Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][OH:17])[C:13](=[O:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:26])[C:13](=[O:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 92.8 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(hydroxymethyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (17.37 g, 46.75 mmol) in DCM (480 mL) was added N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (60.1 g, 280.51 mmol). Then it was cooled to 0° C. and trimethyloxonium tetrafluoroborate (20.74 g, 140.25 mmol) was added. It was then stirred at rt for 6 h. Then it was concentrated under reduced pressure. The residue was then taken up in 100 mL Et2O and filtered, washed with 400 mL Et2O. The organic layer was then washed with 10% citric acid, aq. NaHCO3, brine, dried over MgSO4, filtered and concentrated to afford the desired product (16.73 g, 93%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]2[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]2[CH:18]([CH3:20])[CH3:19])[C:3]=1[C:4]#[N:5].O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C@@H:11]2[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]2[CH:18]([CH3:20])[CH3:19])[N:1]=[C:22]([CH3:29])[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1Oc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(O[C@@H]3C[C@H](C)CC[C@H]3C(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)benzonitrile (Example 122b) and ethyl 3-oxobutanoate as a pale yellow solid (43%). MS 385 (MH+).
Reaction SMILES: Cl.[CH2:2]([NH2:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+].C(N)CCCCCCCCCCCCCCCCC.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:51]=[CH:52][CH:53]=1)[CH2:47][N:48]=[C:49]=[S:50].[N-]=C=S>C(O)C.CCOCC>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:51]=[CH:52][CH:53]=1)[CH2:47][NH:48][C:49]([NH:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[S:50]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: COc1cccc(CN=C=S)c1
Agent: Cl
Agent: [N-]=C=S
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC(=S)NCc1cccc(OC)c1
Temperature: 4 °C
Reaction time: 0.33 h

Procedure:
Octadecyl amine hydrochloride was converted to the amine by mixing an ether solution of the amine hydrochloride with 1 M NaOH, separating and evaporating the ether layer, dissolving the amine in CHCl3, filtering through Whatman 541 filter paper and evaporating the CHCl3. Octadecyl amine (5.9252 g, 22.0 mmol) in 150 ml ethanol was reacted with an excess (4.32 g, 24.1 mmol) of 3-methoxybenzyl isothiocyanate at 40° C. under N2 with stirring. Excess isothiocyanate was used because co-crystallization of octadecyl amine is difficult to prevent when an excess of amine is present. After 2 h the solution was cooled to 4° C., centrifuged at 10,000 rpm for 20 min and the precipitated crystals were washed with ethanol (20 ml). The combined supernatant and wash was evaporated to 20 ml total volume and then cooled to −10° C. to filter off a second batch of crystals. The supernatant was dried and 94.3% of reagents weight was recovered, 74.9%, or 7.40 g as 1-(3-methoxybenzyl)-3-(octadecyl) thiourea of about 76% purity based on the sulfur analysis. The octadecyl amine was difficult to separate from the thiourea by crystallization. Calculated elemental analysis of 1-(3-methoxybenzyl)-3-octadecyl thiourea: C, 72.27; H, 10.78; N, 6.24; S, 7.15. Found: C, 71.96; H, 11.00; N, 5.95; S, 5.46. A recrystallization from acetone/chloroform gave crystals with the composition: C, 72.37; H, 10.98; N, 6.13; S, 6.92.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19]C)=[O:18])=[C:9]1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=[O:18])=[C:9]1[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C)n(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 49.9 %

Procedure:
To a solution of methyl 1-benzyl-2-methyl-1H-indole-3-carboxylate (446 mg, 1.6 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added sodium hydroxide (320 mg, 8 mmol) in water (7 mL), then stirred at 60° C. for 12 hours. The reaction mixture was concentrated in vacuo and acidified to PH=4 with 6 N hydrochloric acid, collected and dried to give 1-benzyl-2-methyl-1H-indole-3-carboxylic acid as a white solid (212 mg, 50%). LRMS (M+H+) m/z: calcd 265.11. found 265.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17]=2[C:15](=[O:16])[O:14][CH2:13][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N)C1C=CC=CC=1.Cl>>[CH2:19]([NH:26][C:15]([C:17]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][OH:14])=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1OCCc2cccc(-c3ccccc3)c21
Reactant: NCc1ccccc1
Agent: Br
Agent: Cl
Product: O=C(NCc1ccccc1)c1c(CCO)cccc1-c1ccccc1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 7.84 parts of 3,4-dihydro-8-phenylisocoumarin and 8 parts of benzylamine hydrobromide in 40 parts by volume of benzylamine is stirred at about 160° C. for about 4 hours. The reaction solution is then cooled and poured into 500 parts by volume of 5% hydrochloric acid. The oil which separates is extracted into methylene chloride and the extracts are washed with several portions of 5% hydrochloric acid, water, dried over anhydrous magnesium sulfate and the solvent removed to give, as a solid, N-benzyl-3-(2-hydroxyethyl)-2-biphenylcarboxamide. The solid is recrystallized from a mixture of chloroform and hexane to give white flocculant crystals melting at about 129°-130° C. This compound has the following formula ##STR13##
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([N+:30]([O-])=O)=[C:20]([CH2:33][N+:34]([O-])=O)[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Ni]>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]([NH2:30])=[C:20]([CH2:33][NH2:34])[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(C[N+](=O)[O-])c([N+](=O)[O-])cc3-c3ccccc3)cc2)CCC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(CN)c(N)cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl(1-(4-(5-nitro-6-(nitromethyl)-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (74 mg, 0.15 mmol) in EtOH (50 mL) was added Raney Nickel (17 mg, 0.15 mmol). The resulting mixture was purged with nitrogen and with H2 and then stirred under H2 (1.5 bars) overnight at room temperature. The black mixture was filtered through celite, rinsed few times with EtOH (making sure that the cake remained wet at all times), dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was used directly without purification.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][NH:30]C(=O)C6C(=CC=CC=6)C(O)=O)[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.C(O)C.NN>>[F:42][C:2]([F:1])([F:43])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][NH2:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1
Reactant: O=C(O)c1ccccc1C(=O)NCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: NN
Solvent: CCO
Product: NCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 60 °C
Yield: 9 %

Procedure:
To a solution of N-[2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-phthalamic acid (0.2000 g, 0.0003281 mol) in ethanol (3 mL, 0.05 mol) was added hydrazine (0.01133 mL, 0.0003609 mol). The mixture was heated to 60° C. overnight, cooled to room temperature and concentrated in vacuo. The crude was purified by reverse-phase HPLC to give 344 (13.6 mg) as a colorless solid. MS(ESI+) 462.1. 1H NMR (400 MHz, DMSO) δ 8.31-8.25 (m, 3H), 7.99 (s, 1H), 7.45 (dd, J=8.3, 1.8, 1H), 7.33 (d, J=1.8, 1H), 5.87 (q, J=8.7, 2H), 4.40 (t, J=5.0, 2H), 4.11 (t, J=6.3, 2H), 3.47 (t, J=5.0, 2H), 2.98 (t, J=6.3, 2H)
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[Na:15][Na].[OH-].[Na+]>>[Na+:15].[Na+:15].[O:1]=[C:2]([O-:14])[C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Reactant: [Na][Na]
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)[O-]

Procedure:
Isolation of D-mannaric acid as its disodium salt. Prior to titration with sodium hydroxide the solution was stirred at 60° C. for approximately 45 min to promote equilibration between D-mannaric acid acid and lactone species. The isolation procedure was then followed as in Example 1 to give crude mannaric acid disodium salt: 144.4 grams (92% based on pure disodium D-mannarate).
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([C:15]2[NH:1][C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1N
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cccc2nc(-c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2,3-diaminobenzoate (3.0 g) in methanol (60 mL) was added 1 N hydrochloric acid (0.6 mL) and benzaldehyde (1.7 mL), and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent under a reduced pressure, to the solution of the obtained residue in dichloromethane was added silica gel. The solvent was evaporated under a reduced pressure, and the resulting residue was heated at 100° C. for 1 hour. By purifying the reaction mixture by a silica gel column chromatography (eluent:hexane/ethyl acetate), the title compound was obtained as crystal (1.8 g).
Reaction SMILES: B(OC)(OC)OC.C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([C:37](=[O:39])[CH3:38])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>C1COCC1>[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([C@H:37]([OH:39])[CH3:38])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: CC(=O)c1cccc(S(C)(=O)=O)c1
Agent: COB(OC)OC
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Solvent: C1CCOC1
Product: C[C@@H](O)c1cccc(S(C)(=O)=O)c1
Reaction time: 8 h
Yield: 81.7 %

Procedure:
B(OMe)3 (62 μL, 0.55 mmol) was added to (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol in THF (5 mL) followed by BH3.Me3S (2M in THF, 1.23 mL, 2.54 mmol). The mixture was stirred for 1 h before 1-[3-(methylsulfonyl)phenyl]ethanone (458 mg, 2.31 mmol) in THF (5 mL) was added over 1.5 h. The resulting mixture was stirred overnight and then quenched with 1M HCl (2 mL). The mixture was concentrated and the crude product was purified by flash column chromatography (CH2Cl2/MeOH 50:1) to give the title compound (378 mg, 18% yield).
Reaction SMILES: C(#N)C.Cl[C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([NH:12][C:13]2[S:14][C:15]([C:18]([NH:20][C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[O:19])=[CH:16][N:17]=2)[CH:6]=1.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[CH3:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:18]([C:15]1[S:14][C:13]([NH:12][C:7]2[CH:6]=[C:5]([N:35]3[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][OH:29])[CH2:33][CH2:34]3)[N:10]=[C:9]([CH3:11])[N:8]=2)=[N:17][CH:16]=1)=[O:19].[OH2:19]
Reactant: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Reactant: OCCN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 32.5 °C
Reaction time: 0.21 h
Yield: 179.2 %

Procedure:
Take 12 ml of acetonitrile in RB flask and charge 1 g of 2-((6-chloro-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Formula I), 1.98 g of 1-(2-Hydroxyethyl)piperazine (Formula II), 1.28 g of triethyl amine and 1.02 g of TBAB. Stir the reaction mass for 10-15 min at 30-35° C. Heat the reaction mixture to 75-80° C. and stir for 20-24 h. Check for the completion of reaction with Thin Layer Chromatography (TLC). Charge 4 mL of water slowly and stir the reaction mass for 30-45 mins at 75° C. Cool the reaction mass to 30-35° C. and stir for 2-3 hrs. Filter the reaction mass and wash with acetonitrile and water mixture (1:1). Dry the material to get 1.15 g of crystalline Dasatinib monohydrate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([OH:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH3:15])[CH:5]=1.[C:16]([NH:23][CH2:24][CH2:25]Br)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[Na+].[Cl-]>CC(N(C)C)=O>[C:19]([O:18][C:16](=[O:17])[NH:23][CH2:24][CH2:25][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([CH3:15])[CH:5]=[C:4]2[Cl:3])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Cl)c2cccc(OCCNC(=O)OC(C)(C)C)c2n1
Reaction time: 1 h
Yield: 90 %

Procedure:
0.6 g Sodium hydride, free of paraffin, was suspended in dimethyl acetamide (50 mL), then 4-chloro-2-methylquinoline-8-ol (1.6 g, 8.26 mmole) was added at RT and the mixture was stirred for 1 h. 2-(boc-amino)ethylbromide was added dropwise and the mixture was kept on stirring for 48 hrs. The content of the flask was poured into half concentrated NaCl solution and extracted with ethyl acetate. The organic phases were washed with water and saturated NaCl solution, dried and concentrated. Dimethyl acetamide was removed in vacuo and the residue was precipitated from isopropyl ether to give a light fawn solid (2.50 g, 90%).
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH:15]=[CH:14][O:13][C:12]2=[NH:16])=[CH:5][CH:4]=1>Cl[Ti](Cl)(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:16]=[C:12]3[N:11]([CH:10]=2)[CH:15]=[CH:14][O:13]3)=[CH:5][CH:4]=1
Reactant: N=c1occn1CC(=O)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Br
Product: Fc1ccc(-c2cn3ccoc3n2)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
The 1-(4-fluorophenyl)-2-(2-iminooxazol-3-yl)-ethanone hydrobromide salt (10.0 g, 0.32 mol) was introduced in a two-neck flask, fitted with a condenser, and flushed with nitrogen. Anhydrous toluene (100 ml) was added and the mixture was cooled to −10° C. TiCl4 (17.5 ml, 0.16 mol) was added over a period of 30 minutes. The reaction becomes deep red and a dark precipitate was formed. The reaction mixture was allowed to warm to room temperature. The mixture was then brought to reflux and kept a reflux for 5.5 hrs. The reaction mixture was cooled to room temperature overnight. The toluene was decanted and iced water (60 ml) was added to the residue (caution!), which turned from dark brown to beige. The resulting suspension was transferred to a large beaker and treated with saturated aqueous sodium carbonate solution until pH 8. A saturated aqueous sodium chloride solution was added (200 ml), followed by 600 ml of ethyl acetate and the mixture was stirred vigorously for one hour. The organic phase was separated and the aqueous phase was further extracted with two portions of 600 ml of ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated in vacuo, yielding 6.84 g of a pale yellow solid. 400 MHz 1H NMR (CDCl3) δ: 7.78-7.72 (m, 2H), 7.37 (d, J=1.8 Hz, 1), 7.31 (d, J=1.8 Hz, 1), 7.24 (s, 1H), 7.10-7.00 (m, 2H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH2:20][O:21][CH:22]([F:24])[F:23])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]([CH2:20][O:21][CH:22]([F:24])[F:23])[C:10]([OH:12])=[O:11]
Reactant: O=C(OCc1ccccc1)[C@@H](COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@H](COC(F)F)C(=O)O
Yield: 79.4 %

Procedure:
Benzyl (2R) 2-dibenzylamino-3-difluoromethoxy-propionate (3.1 g, 6.28 mmol) was stirred with Pd(OH)2 in methanol under H2 overnight. The reaction mixture was filtered and the filtrate concentrated to dryness, then triturated with diethyl ether to give (2R)-2-amino-3-(difluoromethoxy)propanoic acid (773 mg, 68.4%) as a white solid. 1H NMR (300 MHz, MeOD): δ(ppm) 6.49 (wt, 1H), 4.33 (dd, 1H), 4.22 (dd, 1H), and 3.88 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](=[O:17])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[O:4][N:3]=1.I[CH3:37]>C1COCC1>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](=[O:17])[N:10]([CH3:37])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[O:4][N:3]=1
Reactant: CI
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)Nc1ccccc1
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)N(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using THF as the solvent and the following starting materials: 1-{4′-[3-methyl-4-(2-phenylcarbamoyl-ethyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and iodomethane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([CH:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1>O1CCCC1.O>[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([CH:57]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH:16]=[CH:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: CC(N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CC=CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.201 g (0.869 mmol) of 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, 0.335 g (1.04 mmol) of TBTU and 0.33 mL (1.9 mmol) of diisopropylethylamine in 15 mL of tetrahydrofuran is stirred for 10 minutes at ambient temperature and then 0.170 g (0.869 mmol) rac.-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine are added. The mixture is stirred for 16 hours at ambient temperature, combined with water, and extracted three times with ethyl acetate. The combined organic phases are washed once with 2M NaOH and three times with water, dried with sodium sulfate, and concentrated. Yield: 0.34 g (96% of theory); Rf value: 0.50 (silica gel; dichloromethane/ethanol=9:1); C22H21ClN4O2 (408.89); mass spectrum: (M−H)−=407/409 (chlorine isotope) and (M+H)+=409/411 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH2:34][C:35]2[NH:44][C:38]3=[N:39][CH:40]=[C:41](I)[CH:42]=[C:37]3[N:36]=2)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:41]3[CH:42]=[C:37]4[N:36]=[C:35]([CH2:34][CH2:33][C:29]5[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][N:30]=5)[NH:44][C:38]4=[N:39][CH:40]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N(C)c5ccc(Cl)cc5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 32.6 %

Procedure:
A mixture of 0.541 g of N-(4-chlorphenyl)-N-methyl-4-bromo-benzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 027 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 6 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-25:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.17 g of the title compound as a solid of m.p. 191-192° C. The mass spectrum shows the molecular peak MH+ at 534.3 Da.