Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:4]([CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=1)[C:5]#[N:6].[BH4-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4C#N)cc23)ncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(CO)cc4C#N)cc23)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 3-chloro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]-5-formylbenzonitrile (24 mg, 0.06 mmol) in ethanol (IMS grade, 2.0 mL) and THF (2.0 mL) was added sodium borohydride (4 mg, 0.1 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid obtained was filtered and dried. This was then purified by silica gel flash chromatography (0-1% methanol in ethyl acetate) to afford the title compound as a white solid (4.0 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.46 (d, J=2.6 Hz, 1H), 8.71 (d, J=1.2 Hz, 1H), 8.38 (s, 1H), 8.09 (m, 2H), 8.03 (d, J=3.5 Hz, 1H), 5.76 (t, J=5.8 Hz, 1H), 4.71 (d, J=5.8 Hz, 2H), 2.46 (s, 3H). LCMS (Method B): RT=2.78 min, m/z: 410 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=13)[N:8]=[CH:7][N:6]([C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:23])[C:5]2=[O:24].[Cl-].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][Zn+])=[CH:29][N:28]=1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][C:2]2[CH:3]=[C:4]3[C:9](=[C:10]4[N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=24)[N:8]=[CH:7][N:6]([C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])[C:5]3=[O:24])=[CH:31][CH:32]=1
Reactant: Clc1ccc(C[Zn+])cn1
Reactant: CN1CCCc2c(Br)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN1CCCc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-7,8,9,10-tetrahydropyrido[3,2-h]quinazolin-4(3H)-one (40 mg, 0.10 mmol) in THF (0.4 mL) at 0° C. was added (2-chloro-5-pyridyl)methylzinc chloride (0.5 M in THF, 408 μL, 0.20 mmol) and Pd(PtBu3)2. The mixture was warmed to rt and stirred for 30 min. The resulting solution was quenched with water and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (0-5% MeOH/CH2Cl2) afforded 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-7,8,9,10-tetrahydropyrido[3,2-h]quinazolin-4(3H)-one in pure form: 1H NMR (400 MHz, CD3OD); 1H NMR (400 MHz, CDCl3) 8.20 (d, J=2.3 Hz, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.33 (dd, J=2.3, 8.2 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.51 (m, 1H), 3.96 (s, 2H), 3.90 (m, 1H), 3.12 (t, J=5.2 Hz, 2H), 3.08 (s, 3H), 2.56 (t, J=6.5 Hz, 2H), 2.24-2.15 (m, 2H), 2.00-1.92 (m, 2H), 1.89-1.75 (m, 4H), 1.55-1.37 (m, 2H); HRMS (MH+) calcd for C24H28ClN4O2 439.1895. found 439.1894.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.P(Cl)(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[N-:48]=[N+:49]=[N-:50].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]2[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:50]=[N:49][N:48]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: Cc1cc(CC(NC(=O)OCc2ccccc2)C(=O)NCC(C)(C)C)cc2cn[nH]c12
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: Cc1cc(CC(NC(=O)OCc2ccccc2)c2nnnn2CC(C)(C)C)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl 3-(7-methyl-1H-indazol-5-yl)-1-(neopentylamino)-1-oxopropan-2-ylcarbamate (0.17 g, 0.402 mmol) in chloroform (0.5 mL) was added to a mixture of phosphorus pentachloride (0.17 g, 0.802 mmol) and quinoline (0.2 mL) in chloroform (1.0 mL). After stirring at room temperature for 2 h, the solvents were removed in vacuo. The crude mixture was dissolved in acetonitrile (2.0 mL) and treated with sodium azide (78 mg, 3.0 equiv). After stirring the mixture at 40° C. overnight, the solvents were removed and the crude mixture dissolved in methylene chloride which was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded 73 mg (40%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 0.82 (s, 9H), 2.46 (s, 3H), 2.30-3.46 (m, 2H), 3.69 (d, J=14.3, 1H), 3.93 (d, J=14.3, 1H), 4.98-5.13 (m, 2H), 5.30 (m, 1H), 6.02 (d, J=8.9, 1H), 6.86 (s, 1H), 7.25-7.35 (m, 5H), 7.94 (s, 1H). Mass spec.: 448.19 (MH)+.
Reaction SMILES: C[C:2]1([CH3:9])[CH:7](O)[C:5](=[O:6])[O:4]C1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21]C(C=CC(Cl)=O)=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:22]=[CH:21][C:9]([CH:2]=[CH:7][C:5]([OH:4])=[O:6])=[CH:14][CH:13]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: CC1(C)COC(=O)C1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 92.6 %

Procedure:
16.3 g of <R>-pantolactone (0.125 mol) and 28 g of 4-methoxycinnamic acid chloride (about 0.14 mol) are placed in 170 ml of CH2Cl2 while gassing with argon in a 350 ml 4-necked sulphonation flask provided with a thermometer, a reflux condenser, a magnetic stirrer as well as a 20 ml dropping funnel. A solution of 11 g (0.139 mol) of pyridine in 30 ml of CH2Cl2 is now added dropwise within 30 minutes, whereby the temperature rises slowly. The reaction mixture is finally heated to reflux temperature for 3 hours. The reaction mixture is washed with 150 ml of water, 2× with 40 ml of 5% HCl, 2× with 40 ml of 5% NaHCO3 and 1× with 100 ml of water. The organic phase is separated and dried over Na2SO4. The solvent is removed on a rotary evaporator. The thus-obtained crude product is recrystallized from 100 ml of ethyl acetate/hexane (60:100). There are obtained 33.6 g of white crystals of the <R>-pantolactone ester of p-methoxycinnamic acid (yield 92.6%).
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.Cl[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][CH2:19][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH3:16])=[CH:11][CH:10]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NCCC(=O)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NEt3 (60 mL) followed by (S)-1-(4-chloro-phenyl)-ethylamine (20.5 g) was added to a solution of 3-chloro-1-phenyl-propan-1-one (23.2 g) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature overnight. Then, the solution was concentrated, water (100 mL) was added to the residue, and the resulting mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with water and brine and dried (MgSO4). The title compound was obtained after removal of the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][C:13]([O-])(C)C.[K+].ICC>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCn1nc(I)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of 6-chloro-3-iodo-1H-indazole (913 mg, 3.28 mmol) in THF (12 ml) at 0° C. was added KOt-Bu (429 mg, 3.82 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodoethane (0.37 ml, 4.6 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 48 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 10% to 50% EtOAc/heptane to afford 622 mg (62%) of 6-chloro-1-ethyl-3-iodo-1H-indazole as a white powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.37-7.43 (m, 2H), 7.17 (dd, J=8.7, 1.1 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H). Also isolated 174 mg (17%) of 6-chloro-2-ethyl-3-iodo-2H-indazole as a more polar, minor regioisomer. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.66-7.70 (m, 1H), 7.35 (d, J=9.1 Hz, 1H), 7.04-7.12 (m, 1H), 4.56 (q, J=7.2 Hz, 2H), 1.58 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[OH:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([CH:11]([C:13]5[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=5)[OH:12])=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CS(=O)(=O)c1ccc(C(O)c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CS(=O)(=O)c1ccc(C(O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)cc1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methanesulfonyl-phenyl)-methanol was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in General Procedure A. Purification by column chromatography yielded 413. (400 MHz, CDCl3): 3.00 (3H, s, CH3), 3.82-3.84 (4H, m, CH2), 3.99-4.01 (4H, m, CH2), 6.21 (1H, b, NH), 7.29 (1H, d (J=0.80), ar), 7.43 (1H, t (J=7.80), ar), 7.53 (1H, d (J=8.30), ar), 7.66 (2H, d (J=8.26), ar), 7.91 (2H, d (J=8.46), ar), 8.18 (1H, d (J=6.56), ar), 8.91 (1H, s, ar). (M+H)+ 522.21
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>[Pd].CO>[OH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=1[NH:1][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1O
Reaction time: 2 h
Yield: 100.7 %

Procedure:
A mixture of 2-nitro-4-(trifluoromethyl)phenol (310 mg, 1.5 mmol), palladium on carbon (10%, 125 mg) and acetic anhydride (306.3 mg, 3.0 mmol) in methanol was hydrogenated for 2 h at atmospheric pressure. The catalyst was filtered off, the filtrate was concentrated in vacuo to give crude N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide (331 mg). A part (219.16 mg, 1.0 mmol) of N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide was treated with [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (273.27 mg, 1.0 mmol) in the presence of Cs2CO3 (406.25 mg, 1.25 mmol) in DMF (5 mL) at room temperature for 5 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (230 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[K+].Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Cl)ccn1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)ccn1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A mixture containing 1.4 mmol 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester, 4.8 mmol potassium fluoride, 1.4 mmol 4-chloro-2-picoline (commercial) and 0.03 mmol bis(tri-tert.-butylphosphine)palladium in 5 ml deglazed dioxane was stirred at 100° C. for 1.5 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed twice with water. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on a 20 g Flashpack cartridge (Eluent: Heptane/AcOEt) to afford the title compound as a yellow oil (69% yield). MS (m/e): 311.2 ([M+H]+, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O)([O-:15])=[O:14]>C(O)C>[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[N:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=1)([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Yield: 86.3 %

Procedure:
To a solution of ethyl-4-aminobenzoate (5.0 g, 30.3 mmol) in ethanol was added 2-nitrobenzaldehyde (5.03, 33.3 mmol) at room temperature. The reaction mixture was stirred at reflux for 3 h LC-MS showed ester was consumed nearly. The reaction mixture was concentrated in vacuo. The residue was washed by diethyl ether to give ethyl 4-(2-nitrobenzylideneamino)benzoate as yellow solid (7.8 g, yield 86.4%). LC/MS m/e obsd. (ESI+) [(M+H)+] 299.2.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[C:11]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:25][CH:26]([O:29][C:30](=[O:32])[CH3:31])[CH:27]=[CH2:28])(=[O:24])[CH3:23].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:28]=[CH:27][CH:26]([O:25][C:22](=[O:24])[CH3:23])[O:29][C:30](=[O:32])[CH3:31])[CH:16]=3)[C:11]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(OC(C)=O)OC(C)=O
Reactant: O=C1c2ccc(Br)cc2CCN1CCCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OC(C=Cc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O)OC(C)=O
Temperature: 25 °C

Procedure:
To a sealed tube apparatus is added 2-(3-phenylpropyl)-6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline (1.6 g, 4.65 mmol), CH3CN (8 mL), 1,1-diacetoxy-2-propene (3.4 mL, 23.25 mmol), Pd(OAc)2 (84 mg, 0.37 mmol), P(o-tolyl)3 (113 mg, 0.37 mmol) and Et3N (0.78 mL, 5.58 mmol). The reaction vessel is then sealed and the mixture heated to 120° for 48 hours. After cooling to ambient temperature the reaction mixture is diluted with EtOAc (150 mL) and filtered through Celite. The organic phase is washed with saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 9:1 hexane/EtOAc, 1:1 hexane/EtOAc, 1:1 hexane/EtOAc) to give 2-(3-phenylpropyl)-6-(3,3-diacetoxy-1-propen-1-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:26]([O:28][C:29]([C:31]1[CH:47]=[CH:46][C:34]2[NH:35][C:36]([NH:38][CH2:39][CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[N:37][C:33]=2[CH:32]=1)=[O:30])[CH3:27].CO>CN(C)C=O.C(O)(=O)C>[CH2:26]([O:28][C:29]([C:31]1[CH:47]=[CH:46][C:34]2[NH:35][C:36]([NH:38][CH2:39][CH:40]3[CH2:41][CH2:42][N:43]([CH2:5][C:4]4[CH:7]=[C:8]([Cl:10])[CH:9]=[C:2]([Cl:1])[C:3]=4[OH:11])[CH2:44][CH2:45]3)=[N:37][C:33]=2[CH:32]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 3,5-dichloro-2-hydroxybenzaldehyde (0.3 mmol) and sodium triacetoxyborohydride (0.3 mmol) to a solution of 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid ethyl ester (0.1 mmol) in dimethylformamide-acetic acid (10:1) (1.0 ml), the mixture was stirred at room temperature overnight. Methanol (1.0 ml) was added to the reaction mixture to suspend the reaction, and after stirring for 1 hour, the solution was passed through SCX (Bond Elute SCX500MG). The SCX was washed with methanol and then with a mixed solution of chloroform/methanol (1/1), and elution was performed with a 0.5N ammonia-dioxane solution. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to preparative HPLC to obtain 2-{[1-(3,5-dichloro-2-hydroxybenzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-5-carboxylic acid ethyl ester. The compound was identified by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]#[N:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl.C>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[NH:26][CH2:25][CH2:24][N:12]=1
Reactant: Cc1ccc(Cl)c(OCC#N)c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: Cc1ccc(Cl)c(OCC2=NCCN2)c1
Yield: 32.7 %

Procedure:
A mixture of 36.3 g of 4-chloro-m-tolyloxyacetonitrile, 46.6 g of ethylenediamine p-toluenesulfonate and 150 ml of 1,2-dichlorobenzene was heated with stirring in a 500 ml round-bottomed three-necked flask at reflux under a small flow of nitrogen for 1.5 hours, essentially as described in U.S. Pat. No. 3,449,356. The reaction mixture was cooled, diluted with methylene chloride and the solids filtered off. The solids were slurried in water and then basified with 5 normal (N) sodium hydroxide and then filtered. The solids were washed well with water and dried to obtain 42.0 g of the crude product, m.p. 91°-95° C. A 19.5 g portion of the crude product was put in solution in approximately 150 ml of boiling toluene, treated with activated charcoal and filtered. The filtrate was cooled and then filtered, which gave 14.7 g of purified 2-(((4-chloro-m-tolyl)oxy)methyl)-2-imidazoline, m.p. 90°-92° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[S:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([F:32])[C:18]=1[O:33][CH3:34].C(#N)C.O.C(OCC)(=O)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([O:33][CH3:34])[C:19]=2[F:32])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[S:14][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1SC
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1SC
Temperature: 115 °C

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-(methylthio)picolinate (300 mg, 1.2 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (450 mg, 1.6 mmol) Cesium fluoride (370 mg, 2.4 mmol) and his (triphenylphosphine) palladium (II) chloride (84 mg, 0.12 mmol) were combined in 5 ml 1:1 acetonitrile-water and heated in a microwave reactor at 115° C. for 30 m. The mixture was shaken with 30 ml ethyl acetate and 10 ml water. The org. phase was washed with 10 ml sat. NaCl, dried (Na2SO3) and evaporated. The residue was chromatographed on silica with a 0-40% ethyl acetate-hexane gradient. The gummy material was stirred with hexane to produce the written compound as a white solid, 60 mg. Mp: 113-117° C. 1H NMR (400 MHz, CDCl3) δ 7.27-7.24 (m, 2H), 5.31 (s, 2H), 3.98 (d, J=1.1 Hz, 3H), 3.96 (s, 3H), 2.32 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −127.97, −128.06, −140.43, −140.52. ESIMS m/z 375 ([M+H]+), 373 ([M−H]−).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[N:9]=1>CN(C=O)C>[Cl:1][CH2:2][C:3]1[N:7]=[C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10](=[O:21])[N:9]2[CH:5]=1
Reactant: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Reactant: O=C(CCl)CCl
Solvent: CN(C)C=O
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
1,3-Dichloroacetone (2.27 g, 11.92 mmol) was added to a solution of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (4.6 g, 12 mmol) in DMF (135 mL). The mixture was stirred at 150° C. for 30 minutes under microwave irradiation and then the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (2.5 g, 75% yield) as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3(C(O)=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:25])C=CC=CC=1.C([N:37]([CH2:40]C)CC)C>C1(C)C=CC=CC=1>[N:37]([C:9]12[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]1[CH2:7][O:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][C:10]2=1)=[C:40]=[O:25]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: O=C(O)C12CCCCC1COc1ccccc12
Solvent: Cc1ccccc1
Product: O=C=NC12CCCCC1COc1ccccc12

Procedure:
A solution of the compound from Example 70 (1.0 g, 4.30 mmol) and diphenylphosphorylazide (1.3 g, 4.7 mmol) in 1.1 ml triethylamine and toluene was refluxed for 15 hours. Workup and silica gel chromatography gave the title compound (0.71 g) as a clear oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.CO.C(O)(=O)C>[Pd].C1COCC1>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CCc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Reaction time: 24 h

Procedure:
40 mg of 5% palladium on carbon were added to a solution of 416 mg (1.3 mmol) of 3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-acrylic acid in 20 ml of THF, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 24 h. Then 10 ml of methanol and 40 mg of 5% palladium on carbon were added, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for further 24 hours. Then 10 ml of acetic acid were added, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for another 24 h. The mixture was filtered and evaporated under reduced pressure. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 400 mg.