Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>>[C:1]([O:5][C:6](=[O:12])[CH2:7][N:8]([CH2:9][CH2:10][OH:11])[C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: CC(C)(C)OC(=O)CNCCO
Solvent: CI
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N(CCO)CC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
In the same manner as described in Example 2-(5), N-(2-hydroxyethyl)glycine t-butyl ester (0.25 g, 1.43 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (0.714 g, 1.57 mmol) in the presence of EDC·MeI (0.466 g, 1.57 mmol) to give 0.46 g (51%) of N-(2-hydroxyethyl)-N-[(R)-3-tetradecanoyloxytetradecanoyl]glycine t-butyl ester as an amorphous solid: 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.5 Hz), 1.15-1.7 (m, 51H), 2.26 (t, 2H, J=7.5 Hz), 2.60 (dd, 1H, J=6.5, 15 Hz), 2.86 (dd, 1H, J=6.7, 15 Hz), 3.40-4.15 (m, 7H), 5.25 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:3]=12.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:70][C:71]1[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][C:72]=1[C:78]1[CH:83]=[C:82]([NH2:84])[CH:81]=[CH:80][N:79]=1.CC(C)([O-])C>O1CCOCC1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:70][C:71]1[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][C:72]=1[C:78]1[CH:83]=[C:82]([NH:84][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[N:9][N:10]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)[C:3]=23)[CH:81]=[CH:80][N:79]=1
Reactant: Cc1ccc(F)c(-c2cc(N)ccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3nccc(I)c32)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C5CCNCC5)c34)ccn2)c1
Temperature: 120 °C
Yield: 63 %

Procedure:
tert-Butyl 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)piperidine-1-carboxylate (57.0 mg, 0.067 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (41.4 mg, 0.067 mmol), 2-(2-fluoro-5-methylphenyl)pyridin-4-amine (40.4 mg, 0.200 mmol) and t-butoxide (17.91 mg, 0.186 mmol) were dissolved in dioxane (3 mL) and sparged with N2. Palladium(II) acetate (29.9 mg, 0.133 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (41.4 mg, 0.067 mmol) were added next and the mixture was heated at 120° C. for 2 hours. The reaction was cooled to room temperature and diluted with methanol. This mixture was filtered and the filtrate was purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 15-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-1-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (17 mg, 32%)
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][CH3:8])[C:5]([CH:9]=[O:10])=[N:4][C:3]=1[CH3:11].[BH4-].[Na+]>CO>[Br:1][C:2]1[N:6]([CH2:7][CH3:8])[C:5]([CH2:9][OH:10])=[N:4][C:3]=1[CH3:11]
Reactant: CCn1c(C=O)nc(C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCn1c(CO)nc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 87 mg (0.4 mmol) 5-bromo-1-ethyl-4-methyl-1H-imidazole-2-carbaldehyde in 5 ml of MeOH is added 46 mg (1.2 mmol) of NaBH4. The mixture is stirred at room temperature for 3 hours and the solvent is removed in vacuo. The residue is dissolved in 15 ml of EtOAc and washed with 10 ml of water and 10 ml of brine. The organic phase is dried (Na2SO4), filtered and evaporated. This clear oil is used in next step without further purification. MS m/z (M+1)+ 219.
Reaction SMILES: C[Al](C)C.CO[C:7]([CH:9]1[CH2:14][S:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[NH:10]1)=[O:8].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[O:33][CH3:34]>>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:7]([CH:9]2[CH2:14][S:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[NH:10]2)=[O:8])=[CH:28][C:27]=1[O:33][CH3:34]
Reactant: COc1cc(N)ccc1Cl
Reactant: COC(=O)C1CSCC(c2ccc(OC)c(OC)c2)N1
Agent: C[Al](C)C
Product: COc1cc(NC(=O)C2CSCC(c3ccc(OC)c(OC)c3)N2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A 2.0M solution of trimethylaluminum (0.39 ml, 0.78 mmol, 3.5 equivalents) was added to a solution of 5-(3,4-dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid methyl ester (67 mg, 0.22 mmol, 1.0 equivalents) and 4-chloro-3-methoxyaniline (106 mg, 0.68 mmol, 3.0 equivalents). The solution was stirred at 50° C. for 18 hours. The reaction was quenched with 1N NaOH and extracted with dichloromethane. The dichloromethane extracts were dried with MgSO4, filtered and concentrated. The residue was purified on a 1000 micron preparative TLC. 5-(3,4-Dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid (4-chloro-3-methoxy-phenyl)-amide was obtained as a peach solid (71 mg, 76% yield). Analysis H1 NMR (400 MHz, CDCl3): 8.61 (1H, s), 7.58 (1H, m), 7.26 (1H, m), 6.90 (2H, m), 6.78 (1H, d), 4.04 (1H, m), 3.91 (10H, m), 2.98 (1H, m), 2.78 (2H, m), 2.59 (1H, m). MS (LC-MS): Calculated for C20H23ClN2O4S 423.11. Found 423.22.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10]([O:13][CH3:14])([O:11][CH3:12])[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)(=O)[CH3:2].O1CCC[CH2:23]1.N1C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.[CH3-].C[Al]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+4].ClCCl>[CH:1]([O:4][CH:5]1[C:10]([O:13][CH3:14])([O:11][CH3:12])[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)([CH3:23])[CH3:2]
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OC(C)=O
Reactant: C1CCOC1
Agent: [Ti+4]
Agent: C[Al]C
Agent: [CH3-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OC(C)C
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
tert-Butyl 3-acetoxy-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (147a) (1.58 g, 4.94 mmol) was dissolved in toluene (22.5 mL), tetrahydrofuran (7.5 mL) and pyridine (0.75 mL), followed by cooling to −40° C. Tebbe's reagent (0.5 M solution in toluene, 25 mL, 12.5 mmol) was added at the same temperature, and the mixture was stirred at −10 to −40° C. for 1.5 hours. A 1 N aqueous sodium hydroxide solution and dichloromethane were added, and the precipitate was filtered off. The organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. Methanol was added to the resulting residue, and the precipitate was filtered off again. 10% palladium-carbon (wet, 3.0 g) was added to the resulting solution, which was catalytically hydrogenated at room temperature for three hours. The catalyst was filtered off, and then the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate) to obtain 701 mg of the title compound as a colorless solid (47%).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:36])(=[O:35])[NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH:32]1([CH2:31][NH:30][S:29]([C:26]2[CH:27]=[CH:28][C:20]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:21]([CH:25]=2)[C:22]([OH:24])=[O:23])(=[O:36])=[O:35])[CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1Cl
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1N1CCOCC1
Yield: 33 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(cyclopropylmethyl-sulfamoyl)-benzoic acid and morpholine and obtained in 33% yield. MS (m/e): 339.2 (MH−, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Mg].[F:10][C:11]([F:18])([F:17])[C:12](OCC)=[O:13].[NH4+].[Cl-].Cl>C(OCC)C>[F:10][C:11]([F:18])([F:17])[C:12]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:13]
Reactant: Cc1ccccc1Br
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccccc1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A Grignard reagent is prepared from 25.0 g (0.146 mol) of 2-bromotoluene and 4.3 g (0.175 mol) of magnesium in 100 ml of diethyl ether. The Grignard reagent is added dropwise to a solution of 22.8 g (0.161 mol) ethyl trifluoroacetate in 120 ml of diethyl ether at −78° C. The reaction mixture is allowed to warm to room temperature and stirred for one additional hour. 300 ml of NH4Cl aq and 100 ml of 1N HCl are then added to the mixture. The aqueous phase is removed, the organic phase is washed with NH4Cl aq and brine, dried over MgSO4, and concentrated. The residue is purified by flash chromatography on silica gel with hexane as an eluent, yielding 6.3 g of 2,2,2-trifluoro-1-(2-methylphenyl)-ethanone as colorless liquid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC/C=C\CCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCC/C=C\CCCCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
Alcohol 7 (115 mg, 0.541 mmol) in dichloromethane (100 ml) at 0° C. was treated successively with carbon tetrabromide (395 mg, 1.20 mmol) and triphenylphosphine (312 mg, 1.20 mmol), and allowed to warm to room temperature with stirring over 2 h. The reaction mixture was triturated with water and extracted with methylene chloride, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using hexanes as an eluent, thus affording pure 8 as a light oil (105 mg, 0.381 mmol, 70%); δH(270 MHz, CDCl3); 0.87 (3H, t, J=6.1 Hz), 1.1-1.65 (14H, m), 1.85 (2H, quin, J 7.0), 2.03 (4H, m), 3.4 (2H, t, J 6.8) and 5.35 (4H, m); δC(67.5 MHz, CDCl3) 27.06, 27.32 27.72, 27.91, 28.04, 28.96, 29.32, 29.37, 29.71, 29.83, 31.96, 32.82, 34.01, 129.31, 130.47.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>C(O)(C)C>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:15])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc2c(c1C)C(=O)CC2
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc2c(c1C)C(N)CC2

Procedure:
6,7-Dimethyl-1-indanone (2.50 g, 15.60 mmol), NaBH3CN (6.90 g, 0.11 mol) and NH4OAc (36.00 g, 0.47 mol) in isopropanol were reacted according to the protocols as outlined in general procedure E to afford the title indanamine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.6 (br s, 2H), 1.83-1.96 (m, 1H), 2.01-2.11 (m, 1H), 2.26 (s, 3H), 2.31 (s, 3H), 2.72-2.87 (m, 1H), 3.05-3.18 (m, 1H), 4.42-4.50 (m, 1H), 6.95-7.09 (m, 2H).
Reaction SMILES: [H-].[Na+].C([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]2)(=O)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]1([CH2:29][C:30]([C:44]([F:47])([F:46])[F:45])([OH:43])[CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][CH2:27]1.[OH-].[Na+]>CCCCCC.C(OCC)(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]1([CH2:29][C:30]([C:44]([F:47])([F:45])[F:46])([OH:43])[CH:31]([NH:6][C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)[NH:6][C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)[CH2:28][CH2:27]1
Reactant: CC(=O)Nc1cccc2nc(C)ccc12
Reactant: Cc1ccc(S(=O)(=O)OCC(O)(CC2(c3cc(F)ccc3F)CC2)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NC(Nc3cccc4nc(C)ccc34)C(O)(CC3(c4cc(F)ccc4F)CC3)C(F)(F)F)cccc2n1
Yield: 18.4 %

Procedure:
Analogously to Example 76, 60 mg (1.46 mmol) of NaH (60%) and 244 mg (1.23 mmol) of 5-acetylamino-2-methyl-quinoline are reacted with 365 mg (0.81 mmol) of toluene-4-sulfonic acid-3-[1-(2,5-difluorophenyl)-cycloprop-1-yl]-2-(trifluoromethyl)-2-hydroxy-propyl ester. The crude product is treated analogously to Example 76 with 1 M sodium hydroxide solution. After chromatography on silica gel with hexane-ethyl acetate (30-50%), 67 mg of product is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:23]1[C:24]([CH3:46])=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)=[O:29]>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>[CH3:46][C:24]1[C:23]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:37][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][N:34]=[N:33][CH:32]=2)=[O:29])=[C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)Nc2ccnnc2)cc1Br
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: Cc1cc(OCc2ccccc2)c(C(=O)Nc2ccnnc2)cc1-c1cnn(C)c1

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (86 mg, 0.42 mmol), palladium tetrakis (26.1 mg, 0.02 mmol) and Na2CO3 (0.75 ml, 0.75 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 5; 150 mg, 0.38 mmol) in 1,2-dimethoxyethane (3 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.CS(C)=[O:25].OO.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:25])[CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:21][CH:22]=1
Reactant: CS(C)=O
Reactant: N#Cc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared according to the reference: Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989, 949. As described, a solution of 4-(2-(4-aminophenoxy)pyridin-3-yl)picolinonitrile (764 mg, 2.65 mmol) in DMSO (0.883 mL, 2.65 mmol) was cooled to 0° C. 2.7 mL of 30% Hydrogen peroxide in water was added followed by potassium carbonate (37 mg, 0.27 mmol). The solution became a thick, milky white suspension. The mixture was warmed to rt. After 10 min, 1 mL of H2O2 and 20 mg of K2CO3 were added. After 20 min, LC-MS showed that the reaction was completed. The white solid was filtered off and washed with water. The product was dried under vacuum, to afford 4-(2-(4-aminophenoxy)pyridin-3-yl)picolinamide. MS m/z=307 [M+1]+. Calcd for C17H14N4O2: 306.11.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([CH3:14])[NH:11]2)=[CH:6][CH:5]=1.[Br:17]C1C=C2C(=NC=1C(OC)OC)NCCC2>>[Br:17][C:5]1[CH:6]=[C:7]2[C:12](=[N:13][C:4]=1[CH:3]([O:2][CH3:1])[O:15][CH3:16])[NH:11][CH:10]([CH3:14])[CH2:9][CH2:8]2
Reactant: COC(OC)c1ccc2c(n1)NC(C)CC2
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Product: COC(OC)c1nc2c(cc1Br)CCC(C)N2

Procedure:
From (racemic) 7-(dimethoxymethyl)-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 260), synthesized in an analogous manner to intermediate 12, the title compound was obtained as a light brown oil. (UPLC-MS 6) tR 0.90; ESI-MS 301.1/303.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])/[C:5](=[N:7]/C)/[CH3:6].Cl.NO>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:7][O:18][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[Cl:17])=[O:19]
Reactant: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)cc1Cl
Agent: Cl
Agent: NO
Product: COC(=O)c1c(C)noc1-c1ccc(Br)cc1Cl

Procedure:
Following the procedures described in Example 36: 4-bromo-2-chlorobenzoic acid and oxalyl chloride were reacted to provide 4-bromo-2-chloro-benzoyl chloride, which was reacted with 3-methylamino-but-2-enoic acid methyl ester to provide 2-(4-bromo-2-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester. 2-(4-Bromo-2-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester and hydroxylamine hydrochloride were then reacted to provide 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester. Following Example 36, Step 4, 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester was hydrolyzed to 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid. 5-(4-Bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid and (R)-1-(2-chloro-phenyl)-ethanol were then reacted as described in Example 36, Step 5 to provide [5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])=[C:15]([C:26]#[CH:27])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.[H][H]>O1CCOCC1.O.[Pt]>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[O:20])=[C:15]([CH2:26][CH3:27])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C#Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: [H][H]
Agent: [Pt]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 99 %

Procedure:
60 mg (0.143 mmol) of N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-ethynyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is dissolved in 6.0 mL dioxane/water (1:1), combined with 8.0 mg platinum/activated charcoal and hydrogenated for 7 hours with hydrogen (3 bar). Then the catalyst is filtered off and the solvent is distilled off. Yield: 99%; Rf value: 0.15 (Reversed-phase-8; methanol/5%-NaCl solution=3:2); C23H25ClN4O2 (424.93); mass spectrum: (M−H)-=423/425 (chlorine isotope) and (M+H)+=425/427 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(F)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,4-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1.O[Li].O.Cl>O.C1COCC1>[Cl:24][C:19]1[CH:18]=[C:17]([CH:4]([CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:11][CH2:12]2)[C:3]([OH:25])=[O:2])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: COC(=O)C(CCN1CCN(S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCN(CCC(C(=O)O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
A mixture of 1.42 g (3.4 mmol) 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid methyl ester and 0.182 g (4.3 mmol) LiOH.H2O in 30 mL water and 30 mL THF was heated to reflux for 1 h. The mixture was treated with 4N HCl aq. and evaporated to dryness. The residue was used without further purification in the subsequent step. MS(m/e): 395.0 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)[C:12]([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[CH2:11]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=[O:23])[CH2:18][CH2:17]1)[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)CN1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)CN1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of oxalyl chloride (490 μL, 5.6 mmol) in DCM (10 mL) at −78° C. was added DMSO (796 μL, 11.2 mmol) dropwise followed by the addition of a solution of 20b (943 mg, 5.6 mmol) in DCM (2 mL). The mixture was stirred at −78° C. for 30 min and TEA (3.6 mL, 25.5 mmol) was added. The reaction was stirred at −78° C. for 5 min, warmed to rt and stirred at rt for 30 min. The reaction was quenched with water and extracted with DCM. The organic layers were combined and washed with water, dried over magnesium sulfate to give 20c as a yellow semi-solid (880 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:16]([O:19][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)(=[O:18])[CH3:17]
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 99.7 %

Procedure:
m-Phenoxybenzyl chloride (218.5 g; 1 mole), sodium acetate (205 g; 2.5 mole), tetrabutylammonium bromide (10.9 g; 0.034 mole) and water (327 ml) were heated and stirred under reflux for 2 hours. On cooling m-Phenoxybenzyl acetate (241.5 g; 99.8% yield) separated as the upper layer. Its purity was 99%. m-Phenoxybenzyl acetate (242 g; 1 mole), sodium hydroxide (80 g; 2 mole), tetrabutylammonium bromide (12 g; 0.037 mole) and water (240 ml) were stirred at ambient temperature for 4 hours. The upper organic layer was dissolved in toluene (400 ml). The resulting solution was washed with water (2×200 ml) and treated with ion-exchange resin (Zerolit 236) and charcoal. Evaporation of the toluene gave the alcohol with a purity of 98.9% by gas chromatography (198 g, 99% yield).