Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O-])=O.Cl.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)cc1N1CCNCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N2CCCC2)cc1N1CCNCC1

Procedure:
A mixture of 1-nitro-2-piperazinyl-4-pyrrolidinylbenzene (4.57 g), ethanol (110 ml), hydrochloric acid (1.2N, 6 ml) and palladium on carbon (10%, 1 g) is exposed to hydrogen 51 psi at 20°-25° in a Parr flask. After 16 h (49 psi total uptake) the mixture is filtered. Basic workup (chloroform, potassium carbonate) and column chromatography silica gel (50 g) eluting with chloroform/methanol (4/1) gives the title compound as an oil, IR (nujol) 3315, 2947, 2816, 1512, 1258, 1001 and 753 cm-1 ; NMR (CDCl3) 1.8-2.0, 2.9-3.2, 6.52 and 6.6-6.8 δ; MS (electron impact) 246, 204 and 189.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.CN([C:16]([O:20][N:21]1N=NC2C=CC=N[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.CNOC>ClCCl.O>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:21]([O:20][CH3:16])[CH3:22])=[O:12]
Reactant: O=C(O)Cc1ccc(O)cc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(O)cc1Br
Yield: 97.2 %

Procedure:
A mixture of 2-(2-bromo-4-hydroxyphenyl)acetic acid (0.67 g), HATU (1.33 g), triethylamine (0.35 g) and N,O-dimethylhydroxylamine hydrochloride (0.34 g) in dichloromethane (30 mL) was stirred overnight, to which water (30 mL) was added. The organic layer was separated. The water layer was extracted by ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (773 mg).
Reaction SMILES: O[CH2:2][C:3]1[NH:8][C:7](=[O:9])[C:6]2=[CH:10][N:11]=[C:12]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:4]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:2][C:3]1[NH:8][C:7](=[O:9])[C:6]2=[CH:10][N:11]=[C:12]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:4]=1
Reactant: O=c1[nH]c(CO)nn2c(C3CCOCC3)ncc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=c1[nH]c(CCl)nn2c(C3CCOCC3)ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of compound 7 (400 mg, 1.6 mmol) in CH2Cl2 (50 mL) in ice-water bath was added SOCl2 (10 mL) dropwise. The resulting mixture was then stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to afford compound 8 (370 mg, 86% yield) as a white solid. LC-MS: m/z 269.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 12.50 (s, 1H), 8.02 (s, 1H), 4.57 (s, 2H), 3.95 (m, 2H), 3.48 (m, 3H), 1.88 (m, 4H).
Reaction SMILES: N[C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[ClH:18].C(OCC)C>O>[Cl:18][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reaction time: 1.5 h

Procedure:
A solid mixture of 0.52 g of 3-amino-2,4,5-trifluorobenzoic acid (Example 2) and 0.33 g of sodium nitrite is added in portions to a solution of 3 g of cupric chloride in 9 ml of water and 0.5 g of a 36% aqueous solution of hydrochloric acid. The resulting mixture is allowed to stir at 15°-25° C. for 1.5 hours and then additional water (25 ml) is added. Stirring is continued another hour at 25° C. and then 20 ml of diethyl ether is added. The layers are separated and the aqueous layer extracted with 20 ml of diethyl ether. The combined organic extracts are extracted with 5 ml of a 36% aqueous solution of hydrochloric acid and then concentrated on the rotary evaporator to give 0.45 g of 3-chloro-2,4,5-trifluorobenzoic acid as a tan solid; gas chromatography (GC) (98.8%); high performance liquid chromatography (HPLC) (84.8%); (a portion of the 3-chloro- 2,4,5-trifluorobenzoic acid was recrystallized from heptanes; mp 109°-111° C.).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12][CH2:13][CH2:14][C:15](Cl)=[O:16].C(N(C(C)C)CC)(C)C.C(Cl)Cl>O>[N+:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:15](=[O:16])[CH2:14][CH2:13][Br:12])([O-:11])=[O:10]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)CCBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCBr)Nc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 48 h
Yield: 101.1 %

Procedure:
A mixture of 7.8 gm of 4-fluoro-2-nitroaniline, 8.57 gm of 3-bromo propionylchloride (added at a temperature of 0° C. over a period of 0.3 hours), 6.5 gm of diisopropylethylamine and 150 ml CH2Cl2 was kept for 48 hours at 20-25° C. Water (300 ml) was added and the mixture was extracted with CH2C2. The CH2Cl2 extract was collected, washed with water (2×20 ml) and desiccated wtih Na2SO4. The crude product (14.7 gm) obtained after removal of solvents was used without further purification. A sample of this crude material (14.79 gm) exhibited the following data. M+/z of 292.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:8]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([SH:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:5]3[S:6][C:2]([S:32][C:28]4[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][CH:29]=4)=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1
Reactant: Cc1cccc(S)c1
Product: Cc1cccc(Sc2ccc(-c3ccnc(NCCN4C(=O)NC(=O)C4(C)C)n3)s2)c1

Procedure:
The title compound was prepared from 1-{2-[4-(5-iodothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethyl-imidazolidine-2,4-dione and 3-methylthiophenol in a manner analogous to Example 259. MS (M+H)+ 454.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-])=O.P(Cl)(Cl)(Cl)=O.C1(C)C=CC=CC=1>[Fe].C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:13]
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(N)c(Cl)c(N)c1
Yield: 80 %

Procedure:
By reaction with ammonia at about 0° C. to about 20° C., 4-chloro-3,5-dinitrobenzoic acid amide is obtained which is converted into 4-chloro-3,5-dinitrobenzonitrile by reaction with phosphorus oxychloride in boiling toluene. By reduction in boiling toluene/water with iron, 4-chloro-3,5-diaminobenzonitrile (melting point about 172° C.) is obtained in about 80% yield.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][C:10](=[C:13]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]3[S:17][C:16]([C:27]([OH:29])=[O:28])=[CH:15][C:14]2=3)[CH2:9][CH2:8]1.[CH2:30](O)[CH3:31]>>[CH3:6][N:7]1[CH2:8][CH2:9][C:10](=[C:13]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]3[S:17][C:16]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:15][C:14]2=3)[CH2:11][CH2:12]1
Reactant: CN1CCC(=C2c3ccccc3CCc3sc(C(=O)O)cc32)CC1
Reactant: CCO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2c(s1)CCc1ccccc1C2=C1CCN(C)CC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Ethanol (10 mL) was chilled to 0° C., and thionyl chloride (0.24 mL, 0.32 mmol) was added dropwise. Compound 4 (100 mg, 0.29 mmol) was added to the solution, and the mixture was stirred for 30 minutes, and then refluxed while heating for 2 hours. After allowing the refluxed mixture to cool in the air, the solvents were distilled off under a reduced pressure, and the precipitated crystals were separated by filtration and dried, to give 107 mg (100%) of the captioned compound in the form of white crystals.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=[CH:11]2)([OH:7])[CH3:6].Cl>CO>[F:3][C:4]([F:22])([F:23])[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11]2)([OH:7])[CH3:6]
Reactant: COC(=O)c1ccc2cc(C(C)(O)C(F)(F)F)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(O)(c1ccc2cc(C(=O)O)ccc2c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a methanol (15 ml) and 2N sodium hydroxide aqueous solution (5 ml), methyl 6-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-naphthoate (3.45 mmol, 1.0 g) was added and the mixture was stirred for 2 hours at 60° C. Then, the reaction mixture was acidified with 2M hydrogen chloride aqueous solution and partitioned with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate and evaporated to give the title compound as a white solid (0.9 g, quant). 1H NMR (300 MHz, CDCl3) δ ppm 1.81 (3H, s), 6.85 (1H, s), 7.70-8.75 (6H, m), 12.94 (1H, br.s).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH2:10][C:11]#[N:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH2:10][C:11]#[N:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(CC#N)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nn(CC#N)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 32 %

Procedure:
Deprotection of 5-n-butyl-2-cyanomethyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one in 67% aqueous acetic acid was accomplished by the procedure of Example 3, Step B. After work-up, the residue was flash chromatographed over silica gel (15 mL for 0.082 mmole, gradient elution using 3-10% MeOH/CH2Cl2) to give a 32% yield of the desired material as a glassy solid, mp 86°-88° C., homogeneous by TLC in 10% MeOH/CH2Cl2, mass spectrum (FAB) m/e 415 (M+1)+.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[PH3:21]>C1C=CC=CC=1>[CH2:13]([PH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C=CCCCCCC
Reactant: P
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCCCCCCCP
Temperature: 90 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
A 1-liter autoclave was charged with 5 g of azobisisobutyronitrile, 50 g of benzene and 112 g (1 mol) of 1-octene, and 136 g (4 mols) of hydrogen phosphide was condensed thereinto. The whole was heated to 90° C. The pressure initially rose to 70 bars, then dropped gradually to 55 bars, and remained constant after 5 hours. The reaction mixture was analyzed by NMR-spectroscopy. The octene conversion rate was 85%. Primary octylphosphine was obtained in a yield of 70%, secondary octylphosphine was obtained in a yield of 20%, and tertiary octylphosphine was obtained in a yield at 10%, based on the quantity of 1-octene which underwent conversion.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Br:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:20])=[N:10][CH:11]=1>C(OCC)(=O)C>[Br:5][C:6]1[CH:11]=[N:10][C:9]([O:12][C:13]2[CH:19]=[CH:18][C:16]([N:17]=[C:1]=[O:2])=[CH:15][C:14]=2[Cl:20])=[N:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Solvent: CCOC(C)=O
Product: O=C=Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Yield: 95.1 %

Procedure:
Into a flask, a solution of 0.02 mol of phosgene in 30 ml of ethyl acetate was introduced. To this solution, a solution of 3 g of 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline in 10 ml of ethyl acetate was dropwise added at room temperature. The mixture was reacted at room temperature for 3 hours under stirring and further under reflux for one hour. After completion of the reaction, ethyl acetate was distilled off under reduced pressure, and the residue was vacuum-dried to obtain 3.10 g of 4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenylisocyanate having a melting point of from 63 to 68° C. (2) Into a flask, 1.22 g of 4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenylisocyanate obtained in the above step was introduced, and 20 ml of toluene was added thereto. Further, 0.62 g of 2-nitrobenzamide was added under stirring. The mixture was reacted under reflux for 4 hours. After completion of the reaction, 5 ml of methanol was added to the reaction product, and the mixture was cooled. The precipitated crystals were collected by filtration to obtain 0.79 g of the desired product.
Reaction SMILES: [CH3:1][NH:2]C([C@H]1CC[C@H](C2N3C=CN=C(N)C3=C(C3C=CC=C(OCC4C=CC=CC=4)C=3)N=2)CC1)=O.[NH2:35][C:36]1[C:37]2[N:38]([C:42]([CH:61]3[CH2:66][CH2:65][CH:64]([C:67](O)=[O:68])[CH2:63][CH2:62]3)=[N:43][C:44]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][C:53]3[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=3[F:60])[CH:46]=2)[CH:39]=[CH:40][N:41]=1>>[CH3:1][NH:2][C:67]([CH:64]1[CH2:63][CH2:62][CH:61]([C:42]2[N:38]3[CH:39]=[CH:40][N:41]=[C:36]([NH2:35])[C:37]3=[C:44]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][C:53]4[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=4[F:60])[CH:46]=3)[N:43]=2)[CH2:66][CH2:65]1)=[O:68]
Reactant: CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)CC1
Reactant: Nc1nccn2c(C3CCC(C(=O)O)CC3)nc(-c3cccc(OCc4c(F)cccc4F)c3)c12
Product: CNC(=O)C1CCC(c2nc(-c3cccc(OCc4c(F)cccc4F)c3)c3c(N)nccn23)CC1

Procedure:
The amide coupling procedures applied to the synthesis of (trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide was applied to 4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid to afford the title compound; MS (ES+): m/z 492.12 [MH+].
Reaction SMILES: C[N:2]1[CH2:11][C:10](C)(C)[C:9]2[C:4](=[CH:5][C:6]([NH2:14])=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:16]1[N:21]=[C:20]([C:22]2[C:23]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:47])[C:39]4[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=4[F:46])[CH:34]=[CH:35][CH:36]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)[CH:19]=[CH:18][N:17]=1>>[NH2:2][CH:11]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([NH:14][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:31]5[CH:32]=[C:33]([NH:37][C:38](=[O:47])[C:39]6[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=6[F:45])[CH:34]=[CH:35][CH:36]=5)=[N:24][N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=45)[CH:19]=[CH:18][N:17]=3)[CH:5]=2)[CH2:10]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Product: NC1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1

Procedure:
The title compound was prepared following a procedure similar to the Example 177, Step C, from 2,4,4-trimethyl-1,2,3,4-tetrahydro-7-isoquinolinamine (50 mg, 0.26 mmol) (synthesized as described in patent WO 0009486, p. 18) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (101 mg, 0.22 mmol, prepared according to a procedure similar to that described in Example 27, Step C). ESIMS (M+H)+=616.32.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]C1C=CC=CC=1C[Mg]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: Br[Mg]Cc1ccccc1Br
Product: OC(Cc1ccccc1Br)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using commercially available 2-bromobenzylmagnesium bromide (available from Rieke-Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=452/454.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([NH:9][N:10]=[CH:15][CH2:14][CH2:13][CH2:12][OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C1=COCC1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Product: OCCCC=NNc1cccc(Br)c1
Yield: 99.6 %

Procedure:
Under anhydrous conditions a solution of 3-bromophenylhydrazine hydrochloride (22.5 g, 100 mmol) and 2,3-dihydrofuran (7.55 ml, 100 mmol) in 200 ml of dry THF was stirred at ambient temperature for 3 h. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was washed with H2O and brine. After drying (Na2 SO4), the solvent was evaporated to give 25.6 g of the product as a brown oil. The product was of suitable purity for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH2:9]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[CH3:10].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Cl)nn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCSc1ccccc1-c1ccc(N)nn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A mixture of 700 mg of 3-amino-6-chloropyridazine, 1.42 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 148 mg of tris(dibenzylideneacetone)dipalladium(0), 603 mg of tricyclohexylphosphine (18% toluene solution), 3.43 g of tripotassium phosphate, 4.5 ml of 1,4-dioxane and 1.5 ml of water was stirred at 100° C. for 3 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 3-amino-6-(2-ethylsulfanylphenyl)pyridazine.
Reaction SMILES: [CH3:1][C:2]([NH2:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:28]([CH3:32])[C:29](O)=[O:30])=[N:18]2)=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[C:2]([NH:5][C:29](=[O:30])[CH:28]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[N:17]([NH:16][C:14](=[O:15])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)[N:18]=1)[CH3:32])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)N
Reactant: CC(C(=O)O)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C(=O)NC(C)(C)C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methylpropan-2-amine (34.1 mg, 0.467 mmol) in THF (5 mL), were added the product from Example 110 (150 mg, 0.389 mmol), triethylamine (0.163 mL, 1.17 mmol), and 1-propanephosphonic acid cyclic anhydride (50% in EtOAc, 0.463 mL, 0.778 mmol). The mixture was stirred at 70° C. for 16 hours, cooled, quenched with 1M NaHCO3 (10 mL), extracted with EtOAc (2×20 mL), dried (Na2SO4-d6), filtered, and concentrated. The residue was purified by chromatography (SiO2, 0-100% of 1/10 MeOH/EtOAc in hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.31 (d, J=7.8, 1H), 8.01-7.97 (m, 2H), 7.93 (s, 1H), 7.87 (ddd, J=8.2, 5.4, 3.0, 1H), 7.41 (s, 4H), 4.24 (q, J=6.8, 1H), 3.68 (s, 2H), 1.39 (d, J=6.9, 3H), 1.23 (s, 9H); MS (ESI+) M/Z 441 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:3]=1)#[N:20]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethyl)benzene (86 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (20 ml), washed successively with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from 2-butanone/n-hexane to give the title compound (165 mg, 70%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH3:2].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[Cl:18][C:16]1[N:15]=[N:14][C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([NH:10][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=2)[CH:17]=1
Reactant: CCOc1cccc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(OCC)n1
Temperature: 130 °C
Reaction time: 36 h
Yield: 4.5 %

Procedure:
In a sealed reaction tube, 6-ethoxypyridin-2-amine (775 mg, 5.61 mmol) and ethyl 4,6-dichloropyridazine-3-carboxylate (620 mg, 2.8 mmol) were combined with acetonitrile (14 mL) and stirred at 130° C. for 36 h. The mixture was cooled, concentrated to a brown solid, and then chromatographed (80 g Silicycle column, eluent 0 to 10% acetone in dichloromethane, 20 min, then held at 10% for 10 min) to give ethyl 6-chloro-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxylate (40.3 mg, 125 μmol, 4%) as a white solid. MS (EI/CI) m/z: 323.2 [M+H].
Reaction SMILES: C(OC(=O)CC(NC(OCC=C)=O)CO)(C)(C)C.[CH2:19]([O:22][C:23](=[O:40])[NH:24][CH:25]1[CH2:29][C:28](=[O:30])[O:27][CH:26]1[O:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=CC=1)[CH:20]=[CH2:21].C1(CO)CCCC1>>[CH2:19]([O:22][C:23](=[O:40])[NH:24][CH:25]1[CH2:29][C:28](=[O:30])[O:27][CH:26]1[O:31][CH2:32][CH:33]1[CH2:34][CH2:39][CH2:38][CH2:37]1)[CH:20]=[CH2:21]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Agent: OCC1CCCC1
Product: C=CCOC(=O)NC1CC(=O)OC1OCC1CCCC1

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using cyclopentylmethanol (6.5 mL, 60 mmol) to afford 2.98 grams (52% total yield) of the title compound as a mixture of epimers. Purification provided 0.97 grams (17% yield) of the 4(S), 5(R) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.19 (m, 2H), 1.54 (m, 4H), 1.71 (m, 2H), 2.16 (m, 1H), 2.44 (dd, J=17.2, 10.4 Hz, 1H), 2.82 (dd, J=17.2, 8.4 Hz, 1H), 3.44 (dd, J=9.3, 7.2 Hz, 1H), 3.71 (dd, J=9.3, 7.2 Hz, 1H), 4.57 (m, 3H), 5.32 (m, 3H), 5.41 (d, J=5.2 Hz, 1H), 5.91 (ddt, J=17.1, 10.4, 5 Hz, 1H) ppm. LC-MS. (ES+): m/e=284.