Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCC(Oc1ccc(C)cc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C)cc1C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 22.4 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.16 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2,4-dimethylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 70, above] and 37.6 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 180 mg of the title compound as white crystals, melting at between 159° and 160° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[CH3:12])[CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>C1COCC1>[F:13][C:11]([C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][CH:8]=1)([F:14])[CH3:12]
Reactant: CCOC(=O)c1cccc(C(C)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(F)(F)c1cccc(CO)c1
Reaction time: 0.33 h
Yield: 97 %

Procedure:
Add a solution of 3-(1,1-Difluoro-ethyl)-benzoic acid ethyl ester (3.57 mmol) in THF (5 mL) dropwise to a 1M solution of lithium aluminum hydride in THF (4.3 mL) at room temperature. Stir for 20 minutes then add ice followed by a mixture of concentrated sulfuric acid and ice (approximately 1:1 v:v). Extract with ethyl ether, dry the organic extracts over sodium sulfate, filter, and evaporate to give the title compound in 97% yield. GCMS MW 172 (M). 1H NMR (400.43 MHz, CDCl3): δ 7.49 (s, 1H), 7.41-7.39 (m, 3H), 4.70 (s, 2H), 1.94-1.85 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCCCCCCCCCCCCc1ccccc1
Reactant: NCCCCCCN
Solvent: CCO
Product: NCCCCCCNCCCCCCCCCCCCCCCCCCc1ccccc1

Procedure:
Following the procedure of Example XVI a solution of 15.8 grams (0.04 mole) of phenylstearyl bromide and 37.2 grams (0.32 mole) of hexamethylene diamine in 400 ml of ethanol was refluxed for three hours. After the same recovery procedure 15.2 grams (88.4% crude mass yield) of N-phenylstearyl hexamethylene diamine was obtained having the following analysis:
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[CH3:10][O:11]/[N:12]=[C:13](/[C:36]1[N:37]=[CH:38][S:39][CH:40]=1)\[C:14]([NH:16][CH:17]1[C:34](=[O:35])[N:19]2[C:20]([C:31]([O-:33])=[O:32])=[C:21]([CH2:24][S:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15].[Na+]>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5](=[O:9])[O:4][C:3]=1[CH2:2][O:33][C:31]([C:20]1[N:19]2[C:34](=[O:35])[CH:17]([NH:16][C:14](=[O:15])/[C:13](=[N:12]\[O:11][CH3:10])/[C:36]3[N:37]=[CH:38][S:39][CH:40]=3)[C@H:18]2[S:23][CH2:22][C:21]=1[CH2:24][S:25][C:26]1[S:30][N:29]=[CH:28][N:27]=1)=[O:32]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3ncns3)CS[C@H]12)c1cscn1
Reactant: Cc1oc(=O)oc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3oc(=O)oc3C)=C(CSc3ncns3)CS[C@H]12)c1cscn1
Reaction time: 1.3 h
Yield: 31 %

Procedure:
4-Bromomethyl-5-methyl-1,3-dioxolene-2-one (386 mg) was added to a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (522 mg) in N,N-dimethylformamide (5 ml) at -5° C. and the mixture was stirred at this temperature for 1.3 hr. The reaction mixture was then treated in the same manner as in Example 14, giving the title compound (190 mg). ##STR39##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:41]([N:44]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1)[CH2:45][CH2:46][CH3:47])[CH2:42][CH3:43]>C(Cl)(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][N:44]([CH2:45][CH2:46][CH3:47])[CH2:41][CH2:42][CH3:43])=[CH:50][CH:51]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
In chloroform (20 ml) and DMF (8.0 ml), 4-(t-butoxycarbonylaminomethyl)benzoic acid (1.95 g) was dissolved. Then, the solution was added with WSCI hydrochloride (1.50 g) and HOBt (1.08 g), followed by stirring at room temperature at 1 hour. The reaction solution was added with the compound (1.23 g) obtained in Example 19-2 and chloroform (10 ml), followed by stirring at room temperature for 15 hours. The solvent was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (2.86 g) as a yellow oily substance.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28](Cl)=[S:29])=[CH:23][CH:22]=1>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:5])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[S:29])=[CH:23][CH:22]=1
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Reactant: C=CCN(C)CCCCCc1ccc2c(c1)CCN2
Solvent: C1COCCO1
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
130 mg (0.5 mmol) Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine in 0.5 ml dioxane were treated with 0.072 ml (0.5 mmol) chlorothio-formicacid-O-(4-chlorophenyl)-ester at 15° C. The mixture was stirred for 15 min, concentrated and purified by column chromatography on silica gel with a gradient of CH2Cl2/MeOH 99:1 to 97:3 to yield 92 mg 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as colorless oil. The corresponding acetic acid salt was prepared by treatment with acetic acid in CH2Cl2 to yield 101 mg 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester-acetic acid as light brown viscous oil, MS: 429 (MH+, 1Cl).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C1COCC1>[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:1]=[O:3]
Reactant: O=CO
Reactant: Nc1ccccc1F
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccccc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
Formic acid (3 g) was added dropwise to acetic anhydride (5.4 g) which had been cooled to 0° C. The mixture was stirred at 0° C. for 15 minutes and then heated to 55° C. for 2 hours. The mixture was cooled to ambient temperature. THF (5 ml) and a solution of 2-fluoroaniline (2.22 g) in THF (15 ml) were added and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated to give 2'-fluoroformanilide (2.8 g) which was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].CCN(CC)CC.[C:16](Cl)(=[O:24])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20]>O.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:16](=[O:24])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: COC(=O)C(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(CCC)C(=O)N[C@@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A solution of DL-alanine methyl ester hydrochloride (13.7 g, 98 mmole) and Et3N (20.2 g, 200 mmole) in water (50 ml) was added dropwise to an ice-cooled solution of valproyl chloride (15.0 g, 92 mmole) in CH2Cl2 (150 ml). After completion of addition the reaction mixture was stirred for 4 hrs. at RT. The layers were then separated and the aqueous layer extracted with CH2Cl2. The combined organic phases were washed successively with water, satd. NaHCO3, 0.1N HCl and satd. NaCl, dried and evaporated to dryness. The residue was treated with hexane (60 ml), and the resultant solid was collected by filtration, washed with hexane and dried to give 14.2 g (62 mmole, 63%) of the title compound as a white solid, mp 72°-3° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[S:14].Cl[C:16]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:23]([N+]([O-])=O)=[CH:22][C:17]=1[C:18]([O:20]C)=[O:19]>C(O)C>[N+:26]([C:25]1[CH:24]=[C:23]2[C:22](=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=1)[NH:3][C:4]1[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=1[S:14]2)([O-:28])=[O:27]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: NC1C=Cc2ccccc2C1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1Nc1ccc3ccccc3c1S2
Yield: 34.6 %

Procedure:
5 ml of a 2 N aqueous solution of sodium hydroxide was added to a solution of 1.7 g (9.73 mmol) of 2-amino-1-naphthalenethione in ethanol (30 ml) and the obtained mixture was heated under reflux. To this mixture was added 2.54 g(9.76 mmol) of methyl 2-chloro-3,5-dinitrobenzoate and the obtained mixture was heated under reflux for 1 hour. To this mixture were added 10 ml of a 2 N aqueous solution of sodium hydroxide and 40 ml of ethanol and the obtained mixture was heated under reflux for additional 10 hours. Then it was brought back to room temperature and concentrated. After adding water, 1 N hydrochloric acid was slowly added thereto under stirring to thereby regulate the pH value to about 1. The precipitate was recovered by filtration and washed successively with ethanol and methanol to thereby give 1.14 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[S:10].[C:11]([NH:14][NH2:15])(=[O:13])[CH3:12]>O1CCOCC1.CCOCC>[C:11]([NH:14][NH:15][C:9](=[S:10])[NH:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[Br:1])(=[O:13])[CH3:12]
Reactant: S=C=Nc1ccncc1Br
Reactant: CC(=O)NN
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)NNC(=S)Nc1ccncc1Br
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 90.6 %

Procedure:
3-bromo-4-isothiocyanato-pyridine (1 g, 4.650 mmol) and acetylhydrazine (344.5 mg, 4.650 mmol) were dissolved in dry 1,4-dioxane (10 mL) and stirred at 80° C. for 0.75 hrs. The orange suspension was allowed to cool to RT. The viscous suspension was diluted with ether and the solid was collected by filtration and washed with ether (3×5 mL) to give 2-acetyl-N-(3-bromopyridin-4-yl)hydrazinecarbothioamide as a salmon-pink solid (1.2187 g, 91% Yield). MS (ES−) 288.9.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.O=[Si]=O.[CH2:8]([O:10][C:11]([NH:13][NH2:14])=[O:12])[CH3:9]>O>[CH2:8]([O:10][C:11](=[O:12])[NH:13][N:14]=[CH:3][CH2:2][Cl:1])[CH3:9]
Reactant: CCOC(=O)NN
Reactant: O=CCCl
Agent: O=[Si]=O
Solvent: O
Product: CCOC(=O)NN=CCCl
Reaction time: 0.5 h

Procedure:
550 g (3.5 mol) of a 50% aqueous solution of chloroacetaldehyde were diluted with 3000 ml water and were reacted with 10 g Celite 545 in order to react with the precipitating resin. For this purpose the solution was passed through a fluted filter into a three times tubulated round bottom flask of 6 l contents which was provided with a stirrer and thermometer. While cooling with ice a solution of 364 g (3.5 mol) of hydrazinoformicacid ethylester in 360 ml water was added during a period of 15 min. The temperature within the reaction vessel was maintained at between 0° and 5° C. There formed immediately a thick white crystal slurry. Stirring was continued at room temperature for 30 minutes. The crystals were then removed by suction, were washed neutral with about 6 liters water and were dried in a vacuum at 30° C. until the weight remained constant.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[N:21][C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:29])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:36][CH3:37])C1C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:35][N:33]([CH3:34])[CH2:32][CH2:31][NH:30][C:20]([NH:21][C:22]1[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=1[CH3:28])=[N:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:36][CH3:37])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(NC(=Nc3c(C)cccc3C)NCCN(C)C)ncnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(N=C(NCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1O
Yield: 68 %

Procedure:
Using an analogous procedure to that described in Example 10, N-(7-benzyloxy-6-methoxyquinazolin-4-yl)-N′-(2-dimethylaminoethyl)-N″-(2,6-dimethylphenyl)guanidine was reacted with trifluoroacetic acid to give the title compound in 68% yield; NMR Spectrum: (DMSOd6, 100° C.) 2.22 (s, 6H), 2.26 (s, 6H), 2.55 (t, 2H), 3.6 (t, 2H), 3.79 (s, 3H), 6.99 (s, 1H), 7.17 (s, 3H), 7.6 (s, 1H), 8.39 (s, 1H), 9.4 (br s, 1H), 10.8 (br s, 1H); Mass Spectrum: M+H+ 409.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]([CH3:21])[CH2:7][C@H:8]([CH3:20])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.[NH4+]>C1COCC1>[NH2:17][C:13]1[CH:12]=[C:11]([C@@:9]([OH:10])([CH2:1][CH3:2])[C@@H:8]([CH3:20])[CH2:7][N:6]([CH3:21])[CH3:5])[CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H](CN(C)C)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@](O)(c1cccc(N)c1)[C@@H](C)CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
726 ml of ethylmagnesium bromide (1M in THF; 0.726 mol) are added under a nitrogen flow into a 2-liter four-neck flask, provided with mechanical stirrer, thermometer and dropping funnel. A solution of (S)-3-(dimethylamino)-2-methyl-1-(3-nitro-phenyl)-propan-1-one (50 g, 0.242 mol) in 50 ml of THF are dripped maintaining the temperature between 15-30° C. The reaction is stirred at room temperature for 3 hours. It is cooled to about 10° C. and toluene (200 ml) and slowly a 20% ammonium hydrogen sulphate solution (200 ml) are added. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The organic phase is concentrated under vacuum almost to oily residue. Then toluene (200 ml), 30% sodium metabisulfite solution (300 ml) are added. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The aqueous phase is washed 2 times with 200 ml of toluene. The organic phases are eliminated while Cert-butylmethylether (200 ml) is added to the aqueous phase. The pH of the mixture is brought to 11-12 with 28% sodium hydroxide. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The aqueous phase is eliminated while the organic phase is concentrated under vacuum to oily residue which solidifies by cooling. 35 g of a yellowish solid with a 95% HPLC purity are obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH2:24])[CH3:20]>[Pd].C1(C)C=CC=CC=1>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH:24][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[CH3:20]
Reactant: CCN(CC)CCN
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCN(CC)CCNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of 4′-(trifluoromethyl)-4-biphenylcarbaldehyde, (43.6 kg, 1.1 eq., see WO 01/60805), N,N-diethylethylenediamine (21.2 kg, 1.15 equiv.) and 5% palladium on charcoal (Degussa E101 N/W, 50% wet paste, 1.7 kg) in toluene (138 Kg) was hydrogenated at 20±3° C. and 50 psi until completion. The reaction mixture was filtered and the catalyst bed washed with toluene (2×36.7 kg). The solution was washed with water (84.8 kg) and concentrated under reduced pressure to ca. 85 L. This concentrate was used in the next step, Example 6, without further purification.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>>[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(C)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-toluoyl chloride, there is obtained ethyl N-(p-toluoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 384 (9), 355 (15), 194 (100);
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:48]([C:45]3[CH:44]=[CH:43][C:42]([CH2:41][N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)=[CH:47][CH:46]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 33 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), tert-butyl-4-(4-formylbenzyl)piperazine-1-carboxylate (0.050 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.033 g, 33%); 1H-NMR (500 Mz, DMSO-d6): δ 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H), 2.62-2.72 (m, 7H), 3.28-3.36 (m, 4H), 3.55 (s, 2H, NCH2), 3.64 (s, 2H, NCH2), 3.67 (t, J=4.0 Hz, 4H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.76 min—667/669 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 667.2190, calculated for C31H40BrN8O2S (M+H)+: 667.2178.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:49])[CH2:38][N:39]3[C:43]([CH3:44])=[CH:42][C:41]([C:45]([F:48])([F:47])[F:46])=[N:40]3)[CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH2:32][CH2:33][N:34]([C:37](=[O:49])[CH2:38][N:39]3[C:43]([CH3:44])=[CH:42][C:41]([C:45]([F:48])([F:47])[F:46])=[N:40]3)[CH2:35][CH2:36]2)[CH:26]=1)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(N)c2)CC1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(NC(=O)c3cccc(Cl)c3O)c2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-2-hydroxy-benzoic acid (0.11 g, 0.65 mmol) in acetonitrile (10 mL) is added carbodiimidazole (0.11 g, 0.71 mmol). After stirring the reaction mixture at 60° C. for 2 h, 1-[4-(3-amino-phenyl)-piperazin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (0.20 g, 055 mmol) is added, followed by 1,8-diazabicycloundec-7-ene (0.1 mL, 0.82 mmol). After stirring overnight at 60° C., the reaction mixture is cooled down to RT and then solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), 1N HCl (20 mL) and brine (20 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. Cyclohexane is added dropwise to a solution of crude mixture in 1 mL ethylacetate to give after filtration 3-chloro-2-hydroxy-N-(3-{4-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-phenyl)-benzamide (Compound No. I.ao.003) (0.090 g, 26%). 1H-NMR (400 MHz, MeOD): δ=2.31 (s, 3H), 3.21-3.28 (m, 2H), 3.31-3.39 (m, 2H), 3.77-3.83 (m, 4H), 5.25 (s, 2H), 6.47 (s, 1H), 6.87-6.89 (m, 1H), 6.92-6.99 (m, 1H), 7.17-7.22 (m, 1H), 7.28-7.33 (m, 1H), 7.41-7.42 (m, 1H), 7.57-7.61 (m, 1H), 7.90-7.92 (m, 1H). MS: m/z=522 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C.C(OCC)(=O)C.O>[Br:20][C:12]1[C:2]([Br:1])=[CH:3][C:4]2[NH:9][C:8](=[O:10])[CH2:7][O:6][C:5]=2[N:11]=1
Reactant: O=C1COc2ncc(Br)cc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1COc2nc(Br)c(Br)cc2N1
Yield: 79.3 %

Procedure:
7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.5 g, 6.55 mmol) and NBS (5.83, 32.7 mmol) were heated to 80° C. in DMF (30 ml) for 2 hours. The resulting reaction mixture was diluted with ethyl acetate (30 ml) and water (30 ml). The aqueous phase was extracted with fresh ethyl acetate (50 ml×3) and the combined organic layers were washed with brine (50 ml), dried on anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give the title compound (1.6 g, 79%). It was used for the next step without further purification. LCMS (Method D): RT=0.91 min, M+1=309.