Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:16]I.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[CH:8][N:9]2[CH3:16])=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc2c(C=O)c[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(C=O)cn(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 6-methoxy-1H-indole-3-carboxaldehyde (1.65, 9.4 mm) in DMF (10 mL) was cooled to 0° C., and treated with NaH(11.3 mm). After stirring at room temperature for 1 hour, the mixture was cooled to 0° C., treated with CH3I (0.7 mL, 11.3 mm), then allowed to warm to room temperature overnight. After pouring into H2O (200 mL), the mixture was acidified with HCl and extracted with EtOAc (100 mL×2). The combined organic fractions were dried over MgSO4, filtered and evaporated to afford 6-methoxy-1-methyl-1H-indole-3-carboxaldehyde (1.78 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(-c2noc(C3CNCC(c4ccc(OC(F)(F)F)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
425 mg (0.84 mmol) of the compound from Example 177A were initially charged in 55 ml of dichloromethane and, at RT, reacted with 0.65 ml (955 mg, 8.37 mmol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 20 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 340 mg (80% of theory, 80% pure)
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1.[OH-].[Na+]>[Cl:12][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1CO
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ncccc1CCl
Reaction time: 2.5 h

Procedure:
To a solution of 3-hydroxymethyl-2-methylpyridine (10.42 g) in toluene (100 ml) was added dropwise thionyl chloride (9.87 ml) at 25° C. After 2.5 hours, the solvent was removed in vacuo to give a residual solid. The solid was dissolved in 4N-aqueous sodium hydroxide (100 ml) and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over magnesium sulfate. Concentration of the solution gave 3-chloromethyl-2-methylpyridine (9.22 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]2[N:15]=[C:16]([C:18]3[C:27]([CH3:28])=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:17]=[C:4]2[N:3]=1.[OH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.O>CN1CCCC1=O>[CH3:28][C:27]1[C:18]([C:16]2[CH:17]=[C:4]3[N:3]=[C:2]([N:32]4[CH2:33][CH2:34][CH:30]([OH:29])[CH2:31]4)[CH:7]=[C:6]([NH:8][CH:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)[N:5]3[N:15]=2)=[N:19][C:20]2[C:25]([N:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Reactant: O[C@H]1CCNC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc2ccccc2nc1-c1cc2nc(N3CCC(O)C3)cc(NC3CCOCC3)n2n1
Temperature: 80 °C

Procedure:
A suspension of 5-chloro-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (Example 1.001 (g)) (398 mg, 1.01 mmol) and (s)-3-hydroxypyrrolidine (351 mg, 4.03 mmol) in N-methyl-2-pyrrolidinone (5.0 mL) was heated at 80° C. for 6 h. Then the reaction mixture was poured into cold water. The resulting precipitate was collected and purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=7:3) to give 1-[2-(3-methylquinoxalin-2-yl)-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-3-ol (the compound of Example 1.007 listed in the Table of Examples as described hereinafter). 1H-NMR (500 MHz, CDCl3): δ 1.74-1.81 (2H, m), 2.12-2.22 (4H, m), 3.03 (3H, s), 3.58 (2H, dt, J=2.3, 11.9 Hz), 3.65-3.76 (5H, m), 4.08 (2H, dt, J=11.6, 3.2 Hz), 4.64-4.67 (1H, m), 5.16 (1H, s), 6.16 (1H, d, J=8.0 Hz), 6.66 (1H, s), 7.70-7.76 (2H, m), 8.03-8.05 (1H, m), 8.17-8.19 (1H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:24]=[C:8]2[CH2:9][N:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:7]2[N:6]=1)=O.[BH4-].[Na+]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:10]2[C:11]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:7]3[N:6]=[C:5]([CH2:3][OH:2])[N:24]=[C:8]3[CH2:9]2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1nc2n(n1)-c1cccnc1N(c1ccc(Cl)cc1)C2
Agent: [BH4-]
Agent: [Na+]
Product: OCc1nc2n(n1)-c1cccnc1N(c1ccc(Cl)cc1)C2

Procedure:
using 7.90 g (0.023 mol) of 5-(4-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid methyl ester and 4.37 g (0.116 mol) of sodium borohydride there is obtained 5-(4-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-methanol having a melting point of 240°-245° with decomposition;
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](Cl)=[O:24]>>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:23](=[O:24])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-(thiophen-2-yl)acetyl chloride were treated using a method similar to that described in Example 53 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.88-11.97 (m, 1H), 8.41-8.48 (m, 1H), 8.13 (td, J=7.7, 1.6 Hz, 1H), 8.00-8.09 (m, 2H), 7.43 (dd, J=5.1, 1.3 Hz, 1H), 7.04-7.08 (m, 1H), 7.01 (dd, J=5.1, 3.5 Hz, 1H), 3.96 (d, J=0.9 Hz, 2H); MS (ESI−) M/Z 352 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)O1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: OBO
Product: c1cncc(N2CCc3c(-c4ccncc4)nc(N4CCOCC4)nc32)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a boronic acid, the desired compound was obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:26]2)[CH2:22][CH2:23]1
Reactant: COc1ccccc1N1CCN(CC2CCCNC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50(mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (1.08 g, 79% yield). An ethanolic solution of the product was treated
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[C-:23]#[N:24].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2cccc(Br)c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
A mixture of toluene-4-sulfonic acid 4-(3-bromophenyl)butyl ester (2.3 g, 6 mmol) and powdered sodium cyanide (0.65 g, 13 mmol) in DMSO was heated up to 80° C., stirred for 1.5 hours and monitored by NMR. When the reaction was complete, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of this residue on silica gel (ISCO) using (hexanes/EtOAC 9.5/0.5) as the eluting solvent gave 5-(3-bromo-phenyl)pentanenitrile as a colorless oil (1.12 g, 78% yield). m/e (M)+ 237; 1H NMR (400 MHZ, DMSO-d6) δ ppm, 2.63-2.65 (m, 2H), 2.75-2.78 (m, 2H), 2.35-2.38 (m, 2H), 2.60-2.63 (m, 2H), 7.05-7.10 (m, 2H), 7.25-7.28 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:26])[CH:10]([O:17]C(=O)C2C=CC=CC=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[OH:17][CH:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:26]
Reactant: COc1ccc(C(=O)C(OC(=O)c2ccccc2)c2cccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)C(O)c2cccnc2)cc1
Reaction time: 24 h
Yield: 43.3 %

Procedure:
To a solution of benzoic acid 2-(4-methoxy-phenyl)-2-oxo-1-pyridin-3-yl-ethyl ester (1.21 g, 3.38 mmol) prepared in Step 2 in 3 mL of tert-butanol was slowly added 6.5 mL of 1.0 M potassium tert-butoxide under nitrogen atmosphere. The resulting mixture was stirred for 1 day and concentrated under reduced pressure to remove the solvent. The concentrate was diluted with 50 mL of ethyl acetate and 50 mL of water to dissolve salts, followed by separation of layers. The obtained organic layer was successively washed twice with 50 mL of a brine solution. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography, to give 356 mg (yield: 49%) of 2-hydroxy-1-(4-methoxy-phenyl)-2-pyridin-3-yl-ethanone of the following formula.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH3:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH2:32]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: CC1CNc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)c2ccccc21

Procedure:
0.15 g (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 61 mg (0.37 mmol) 3-methyl-2,3-di-hydro-1H-indole, 150 μL (0.87 mmol) DIPEA and 0.13 g (0.41 mmol) TBTU in 1.8 mL DMF were stirred for 1 h at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:4][C:5]([NH2:8])=[N:6][N:7]=1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[CH3:15][C:13]1[CH:12]=[C:11]([OH:16])[N:6]2[N:7]=[C:3]([C:2]([F:10])([F:9])[F:1])[N:4]=[C:5]2[N:8]=1
Reactant: Nc1nnc(C(F)(F)F)[nH]1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(C(F)(F)F)nc2n1
Yield: 52.3 %

Procedure:
To a well-stirred solution of 5-(trifluoromethyl)-4H-1,2,4-triazol-3-amine (1 g, 6.58 mmol) in 15-20 mL glacial acetic acid, was added ethyl acetoacetate (2.57 g or 2.5 mL, 19.77 mmol) and the reaction mixture was refluxed for 6-6.5 h. Reaction progress was monitored by TLC. After completion, the reaction mixture was brought to room temperature and the excess glacial acetic acid was evaporated in vacuo. The light pinkish white solid, thus obtained, was filtered off, washed with dichloromethane and dried to yield 0.750 g (52.3%) of the titled compound.
Reaction SMILES: [C:1]1([C:7]([CH2:11][N:12]([CH3:14])[CH3:13])([OH:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:27]Cl)[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]>>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:22]=1[O:23][CH3:24])[CH2:27][O:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:8][CH3:9])[CH2:11][N:12]([CH3:14])[CH3:13]
Reactant: CCC(O)(CN(C)C)c1ccccc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Product: CCC(CN(C)C)(OCc1cc(OC)c(OC)c(OC)c1)c1ccccc1

Procedure:
Prepared according to the process described in Example 3 from 1-phenyl-1-dimethylaminomethyl-1-propanol and from 3,4,5-trimethoxy-α-chlorotoluene.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH2:12])=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[CH2:1]([NH:9][C:10]1[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(=S)NCCc1ccccc1
Reactant: O=C(O)C(=O)CBr
Solvent: CO
Product: O=C(O)c1csc(NCCc2ccccc2)n1
Yield: 94.8 %

Procedure:
2-Phenethylamino-thiazole-4-carboxylic acid (235 mg) was prepared according to General Procedure B using phenethyl-thiourea (180 mg) and 3-bromo-2-oxo-propionic acid (167 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[CH:29]=[CH2:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(NC(=O)OC(C)(C)C)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(Cl)c(F)c2)c(F)c1NC(=O)OC(C)(C)C
Yield: 65.7 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-3-chloro-6-(4-chloro-3-fluorophenyl)-5-fluoropicolinate (1.5 g, 3.46 mmol), tributyl(vinyl)stannane (2.196 g, 6.92 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.365 g, 0.519 mmol) were combined in 1,2-dichloroethane (4.62 mL) and irradiated in a microwave at 130° C. in a sealed vial for 30 min. The cooled reaction mixture was applied directly to a silica gel column and eluted with a 5-40% ethyl acetate/hexanes gradient to provide methyl 4-(tert-butoxycarbonylamino)-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-vinylpicolinate (0.966 g, 2.274 mmol, 65.7%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[S:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:22])[C:9]2[S:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2sc(-c3ccccc3)nc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (2.10 g, 7.01 mmole), N-bromosuccinimide (1.31 g, 7.36 mmole) and benzoyl peroxide (84.9 mg, 0.35 mmole) in carbon tetrachloride (40 ml) was refluxed for 2 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 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 dichloromethane to give the title compound as a white solid (1.89 g). MS: (+) m/z 379.18, 381.18 (M+1, 79Br/81Br).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:19].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C>O1CCCC1.[Pd]>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][C:24]1[C:29]([NH:30][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=2)=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:19]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CNc1ncccc1N
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(F)cc1
Yield: 5.6 %

Procedure:
Under a nitrogen atmosphere, triethylamine (31.8 g, 0.315 mole) and 4-fluorobenzoyl chloride (50 g, 0.315 mole) were added simultaneously, dropwise, to a stirred and chilled solution of freshly prepared N-[[3-amino]-2-pyridinyl]glycine ethyl ester (0.33 mole) by palladium/carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester, (75.3 g, 0.33 mole) in dry tetrahydrofuran (~800 ml). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (300 ml) and water (300 ml), the insoluble material was filtered off, the layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed three times with water, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to give 76.8 g of crude solid (77% yield). A 6.8-g portion of the solid was recrystallized from isopropyl alcohol and water to give 5.63 g of title compound, mp 127° -128.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH2:22]([C:24]1[O:25][C:26]2[C:32](I)=[CH:31][C:30]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][C:27]=2[CH:28]=1)[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:22]([C:24]1[O:25][C:26]2[C:32]([C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3](=[O:21])[N:2]([CH3:1])[CH:11]=3)=[CH:31][C:30]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][C:27]=2[CH:28]=1)[CH3:23]
Reactant: CCc1cc2cc(S(C)(=O)=O)cc(I)c2o1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc2cc(S(C)(=O)=O)cc(-c3cn(C)c(=O)c4ccccc34)c2o1
Temperature: 90 °C
Yield: 32.6 %

Procedure:
To a solution of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (82 mg, 286 umol) and the title compound from Step 1 (100 mg, 286 umol) in H2O (2 mL) and dioxane (20 mL) was added Pd(dppf)Cl2 (21 mg, 28.6 umol, 0.10 Eq) and Na2CO3 (61 mg, 572 umol). The mixture was degassed with nitrogen and heated to 90° C. for 4 h. It was then cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA=3:1 to 1:1) followed by prep-HPLC to afford the title compound (35.57 mg, 33%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.56 (d, J=7.2 Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.60-7.57 (m, 2H), 7.29-7.27 (m, 2H), 6.60 (s, 1H), 3.73 (s, 3H), 3.15 (s, 3H) 2.75 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H). LCMS: 382.0 (M+H+)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCc1ccc(C(F)(F)F)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 82 %

Procedure:
The title compound is prepared in analogy to Example 3a) from 4-fluoro-nitro-benzene and 4-trifluoromethyl-benzyl alcohol. Yield 82% of a slightly brown solid. Mp.=80.5–81.5° C.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])=[C:21]=[S:22].O(C(C)C)C(C)C>O1CCCC1>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:20][C:21]([N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)=[S:22])([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Reactant: CCOC(=O)N1CCC(NCc2ccccc2)CC1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(N(Cc2ccccc2)C(=S)Nc2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 42.5 parts of ethyl 4-[(phenylmethyl)amino]-1-piperidinecarboxylate, 30 parts of 1-isothiocyanato-2-nitrobenzene and 270 parts of tetrahydrofuran was stirred for 3 hours at room temperature. 2,2'-Oxybispropane was added and stirring was continued overnight. The precipitated product was filtered off and dried, yielding 48.5 parts (68.5%) of ethyl 4-[[[2-nitrophenyl)-amino]thioxomethyl(phenylmethyl)amino]-1-piperidinecarboxylate; mp. 140° C.; (intermediate 30).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.CC1(C)C(C)(C)OB([C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH2:23])O1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:12][C:9]1[CH:10]=[CH:11][C:2]2[C:3](=[C:4]([OH:6])[N:23]=[C:22]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:21]3)[CH:8]=1
Reactant: COC(=O)c1cc(F)ccc1Br
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCO
Product: Oc1nc2ccccc2c2ccc(F)cc12
Temperature: 80 °C
Yield: 65.8 %

Procedure:
A mixture of methyl 2-bromo-5-fluorobenzoate (0.250 g, 1.07 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.235 g, 1.07 mmol), palladium acetate (2.4 mg, 0.01 eq.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (8.81 mg, 0.021 mmol), and sodium carbonate (0.114 g, 1.073 mmol) in ethanol (5.4 mL) was heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was triturated with hexane, and isolated by vacuum filtration, washed with water, and dried to provide the title compound (0.15 g, 65% yield) which was used without further purification.