Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:12][Zn]C>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.O1CCOCC1>[Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Brc1cc(I)cc2nnsc12
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cc(Br)c2snnc2c1
Temperature: 50 °C
Yield: 59.5 %

Procedure:
To a solution of 7-bromo-5-iodo-1,2,3-benzothiadiazole (30 mg, 0.088 mmol), Pd(PPh3)4 (10.2 mg, 0.0088 mmol) and 1,4-dioxane (5 mL) was added dimethylzinc (2 M in toluene, 0.1 mL, 0.210 mmol), and the reaction was heated to 50° C. for 3 h. The solution was quenched with MeOH (1 mL), adsorbed onto silica gel, and purified by ISCO chromatography (1 to 3% EtOAc:heptane) to afford 12 mg (60%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.52 (s, 3 H), 7.58 (s, 1 H), 8.27 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]([NH:5][C:6]([NH2:8])=[S:7])=[O:4].O.[OH-].[Na+].I[CH2:14][CH3:15]>CO>[CH3:1][N:2]([CH3:9])[C:3](=[O:4])[NH:5][C:6](=[NH:8])[S:7][CH2:14][CH3:15]
Reactant: CN(C)C(=O)NC(N)=S
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCSC(=N)NC(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 58.5 parts of 1,1-dimethyl-4-thiobiuret in 200 parts of water, 200 parts of methanol and 32 parts of 50% aqueous sodium hydroxide are added at 25° C. within 10 minutes 62.5 parts of iodoethane. The reaction mass is then stirred at 25° C. for 2 hours. Evaporation of the methanol and part of the water under vacuum gives 64 parts of crude ethyl 4,4-dimethylthioallophanimidate (a compound of formula II), which is recrystallized from water-methanol (50:50) and shows a melting point of 90°-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:44][C:45]1[N:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:52][CH2:51][C:48]1[CH:49]=[N:50][C:45]([CH3:44])=[CH:46][CH:47]=1)=[O:7]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Cc1ccc(CN)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1C(=O)NCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Methoxy-4-nitrobenzoic acid (293 mg, 1.49 mmol) is dissolved in DMF (2 mL) and 4-methylmorpholine (220 μL, 3.0 mmol) and TBTU (1.79 g, 1.7 mmol) are added. The mixture is stirred at rt for 30 min and C-(6-methylpyridin-3-yl)methylamine (400 mg, 3.27 mmol) is added. Stirring is continued at rt for 12 h. DCM (10 mL) is added and the organic phase is washed with Na2CO3 (5% aq.), HCl (3% aq.) and water, and then dried over Na2SO4. After evaporation of the solvents, the residue is triturated with ether-hexane to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22].Br[CH2:29][CH2:30][Cl:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:31][CH2:30][CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(O)cc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(OCCCl)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.7 %

Procedure:
The suspension of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (50 mg, 0.14 mmol), 1-bromo-2-chloroethane (0.015 ml, 0.15 mmol), and potassium carbonate (23 mg, 0.17 mmol) in DMF (5 mL) was stirred for 3 days at room temperature. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (1×20 mL) and brine (1×20 mL) and was dried over MgSO4. After filtration and evaporation, the crude product was obtained, which was washed with hexane and dried to give 48 mg of 2-(6-(2-chloroethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide as light brown solid (79%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[C:9]([C:13]([OH:15])=[O:14])=[CH:8]2)=O.[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].ClCCl.CO>ClCCl.CO.O>[CH3:12][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][N:27]2[CH2:28][CH2:29][N:24]([C:22]([C@@H:18]3[CH2:19][CH2:20][CH2:21][N:17]3[CH3:16])=[O:23])[CH2:25][CH2:26]2)[CH:8]=[C:9]1[C:13]([OH:15])=[O:14]
Reactant: CN1CCCC1C(=O)N1CCNCC1
Reactant: Cn1c(C(=O)O)cc2cccc(C=O)c21
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN1CCC[C@H]1C(=O)N1CCN(Cc2cccc3cc(C(=O)O)n(C)c23)CC1

Procedure:
7-formyl-1-methyl-1H-indole-2-carboxylic acid and (1-methyl-pyrrolidin-2-yl)-piperazin-1-yl-methanone are used as reaction partners. After the reaction has ended the solvents are eliminated in vacuo and the residue is taken up in a little dichloromethane/methanol 80:20. The solution is added to a short layer of silica gel and sucked into a vacuum suction flask by the application of reduced pressure. Then dichloromethane/methanol/water 1:1:0.1 is added in several small batches and again the solution is sucked into a vacuum suction flask by the application of reduced pressure. The fractions containing the product are combined and evaporated down in vacuo.
Reaction SMILES: NC1C=CC(O[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=CC=1.[CH2:22]([N:26]1[CH:30]=[C:29]([C:31]2[S:35][C:34]([C:36]([OH:38])=O)=[CH:33][CH:32]=2)[CH:28]=[N:27]1)[CH:23]([CH3:25])[CH3:24].C(OC([N:49]1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[CH2:22]([N:26]1[CH:30]=[C:29]([C:31]2[S:35][C:34]([C:36]([NH:49][C@@H:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]3)=[O:38])=[CH:33][CH:32]=2)[CH:28]=[N:27]1)[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: CC(C)Cn1cc(-c2ccc(C(=O)O)s2)cn1
Product: CC(C)Cn1cc(-c2ccc(C(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)s2)cn1

Procedure:
The title compound was prepared as described in Example 1A, substituting (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 5-(1-isobutyl-1H-pyrazol-4-yl)thiophene-2-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 82.7 %

Procedure:
0.8 g (0.00323 mol) of ethyl 1-benzylpiperidine-4-carboxylate was dissolved in a mixture of 5 ml of dioxan, 2 ml of water and 3.5 ml (0.0035 mol) of 1N aqueous NaOH. After stirring for 15 min. 3.5 ml (0.0035 mol) of 1N aqueous HCI were added, the mixture was diluted with 20 ml of water, the dioxan was removed by distillation and the residue which remained was lyophilized. The residue was boiled twice with 100 ml of isopropanol each time and the combined organic phases were filtered and concentrated. The product crystallized out in the cold. 0.586 g (83%) of 1-benzylpiperidine-4-carboxylic acid was obtained as white crystals; m.p. 167°-168°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]34[CH2:24][CH2:23][C:20]([O:25]C)([CH2:21][CH2:22]3)[CH2:19][CH2:18]4)=[N:15][N:16]=2)[N:13]=1.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>Br>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]34[CH2:24][CH2:23][C:20]([OH:25])([CH2:19][CH2:18]3)[CH2:21][CH2:22]4)=[N:15][N:16]=2)[N:13]=1
Reactant: COC12CCC(c3nnc4cc(-c5ccc(Cl)cc5)c(-c5ccccc5Cl)nn34)(CC1)CC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: OC12CCC(c3nnc4cc(-c5ccc(Cl)cc5)c(-c5ccccc5Cl)nn34)(CC1)CC2
Temperature: 120 °C
Yield: 75.2 %

Procedure:
To a suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(4-methoxybicyclo[2.2.2]octan-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 18) (48 mg, 0.1 mmol) in aqueous (48%) hydrobromic acid solution (0.37 mL) was added dropwise acetic anhydride (0.33 mL). After addition, the reaction tube was sealed, and heated at 120° C. for 16 h. After cooling to room temperature, the reaction mixture was adjusted to pH 7-8 by careful addition of saturated aqueous NaHCO3, then extracted with EtOAc (10 mL×2). The combined organic was washed with water, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 70% to 100% B, 18 min gradient, 100% B hold for 3 min, (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to afford 35 mg (75%) of the title compound as a white solid. HPLC/MS (method A): retention time 3.61 min, (M+H)+=465.2.
Reaction SMILES: C(O)(=O)CCCCCCCC=CCCCCCCCC.[C:21]([Cl:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH2:31][CH:32]=[CH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:21]([Cl:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCC=CCC=CCCCCCCCC(=O)Cl
Agent: CCCCCCCCC=CCCCCCCCC(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)Cl
Yield: 85 %

Procedure:
Octadec-9-enoyl chloride (25.5 parts, boiling point 160°-180° C. at 0.12 Torr, 85% yield) was prepared from 28.1 parts of octadec-9-enoic acid using the procedure described in part A of Example 3 for the preparation of octadec-9,12-dienoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:9]=[C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(N3CCCC3)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(N3CCCC3)cn2c1C(=O)O
Temperature: 40 °C
Reaction time: 20 h

Procedure:
90 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methyl-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (Example 32A; 0.217 mmol, 1 equivalent) were dissolved in 6 ml of THF/methanol 5:1, 1.1 ml of 1N aqueous lithium hydroxide solution (1.1 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 20 h. The mixture was cooled, acidified to pH 4 with 6 N hydrochloric acid and concentrated. Water was added to the solid formed and the product was triturated, filtered off with suction, washed with water and dried under reduced pressure. This gave 87 mg of the title compound (93% of theory).
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][C:27]1[CH2:28]CNC[CH:32]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][C:27]1[CH2:28][CH2:19][N:16]([CH2:15][C:4]2[C:5]3[CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]=3[NH:2][N:3]=2)[CH2:18][CH:32]=1
Reactant: C1=C(CCc2ccco2)CCNC1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C1=C(CCc2ccco2)CCN(Cc2n[nH]c3c2CCc2ccccc2-3)C1

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.42 g), 4-(2-furan-2-ylethyl)-1,2,3,6-tetrahydropyridine (0.20 g) and diisopropylethylamine (0.20 cm3) in DMF (10 cm3) was heated under argon at 90° C. for 24 hours. The mixture was cooled, poured into water (50 cm3) and extracted with 10% ethyl acetate-diethyl ether (2×25 cm3). The extracts were dried (MgSO4), filtered and concentrated to give a brown oil. Preparative thin layer chromatography on silica, eluting with 10% methanol-dichloromethane+1% ammonia, gave the title compound as a brown off, which was recrystallised as its half-oxalate salt from ethanol-hexane (0.083 g; 18%), m.p. 205°-208° C. (from EtOH-hexane); Found: C, 70.85; H, 6.5; N, 10.05. C23H25N3O.0.5(CO2H)2.0.2(H2O) requires C, 70.6; H, 6.5; N, 10.3%. δH (360 MHz; d6 -DMSO) 2.16 (2H, broad s, NCH2CH2), 2.27 (2H, t, J 7.7, --CH2 --), 2.67-2.73 (4H, m, 2 x --CH2 --), 2.86-2.90 (4H, m, 2 x --CH2 --), 3.22 (2H, broad s, NCH2CH=C), 3.88 (2H, broad s, --CH2N), 5.42 (1H, broad s, NCH2CH=C), 6.1 (1H, d, J 3, furyl-H3), 6.33 (1H, dd, J 3 and 2, furyl-H4), 7.18-7.29 (3H, m, 3 of ArH), 7.48 (1H, d, J 2, furyl-H5) and 7.64 (1H, d, J 6.6, 1 of ArH); m/z (CI+ ; NH3) 360 (MH+ ; 30%), 204 (50) and 174 (100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].CCN(C(C)C)C(C)C.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S([O-])([O-])(=O)=O.[Mg+2]>CN(C=O)C>[CH2:17]([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)CN
Reactant: CCCCCCCCBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCNCC(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
Under argon condition, glycine methyl ester (358 mg, 2.85 mmol) was dissolved in 2 mL of dry DMF, and then DIPEA (620 μL, 3.56 mmol) and 1-bromooctane (123 μL, 0.712 mmol) were added, and the reaction mixture was stirred for one day at room temperature. Upon completion of the reaction, the reaction was terminated by adding 5 mL of water, and the reaction mixture was extracted with diethyl ether (4 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 31.6 mg (0.157 mmol, 22%) of the desired compound.
Reaction SMILES: [P:1]([O-:20])([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21]([O-:25])(C)([CH3:23])[CH3:22].[Na+].[CH2:27]([CH2:39][C:40](=[S:42])C)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]CC>COC(C)(C)C>[CH2:40]([S:42][CH2:22][C:21]([OH:25])([CH3:23])[P:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:20])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:39][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCCCCCCCCC(C)=S
Reactant: CCCCCCCCOP([O-])OCCCCCCCC
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CCCCCCCCCCCCSCC(C)(O)P(=O)(OCCCCCCCC)OCCCCCCCC

Procedure:
25.6 g (83.6 mmol) of dioctyl phosphite are initially introduced into 100 ml of tert-butyl methyl ether, 0.4 g of sodium tert-butanolate are added, and 20.0 g (77.4 mmol) of dodecylthioacetone are subsequently introduced.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:30]=[C:29]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])[CH:35]=5)[CH:28]=[CH:27][C:24]=4[C:25]=3[N:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[Cl:46]N1C(=O)CCC1=O.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([N:12]2[C:16]([Cl:46])=[CH:15][N:14]=[C:13]2[C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:30]=[C:29]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])[CH:35]=5)[CH:28]=[CH:27][C:24]=4[C:25]=3[N:26]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4C4CN(C(=O)OC(C)(C)C)C4)nc2-3)cn1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncc(Cl)n4C4CN(C(=O)OC(C)(C)C)C4)nc2-3)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 3-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (90.0 mg, 0.179 mmol) in N,N-Dimethylformamide (3.35 mL, 43.3 mmol) was added N-Chlorosuccinimide (19 mg, 0.14 mmol) and 1.00 M of Hydrogen chloride in Water (0.018 mL). The reaction was stirred at rt 4 h. the reaction was quenched with water then extracted with EtOAc 3×. The organic layer was dried Na2SO4, concentrated. The crude product was purified by isco column to give 3-(5-Chloro-2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (EtOAc/Hep eluted at 75%). MS: (ESI+)=483.1
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH3:22])[CH:13]=1)(=[O:10])[O:6][CH2:7][CH2:8][OH:9].[H][H]>CCO.[Pd]>[OH:9][CH2:8][CH2:7][O:6][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH3:22])[CH:13]=1)(=[O:10])[O:4][CH2:3][CH2:2][OH:1]
Reactant: [H][H]
Reactant: COc1cc(CP(=O)(OCCO)OCCO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CP(=O)(OCCO)OCCO)ccc1N
Yield: 82.4 %

Procedure:
A mixture of bis(2-hydroxyethyl)(3-methoxy-4-nitrobenzyl)phosphonate (Compound 133B, 1.2 g, 3.58 mmol) and 5% Pd/C (0.2 g) in EtOH (80 mL) was hydrogenated under 50 psi hydrogen pressure at 40° C. for 6 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (0.9 g, 82%).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=[C:9]2[CH2:8][CH2:7]1)(C)(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.N1C2C(=CC=CC=2)C=N1>C(Cl)Cl.Cl.CO>[NH:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=[C:9]2[CH:8]=[CH:7]1
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(C(=O)O)cnc21
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: c1ccc2[nH]ncc2c1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cnc2[nH]ccc2c1
Temperature: 25 °C
Yield: 3 %

Procedure:
A solution of crude acid 10 in CH2Cl2 (5 mL) was treated with DDQ in small portions until TLC analysis revealed no starting material left. The mixture was concentrated to afford a solid residue containing azaindole 11. The residue was dissolved in a 5% solution of HCl in MeOH (5 mL), and stirred at r.t. After 1.5 h the mixture was concentrated and diluted with CHCl3 and saturated brine. The mixture was basified with 50% NaOH solution to pH 11. The organic layer was discarded. The aqueous layer was neutralized with 6 M HCl and extracted with AcOEt (4×). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by PTLC using CH2Cl2:MeOH=9:1 as eluent to afford acid 12 (3.19 mg, 3% over 3 steps). 1H NMR (400 MHz; CD3OD) δ 6.58 (d, J=3.5 Hz, 1H), 7.42 (d, J=3.5 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.85 (d, J=1.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (20%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N+:35]([O-:37])=[O:36]>O>[N+:35]([C:26]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:25]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:37])=[O:36]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Indoline (402 μl, 3.59 mmol, commercially available product) and N,N-diisopropylethylamine (619 μl, 3.59 mmol) were sequentially added at 0° C. to a N,N-dimethylformamide (DMF; 2 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (498 mg, 2.38 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for one hour. The mixture was then heated at 70° C. for 5.5 hours with stirring. The mixture was cooled to room temperature. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=20/1). Thus, 1-(2-nitro-4-(trifluoromethyl)phenyl)indoline (730 mg, 99.4%) was yielded as a deep red oily material.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:23])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH:21]=C)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)(=[O:26])C>ClCCl>[C:1]12([CH2:11][NH:12][C:13](=[O:23])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH:21]=[O:26])[CH:15]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(=O)O
Reactant: C=Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Solvent: ClCCl
Product: O=Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: -78 °C

Procedure:
N-(1-Adamantylmethyl)-5-chloro-2-vinylisonicotinamide (Example 29(i)) (1.70 g) was dissolved in dichloromethane (50 mL), treated with acetic acid (1 mL) and cooled to −78° C. under nitrogen. Ozone was bubbled through the resulting solution for 2 hours while maintaining the temperature. Nitrogen was subsequently bubbled through the solution for 10 minutes and dimethylsulfide (2 mL) was added. The solution was warmed to room temperature washed with sodium bicarbonate (2×10 mL) and brine (30 mL); the organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:dichloromethane (1:20) to afford the sub-titled compound (1.13 g).