Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]([NH2:16])=O)[C:8](=[CH:12][CH:13]=1)[C:9]([NH2:11])=O)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[C:1]([C:5]1[CH:6]=[C:7]([C:14]#[N:16])[C:8](=[CH:12][CH:13]=1)[C:9]#[N:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(N)=O)c(C(N)=O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(C#N)c(C#N)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
4-t-butylphthalonitrile was prepared by fitting a 500 milliliter three-necked flask with a nitrogen inlet, a 100 milliliter pressure equalizing funnel, and a stopper, placing the flask in an ice bath, and charging the flask with 60 grams (0.2713 mole) of 4-t-butylphthalamide and 400 milliliters of pyridine. The resulting mixture was kept under a constant flow of nitrogen. Phosphorus oxychloride (49.7 milliliters, 0.5426 mole) was placed in the dropping funnel and added slowly to the pyridine solution to keep the temperature at about 4° C. The reaction was magnetically stirred for 4 hours and the mixture was then poured into a beaker containing 200 milliliters of crushed ice. Water was added until the total volume was 1,600 milliliters and a light brown solid was produced. The solid was removed by suction filtration, resulting in 31.24 grams (0.1696 mole) of 4-t-butylphthalonitrile, which exhibited a melting point of 58° to 59° C. The identity of the 4-t-butylphthalonitrile product was confirmed by IR spectrum.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)(O)[O-:20].[Na+]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)(=[O:20])[NH2:2]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(-c2ccnc(C#N)c2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2ccnc(C(N)=O)c2)cc1

Procedure:
A solution of methyl 4-(2-cyano-pyridin-4-yl)-benzoate (400 mg, 1.68 mmol) (reference example 57) in 80% sulphuric acid (3 mL) is stirred at room temperature for 12 hours. The resulting solution is poured onto ice and the mixture brought to pH 8 with sat. sodium bicarbonate solution then extracted with ethyl acetate, washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 40% ethyl acetate in chloroform) to give 340 mg of the title compound. 1H NMR (CDCl3) δ 3.94 (s, 3H), 5.72 (bs, 1H), 7.67 (dd, J=5, 1 Hz, 1H), 7.75 (d, J=8 Hz, 2H), 7.9 (bs, 1H), 8.15 (d, J=8 Hz, 2H), 8.46 (bs, 1H), 8.63 (d, J=5 Hz, 1H). MS (EI) m/z 256.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[CH2:25][CH2:26][Mg]Br.[NH4+].[Cl-]>O1CCCC1>[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[CH2:25][CH2:26][CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: Br[Mg]CCC1OCCCO1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCC1OCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (200 mg, 0.74 mmol) in tetrahydrofuran (2 ml) was added slowly a 0.5 M solution of (1,3-dioxan-2-ylethyl)magnesiumbromide in tetrahydrofuran (2.06 ml, 1.03 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred 1 h at ambient temperature, saturated aqueous NH4Cl solution was added (15 ml) and the mixture was extracted two times with ethyl acetate. The combined organic layers were washed two times with brine/ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give 280 mg (0.72 mmol, 98%) of the title compound as colorless oil which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C1C(=O)N([Br:32])C(=O)C1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Br:32][C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][CH:18]=2)=[N:10][N:11]=1
Reactant: Brc1ccccc1-n1cnnc1-c1ccc(-c2ccccc2)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccccc1-n1c(Br)nnc1-c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
5-[4-(2-Bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine prepared in the Production Example 2 was dissolved in a mixture solvent of carbon tetrachloride (100 ml) and acetic acid (100 ml), followed by addition of n-bromosuccinimide (5.90 g), and refluxed under heating for 3 hours. After the reaction solution was cooled to ambient temperature, the solution was concentrated-under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and extracted with chloroform. Subsequently, the organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1), to afford the entitled compound as yellow solid (6.96 g, 69%). The physico-chemical values are as follows.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][NH:8][C:7]=2[CH:15]=1)#[N:2].[NH2:16][C:17]1[CH:22]=[C:21]([O:23][C:24]([O:26][CH3:27])=[O:25])[C:20]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19][C:18]=1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>ClCCl>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([C:18]2[CH:19]=[C:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:23][C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:17]=2[NH:16][C:12]([CH:10]2[CH2:9][NH:8][C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11]2)=[O:14])[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: N#Cc1ccc2c(c1)NCC(C(=O)O)O2
Reactant: COC(=O)Oc1cc(N)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(C#N)ccc3O2)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Yield: 76.5 %

Procedure:
6-Cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (146 mg, 0.72 mmol), tert-butyl 4-(2-amino-5-cyclopentyl-4-methoxycarbonyloxy-phenyl)piperidine-1-carboxylate (300 mg, 0.72 mmol), T3P (570 mg, 533 μL of 50% w/w solution, 1.79 mmol) were dissolved in pyridine (142 mg, 145 μL, 1.79 mmol) and dichloromethane (10 mL) and stirred for 30 min at room temperature. Purification by silica gel chromatography (10-75% ethyl acetate/hexanes) provided tert-butyl-4-[2-[(6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carbonyl)amino]-5-cyclopentyl-4-methoxycarbonyloxy-phenyl]piperidine-1-carboxylate (333 mg, 77% yield). LC/MS m/z 605.6 [M+H]+.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])C(=O)C=1)C1C=CC=CC=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][NH:39][C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1.BrCC(C1C=CC(CO)=CC=1)=O>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][N:39]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[O:17])[C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Reactant: O=c1cc(OCc2ccc(F)cn2)cn[nH]1
Agent: O=C(CBr)c1ccc(CO)cc1
Product: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CO)cc1

Procedure:
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 15b (with acetonitrile as solvent) from 350 mg (1.58 mmol) 5-(5-fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 19b) and 399 mg (1.74 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:14](=[O:16])[CH3:15])[CH:6]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(N)nc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Cl)nc(NC(C)=O)c1

Procedure:
A mixture of 14 g 2-amino-6-chloro-isonicotinic acid ethyl ester (Temple et al. J. Heterocycl. Chem. 1970, 7, 451) (70 mmol) in 150 ml acetic anhydride (large excess) and 150 ml pyridine (large excess) is stirred at 60° C. in the presence of 244 mg (2 mmol) DMAP for 16 h. The mixture is concentrated in vacuo, taken up in EtOAc and washed with 1N HCl, brine and 10% aq Na2CO3 to yield the title compound in the form of yellowish crystals (EtOH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:7][Br:20])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)Oc1cccc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1cccc2ccccc12
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.15 g, 4.48 mmol) in carbon tetrachloride (24.9 mL) was treated with N-bromosuccinimide (0.87 g, 4.93 mmol) and benzoyl peroxide (87 mg, 0.35 mmol). The reaction was then heated to reflux for 5 h. At this time, the reaction was cooled to 25° C. and then was placed in the freezer over the weekend. At this time, the reaction was removed from the freezer and allowed to thaw. The resulting precipitate was removed by filtration and was rinsed with carbon tetrachloride (5 mL). The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded impure 4-bromo-3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.28 g, 85%) as a light purple oil. The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:27][C:21]2=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=[C:20]2[N:19]=1)=[S:17].Br.CC(O)=O.CS(C)=O.[OH-].[NH4+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([C:18]3[NH:27][C:21]4=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=[C:20]4[N:19]=3)[S:17][C:5]=2[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=S)c1nc2ccc(C)nc2[nH]1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(C)nc4[nH]3)nc12
Reaction time: 2 h
Yield: 41 %

Procedure:
0.3 g 5-Methyl-3H-imidazo[4,5-b]pyridine-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.8 mmol) was dissolved in ethyl acetate (3 ml), heated to reflux and treated with 0.27 ml HBr in AcOH (5.7M, 1.6 mmol) and 0.067 ml DMSO (0.94 mmol). Stirring at reflux was continued for 2 h. Upon cooling a precipitation formed, which was isolated and dissolved in water (2 ml). The pH was adjusted to 10 with 25% ammonium hydroxide in water. Once again a precipitation formed, which was filtered. The residue on the filter was washed with water and dried in vacuo. One obtained 0.125 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-5-methyl-3H-imidazo[4,5-b]pyridine (42%) as a yellow solid; M.p.: 200–210° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:15][C:14]=1[O:27][CH3:28])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=1[O:27][CH3:28])=[O:11]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)c1cc2ccccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)ccc1NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
In methylene chloride (20 ml) was dissolved tert-butyl (4-((2-indolylcarbonyl)amino)-3-methoxyphenyl)acetate (1.31 g, 3.44 mmol). To the resulting solution was added TFA (10 ml) at 0° C. After the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was distilled under reduced pressure to remove the solvent, whereby (4-((2-indolylcarbonyl)amino)-3-methoxyphenyl)acetic acid (1.11 g, 99%) was obtained as a brown solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[N:4][C:3]=1[CH2:19][N:20]([CH3:30])[C:21]([C:23]1[C:24]([CH3:29])=[N:25][O:26][C:27]=1[CH3:28])=[O:22].[C:31]([Cu])#[N:32].[C-]#N.[K+]>CN(C=O)C.CCOC(C)=O>[C:31]([C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[N:4][C:3]=1[CH2:19][N:20]([CH3:30])[C:21]([C:23]1[C:24]([CH3:29])=[N:25][O:26][C:27]=1[CH3:28])=[O:22])#[N:32]
Reactant: Cc1noc(C)c1C(=O)N(C)Cc1nc(NC(=O)NCc2cccc(F)c2)sc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1C(=O)N(C)Cc1nc(NC(=O)NCc2cccc(F)c2)sc1C#N

Procedure:
Example: A mixture of 3,5-dimethyl-isoxazole-4-carboxylic acid {5-bromo-2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide (Ex. 151) (100 mg, 0.2 mmol), CuCN (180 mg, 2.0 mmol) and KCN (13 mg, 0.2 mmol) in DMF (1 mL) was heated to 120 C for 5 hours. Upon cooling the mix was diluted with EtOAc (50 mL), filtered, washed with brine, dried and evaporated. Flash chromatography afforded 3,5-dimethyl-isoxazole-4-carboxylic acid {5-cyano-2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:5]2[N:10]=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)[C:8]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[C:7]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[N:6]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: C1CCNCC1
Product: Fc1ccc(COc2nc(N3CCCCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 48 mg, 0.085 mmol) was reacted in excess neat piperidine at 80° C. overnight by the general procedure described in Example 31, Step A. Workup (solvent removal under reduced pressure, then toluene azeotrope) and flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate) afforded the title compound. HPLC Rt=5.36 min. 1H-NMR 500 MHz (CDCl3): δ 1.63 (m, 4H), 1.71 (m, 2H), (bs, 4H), 3.83 (m, 4H), 5.36 (s, 2), 7.02 (d, J=8 Hz, 2H), 7.08-7.20 (m, 7H), 7.31(d, J=1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](N(CC)CC)=[O:7])=[C:4]([CH2:15][C@H:16]([OH:18])[CH3:17])[CH:3]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:13][CH:14]=1)[C:6](=[O:7])[O:18][C@H:16]([CH3:17])[CH2:15]2
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C[C@@H](C)O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Temperature: 25 °C

Procedure:
A solution of 4-bromo-N,N-diethyl-2-[(2R)-2-hydroxypropyl]benzamide (12.2 g, 38.8 mmol) dissolved in 4N HCl in Dioxane (200 mL) was stirred at room temperature and monitored by tlc. After 3 days the reaction was partitioned between EtOAc (300 mL) and water (300 mL). The aqueous phase was further extracted with EtOAc (2×250 mL). The combined organic layers were then washed with water (200 mL), brine (200 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was then purified via MPLC (15-30% EtOAc/Hexane) to afford (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [CH3:1][CH:2]([C:4](=O)[C:5](=O)[CH:6]([CH3:8])[CH3:7])[CH3:3].[CH:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH2:17].O>C(O)(=O)C>[CH:2]([C:4]1[C:5]([CH:6]([CH3:8])[CH3:7])=[N:18][C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:17]=1)([CH3:3])[CH3:1]
Reactant: CC(C)C(=O)C(=O)C(C)C
Reactant: NC1CCCCC1N
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1nc2c(nc1C(C)C)CCCC2

Procedure:
8.7 g of 2,5-dimethyl-3,4-hexanedione and 11.2 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 30 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 6.8 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[NH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[N+:28]([O-:33])[CH:29]=[C:30]([Cl:32])[CH:31]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:32][C:30]1[CH:29]=[N+:28]([O-:33])[CH:27]=[C:26]([CH2:25][CH2:24][NH:23][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:31]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: NCCc1cc(Cl)c[n+]([O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)C[C@H](Nc2nc(NCCc3cc(Cl)c[n+]([O-])c3)ncc2C#N)CC[C@@H]1O
Temperature: 85 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (80 mg, crude), 3-(2-aminoethyl)-5-chloropyridine 1-oxide (80 mg, crude) and DIEA (169 mg, 1.31 mmol) in THF (2 mL) was stirred at 85° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by standard methods to afford the title product (32.6 mg, 0.08 mmol, 22% yield, over three steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.30 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.51 (s, 1H), 4.32-4.25 (m, 1H), 3.77-3.65 (m, 2H), 3.42-3.40 (s, 1H), 2.99-2.93 (m, 2H), 1.95-1.50 (m, 6H), 1.03 (s, 3H), 0.99 (s, 3H). MS (ESI) m/z 417.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.[BH3-]C#N.[Na+]>ClCCCl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:19][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(CNCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 27 %

Procedure:
A mixture of 4-nitrobenzaldehyde (3.0 g, 19.8 mmol), 4-pyridylmethylamine (2.36 g, 21.8 mmol), and NaBH3CN (1.75 g, 27.7 mmol) in 1,2-dichloroethane (40.0 mL) was stirred at room temperature for 36 h and then concentrated to dryness. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (MeOH/DCM=1/400) to afford 1.3 g of N-(4-nitrobenzyl)-1-(pyridin-4-yl)methanamine as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[CH2:35]1C[O:38][CH2:37][CH2:36]1.CCN(CC)CC.C(Cl)(=O)CC>CCOC(C)=O.C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH:15][C:37](=[O:38])[CH2:36][CH3:35])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccncc2)c1=O
Reactant: C1CCOC1
Agent: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
To a round bottom flask was added 5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (200 mg, 0.41 mmol), THF (5 ml), Et3N (124 mg, 1.232 mmol) followed by propionyl chloride (57 mg, 0.616 mmol). The reaction was then stirred at rt for 20 min. The reaction mixture was diluted with EtOAc (30 ml). The resulting solution was wash with water (2×10 ml) and saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 12 gm silica gel) eluting with 100% EtOAc for 10 min, then 5% MeOH in CH2Cl2 to give product N′-(4-(4-chlorophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridazin-3-yl)propionohydrazide as light yellow solid 140 mg(63% yield). HPLC retention time (method A)1.892 min; LCMS (M+1)=543.3.
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH:6]=[CH:5][CH:4]=1)#[N:2].[CH2:9]([N:16]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1>[CH2:9]([N:16]1[C:20](=[O:21])[CH:19]2[CH:18]([C:3]3([C:1]#[N:2])[CH2:8][CH2:7][CH:6]2[CH:5]=[CH:4]3)[C:17]1=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC1=CC=CCC1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: Cc1ccccc1C
Product: N#CC12C=CC(CC1)C1C(=O)N(Cc3ccccc3)C(=O)C12

Procedure:
39 g (0.35 mol) of 1-cyano-cyclohexa-1,3-diene are heated at 100° C. with 65.5 g (0.35 mol) of N-benzyl-maleimide in 700 ml of xylene for one hour and then under reflux for 1 hour. After cooling, the crystals are filtered off with suction and recrystallized from xylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]3[O:20][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[O:13]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(=O)O
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Yield: 39.8 %

Procedure:
A mixture of 4-(4-chlorophenyl)benzaldehyde (21.6 g.), 2-hydroxy-2-methylpropionic acid (10.2 g.) and cationic sulphonated polystyrene ion exchange resin (`AMBERLITE` *IR 120, free acid form; 2.0 g.) in chlorobenzene (125 ml.) was heated under reflux for 24 hours with continuous removal of water by azeotropic distillation. The mixture was cooled and the resin was separated by filtration. Pyridine (3 ml.) was added to the filtrate which was then evaporated. The residue was dissolved in hot 2-propanol (200 ml.). A small quantity of insoluble material was removed by filtration and the subsequent filtrate was allowed to cool to give 2-[4-(4-chlorophenyl)phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (11.8 g.), m.p. 108°-110° C.