Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:2]1.NN.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][NH:7][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:2]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCOC1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(tetrahydro-3-furanyloxy)-1H-isoindole-1,3(2H)-dione (1.5 mmol, 357 mg) was combined with hydrazine (1.7 mmol, 0.053 mL) in anhydrous THF (3 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 1 hour. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (1.5 mmol, 316 mg) and diisopropylethylamine (1.8 mmol, 0.320 mL) was added. After stirring at room temperature for 18 hours, the reaction was concentrated to a solid. The resulting solid was partitioned between ethyl acetate and 1N HCl, and the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate). The purified product was then combined with ether and filtered to remove the residual phthalimide-hydrazine biproduct. The filtrate was then crystallized by adding hexanes providing 203 mg (48%) white crystals. Rf=0.2 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.82 (2H,d), 6.99 (2H,d), 6.85 (1H,s), 4.82-4.79 (1H,m), 3.97-3.87 (2H,m), 3.87 (3H,s), 3.83-3.70 (2H,m), 2.12-1.99 (2H,m).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1.[F:19][C:20]([F:31])([F:30])[C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]([F:30])([F:31])[C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([N:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[CH2:8][O:9][C:10]2[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:28])[CH2:25][CH2:26]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: Cl
Product: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 1 Step 3) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].O[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([O:41][CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])=[O:40])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH2:8]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][C:36]2([C:39]([O:41][CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])=[O:40])[CH:35]=[CH:34][C:33]([C:30]3[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=3)=[CH:38][CH2:37]2)=[O:22])=[CH:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCCCCCCOc1ccc(C(=O)OC2(C(=O)OCC(C)CC)C=CC(c3ccccc3)=CC2)cc1
Reaction time: 8 h
Yield: 45 %

Procedure:
9 g of p-(7-octenyloxy)benzoic acid obtained in 15.(1) was suspended in toluene, and the suspension was cooled in an ice bath. Added dropwise thereto was 6 g of thionyl chloride. After conclusion of the dropping, the temperature was raised and reaction was carried out for 6 hours at 80° C. After conclusion of the reaction, the reaction solution was concentrated under reduced pressure, to obtain an acid chloride compound. Toluene was added to the acid chloride compound, and the resulting toluene solution was cooled in an ice bath. A toluene solution containing 10 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate and 3 g of pyridine was added dropwise into the above-described toluene solution of the acid chloride compound. After conclusion of dropping, the temperature was raised, and reaction was carried out for 8 hours at 50° C. After conclusion of the reaction, the product was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol, to obtain 8.2 g of the objective ester compound. (Yield: 45%)
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH:41]1([CH:44]=O)[CH2:43][CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:41]1([CH2:44][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:43][CH2:42]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=CC1CC1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NCC3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.022 g, 0.040 mmol) in DCE (0.25 mL) was added cyclopropanecarbaldehyde (2.84 mg, 0.040 mmol) and titanium (IV) isopropoxide (0.015 mL, 0.051 mmol). The mixture was stirred at rt for 1 h and sodium triacetoxyborohydride (0.017 g, 0.081 mmol) was added. After stirring the mixture for 16.75 h, the mixture was diluted with 3 mL of water and was filtered through a pad of celite, then was extracted with dichloromethane (3×4 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (0.024 g, 0.040 mmol, 99% yield) as a clear film. The crude product was used in the next step with no additional purification. LCMS: m/e 598.6 (M+H)+, 2.13 min (method 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14](#[N:17])[CH2:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:14](=[NH:17])[CH2:15][CH3:16])[CH2:9][CH2:10]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CCC#N
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine (5.34 g), propionitrile (4.7 g) and anhydrous aluminium chloride (12 g) was heated at 160°-170° C. for six hours to yield N-(2-morpholinophenyl)propionamidine (m.p. 114° C.) which was recrystallised from hexane.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.C(OC(=O)[N:14]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1)(C)(C)C.C(OCC)(=O)C.CCCCCCC>CN(C)C=O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([N:3]3[CH:7]=[CH:6][CH:5]=[N:4]3)[N:16]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: Clc1ccc(Nc2cncc(-n3cccn3)n2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Sodium hydride (60% in mineral oil, 156 mg, 3.90 mmol) was added to a suspension of pyrazole (260 mg, 3.82 mmol) in N,N-dimethylformamide (5 mL) and the mixture was heated to 50° C. for 20 minutes. (4-Chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester (260 mg, 0.76 mmol) was added and stirring was continued for 30 minutes at the same temperature. The temperature was raised to 100° C. and the mixture was stirred overnight. The reaction mixture was quenched with brine and extracted with ethyl acetate (4×15 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtrated and evaporated to give the crude product. Flash chromatography (ethyl acetate/heptane as eluent) gave (4-chloro-phenyl)-(6-pyrazol-1-yl-pyrazin-2-yl)-amine (56 mg, 27%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][C@H:23]2[CH2:32][OH:33])(=[O:21])=[O:20])=[C:14]([CH3:34])[CH:13]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH3:34])[C:15]([S:19]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][C@H:23]2[CH2:32][O:33][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:20])=[O:21])=[C:16]([CH3:18])[CH:17]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2CO)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-bromoacetate (1.358 g, 6.972 mmol) and tetra-n-butylammonium hydrogen sulfate (110 mg, 0.332 mmol) were stirred in sodium hydroxide solution (26 ml, 50% aq) and toluene (20 ml). A solution of (S)-(1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methanol (1.2 g, 3.32 mmol) in toluene (10 ml) was added slowly. The addition was exothermic, cooling was achieved with an ice bath. After stirring at room temperature for 1 h, the phases were separated and the aqueous phase was extracted with diethylether (2×50 ml). The combined organic phases were washed with saturated sodium chloride solution (30 ml), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/ethyl acetate 5/1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:39])[C@@H:28]([NH:38][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 6.7 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 40 ml of DMF, 3 g of HOBT and 3.7 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 9.4 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[NH:86]1[CH2:91][CH2:90][O:89][CH2:88][CH2:87]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:86]3[CH2:91][CH2:90][O:89][CH2:88][CH2:87]3)[CH:3]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: C1COCCN1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(Br)c1)C2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(N3CCOCC3)c1)C2
Temperature: 100 °C

Procedure:
A mixture of (R)-6-(5-bromopyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene (0.15 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.035 g), tris(dibenzylideneacetone)dipalladium (0.026 g), sodium tert-butoxide (0.049 g), morpholine and tetrahydrofuran was heated at 100° C. in a microwave reactor for 30 minutes. The mixture was filtered through Celite, and the pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4:1 by volume), to afford a yellow oil. The yellow oil was purified by preparative reverse-phase HPLC, eluting with a mixture of methanol and water containing 0.1% formic acid (9:20 to 4:3 by volume) to afford the title compound as a white solid (0.097 g). LCMS (Method C): 540 (M+H)+, Retention time 10.6 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.BrC1C=CC(C(CCCCCCC(OCC)=O)=O)=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].S1C=CC(B(O)O)=C1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1ccc(Br)nc1
Agent: CCOC(=O)CCCCCCC(=O)c1ccc(Br)cc1
Agent: OB(O)c1ccsc1
Product: COc1ccc(-c2ccc(Br)cn2)cc1OC
Yield: 78 %

Procedure:
Following the procedure described in Example 67, step 1, but substituting respectively 2,5-dibromopyridine for 49d and 3,4-dimethoxyphenyl boronic acid for 3-thiophene boronic acid, the title compound 147 was obtained in 78% Yield. 1H NMR (300 MHz, CDCl3): δ 8.65 (dd, J=2.4, 0.9 Hz, 1H), 7.77 (dd, J=8.4, 5.4 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.53 (dd, J=8.4, 0.9 Hz, 1H), 7.73 (dd, J=8.4, 2.1 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 55.92, 55.93, 109.64, 111.01, 118.46, 119.25, 120.92, 131.05, 139.09, 149.28, 150.21, 150.3 6, 155.40.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=[CH:5][N:4]=1.O1CCCC1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[C:27]([Cl:35])=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O>[Cl:2][C:3]1[C:8]([CH2:9][NH:10][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[C:27]=2[Cl:35])=[S:34])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: NCc1cccnc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: S=C(NCc1cccnc1Cl)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To an oven-dried, N2-purged, 25-mL, round-bottomed flask containing a magnetic stir bar were added the product of Example 141A, anhydrous tetrahydrofuran (5 mL), and diisopropylethylamine (646 mg, 0.886 mL, 5.00 mmol). The flask was sealed with a septum and neat dichlorophenylisothiocyanate (306 mg, 0.213 mL, 1.50 mmol) was added via syringe. The reaction mixture was stirred at room temperature overnight. Water (10 mL) was added, and the reaction was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown solid. The product was recrystallized from ethyl acetate/hexanes to give 197 mg (47%) of the title compound as a white powder. MS (ESI″) m/z 345.9 (M+H)+; 1H NMR (DMSO-d6) δ 4.75 (d, J=5.1 Hz, 2H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.46 (dd, J=7.5, 4.7 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.76 (dd, J=7.6, 1.5 Hz, 1H), 8.32 (dd, J=4.7, 1.7 Hz, 1H), 8.44 (br s, 1H), 9.68 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[C:16]1([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)(=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(C(=O)c3ccccc3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and phenyl(piperidin-4-yl)methanone. MS (+ESI) m/z 381 (MH+).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.Cl.[NH:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[NH2:18].C([O-])(=O)C.[Na+]>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1
Reactant: NNc1ccncc1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccncc2)n1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (16.7 g, 82.4 mmol), 4-hydrazinopyridine hydrochloride (12.0 g, 82.4 mmol) and sodium acetate (8.10 g, 98.9 mmol) in ethanol (300 mL) was heated under reflux for 30 minutes. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water and the resulting crude crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (11.9 g, 49% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCOCC1.[CH:22]([N:25]([BH2:29])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>[Pd].CCOCC>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([BH:29][N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[CH:3][CH:4]=1
Reactant: BN(C(C)C)C(C)C
Reactant: Cc1ccc(I)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(BN(C(C)C)C(C)C)cc1
Temperature: 70 °C

Procedure:
0.343 g (0.49 mmol) of palladium catalyst (Ph3P)2PdCl2, 2.129 g (9.8 mmol) of p-iodotoluene, 6.8 ml (49 mmol) of triethylamine, 30 ml of dioxane and 3 ml (19.5 mmol) of diisopropylaminoborane were introduced into a 250 ml Schlenk vessel dried beforehand under argon. The Schlenk vessel was subsequently equipped with a reflux condenser connected at the top to a bubbler. The reaction mixture was stirred magnetically and heated at 70° C. for 15 h. The reaction mixture was subsequently allowed to return, under argon, to ambient temperature. The solvent and the excess reactants were evaporated under the vacuum of a vane pump. The residue obtained was taken up in anhydrous ether and then filtered under argon through dry Celite® 545. The filtrate was again evaporated and the residue was distilled in a Kügelrohr distillation apparatus (T=30–35° C.) under a vacuum of 0.01 mmHg. 1.694 g (Yd=85%) of a colorless oil were isolated. The spectroscopic characteristics are as follows:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16].[C:17](Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1C=CC=CC=1>CCCCCC>[C:17]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[CH:15][S:14][CH:13]=[C:5]12)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)Cl
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 7 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.6 g. (4.8 ml.) of hexanoyl chloride in 70 ml. of benzene is heated with stirring under reflux for 3 hours. The reaction mixture is stirred with cooling in an ice bath for 2 hours, 150 ml. of hexane is added and the mixture is placed in a chill room. The solvents are removed in vacuo on a steam bath. A 10 ml. portion of ether is added to the residue and the mixture is returned to the chill room. The tan crystals are collected by filtration, washed with ether and dried. The ether is concentrated giving a green oil which is triturated twice with hexane and once with a mixture of hexane and ether, giving crystals which are collected, washed with ether and dried. The two crops of crystals are combined, dissolved with warming in 75 ml. of ether and filtered. The filtrate is concentrated to 35 ml. and stored in a cold room for 4 hours. The solid is collected, washed with ether then hexane and dried, giving the desired product, mp. 76°-77° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1.[H-].[Na+].[CH:14](I)([CH3:16])[CH3:15].O>CN(C)C=O.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][N:9]([CH:14]([CH3:16])[CH3:15])[N:8]=2)[S:5][CH:6]=1
Reactant: Brc1csc(-c2cc[nH]n2)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ccc(-c2cc(Br)cs2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
3-(4-bromo-2-thienyl)-1H-pyrazole (8.7 mmol) was dissolved in 20 mL dry N,N-dimethylformamide under argon atmosphere. Sodium hydride (10.5 mmol, 60% dispersion in mineral oil) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 15 min. Isopropyl iodide (13.1 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 100:0 to 0:100) to afford 1.90 g 3-(4-bromo-2-thienyl)-1-isopropyl-1H-pyrazole (71% yield). Traces of the minor regioisomer 5-(4-bromo-2-thienyl)-1-isopropyl-1H-pyrazole were collected and analyzed as well.