Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([S:11][CH3:12])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH2:8])=[C:4]([S:11][CH3:12])[CH:3]=1
Reactant: CSc1cc(F)ccc1C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CSc1cc(F)ccc1CN
Temperature: 25 °C

Procedure:
A slurry of 4-fluoro-2-(methylthio)benzamide (9 g, 48.6 mmol) in diethyl ether (500 mL) was cooled to zero degrees C. under nitrogen and lithium aluminum hydride (5.53 g, 145.8 mmol, 1.0 M in diethyl ether) was added dropwise. The reaction was allowed to stir with slow warming to 25 degrees C. overnight. The reaction was quenched via the addition of water (5.53 mL), 15% NaOH (5.53 μL) and water (16 mL). The mixture was stirred, the lithium salts precipitated out and were filtered off. The organic filtrate was washed with saturated sodium bicarbonate (300 mL) and brine (300 mL), dried over Na2SO4, filtered and reduced to a small volume. The resulting brown oil was placed under high vacuum to give the desired compound as a free base.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:15][CH2:16][CH2:17][CH3:18])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][CH:44]=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][CH2:44][N:15]([C@@H:13]([CH3:14])[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=2)[CH2:16][CH2:17][CH3:18])[CH2:35][CH2:34]1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCCN[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCCC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCN(CCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
A mixture of [(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamine hydrochloride (2.05 g, 7.03 mmole), triethylamine (0.98 mL, 7 mmole), 5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.0 g, 7.03 mmole), and sodium triacetoxyborohydride (2.23 g, 10.5 mmole) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 15 hours. The mixture was concentrated, and the residue was partitioned between diethyl ether and saturated sodium carbonate. The organic phase was dried (magnesium sulfate) and concentrated to give 4-(4-{[(S)-2-(4-methane-sulfonylphenyl)-1-methylethyl]propyl-amino}butyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.6 g) as a heavy syrup. M+H=524. The hydrochloride salt was recrystallized from acetone/diethyl ether, m.p. 156–158° C.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][C@@H:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](C)[CH:30]=2)=[O:27])[C:9]1=[O:36])=[O:6])([CH3:4])([CH3:3])[CH3:2].[N-:37]=[C:38]=[O:39].[C:40]1(C)C=CC=CC=1>>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][C@@H:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:37]([CH:38]=[O:39])[CH3:40])[CH:30]=2)=[O:27])[C:9]1=[O:36])=[O:6])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccccc1
Reactant: Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: [N-]=C=O
Product: CN(C=O)c1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Yield: 65 %

Procedure:
The resolved aminobenzodiazepine of Example 26 (980 mg, 2.8 mmol) in toluene (10 ml) was treated with the isocyanate prepared from the acid of Example 56B (985 mg, 5.5 mmol) following the method of Example 38. The product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 75:25 v/v) to provide the title compound (960 mg, 65%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2C=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.N1CCCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:30]2[CH2:36][CH2:37][CH2:38][CH2:33][CH2:34]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].[Cl:12][C:13](Cl)(Cl)[S:14]Cl.[OH-].[Na+].O>ClCCl>[Cl:12][C:13]1[S:14][N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[Cl:2])[N:6]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccccc1Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2ccccc2Cl)ns1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 37 g of 2-chlorobenzamidine hydrobromide in 160 ml of dichloromethane, cooled to -10° C., are added dropwise 36 g of trichloromethanesulphenyl chloride dissolved in 160 ml of dichloromethane. After stirring for 30 min, 65 ml of aqueous 50% NaOH solution are added dropwise to the medium, still at -10° C. The solution is allowed to return to room temperature and is stirred for 2 h. Water is added to the reaction medium and the phases are separated after settling has taken place. The organic phase is washed with water, dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20](O)=[O:21])[CH2:10][N:9]4[CH3:23])=[CH:5]1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN(C)C=O>[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:20]([C@@H:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][C:6]4[C:19]5[C:18](=[CH:17][CH:16]=[CH:15][C:14]3=5)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=4)[N:9]([CH3:23])[CH2:10]2)=[O:21])[CH2:39][CH2:38]1
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)O)CN(C)[C@@H]1C2
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)N[C@H]3CC[C@H](N)CC3)CN(C)[C@@H]1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.07 g of (8β)-1-isopropyl-6-methylergoline-8-carboxylic acid in 300 ml of dimethylformamide were added 5.5 g of 1,1'-carbonyldiimidazole. After stirring at room temperature for 3 hours, this solution was added to a solution of 36.9 g of trans-1,4-diaminocyclohexane in 600 ml of dimethylformamide; the addition was made dropwise over a period of 3.5 hours. After the addition was complete, the reaction mixture was allowed to stir at room temperature overnight. The solution was poured into 4 liters of ice and the aqueous solution extracted 8 times with 500 ml each of methylene chloride. The combined organic extracts were washed three times with water, one time with a saturated sodium chloride solution, dried over sodium sulfate, and then concentrated in vacuo to provide 12.5 g of title compound as a yellow solid. A portion of this free base material was treated with p-toluenesulfonic acid in ethyl acetate/ethanol to provide the ditosylate salt, m.p. 236°-239° C. NMR, MS.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([C:8](=[O:19])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=[C:4]([CH3:20])[NH:3]1.S(Cl)([Cl:24])(=O)=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([Cl:24])([C:8](=[O:19])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[C:4]([CH3:20])=[N:3]1
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)c2c(C)[nH]n(C)c2=O)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Product: CC1=NN(C)C(=O)C1(Cl)C(=O)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a suspension of 2.65 g of 1,3-dimethyl-4-(2-nitro-5-methylbenzoyl)-5-pyrazolone in 20 ml of dry benzene was added 1.62 g of sulfuryl chloride and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in the Example 1 to give 2.0 g of the desired product melting at 110° - 111° C. (Yield 64.72%)
Reaction SMILES: C1(C2C=CC=CC=2CO)C2C(=CC=CC=2)C=CC=1.[Mg].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[O:34]>>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:34]
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: Brc1ccccc1
Agent: OCc1ccccc1-c1cccc2ccccc12
Agent: [Mg]
Product: OC(c1ccccc1)(c1ccccn1)c1ccccn1

Procedure:
With the same method as for Compound 13, a Grignard reagent was prepared from magnesium (Wako Pure Chemical Industries, Ltd.) and bromobenzene (Wako Pure Chemical Industries, Ltd.), and di-2-pyridyl ketone (Aldrich) was allowed to react with the reagent, to thereby obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([O:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])[CH2:28][CH2:27][CH2:26]1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH:25]1([O:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(OC1CCC1)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 12 h

Procedure:
To a solution of 6.0 g (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester in 50 ml DMF were added 3.3 g piperazine-1-carboxylic acid cyclobutyl ester, 9.1 ml N-ethylmorpholine and 5.9 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 11.1 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C(C)(C)C)=[C:5]([CH3:16])[C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].Cl.[OH-].[Na+].CCOC(C)=O>CCO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:18])([F:19])[F:20])[C:5]=1[CH3:16]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc(C#N)c1C(F)(F)F
Temperature: 70 °C

Procedure:
The crude N-[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide from Example 191B was dissolved in EtOH (5 mL) and conc. HCl (5 mL). The resulting mixture was heated to 70° C. for 20 min. The cooled reaction's pH was adjusted to ca. 8 with 6 N NaOH. EtOAc (20 mL) was added and the isolated organic portion was dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (ES) m/z 201 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)cc1

Procedure:
To a solution of 6-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline in DCM (7 mL) was added 4-Methoxy-benzoyl chloride in DCM, followed by triethylamine. The reaction was quenched with aq. NaHCO3 and DCM work up. The crude product was purified on a silica gel column to obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)C.[BH4-].[Na+]>C(Cl)(Cl)Cl>[OH:3][CH:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(O)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
60.98 g (0.24 mol) of benzyl 4-acetylbenzoate (II-19), 100 ml of ethanol and 300 ml of chloroform were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 4.6 g (0.12 mol) of sodium borohydride was added at 15°-25° C. over a period of 10 minutes. The mixture was kept at the same temperature for 2 hours and the resulting reaction mixture was poured into ice-water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 58.37 g (95% yield) of benzyl 4-(1-hydroxyethyl)phenylcarboxylate (III-19). nD25 =1.5682.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>S(=O)(=O)(O)O.O>[Br:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(=O)CBr
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(CBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-Bromopyruvic acid (170 g) is suspended in cold sulfuric acid (0.85 L) and maintained at 0° C. while benzene (0.255 L) is added over 1.5 hours. The temperature is allowed to warm to 35°-36° C. and then kept at 25° C. for three hours. Pouring over crushed ice (4 L) followed by trituration in cold water and recrystallization from 95% ethanol affords 76 g of 3-bromo-2,2-diphenylpropionic acid (mp 201°-202° C.). This acid (75 g) is suspended in benzene and thionyl chloride (55 ml) is added. After refluxing, the mixture is filtered, and the filtrate affords 40 g of the acid chloride (mp 98°-100° C.). The acid chloride is added portionwise to aqueous ammonium hydroxide with stirring and left overnight, with filtration yielding 3-bromo-2,2-diphenylpropionamide. The amide (10 g) is added portionwise with stirring to a solution of sodium (1.5 g) in absolute ethanol (0.2 L), and the resulting solution is heated for one hour on a steam bath. Dilution with water affords a solid (mp >310° C.), 2,2-diphenyl azetidin-2-one. The azetidinone (2 g) is heated at reflux in methanol saturated with HCl (50 ml) affording the title compound after crystallization from methanol/ether (mp 207°-208° C.).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(=O)(OC)OC.Cl.Cl[S:17]([OH:20])(=[O:19])=[O:18]>C1CCCCC1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Oc1cccc(O)c1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: C1CCCCC1
Solvent: COC(=O)OC
Product: O=S(=O)(O)c1ccc(O)cc1O
Temperature: 60 °C

Procedure:
15.0 g (0.136 moles) of resorcinol, 102 g dimethyl carbonate and 68 g cyclohexane were charged under nitrogen to a 4-necked one litre reactor fitted with stirrer, thermometer and condenser attached to an HCl scrubber system. The reaction mixture was heated to 60° C. and 15.1 g (0.13 moles) of chlorosulphonic acid added over a period of 4 h with removal of hydrogen chloride gas. On completion of the addition, the reaction mixture is heated to 70-72° C. for 1 h, and then cooled to 20° C. The reaction mixture separated into two layers with the lower layer containing 2,4-dihydroxybenzene sulphonic Acid (63.2% by hplc) and resorcinol (31.5% by hplc).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][N:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18]2)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C(Cl)Cl.C(N(CC)CC)C.[CH3:39][O:40][C:41](Cl)=[O:42]>O>[CH2:22]([N:17]1[CH2:18][CH:19]2[N:14]([CH2:13][C@H:2]([NH:1][C:41](=[O:42])[O:40][CH3:39])[CH2:3][O:4][C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=3)[CH:15]([CH2:21][CH2:20]2)[CH2:16]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc(OC[C@@H](N)CN2C3CCC2CN(Cc2ccccc2)C3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N[C@H](COc1ccc(C#N)cc1)CN1C2CCC1CN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
4-{[(2S)-2-Amino-3-(3-benzyl-3,8-diazabicyclo[3.2.1]oct-8-yl)propyl]oxy}benzonitrile (3.7 g, 9.8 mmol; from step (f) above) was mixed with DCM (50 mL) and triethylamine (2.1 g, 21.5 mmol). The mixture was cooled to 0° C. and methylchloroformate (0.8 mL, 10.7 mmol) was added dropwise. The reaction was performed under an argon atmosphere. After 2 h, the temperature was allowed to reach r.t, at which temperature it was then stirred overnight. Water was added, the organic layer was separated, dried and evaporated. Purification by chromatography (CHCl3:MeOH (95:5)) gave 2.9 g (68%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:21]=[C:20]2[N:15]([C:16](Cl)=[N:17][C:18]([O:22][CH3:23])=[CH:19]2)[N:14]=1)(=[O:12])=[O:11].[CH3:25][OH:26].C[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:21]=[C:20]2[N:15]([C:16]([O:26][CH3:25])=[N:17][C:18]([O:22][CH3:23])=[CH:19]2)[N:14]=1)(=[O:12])=[O:11]
Reactant: COc1cc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn2c(Cl)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn2c(OC)n1

Procedure:
N-(2,6-Dichlorophenyl)-5-chloro-7-methoxy-1,2,4-triazolo[1,5-c]pyrimidine-2-sulfonamide (0.8 g, 0.002 mol) was mixed with 25 ml of methanol and 1.34 ml of 25 percent sodium methoxide in methanol (0.006 mol) added with stirring. After 10 min 2 ml of acetic acid was added and the mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride and the solution extracted with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was mixed with carbon tetrachloride, collected by filtration, and dried to obtain 0.5 g of the title compound as an off-white powder melting at 211°-212° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:18]/[CH2:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:31][C:32]([O:34]CC)=[O:33])=[N:21]1.C(O)C.C>O>[F:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:18]/[CH2:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:31][C:32]([OH:34])=[O:33])=[N:21]1
Reactant: CCOC(=O)Cc1nn(C/C=C/c2cccc(C(F)(F)F)c2F)c(=O)c2ccccc12
Agent: C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1nn(C/C=C/c2cccc(C(F)(F)F)c2F)c(=O)c2ccccc12
Reaction time: 2 h

Procedure:
A solution of 183.6 g (2.185 mol) of sodium bicarbonate in 4.2 1 of water is rapidly added to a suspension of 474.4 g (1.092 mol) of ethyl (E) -3-[3-[2-fluoro-3-(trifluoromethyl)phenyl]-2-propenyl]-3,4-dihydro-4-oxo-1-phthalazineacetate in 4.2 1 of ethanol and heating is carried out for 2 h at reflux. A solution of 36.7 g (0.436 mol) of sodium bicarbonate in 800 ml of water is added and heating is carried out for 4 h 30 at reflux. 50 g of Norit are added and heating is carried out for a further 1 h at reflux. The mixture is filtered while hot through Hyflo and the ethanol is evaporated under vacuum. The residual aqueous phase is diluted with water to a volume of 10 l, cooled and acidified to pH=2 with 6N HCl (approximately 300 ml). The precipitate obtained is filtered, washed with water and dried under vacuum at 60° C. and then recrystallized from a hexane/ethyl acetate mixture to give a solid melting at 170°-172° C. Weight obtained: 382 g (Yd. 86%)
Reaction SMILES: CCN(CC)CC.[NH:8]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]([CH3:32])[C:29]([NH2:31])=[O:30])[C:17]([C:33]([F:36])([F:35])[F:34])=[CH:16][N:15]=2)[CH:10]=[N:9]1>CN(C=O)C.CCOC(C)=O.[Pd]>[NH:8]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]([CH3:32])[C:29]([NH2:31])=[O:30])[C:17]([C:33]([F:35])([F:34])[F:36])=[CH:16][N:15]=2)[CH:10]=[N:9]1
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cn[nH]c2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cn[nH]c2)ncc1C(F)(F)F
Reaction time: 16 h
Yield: 26 %

Procedure:
Et3N (0.5 mL) was added to 2-(2-((2-((1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)propanamide A63 (0.211 g, 0.527 mmol) and 10% Pd/C (0.155 g) in DMF (4 mL) and EtOAc (16 mL) and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered through Celite, concentrated under reduced pressure and purified using silica gel column chromatography (80-100% EtOAc in petroleum benzine 40-60° C. then 0-10% MeOH in EtOAc). The resulting product was further triturated with a mixture of Et2O and acetone and the precipitate was collected by vacuum filtration to give the title compound 54 (0.055 g, 26%). LCMS-D: rt 3.178 min; m/z 405.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.BrCC[C:22]1[CH:32]=[CH:31][CH:30]=[C:24]2[C:25]([NH:27][C:28](=[O:29])[C:23]=12)=[O:26].C(=O)([O-])[O-].[K+].[K+].[ClH:39].[CH3:40][C:41](C)=O>CCOCC>[ClH:39].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:14][CH2:15][N:16]([CH2:40][CH2:41][N:27]3[C:28](=[O:29])[C:23]4=[CH:22][CH:32]=[CH:31][CH:30]=[C:24]4[C:25]3=[O:26])[CH2:17][CH2:18]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(N3CCNCC3)c2c1
Reactant: CC(C)=O
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccc2cccc(N3CCN(CCN4C(=O)c5ccccc5C4=O)CC3)c2c1
Reaction time: 24 h
Yield: 63 %

Procedure:
A mixture of 1.5 g of (7-methoxy-1-naphthyl)piperazine and 1.5 g of (2-bromoethyl)phthalimide in 100 ml of acetone is brought to reflux in the presence of 1.6 g of potassium carbonate. The mixture is stirred for 24 hours. The mixture is cooled, it is concentrated. The oil obtained is ground in ether. The requisite quantity of ethereal hydrogen chloride is added to obtain the expected hydrochloride.