Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.[Br:14]Br>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([Br:14])=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Temperature: 70 °C
Yield: 80 %

Procedure:
A 100 ml three-necked flask, fitted with an efficient reflux condenser and drying tube, and addition funnel, was charged with a mixture of AlC3 9.5 g (71.4 mmol) and 3 ml of CH2Cl2. The 3,4-dihydro-4,4-dimethyl-1(2H)-naphthalenone (5.0 g, 28.7 mmol), was added dropwise with stirring (Caution: Exothermic Reaction!) to the mixture at room temperature. Bromine, 5.5 g (34.5 mmol), was then added very slowly, and the resulting mixture stirred for 2 hours at room temperature. (Note: if stirring stops, the mixture can be warmed to 70° C. until stirring resumes.) The reaction was then quenched by the slow addition of ice-cold 6M HCl. The mixture was extracted with Et2O and the combined organic layers washed with water, saturated aqueous NaHCO3, and saturated NaCl, before being dried over MgSO4. Removal of the solvent under reduced pressure, and distillation of the residue afforded 5.8 g (80%) of the product as a pale-yellow oil which solidified on standing, bp: 140° C./0.4 mm Hg. 1H NMR (CDCl3): δ 8.11 (1H, d, J=3.0 Hz), 7.61 (1H, dd, J=3.0, 9.0 Hz), 7.31 (1H, d, J=9.0 Hz), 2.72 (2H, t, J=6.0 Hz), 2.01 (2H, t, J=6.0 Hz), 1.28 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:23])([F:22])[F:11])=[CH:14][CH:15]=2)[N:3]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cn(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 11.1 %

Procedure:
Using a crude product of methyl 3-methyl-1H-pyrazole-4-carboxylate (8.9 g) synthesized in Example 1(3) and 4-trifluoromethylphenylboronic acid (13.3 g) and in the same manner as in Example 17(1), the title object compound (2.0 g, 11%) was obtained as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH:19]([CH3:21])[CH3:20])[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:24][N:25]1[C:29]([CH3:30])=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]([CH3:40])=[N:26]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH:19]([N:17]([CH3:18])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:28]2[C:27]([CH3:40])=[N:26][N:25]([CH3:24])[C:29]=2[CH3:30])[CH2:12]1)([CH3:21])[CH3:20]
Reactant: CC(C)N(C)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(C)C(C)C)C2
Reaction time: 4 h
Yield: 55.8 %

Procedure:
(S)-6-(Isopropyl(methyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (184 mg, 0.524 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (142 mg, 0.602 mmol) and Pd(PPh3)4 (60 g, 0.0524 mmol) were added to a solution of K2CO3 (145 mg, 1.047 mmol) in a mixture of 1,2-dimethoxyethane (7 mL) and H2O (1 mL). The reaction mixture was purged with Ar (g) for 10 min, and warmed up to reflux. The reaction was completed in 4 h. It was allowed to reach room temperature, diluted with CH2Cl2 (20 mL) and acidified with HCl aqueous solution (10%, 30 mL). The organic layer was discarded, and the aqueous layer was taken to pH=9-10 with NaOH aqueous solution (10%). It was extracted with CH2Cl2 (3×20 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The obtained crude was purified by flash chromatography on silica gel (5% Et3N/AcOEt), to afford 91 mg of the desired product (yellow oil, 56% yield).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.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>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[CH:10][CH:9]=1
Reactant: Clc1ccccc1I
Reactant: Cc1ccc(B(O)O)cc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccccc2Cl)cc1
Yield: 96.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (637 mg, 0.551 mmol), Na2CO3 (5 mL, 1M) and 4-methylbenzene boronic acid (1.5 g, 11.0 mmol) were added to a solution of 2-chloroiodobenzene (1.315 g, 5.514 mmol) in toluene (98 mL) and EtOH (20 mL). The reaction mixture was heated at reflux for 3 h. The cooled solution was diluted with EtOAc, and the organic solution was washed with water (2×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes to 10% EtOAC/hexanes) to afford 4′-methyl-2-chlorobiphenyl (1.08 g). 1H NMR (CDCl3 400 MHz) δ 7.49-7.21 (m, 8H), 2.39 (s, 3H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9])C(C)=O.[ClH:16]>>[ClH:16].[ClH:16].[NH2:1][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: CC(=O)NCCNC(=O)c1ccccn1
Agent: Cl
Product: NCCNC(=O)c1ccccn1

Procedure:
12.0 g of N-(2-acetaminoethyl)-2-pyridine- carboxamide were suspended in 100 ml of alcohol and 116 ml of 2N hydrochloric acid and the suspension was heated to reflux overnight. The reaction mixture was thereafter concentrated under reduced pressure, the solid residue (13.4 g) was boiled up with methanol, cooled, suction filtered and dried. There was obtained N-(2-aminoethyl)-pyridine-2-carboxamide dihydrochloride as white crystals, m.p. 262° (dec.).
Reaction SMILES: [Br:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][NH:13][C:14]([C:16]3[C:17](Cl)=[C:18]4[CH:24]=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)=[O:15])[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.O>CN1CCCC1=O>[Br:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[N:12]3[C:17]4=[C:18]5[CH:24]=[CH:23][NH:22][C:19]5=[N:20][CH:21]=[C:16]4[C:14](=[O:15])[NH:13]3)[CH2:3]1)[CH2:9]2
Reactant: O=C(NNC1C2CC3CC1CC(Br)(C3)C2)c1cnc2[nH]ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]n(C2C3CC4CC2CC(Br)(C4)C3)c2c1cnc1[nH]ccc12
Temperature: 200 °C
Yield: 49.8 %

Procedure:
To a solution of N′-(5-bromoadamantan-2-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbohydrazide (200 mg) in 1-methyl-2-pyrrolidone (1.5 ml) was added triethylamine (0.2 ml), and the mixture was stirred at 200° C. using a microwave reaction system for 2 hours. After the reaction solution was cooled, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain 1-(5-bromoadamantan-2-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine-3(2H)-one (91 mg).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[CH3:26][C@H:27]1[O:32][C@H:31]([CH3:33])[CH2:30][NH:29][CH2:28]1.O>O1CCCC1>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][N:29]2[CH2:28][C@H:27]([CH3:26])[O:32][C@@H:31]([CH3:33])[CH2:30]2)[CH2:12]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C[C@@H]1CNC[C@@H](C)O1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(CC(=O)[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]23C)C[C@H](C)O1
Yield: 14 %

Procedure:
21-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (1 g.) was dissolved in dry tetrahydrofuran (50 ml.) and cis/trans-2,6-dimethylmorpholine (1 ml.) added to the solution. The mixture was refluxed for 4 hours. The mixture was poured into water, the emulsion extracted into ether, and the combined extracts washed with water, dried over anhydrous sodium sulphate and evaporated to a pale yellow foam (1.07 g.) which was purified by preparative T.L.C. in ethyl acetate. The faster running band (Rf ~0.6) gave 3α-hydroxy-21-(trans-2',6'-dimethylmorpholino)-5α-pregnane-11,20-dione (150 mg., 14%) as a white foam. [α]D + 70.5° (c 0.42).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[N:17]=[N:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)c1ccc(F)cc1

Procedure:
Following the procedure of Example 6, making variations only as required to use 4-fluorobenzoyl chloride in place of phenoxyacetyl chloride to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a light yellow solid (62% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.78-7.85, 7.77, 7.66, 7.52, 7.44, 7.25-7.35, 3.10-3.80.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]2[N:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([F:34])[CH:21]=3)[C:12]2=[N:11][CH:10]=1>>[F:34][C:22]1[CH:21]=[C:20]([O:19][C:18]2[C:12]3=[N:11][CH:10]=[C:9]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[N:14]=[C:13]3[N:15]=[CH:16][CH:17]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(Cl)cnc23)cc1F
Product: CN1CCN(c2cnc3c(Oc4ccc(NC(=O)OC(C)(C)C)c(F)c4)ccnc3n2)CC1

Procedure:
Method D6 was used with N-methylpiperazine and tert-butyl 4-(3-chloropyrido[2,3-b]pyrazin-8-yloxy)-2-fluorophenylcarbamate to give the title compound as a yellow solid. Yield: 142 mg (92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]#[N:16])=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:21]2[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]2)=[NH:16])=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: N#CNc1ccccc1-c1ccc(F)cc1
Solvent: CCO
Product: N=C(Nc1ccccc1-c1ccc(F)cc1)N1CCC(O)CC1

Procedure:
A mixture of 4'-fluoro-2-biphenylylcyanamide (1 g) and 4-hydroxypiperidine (0.6 g) in ethanol (10 ml) was heated at 90°-95° C. for 3 hours to give N-(4'-fluoro-2-biphenylyl)-4-hydroxypiperidine-1-carboxamidine as a colourless solid (m.p. 132°-133° C.) which was recrystallised from ethylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: COCCN1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: COCCN1CCN(Cc2ccc(Br)cc2)CC1
Yield: 64.2 %

Procedure:
4-Bromobenzyl bromide (2.0 g) and 1-(2-methoxyethyl)piperazine (2.31 g) were stirred in dimethylformamide (30 ml) for 18 h. The mixture was partitioned between diethyl ether (30 ml) and water (30 ml). The aqueous phase was extracted further with ether (30 ml) and the combined organics were washed with water (50 ml), dried (MgSO4), concentrated in vacuo and purified by Bondelute® chromatography, eluting with 0-100% ethyl acetate/iso-hexane followed by 10-50% methanol/ethyl acetate to give the product as a yellow oil (1.61 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].[Se](=O)=[O:17]>O1CCOCC1>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CCOC(=O)Cc1cccc(NC=O)n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1cccc(NC=O)n1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (26 g.) in dioxane (260 ml.) was added selenium dioxide (16.65 g.) in small portions at 85° to 90° C. over one hour and stirred at the same temperature for one hour. After cooling the resultant solution the dioxane layer was separated and concentrated under reduced pressure and then the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and treated with activated chrcoal and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (14.3 g.), mp 124° to 126° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
Methanesulfonyl chloride (186.3 mg, 125.9 μL, 1.626 mmol) was added dropwise to a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (350 mg, 1.626 mmol) and DIPEA (222.8 mg, 300.3 μL, 1.724 mmol) in DCM (5 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature over 16 hours then treated with water. The phases were separated and the aqueous phase extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a white solid (505 mg, >100% Yield) that was used directly assuming 100% yield and purity. MS (ES+-t-Bu) 238.0.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl.[OH-].[NH4+].C(Cl)(Cl)Cl>C(O)C.O.[Fe]>[NH2:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[C:2]([Cl:1])[CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccc2)c(Cl)c1
Yield: 69 %

Procedure:
To a solution of 2-chloro-4-nitrobenzophenone (27 grams, 0.103 mole) in hot ethanol (400 ml.) and water (200 ml.) was added iron (30 grams), followed by concentrated hydrochloric acid (25 ml.) dropwise and with stirring. After the addition, the reaction mixture was stirred at reflux during 1.5 hours, cooled, then made alkaline with ammonium hydroxide and chloroform extracted. After drying the chloroform layer (anhydrous MgSO4) and filtering, the solution was evaporated to an orange solid, melting point 120° C.-130° C. Crystallization from benzene-hexane gave faint yellow crystals of 4-amino-2-chlorobenzophenone having a melting point of 144° C.-145° C., and recovering 16.5 grams which amounts to a 69% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:22]=[N:23]O)=[N:11][CH:12]=[C:13]([N:15]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]3)[N:14]=2)=[CH:4][CH:3]=1.CO>[Ni].C(O)C>[NH2:23][CH2:22][C:10]1[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:14][C:13]([N:15]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]2)=[CH:12][N:11]=1
Reactant: Cc1cc(C)n(-c2cnc(C=NO)c(Nc3ccc(Cl)cc3)n2)n1
Agent: [Ni]
Solvent: CCO
Solvent: CO
Product: Cc1cc(C)n(-c2cnc(CN)c(Nc3ccc(Cl)cc3)n2)n1
Reaction time: 1 h
Yield: 28.6 %

Procedure:
Raney nickel (50% slurry in water, 1 mL) was added to a solution of 3-(4-chloro-phenylamino)-5-(3,5-dimethyl-pyrazol-1-yl)-pyrazine-2-carbaldehyde oxime (60 mg, 0.17 mmol) in ethanol (99%, 6 mL). The reaction mixture was stirred under a hydrogen atmosphere for one hour. Methanol was added followed by filtration and evaporation. The crude product was purified by flash chromatography (dichloromethane/methanol as eluent) to give [3-aminomethyl-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-(4-chloro-phenyl)-amine (16 mg, 28%) as a white solid. Mp.=156-160° C.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([N:8]2[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:5][O:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[Br:37][CH2:2][C:3]1[C:4]([N:8]2[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:5][O:6][CH:7]=1
Reactant: COc1nn(C)c(=O)n1-c1cocc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1nn(C)c(=O)n1-c1cocc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of the title compound of Step F (3.6 g), and triphenylphosphine (5.1 g) in methylene chloride (40 mL) under N2 at 0° C. was added carbon tetrabromide (8.0 g). The resulting orange solution was allowed to stir overnight at room temperature and then was concentrated under reduced pressure to give a brown oil. The residue was purified by flash chromatography (1:2 ethyl acetate:hexane as eluent) to afford 3.6 g (78%) of the title compound of Step G, a compound of the invention, as a white solid melting at 147-149° C.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[C:6]([C:13]([CH3:15])=O)[C:7]([O:9]CCCl)=[O:8])#[N:2].[NH2:20]/[C:21](/[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[C:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[NH:20][C:13]([CH3:15])=[C:6]1[C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCOC(=O)/C=C(\N)C(OCC)OCC
Reactant: CC(=O)C(=Cc1ccccc1C#N)C(=O)OCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)O)C1c1ccccc1C#N
Yield: 82.5 %

Procedure:
A mixture of 2-chloroethyl 2-(2-cyanobenzylidene)acetoacetate (4.72 g) and ethyl 3-amino-4,4-diethoxycrotonate (4.06 g) was heated for 3 hours at 100°~105° C. with stirring. After cooling, the reaction mixture was dissolved in ethyl acetate, and the solution was washed twice with an aqueous solution of sodium chloride and then dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residual oil was chromatographed over silica gel with a mixture of benzene and ethyl acetate (5:1 V/V) to give 2-chloroethyl ester of 4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (5.81 g).
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[S:27](=[O:34])(=[O:33])[NH:28]C(C)(C)C)=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[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[S:27](=[O:33])(=[O:34])[NH2:28])=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH:10]([CH3:11])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
Anisole (2 drops) was added to a solution of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-2-isopropyl-3H-1,2,4-triazol-3-one (from Step H) (97.5 mg; 0.201 mmole) in 2 ml of trifluoroacetic acid stirred under N2 at room temperature. After 24 hours, the solution was concentrated in vacuo. Chromatography of the residue on silica gel (gradient elution with 1.5 to 2% MeOH in CH2Cl2, containing 0.2% concentrated ammonium hydroxide) afforded 67.4 mg (78%) of the title compound as a white solid; satisfactory purity by TLC in 98:2:0.2 CH2Cl2 --MeOH-concd. NH4OH; mass spectrum (FAB) m/e 429 (M+1)+.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.C([O-])=O.[Na+].I[C:13]1C=[CH:17][N:16]=[C:15]([C:19]2([NH:22][C:23]([C:25]3([NH:28][C:29]([C:31]4[N:35]5[C@@:36]([CH2:49][C:50]6[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[CH:52][CH:51]=6)([CH3:48])[C:37](=[O:47])[N:38]([C:39]6[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41]([Cl:46])[CH:40]=6)[C:34]5=[N:33][CH:32]=4)=[O:30])[CH2:27][CH2:26]3)=[O:24])[CH2:21][CH2:20]2)[CH:14]=1.[Cl-].[Li+]>CN(C=O)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:56]([C:53]1[CH:54]=[CH:55][C:50]([CH2:49][C@@:36]2([CH3:48])[N:35]3[C:31]([C:29]([NH:28][C:25]4([C:23]([NH:22][C:19]5([C:15]6[CH:14]=[CH:13][C:6]([C:5]([OH:4])=[O:7])=[CH:17][N:16]=6)[CH2:20][CH2:21]5)=[O:24])[CH2:26][CH2:27]4)=[O:30])=[CH:32][N:33]=[C:34]3[N:38]([C:39]3[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41]([Cl:46])[CH:40]=3)[C:37]2=[O:47])=[CH:51][CH:52]=1)#[N:57]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(I)ccn5)CC4)CC3)n21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ccc(C(=O)O)cn5)CC4)CC3)n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
Acetic anhydride (0.58 mL, 6.13 mmol), sodium formate (625 mg, 9.19 mmol) diisopropylethylamine (1.06 mL, 6.13 mmol) and anhydrous DMF (10 mL) were added to a 50 mL glass pressure tube. The cap was sealed and reaction allowed to stir for 30 min To this mixture was then added (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(4-iodo-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide (2.35 g, 3.07 mmol) as a solution in 5 mL of anhydrous DMF, followed by lithium chloride (389 mg, 9.19 mmol) and palladium acetate (34 mg, 0.15 mmol). The mixture was capped and then allowed to stir at 80° C. in an oil bath overnight (20 h). The reaction was cooled to room temperature. The reaction was diluted with 2N HCl (15 mL) and extracted with ethyl acetate (2×20 mL). The combined organics were dried (MgSO4) and concentrated. The residual material was dissolved in DMF and purified by reversed phase HPLC using 30-100% CH3CN/H2O as gradient to afford 1.56 g of the title compound.