Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]([C:17]1[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:51]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.O>[CH2:51]([N:58]1[CH2:63][CH2:62][N:61]([C:25](=[O:27])[CH2:24][NH:23][C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:29][CH:28]=2)[CH2:60][CH2:59]1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: O=C(O)CNC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(Cc2ccccc2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
DIPEA (0.114 mL, 0.66 mmol) was added drop wise to (4-phenoxy-benzoylamino)-acetic acid (60 mg, 0.22 mmol) in DMF (5 mL). EDCI (106 mg, 0.55 mmol) and HOBT (35 mg, 0.27 mmol) were then added, and after 10 mins, 1-Benzyl-piperazine (46 mg, 0.27 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was added, and the resulting solid was isolated by filtration under reduced pressure to afford N-[2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-4-phenoxy-benzamide in 58% yield. LC-MS purity: 99%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.5 (t, 2H), 7.3 (m, 7H), 7.1 (m, 4H), 4.1 (d, 2H), 3.6 (s, 2H), 3.5 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[N+:20]([O-])([OH:22])=[O:21]>>[CH3:7][CH:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[CH:5]=[CH:6][N:1]1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1C=C([N+](=O)[O-])C=CN1O
Temperature: 5 °C

Procedure:
2-Picoline-N-oxide (14)(21.9 g, 0.2 mmol) was added to a concentrated sulphuric acid (76 mL), maintaining the temperature below 40° C. The mixture was cooled to 5° C.; fuming nitric acid (60 mL) was the added dropwise over 15 minutes, maintaining reaction temperature below 10° C. After the addition was complete the reaction mixture was heated to 100° C. for 1.5 hours. The reaction was then cooled to rt and poured over ice (ca 500 g), the resultant green/yellow solution was neutralised by addition of sodium carbonate (ca 205 g over 1 hour). The mixture was then filtered and washed with water (2 L). The solid cake was then dissolved in DCM (500 mL) and dried over Na2SO4. Hexane (100 mL) was added to the DCM solution resulting in a yellow suspension which was filtered off and dried. Single peak in LC-MS analysis, (25.40 g 82.5%) no purification performed and taken through crude to next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[O:5][CH:6]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[O:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(Br)co1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)co1
Temperature: 80 °C

Procedure:
Under argon, 100 mg (0.46 mmol) of the compound from Example 3A are provided in 3 ml of 1,2-dimethoxyethane, and 107 mg (0.69 mmol) of 3-chlorophenylboronic acid, 2.4 ml (2.28 mmol) of an aqueous sodium carbonate solution (10%) and 32 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. Under microwave irradiation, the mixture is heated in a closed vessel at 80° C. for 15 min. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 81.0 mg (71% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]([C:26]#[N:27])=[CH:19]2.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([I:15])[CH:17]=3)[N:22]=[CH:21][C:20]=2[C:26]#[N:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1cnc2ccc(I)cc2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(I)cc23)CC1

Procedure:
Similar procedure as described in example 28a was used, starting from 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester, 6-iodo-quinoline-3-carbonitrile (example 14c) and sodium hydride to give 4-(3-cyano-6-iodo-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester. LC-MS m/e 480 (MH+).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.CCCCCC.C([Li])CCC.[C:21](#[N:23])[CH3:22].[CH3:24][O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][CH:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]2=O)=[CH:28][CH:27]=1>O1CCCC1.O>[CH3:24][O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][CH:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)/[C:32]/2=[CH:22]\[C:21]#[N:23])=[CH:28][CH:27]=1
Reactant: CC#N
Reactant: COc1ccc2c(c1)C(=O)C(c1ccccc1)C2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc2c(c1)/C(=C/C#N)C(c1ccccc1)C2
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (2.19 g, 13.6 mmol.) in tetrahydrofuran (80 ml) was gradually added dropwise, under argon atmosphere at -78° C., a normal butyl lithium hexane solution (1.56 M, 8.72 ml, 13.6 mmol.). The mixture was stirred for 10 minutes, to which was then added dropwise acetonitrile (0.65 ml, 12.4 mmol.). The mixture was stirred for further 20 minutes, to which was added dropwise a solution of 6-methoxy-2-phenyl-1-indanone (2.70 g, 11.3 mmol.) in tetrahydrofuran (10 ml), and the mixture was stirred for one hour. The temperature of the reaction mixture was gradually reverted to room temperature while pouring water thereto, and the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was dissolved in toluene (100 ml), to which was added 10-camphor-sulfonic acid (0.5 g). The reaction mixture was heated for 2 hours under reflux. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue thus obtained was recrystallized to afford the titled compound (yield 0.47 g, yield 16%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][S:8]([C:4]1[CH:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cccc(N2CCNCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 1-bromo-3-methanesulfonyl-benzene (0.8 g), piperazine (1 g), sodium tert-butoxide (0.5 g) BINAP (42 mg) and [Pd2(dba)3 (38 mg) in toluene (7 ml) was heated under argon at 80° C. for 24 h. After cooling to room temperature, the solvent was evaporated to dryness. The crude material was purified by flash chromatography on silica gel using EtOAc. Yield 0.48 g: MS m/z (rel. intensity, 70 eV) 240 (M+, 17), 199 (12), 198 (bp), 119 (9), 56 (7).
Reaction SMILES: F[C:2](F)(F)C1N(C)N=C(O)C=1.[F:12][C:13]([F:23])([F:22])[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].S(OC)(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].COS([O-])(=O)=O.C([N+](CC)(CC)C)C>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH:15]=[C:14]([O:21][CH3:2])[C:13]([F:22])([F:23])[F:12])[CH3:20]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cn1nc(O)cc1C(F)(F)F
Agent: CC[N+](C)(CC)CC
Agent: COS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(F)(F)F

Procedure:
An alternative method of forming the 5-trifluoromethyl-3-hydroxy-1-methylpyrazole involves reacting ethyl 4,4,4-trifluoroacetoacetate in acetone with dimethyl sulfate in the presence of anhydrous potassium carbonate and preferably triethylmethylammonium methylsulfate to form 3-methoxy-4,4,4-trifluoro-2-butenoic acid ethyl ester. This ester is then reacted directly with methylhydrazine to form the 3- and 5-hydroxy isomer mixture of the pyrazole. The desired isomer can be separated as described above.
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[C:10]([O:19][CH:20]([CH3:22])[CH3:21])[CH:9]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[C:10]([O:19][CH:20]([CH3:22])[CH3:21])[CH:9]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Oc1cc(O)cc2nc[nH]c(=O)c12
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OC(C)C)c2c(=O)[nH]cnc2c1
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 66.1 %

Procedure:
Pyridine (0.18 ml, 1.5 mmol) was added to a suspension of 7-hydroxy-5-isopropoxyquinazolin-4(3H)-one (3.3 g, 15 mmol) in acetic anhydride (10 ml, 75 mmol) and the mixture was stirred at 75° C. for 45 minutes. The mixture was evaporated under reduced pressure and the residue obtained was stirred in water (50 ml) at 75° C. for 1 hour and then cooled to ambient temperature and filtered to afford 5-isopropoxy-4-oxo-3,4-dihydroquinazolin-7-yl acetate (2.6 g, 65% yield) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=1.[OH-].[Na+].Cl.[K+].[Br-]>[Zn].O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccccc1C2
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: COc1ccc2cc3ccccc3cc2c1

Procedure:
A well-stirred mixture of 20 g zinc dust, 2 ml Fehling I solution, and 120 ml of water was added to a suspension of 8 g 2-methoxy-9-anthrone and 200 ml of 10% aqueous sodium hydroxide. The mixture was refluxed for 30 minutes and filtered hot to give a gray solid. The solid was heated on a steam bath and swirled vigorously while 120 ml of conc. hydrochloric acid were added drop by drop over a 40 min. period. A crude, slightly yellow solid was collected on a Buchner funnel, washed with 100 ml water and 50 ml methanol, and then crystallized from benzene twice to give 6.4 g (86%) of plate-like crystals: mp. 182.5°-183.5° C. (lit.* mp 163-165). IR (KBr): 1635, 1480, 1465, 1435, 1345, 1220-1175, 1300-1270, 1025, 950, 880, 800, 740 cm-1. 1H NMR (CDCl3 /TMS): δ8.3 (1 H, s, anthrancenyl meso proton), 8.2 (H, s, anthracenyl meso proton, 7.75-8.05 (3 H, m, oxyanthracenyl protons), 7.05-7.50 (4 H, m, oxyanthracenyl protons), 3.95 (3 H, s, ArOCH3).
Reaction SMILES: [CH3:1][C:2]([N:5]1[N:9]=[N:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)=[N:6]1)([CH3:4])[CH3:3]>FC(F)(F)C(O)=O>[CH3:4][C:2]([N:5]1[N:9]=[N:8][C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(Cc2nnn(C(C)(C)C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnc(Cc2ccc(CCC(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
1,1-dimethylethyl 4-[[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]methyl]benzenepropanoate (3.0 g. 8.7 mmol) was dissolved in trifluoroacetic acid (33 mL) and stirred at room temperature under argon for 12 hours. The mixture was concentrated and then dissolved in water (50 ml). After adding enough sat. NaHCO3 to raise the pH to 8, the solution was washed with diethyl ether (2×25 mL). The aqueous layer was acidified to pH 3 with 1N HCl and the product collected by suction filtration. Recrystallization from hexanes gave 4-[[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]methyl]benzene-propanoic acid (1.5 g, 5.7 mmol) in 66% yield, mp. 139°-141° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH2:17][NH:18][CH:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:37](Cl)(Cl)=[O:38]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([CH:19]([CH:25]([CH3:26])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:37]2=[O:38])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NCCNc1ccc(OCc2ccccc2)cc1)C(C)C
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C(C)C)N1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 0 °C
Yield: 81.5 %

Procedure:
Ethyl 2-(2-(4-benzyloxyphenylamino)ethylamino)-3-methylbutyrate (100 mg; 0.27 mmol) was dissolved in toluene (5 ml) and cooled to 0° C. DIEA (141 μl; 0.81 mmol) and phosgene (20% strength in toluene; 202 μl; 0.40 mmol) were added thereto. The mixture was allowed to reach RT over the course of 3 h, and then the solvent was removed under reduced pressure. The residue was partitioned between water (10 ml) and EtOAc (10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×; 5 ml). The combined organic phases were dried over MgSO4. After removal of the solvent whilst under reduced pressure, ethyl 2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (90 mg; 0.22 mmol) was obtained. MS: 397.15 (M+H); Rt: 1.90 min (method: gradient 0 min 90% H2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:28][CH2:29][C@@H:30]1[CH2:34][CH2:33][C@@:32]([C@@H:36]([CH3:41])/[CH:37]=[CH:38]/[CH2:39][OH:40])([CH3:35])[C:31]1([CH3:43])[CH3:42])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Si:11]([O:28][CH2:29][C@@H:30]1[CH2:34][CH2:33][C@@:32]([C@@H:36]([CH3:41])/[CH:37]=[CH:38]/[CH:39]=[O:40])([CH3:35])[C:31]1([CH3:42])[CH3:43])([C:24]([CH3:26])([CH3:27])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H](/C=C/CO)[C@@]1(C)CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](/C=C/C=O)[C@@]1(C)CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To a solution of oxalyl chloride (0.6377 mL, 7.31 mmol) in dry CH2Cl2 (15.0 mL) was added dropwise DMSO (0.7786 mL, 10.96 mmol) at −78° C. over a period of 10 minutes and the mixture was stirred at −78° C. for 15 minutes. A solution of intermediate (12) (0.820 g, 1.83 mmol) in dry CH2Cl2 (5.0 mL) was then added dropwise at −78° C. over a period of 30 minutes and the reaction mixture was stirred at −78° C. for 30 minutes. Triethylamine (2.04 mL, 14.6 mmol) was added dropwise at −78° C. over a period of 10 minutes and the reaction mixture was stirred at −78° C. for 1 hour. The temperature of the mixture was allowed to rise to −10° C. over a period of 3.5 hours and then H2O (50 mL) was added. The organic layer was separated, the aqueous layer was extracted with diethyl ether (3×20 mL), the combined organic layers were dried over anhydrous MgSO4, and the solvent was removed under reduced pressure and the resulting residue was purified over silica (n-hexane/EtOAc, 97:3) to afford 0.776 g (92% yield) of the desired intermediate (13) which was characterized as follows:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH2:43]([N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1)[CH:44]([CH3:46])[CH3:45]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:43]([N:47]1[CH:51]=[C:50]([C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11](=[O:12])[C:10]([C:13]4[CH:14]=[CH:15][C:16]([C:19]5([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:20][CH2:21][CH2:22]5)=[CH:17][CH:18]=4)=[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:8][C:7]=23)[CH:49]=[N:48]1)[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)Cn1cc(-c2nccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
tert-Butyl 1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate (0.050 g, 0.1 mmol), sodium carbonate (0.032 g, 0.3 mmol) and 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.025 g, 0.100 mmol) were dissolved in dioxane (5 mL) and water (1 mL). The reaction mixture was degassed, PdCl2(dppf)-CH2Cl2 adduct (0.012 g, 0.0150 mmol) added and heated at 80° C. After 16 hours, the reaction mixture was filtered through Celite®, washed with ethyl acetate, evaporated and purified by column chromatography using 0-40% ethyl acetate in hexane to give the title compound (40 mg, 68%). LC-MS (Method I): RT=8.27 min, [M+H]+=591.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[C:17]([CH3:24])=[C:16]([CH3:25])[N:15]=1.C(N(CC)CC)C.C(=O)([O-])N>CN(C)C=O>[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[C:17]([CH3:24])=[C:16]([CH3:25])[N:15]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: NC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.2 %

Procedure:
A solution of tert-butyl 3-aminopropylcarbamate (121.39 g, 697 mmol) in N,N-dimethylformamide (200 mL) was slowly added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (110 g, 498 mmol) and triethylamine (104 mL, 746 mmol) in N,N-dimethylformamide (900 mL). After stirring at ambient temperature for 20 hours the reaction mixture was heated to 55° C. At 24 hours 0.1 equivalents of the carbamate was added. The reaction mixture was allowed to cool to ambient temperature overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (3 L). The solution was divided into 3 aliquots (1 L each). Each aliquot was washed with water (2×1 L). The pH of the aqueous washes was adjusted to 10 with potassium carbonate and then they were extracted with ethyl acetate. All of the ethyl acetate layers were combined, dried over sodium sulfate and then concentrated under reduced pressure to provide 181 g of crude product. This material was recrystallized from acetonitrile to provide 138 g of tert-butyl 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propylcarbamate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([N:22]1[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]2[CH:25]=[CH:26][C:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:36]
Reactant: O=C(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccccc1Br)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1

Procedure:
In the manner given in Example 23, 4-[4-[[7-chloro-4-quinolinyl]amino]benzoyl]piperazine is reacted with o-bromophenyl isocyanate to give 1-[[(2-bromophenyl)amino]carbonyl]-4-[4-[[7-chloro-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=[C:7]3[C:6]=2[CH:20]=1.C(=O)(O)[O-].[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>COCCOCCOC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:27])[CH2:9][N:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=[C:7]3[C:6]=2[CH:20]=1
Reactant: O=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: S=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Yield: 40 %

Procedure:
A mixture of 3.74 g 2-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 2.58 g sodium bicarbonate, and 13.67 g P2S5 in 85 ml diglyme was heated at 105°-120° C. under nitrogen for one and a half hours. The cooled reaction mixture was diluted with water to precipiate a solid. Recrystallization from toluene yielded 1.58 g solid, which decomposed at 265° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[NH2:30]>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:30][C:26]2[S:25][CH:29]=[CH:28][N:27]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Yield: 45.3 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 19) and thiazol-2-ylamine afforded 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-N-thiazol-2-yl-propionamide as a white solid (53.9 mg, 45.3%); ES+-HRMS m/e calcd for C21H22N4O3S [M+H+] 411.1486, found 411.1485. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.02-1.87 (m, 9H), 1.97 (m, 1H), 2.26 (m, 1H), 5.54 (dd, J=4.4, J=10.7 Hz, 1H), 5.57 (d, J=2.7 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 7.30 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.5 Hz, 1H), 7.49 (d, J=3.6 Hz, 1H), 7.53 (t, J=7.5 Hz, 2H), 8.16 (d, J=2.7 Hz, 1H), 12.55 (s, 1H).