Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]2)[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][N:6]=1
Reactant: NC(=O)C1CCN(c2nc(Cl)ncc2Br)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)C1CCN(c2nc(Cl)ncc2-c2ccccc2)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 1-(5-bromo-2-chloropyrimidin-4-yl)piperidine-4-carboxamide E31 (0.10 g, 0.31 mmol), benzene boronic acid (46 mg, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 5 mol %) in DME (8 mL) was added a 0.5 M solution of sodium carbonate. The mixture was heated at relfux for 22 h, then cooled to r.t. and purified on an SCX-2 cartridge (MeOH, followed by 0.5 M NH3 in MeOH). The crude product was purified by chromatography on silica gel (CH2Cl2, MeOH, 98:2) to furnish the title compound as a white solid (58 mg, 59%), m/z 317 (100%, MH+); m/z (ESI) C16H18BrClN4O requires 317.1165 found [M+H]+ 317.1161.
Reaction SMILES: [O:1]=[C:2]1[NH:21][CH2:20][CH2:19][C:4]2([CH2:8][C@H:7]([C:9]([O:11]CC3C=CC=CC=3)=[O:10])[CH2:6][CH2:5]2)[O:3]1>CO.[Pd]>[O:1]=[C:2]1[NH:21][CH2:20][CH2:19][C:4]2([CH2:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5]2)[O:3]1
Reactant: O=C1NCCC2(CC[C@@H](C(=O)OCc3ccccc3)C2)O1
Agent: [Pd]
Solvent: CO
Product: O=C1NCCC2(CC[C@@H](C(=O)O)C2)O1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of (2R)-benzyl 7-oxo-6-oxa-8-azaspiro[4.5]decane-2-carboxylate (from step C, 22 mg, 0.076 mmol) in MeOH (1 mL) was added palladium on carbon (10% wt., 8.09 mg, 7.60 μmol). The resulting mixture was stirred under a hydrogen balloon for 30 min. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to yield (2R)-7-oxo-6-oxa-8-azaspiro[4.5]decane-2-carboxylic acid (15 mg, 0.075 mmol, 99% yield) as an oil. MS=200 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([Br:13])[CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Br:13])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(N)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Br)c(C(=O)O)cc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
A solution of the intermediate methyl 4-amino-2-bromo-5-fluorobenzoate (5.24 mmol, 1.3 g) in tetrahydrofuran (15 mL) was treated with a solution of lithium hydroxide (15.72 mmol, 0.66 g) in water (15 mL) and stirred at 60° C. for 4 hours. The reaction mixture was then cooled to room temperature, taken to ˜pH 5 with dilute hydrochloric acid and concentrated under vacuum. The residue was dissolved in tetrahydrofuran and purified by column chromatography (9:1 dichloromethane/methanol) to give the title compound (1.1 g). 1H NMR ((CD3)2SO, 400 MHz): δ6.11 (2H, s), 7.02 (1H, d), 7.52 (1H, d)
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:15][CH2:14][C:9]1([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: N#CC1(N(Cc2ccccc2)Cc2ccccc2)CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(N(Cc2ccccc2)Cc2ccccc2)CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a cooled solution of 3-(dibenzylamino)tetrahydrofuran-3-carbonitrile (2.2 g, 7.5 mmol) in tetrahydrofuran (50 mL) at 0° C., was added lithium aluminium hydride (855 mg, 22.5 mmol). After the mixture being stirred for 16 hours at room temperature, the reaction was quenched by addition of water (5 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo to afford 1.3 g of the crude product (yield was 58%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12](=[O:49])[NH:13][CH:14]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]([C:35](=[O:38])[NH:36][CH3:37])[CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[CH2:19][CH:18]2[CH2:39][CH3:40])=[O:16])[CH2:9]1)=O)(C)(C)C.ClCCCl.C(Cl)Cl.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].O>>[F:60][C:59]([F:62])([F:61])[C:57]([OH:63])=[O:58].[CH2:39]([CH:18]1[CH2:19][N:20]([CH:23]([C:35](=[O:38])[NH:36][CH3:37])[CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:21][CH2:22][N:17]1[C:15](=[O:16])[CH:14]([NH:13][C:12]([CH:10]1[CH2:11][NH:8][CH2:9]1)=[O:49])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=1)[CH3:40]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[2-[2-ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-azetidine-1-carboxylic acid tert-butyl ester is dissolved in DCM/TFA/H2O (2/1/0.1) (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added, the solvent removed in vacuo to give a residue which is purified by preparative HPLC to afford 300 mg of the desired product. 1H NMR (CDCl3, 300 MHz, δ): 7.71–7.64 (m, 3H), 7.55–7.54 (m, 1H), 7.40–7.31 (m, 2H), 7.26–7.13 (m,3H), 6.97–6.87 (m, 3), 5.00 (t, J=7.7 Hz, 1H), 4.46 (br s, 0.5H), 4.32 (d, J=13.8 Hz, 0.5H), 4.08–3.86 (m, 6H), 3.68–3.63 (m, 0.5H), 3.60–3.49 (m, 1.5H), 3.47–3.41 (m, 0.5H), 3.25–3.00 (m, 2H), 3.14–3.03 (m, 3H), 2.98–2.65 (m, 5.5H), 2.54–2.35 (m, 3H), 1.77–1.56 (m, 1.5H), 1.55–1.36 (m, 0.5), 0.69–0.58 (m, 3H); 13C NMR, (CDCl3, 75 MHz) δ 175.0, 173.0, 172.0, 166.0, 163.0, 135.4, 134.1, 133.0, 132.9, 132.8, 132.7, 129.7, 129.5, 129.4, 129.0, 128.9, 128.8, 128.7, 127.7, 127.6, 127.3, 127.1, 117.1, 116.8, 116.5, 71.3, 71.2, 56.8, 53.9, 53.4, 52.2, 52.0, 51.9, 50.7, 50.3, 50.1, 50.0, 49.1, 41.6, 39.7, 38.4, 37.0, 35.7, 26.4, 24.0, 23.4, 11.1; HRFAB(positive) m/e 574.317945 calculated for C33H40FN5O3 (M+H)+, Found 574.319344.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:23][CH:24]([CH3:28])[CH2:25][CH2:26][OH:27])=[N:5][C:6]([CH2:21][CH3:22])=[C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)[N:8]=1)[CH3:2].I[CH2:30]C.IC>>[CH2:1]([C:3]1[C:4]([NH:23][CH:24]([CH3:28])[CH2:25][CH2:26][O:27][CH3:30])=[N:5][C:6]([CH2:21][CH3:22])=[C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)[N:8]=1)[CH3:2]
Reactant: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCO
Reactant: CCI
Solvent: CI
Product: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCOC
Yield: 87 %

Procedure:
Following the general procedure of Example 13 Step 3 and making non-critical variations but substituting (2S)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol with 3-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}butan-1-ol (Example 39, 95 mg, 0.24 mmol) and iodoethane with iodomethane the reaction was carried out and gave 108 mg of a crude yellow oil. This material was purified by Biotage MPLC (40 g column, 20% ethyl acetate in heptane) to give 85 mg (87%) of 3,6-diethyl-N-(3-methoxy-1-methylpropyl)-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-amine as a clear oil. Rf 0.30 (5% acetone in toluene). IR (liq.) 2965, 2933, 2873, 1567, 1551, 1494, 1465, 1446, 1392, 1248, 1233, 1204, 1197, 1121, 1110 cm−1. OAMS supporting ions at: ESI+398.2.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:9]=1[C:10](=[O:21])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:5])C.[OH-].[K+].Cl>O1CCOCC1>[C:4]([CH2:6][O:7][C:8]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:9]=1[C:10](=[O:21])[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1c(CC=C(C)C)c(OC)cc(OC)c1C(=O)C=Cc1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Then, 23.7 g of 2'-ethoxycarbonylmethoxy-4,4',6'-trimethoxy-3'-(3-methyl-2-butenyl)chalcone was dissolved in 100 ml of dioxane, and 100 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 30 minutes to effect a reaction. After the reaction, the reaction mixture was made acidic by hydrochloric acid to obtain a yellow precipitate. The precipitate was recovered by filtration, washed with water, dried and recrystallized from ethyl acetate to obtain 18.5 g (yield=83.0%) of 2'-carboxymethoxy-4,4',6'-trimethoxy-3'-(3-methyl-2-butenyl)chalcone in the form of a light-yellow prism.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.O.[NH2:11][NH2:12]>C(O)C>[Br:1][C:2]1[C:3]([NH:11][NH2:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nc(Cl)ncc1Br

Procedure:
A 500 mL round bottom flask was charged with 5-bromo-2,4-dichloropyrimidine (13.5 g, 59.2 mmol), hydrazine hydrate (8.8 mL, 181 mmol) and absolute ethanol (300 mL). The resulting solution was refluxed under N2 for 12 h. Work-up: the resulting crystalline solid was collected by filtration. The solid was washed with ethanol (100 mL), and dried to afford 17 g (quantitative) of the product as a yellow solid, which was used in the next step without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:44]([OH:46])=O)[CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[CH3:48][C:49]1[N:53]=[C:52]([CH:54]([NH2:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:51][N:50]=1.C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29](=[O:30])[NH:31][C@@H:32]([C:44](=[O:46])[NH:62][C@@H:54]([C:52]1[O:51][N:50]=[C:49]([CH3:48])[N:53]=1)[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: Cc1noc(C(N)Cc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Yield: 80.3 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.3 g, 32.9 mmol) and 1-hydroxybenzotriazole monohydrate (5.0 g, 32.9 mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)-alanine (10.4 g, 32.9 mmol) in N,N-dimethylformamide (140 ml). After 1 h at 20° C. a mixture of 1-(3-methyl-[1,2,4]oxadiazole-5-yl)-2-phenylethylamine hydrochloride (5.6 g, 23.5 mmol) and triethylamine (2.37 g, 23.5 mmol) in N,N-dimethylformamide (100 ml) were added. After 18 h at 20° C. the reaction mixture was poured onto water (1.4 L) and extracted several times with ethyl acetate (total 1.4 L). The combined organic phases were washed with aqueous citric acid (10%, 200 ml), a saturated solution of sodium hydrogencarbonate (200 ml) and water (3×200 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from ethyl acetate and heptane to give 9.45 g of {(1R)-1-{(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+].[IH:27]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([I:27])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: I
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(I)cnn1Cc1ccccc1
Temperature: 115 °C

Procedure:
2-Benzyl-4,5-dichloropyridazin-3(2H)-one (32.3 g, 127 mmol) was dissolved in hydriodic acid (223 mL) and the mixture was refluxed at 115° C. overnight. The mixture was poured into dichloromethane and 30% sodium thiosulphate (250 mL), and extracted with dichloromethane (3×250 mL). The combined organics were washed with 30% sodium thiosulphate several times (total 1 L), dried (sodium sulfate), and concentrated. Dichloromethane was added to the residue and the precipitate was collected by filtration to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.17 (s, 1H); 7.61 (s, 1H); 7.23-7.33 (m, 5H); 5.17 (s, 2H). LRMS (APCI) calc'd for (C11H10IN2O) [M+H]+, 313.0. found 313.0.
Reaction SMILES: Br[C:2]1[C:3]([Cl:27])=[C:4]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[I-].[C:29]([O:33][C:34]([N:36]1[CH2:39][CH:38]([Zn+])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C)C(=O)C.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].[Cu]I>[C:13]([O:12][C:11]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]1[C:3]([Cl:27])=[C:2]([CH:38]2[CH2:37][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:39]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(Br)c2Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(C3CN(C(=O)OC(C)(C)C)C3)c2Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (1 g, 1.882 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.129 g, 0.188 mmol), and copper(I) iodide (0.072 g, 0.376 mmol) in N,N-Dimethylacetamide (0.6 mL) in a dry microwave vial was evacuated and backfilled with N2 for 3 times. (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (5.94 mL, 5.64 mmol, approximately 0.95 M solution in N,N-dimethylacetamide prepared as described in the Journal of Organic Chemistry, 2004, 69, 5120) was then added. The mixture was evacuated and backfilled with N2 one more time and then heated at 80° C. for overnight. After cooling to RT, the reaction was partitioned between EtOAc and sat. aq. NH4Cl solution. This was left stirring for 30 min. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine and dried with sodium sulfate. Removal of the solvents followed by silica gel chromatography eluting with hexane containing 5 to 15% EtOAc to afford tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)azetidine-1-carboxylate (0.98 g).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:16][CH2:17]O)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>>[CH3:1][C@@:2]1([CH2:16][CH2:17][Cl:39])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCCl)O2
Yield: 79.2 %

Procedure:
A mixture of 2 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman, 8 g of carbon tetrachloride and 2.6 g of triphenylphosphine was refluxed for 3 hours, after which the reaction mixture was allowed to cool, the precipitate formed was filtered off under suction and the filtrate was chromatographed over silica gel, using a 5:1 hexane/acetone solvent mixture. 1.7 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-chroman were obtained. [α]D20 =-9.1° (c=2, chloroform), mp.=111° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NC1CCN(CCO)CC1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCOC(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
1.4 Milliliters (0.012 mol) of benzoylchloride were added to a stirred solution of 2.48 grams (0.01 mol) of 4-benzamido-1-(2-hydroxyethyl)piperidine and 2.8 milliliters (0.02 mol) of triethylamine in 10 milliliters of dichloromethane. The solution was stirred at room temperature for 2 hours, then washed with water, dried and evaporated. The residue was crystallised from n-butyl acetate to give 2.5 grams (75% yield) of the title compound m.p. 139°-40° C. Treatment of a solution of the base in ethanol with ethanolic hydrogen chloride precipitated the hydrochloride, m.p. 217°-18° C.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:23]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][S:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)([CH3:23])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C(SC)c1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(SC)c1cccc(Oc2ccccc2)c1
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Methyl α-methylthio(m-phenoxyphenyl)acetate (1.963 g) was dissolved in anhydrous dimethylformamide, and under ice cooling, 280 mg (65% content) of sodium hydride was added. The mixture was stirred for 10 minutes. Then, 0.60 ml of methyl iodide was added, and the mixture was stirred under ice cooling for 5 minutes and then at room temperature for 30 minutes. After adding an aqueous solution of ammonium chloride (500 mg/40 ml), the reaction mixture was extracted three times with 20 ml of diethyl ether. The organic layer was washed three times with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane and benzene as eluents to afford 1.930 g of methyl α-methylthio-α-(m-phenoxyphenyl)propionate as an oil in a yield of 94%. Distillation of this substance gave a fraction boiling at 147°-149° C./0.08 mmHg.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27](Cl)=[O:28])[CH:22]=1.Cl>ClCCCl>[CH3:30][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:27]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:27](=[O:28])[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:30])[CH:22]=3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:28]
Reactant: c1ccc(OCCOc2ccccc2)cc1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cccc(C(=O)c2ccc(OCCOc3ccc(C(=O)c4cccc(C)c4)cc3)cc2)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of anhydrous aluminum chloride (24 g) in 300 ml dry 1,2-dichloroethane is added 1,2-diphenoxyethane (17.8 g, 0.083 mole) at room temperature. To this mixture is added over a period of 30 minutes m-toluoyl chloride (27 g, 0.17 mole). The temperature of the reaction rises to 40° (all temperatures are Centigrade) and hydrogen chloride gas evolves from the mixture. Following the addition of the m-toluoyl chloride the reaction is externally heated to 65° plus or minus 3°. This temperature and stirring are maintained for 22 hours. The mixture is then allowed to cool to room temperature and poured on 1 kg of crushed ice to destroy the aluminum chloride complex. The ice is allowed to melt and the water separates from the organic layer. The latter is washed twice with 200 ml of 10% hydrochloric acid, three times with water and the solvent removed by distillation. The residual crude crystals are crystallized from dichloroethane, yield 15.9 g (43%) mp 164° - 167°. Calculated for C30H26O4 : C, 79.98%; H, 5.82%. Found: C, 79.65%; H, 5.88%.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:39])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:39][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][N:36]([CH3:37])[CH3:38])=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CN(C)Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CN(C)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)cc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(4-dimethylaminomethyl-phenyl)2H-pyrazol-3-ylamine. Title compound: ES-MS: 506.49 [M-H]+; RTT=1.30 min (HPLC System 3).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.92 min, m/z=459.1-460.1 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.61 (m, 1H) 1.78-1.88 (m, 1H) 2.17-2.25 (m, 1H) 2.96 (dd, J=11.00, 6.60 Hz, 1H) 3.10-3.37 (m, 5H) 4.60 (t, J=5.14 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.48 (dd, 1H) 7.81 (dt, J=7.82, 1.83 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.20 Hz, 1H) 8.57 (dd, J=4.65, 1.47 Hz, 1H) 8.64 (d, J=1.96 Hz, 1H) 8.76 (d, J=2.45 Hz, 1H) 10.17 (s, 1H).