-4-(5-Ethoxycarbonyl-3-phenoxymethyl-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.91 g, 1.9 mmol) was dissolved in a 4M solution of HCl in dioxane (9.8 mL) and the solution was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue was taken up in MeOH (10 mL) and K2CO3 (0.82 g, 5.96 mmol) was added. The mixture was stirred at 100° C. for 5 minutes under microwave irradiation. Then mixture was diluted with DCM. The solid was filtered off and the filtrate solvent was evaporated in vacuo. The residue was purified by flash column chromatography (silica, MeOH in AcOEt 0/100 to 10/90). Desired fractions were collected and the solvents evaporated in vacuo to yield (S)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.33 g, 61% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27-3.33 (m, 1H), 3.46-3.54 (m, 1H), 3.73-3.84 (m, 1H), 4.30 (dd, J=13.4, 5.8 Hz, 1H), 4.38 (dd, J=12.9, 5.3 Hz, 1H), 5.05 (s, 2H), 5.18 (br. s., 1H), 6.77 (s, 1H), 6.91-6.98 (m, 1H), 6.99-7.07 (m, 2H), 7.25-7.35 (m, 2H), 8.26 (d, J=2.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>ClC1N=C(Cl)C=C(C2C=CC=CC=2)N=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(I)cc1
Agent: Clc1cc(-c2ccccc2)nc(Cl)n1
Product: N#Cc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
4-bromo-4′-cyanobiphenyl was synthesized by the same method as in syntheses of 2,4-dichloro-6-phenylpyrimidine in the above (3-1-1), except that 4-bromoiodobenzene was used in place of 2,4,6-trichloropyrimidine and that 4-cyanophenylboronic acid was used in place of phenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[OH:17].Cl[C:19]1[N:24]=[C:23]([C:25]([NH2:27])=[O:26])[C:22]([CH3:28])=[N:21][C:20]=1[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(O)C.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([C:19]2[N:24]=[C:23]([C:25]([NH2:27])=[O:26])[C:22]([CH3:28])=[N:21][C:20]=2[CH3:29])[CH:5]=[CH:4][C:3]=1[OH:17]
Reactant: Cc1nc(C)c(C(N)=O)nc1Cl
Reactant: CC1(C)OB(c2ccc(O)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: COCCOC
Product: Cc1nc(C)c(-c2ccc(O)c(F)c2)nc1C(N)=O
Temperature: 80 °C

Procedure:
A suspension of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Intermediate 31-4; 348 g, 1169 mmol) (80% strength by proton NMR), 6-chloro-3,5-dimethylpyrazine-2-carboxamide (217 g, 1169 mmol) and potassium phosphate tribasic (298 g, 1403 mmol) in DME (3.6 L), ethanol (0.9 L) and water (1.8 L) was stirred. The mixture was degassed with nitrogen for 30 minutes at 30° C. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (8.60 g, 10.5 mmol) was then added to the suspension. The reaction was further degassed for 10 minutes before being heated to 80° C., stirred for 4 hours. The reaction was cooled to 25° C. The solvents were then removed in vacuo until a slurry in water remained. A solution of citric acid (640 g) in water (6.0 L) was then added slowly with stirring. The suspension was filtered, washed with water (2×2.5 L), MTBE (2.5 L), sucked dry on the sinter and then dried at 65° C. in a vacuum over for 48 hours. Gave 6-(3-fluoro-4-hydroxyphenyl)-3,5-dimethylpyrazine-2-carboxamide (295 g, 97%) as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:3]1=[O:26].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:26]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2ccccc2)C2(CCCNCC2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A diastereomeric mixture of tert-butyl 2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.6]undecane-8-carboxylate (step 4) (683.1 mg; 1.906 mmol) in DCM (6 ml) was treated with TFA (5.8 ml, 76 mmol) and stirred at RT for 10 minutes. The mixture was concentrated in vacuo and the crude product was dissolved in MeOH and applied to a 10 g pre-wetted (MeOH) SCX-2 cartridge. The column was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The clean fractions were concentrated in vacuo to afford the title compound;
Reaction SMILES: [N:1]12[CH2:11][S:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][N:4](C(OCC)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+]>O>[N:1]12[CH2:11][S:10][CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3][NH:4][CH2:5]1
Reactant: CCOC(=O)N1CC2CC3CSCN3C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C1NCC2C1CC1CSCN12

Procedure:
12.5 g (50 mmol) of ethyl 10-thia-1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate together with 32 g of Ba(OH)2 ×8H2O are refluxed overnight in 225 ml of water. Potassium carbonate is added, barium carbonate is filtered off with suction, and the filtrate is extracted ten times using 100 ml portions of chloroform. The extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)=[CH:3][CH:2]=1.C([SiH](CC)CC)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>CN(C=O)C>[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2[nH]nc(-c3ccncc3)c2c1

Procedure:
N—((R)-1-((S or R)-2-(Dimethylamino)-1-(2-fluorophenyl)-2-oxoethyl)piperidin-3-yl)-3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (53 mg, 0.071 mmol) was stirred in TFA (0.5 mL) at room temperature for 30 minutes. triethylsilane (0.015 mL, 0.093 mmol) was added and the reaction mixture diluted with DMF (1 mL). The solution was purified by reverse-phase, mass-triggered prep-HPLC. The product fraction was lyophilized to give the bis TFA salt of N—((R)-1-((S or R)-2-(dimethylamino)-1-(2-fluorophenyl)-2-oxoethyl)piperidin-3-yl)-3-(pyridin-4-yl)-1H-indazole-5-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH2:6]CO.P(Br)(Br)[Br:20]>C(Cl)Cl>[N+:16]([C:4]1[C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:5]=1[CH2:6][Br:20])([O-:18])=[O:17]
Reactant: BrP(Br)Br
Reactant: COc1cc(CCO)c([N+](=O)[O-])c(OC)c1OC
Solvent: ClCCl
Product: COc1cc(CBr)c([N+](=O)[O-])c(OC)c1OC
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of the 3,4,5-Trimethoxy-2-nitrobenzoic acid (5 g, 19.40 mmol) in THF (30 ml) was added by BH3 (1.0 M in THF, 29.1 ml) under nitrogen. The mixture was stirred and refluxed for 2 hours. After cooling, the reaction mixture was extracted with water and CH2Cl2. The combined organic layers were dried over MgSO4, and then evaporated to afford 3,4,5-Trimethoxy-2-nitrobenzyl methanol. The crude 3,4,5-trimethoxy-2-nitrobenzyl methanol was dissolved in anhydrous CH2Cl2 (20 mL) and was subjected to PBr3 (2.40 ml, 25.22 mmol) in an ice bath. After 2 h, the mixture was extracted with water and CH2Cl2. The organic layers were combined and evaporated. The residue was purified by flash chromatography (EtOAc:n-hexane=1:2) to afford B1 as a pale yellow oil, yield 68%. 1H NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 3.92 (s, 3H), 3.98 (s, 3H), 4.44 (s, 2H), 6.72 (s, 1H).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.[BH4-].[Na+]>C(O)C.C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C@@H:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: COC(=O)c1ccc2c(c1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)CC[C@@H]2N[C@@H](C)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To 713 mg of methyl 1-oxoindane-5-carboxylate were added 612 mg of (1S)-1-(4-methoxyphenyl)ethanamine, 0.23 ml of acetic acid, 600 mg of Molecular Sieves 4A, and 12 ml of toluene, followed by heating to reflux using a Dean-Stark type reflux device for 4 hours under reduced pressure (213 mbar). Then, 0.23 ml of acetic acid and 300 mg of Molecular Sieves 4A were added thereto, followed by heating to reflux using a Dean-Stark type reflux device for 4 hours under reduced pressure (213 mbar). The insoluble material was removed by filtration and the solvent was then evaporated under reduced pressure to obtain an intermediate product. To a solution of the obtained intermediate product in 13 ml of ethanol was added 161 mg of sodium borohydride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The solvent was evaporated under reduced pressure, and to the obtained residue were added water, a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 452 mg of methyl (1S)-1-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}indane-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]#[N:14])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1>CO.N.[Ni]>[NH2:14][CH2:13][CH:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][CH2:9][CH2:8]1
Reactant: COc1ccc2c(c1)OCC=C2C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc2c(c1)OCCC2CN

Procedure:
The product from Example 1 was hydrogenated with RaNi in MeOH and NH3 at 4 atm. pressure and gave the desired product, (M+H)+ 194.