Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([F:34])[CH3:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([F:34])[CH3:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:35])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC(C)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: [Li+]
Agent: [OH-]
Product: COc1cn(C(CC(C)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
170 mg (purity 91%, 0.29 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoyl}amino)benzoate (mixture of racemic diastereomers) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 67 mg (45% of theory)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH:2]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26](OCC)=[O:27])=[CH:18][CH:17]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:25]([CH2:24][CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=3)[C:26]2=[O:27])[CH:2]=1
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1cccnc1

Procedure:
The procedure of Example 1 was repeated using 2-(pyridin-3-ylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 3), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq., prepared in Synthetic Example 10) and LDA (1.5 eq.) to obtain 1-(pyridin-3-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 178 to 180° C./DMF-EtOH.
Reaction SMILES: C([O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([OH:16])=[O:8]
Reactant: CN(C)CCCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCC(=O)O

Procedure:
85 g (380 mMol) 4-dimethylamino butyric acid benzylester 19 was stirred with 1 g Pd/C (5%) in 500 ml methanol. The reaction mixture was treated with hydrogen for 4 h. After removing the catalyst, methanol was distilled. A small volume of ethylacetate was added to the remaining residue so that the product would crystallise. The product was then filtered off and washed with ethylacetate.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([O:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)CC(=O)C>O>[OH:13][C:11]1([CH2:12][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)[CH2:14][CH2:15][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of 37.5 parts of 6-(phenylmethyl)-1-oxa-6-azaspiro[2.5]octane, 24.9 parts of ethyl 4-hydroxybenzoate, 20.7 parts of potassium carbonate and 200 parts of 4-methyl-2-pentanone was stirred overnight at reflux temperature. After cooling, water was added. The precipitated product was filtered off, washed with water and crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 23 parts (41.5%) of ethyl 4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzoate; mp. 100.2° C. (int. 78).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].BrC1C=CC=CC=1.[C:16]([CH:24]1[CH2:33][N:32]2[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]1)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC.O>[C:1]1([C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:24]2[CH2:33][N:32]3[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:26][CH2:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: O=C(c1ccccc1)C1CCC2CCCCN2C1
Agent: [Li]
Solvent: Brc1ccccc1
Solvent: O
Solvent: CCOCC
Product: c1ccc(C(=C2CCC3CCCCN3C2)c2ccccc2)cc1

Procedure:
To a solution of phenyl lithium, which had been prepared by the reaction of 1.23 g. of lithium and 16.80 g. of bromobenzene, in 50 ml. of absolute ether was dropwise added a solution of 120 g. of 3-benzoylquinolizidine in absolute ether. The mixture was refluxed for 30 mins. with stirring. After the excess of phenyl lithium was decomposed with water, the reaction mixture was extracted with ether. The thus obtained etheral layer was washed with water and dried. After removing the solvent by distillation, α,α-diphenyl-quinolizidine-3-methanol showing a melting point of 166° to 167° C. was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.Cl.[NH2:17][CH:18]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:19]([NH:21][C:22]1([C:31]#[N:32])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]1)=[O:20]>>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6](=[N:17][CH:18]([C:19](=[O:20])[NH:21][C:22]1([C:31]#[N:32])[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:27]1)[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC2CCCCC2)N=C(NC(=O)OCC)N2CCOCC2)CC1

Procedure:
The title compound was prepared starting from (morpholine-4-carbothioyl)-carbamic acid ethyl ester and 2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt according to the procedure from Example 5, step b, except that the compound was first purified by chromatography over silica gel using 9:1 methylene chloride:methanol as the eluant prior to reverse phase HPLC purification. MS, m/z 505=M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2O.S(Cl)([Cl:20])=O>CN(C)C=O>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[N:7][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1nnc2ccc(Cl)cc2c1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc2ccc(Cl)cc2c1Cl

Procedure:
A solution of 6 g of ethyl 6-chloro-4-hydroxy-3-cinnolin carboxylate in 300 cm3 of thionyl chloride and 1 cm3 of dimethyl formamide was stirred for 16 hours at reflux and the thionyl chloride was concentrated under reduced pressure. The residue was taken up several times in 50 ml of toluene to obtain 6 g of ethyl 4,6-dichloro-3-cinnolin carboxylate as a greenish residue melting at ≈50° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([O-:20])=[O:19].[K+].N>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[C:8]=2[N+:18]([O-:20])=[O:19])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2nc(C)ccc2c1
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc2c([N+](=O)[O-])c(C)ccc2n1

Procedure:
3 g (19.08 mmol) of 2,6-dimethylquinoline is introduced into 15 ml of concentrated sulfuric acid at 10° C. After one-half hour, a solution of 2.03 g of potassium nitrate in 11.4 concentrated sulfuric acid is added in drops, specifically so that the temperature remains between 5° and 15° C. The batch is stirred for one more hour and then poured onto ice water. It is made ammonia-alkaline, and the deposited precipitate is suctioned off. After washing with water, the crude product is dissolved in ethyl acetate and shaken from water. The organic phase is treated as usual. After the solvent is spun off, 3.69 g (95.6%) of the desired compound remains, which is used in the reduction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1>Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:23]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Agent: Cl
Product: Nc1ccc2ncn(C(CC(=O)O)c3ccccc3)c2c1

Procedure:
A solution of ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate, (25 mg, 81 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 96 hours. The solution was evaporated in vacuo and purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=2.59 min, MH+ 282].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]([NH2:22])[CH2:15][CH:14](CCC3C=CC=CC=3)[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:32]1[CH:33]=[C:34]2[C:42](=[CH:43][CH:44]=1)N[C:40]1CCC(NCCC3C=CC=CC=3)C[C:35]2=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:13]1[CH2:14][CH2:15][CH:16]([NH:22][CH2:40][CH2:35][C:34]3[CH:42]=[CH:43][CH:44]=[CH:32][CH:33]=3)[CH2:17][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC(CCc2ccccc2)Cc2c1[nH]c1ccc(OCc3ccccc3)cc21
Reactant: Oc1ccc2[nH]c3c(c2c1)CC(NCCc1ccccc1)CC3
Product: c1ccc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cc1

Procedure:
Beginning with 0.336 gm (0.85 mMol) 6-benzyloxy-3-(2-phenyleth-1-yl)-amino-1,2,3,4-tetrahydro-9H-carbazole, 0.175 gm (67%) of 6-hydroxy-3-(2-phenylethyl)amino-1,2,3,4-tetrahydro-9H-carbazole were prepared by the procedure described in detail in EXAMPLE B-35. The hydrochloride salt was prepared and crystallized from ethanol/diethyl ether to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[CH3:7][C:8]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][C:8]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]1[N:16]([C:3](=[S:4])[N:2]([CH3:6])[CH3:1])[CH2:15][CH2:14][N:13]=1
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(OCC2=NCCN2C(=S)N(C)C)c1C

Procedure:
A solution of dimethylthiocarbamoyl chloride (2.47 g; 0.020 mole) in chloroform (10 ml) was added dropwise during 10 minutes, to a stirred solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (4.08 g; 0.020 mole) prepared as in Example 1--and triethylamine (2.0 g; 0.20 mole) in chloroform (50 ml) cooling to keep the reaction below 5° C. The reaction temperature was then allowed to rise to room temperature and finally the reaction was refluxed for 5 hours. After cooling the reaction mixture was washed with water, dried and evaporated. The residue was recrystallised from isopropanol to yield white crystals of 2-(2,3-dimethylphenoxymethyl)-1-(N,N-dimethylthiocarbamoyl)-2-imidazoline, m.p. 124°-127° C. Analysis: Calculated C 61.84, H 7.27, N 14.42%. Found: C 62.15, H 7.64, N 14.35%.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=O)=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].S(Cl)(Cl)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN(C)C=O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)(=[O:20])=[O:22])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)N4CCN(C)CC4)cc3)nc2n(CC)c1=O
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (5.0 g, 0.014 moles) and N,N-dimethylformamide (150 ml) is cooled to 0° and treated with thionyl chloride (3.3 g, 0.027 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry results. To this slurry is added N-methylpiperazine (13.7 g, 0.137 moles) in one portion, the mixture is stirred until a clear solution is obtained, and concentrated on a rotary evaporator. The residue is taken up in water, filtered, recrystallized from ethanol, and dried at 48° to yield 5.12 grams of 1-[[4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)phenyl]sulfonyl]4-methylpiperazine, mp 305°-307° C.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:36][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:34][CH3:35])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 82.7 %

Procedure:
A mixture of (N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 104, 360 mg, 0.74 mmol), iron (247 mg, 4.43 mmol) and NH4Cl (27.6 mg, 0.52 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 2 h. The crude mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (280 mg, 83%) as a beige foam; 1H NMR: 1.69-1.83 (1H, m), 1.97-2.10 (1H, m), 2.18 (6H, s), 2.78-2.87 (1H, m), 2.88-2.98 (2H, m), 3.11 (1H, dd), 3.15-3.22 (1H, m), 3.74 (3H, s), 3.87 (3H, s), 4.29 (2H, br s), 6.70 (1H, s), 7.1-7.19 (2H, m), 7.21-7.28 (1H, m), 7.46 (1H, s), 7.51 (1H, d), 7.78 (1H, s), 8.25 (1H, d), 8.29 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 458.35.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[CH:24][CH:23]=[CH:22]5)=[CH:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.NC1C=CC=CC=1.ClC1C=C(C=CC=1)N>>[C:4]1([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[CH:24][CH:23]=[CH:22]5)=[CH:16][N:17]=3)[N:14]=2)[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Nc2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)c1
Solvent: Nc1cccc(Cl)c1
Solvent: Nc1ccccc1
Product: c1ccc(Nc2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1

Procedure:
The title compound was prepared in analogy to the compound of Example 121 using aniline as starting material instead of 3-chloroaniline and with a preparative LCMS purification instead of a flash chromatography (tR 4.30 min (conditions 4), MH+=352.3, 1H-NMR in DMSO-d6: 8.91 (m, 1H); 8.36 (m, 1H); 8.17 (d, 1H); 8.08 (s, 1H); 8.03 (d, 1H); 7.96 (m, 1H); 7.79 (m, 1H); 7.58 (dd, 1H); 7.50 (m, 2H); 7.35 (d, 1H); 7.25 (t, 2H); 7.01 (t, 1H); 4.59 (s, 2H)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:6]([Cl:19])[N:5]=[CH:4][CH:3]=1.[CH:20](=O)[C:21]1[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C(#N)C.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:19][C:6]1[C:7]2[C:8](=[O:9])[N:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[NH:1][C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1ccnc(Cl)c1C(=O)NCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1C1Nc2ccnc(Cl)c2C(=O)N1CCc1ccccc1
Temperature: 20 °C
Yield: 93.6 %

Procedure:
To a solution of 4-amino-2-chloro-N-phenethyl-nicotinamide (808 mg, 2.93 mmol) in 8 mL of acetonitrile at 20° C. was added 0-anisaldehyde (399 mg, 2.93 mmol) and a catalytic amount of p-toluenesulfonic acid (10 mg, 0.059 mmol). The resulting solution was then heated to reflux under Dean-Stark trap for 12 hours. The reaction mixture was cooled to 20° C. and diluted with ethyl acetate. The mixture was then partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed 3× with NaHCO3, 1× with water, 1× with brine and then dried over anhydrous Na2SO4, filtered and evaporated to dryness. 1.08 g of pale yellow sticky solid was obtained. The resulting crude material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([I:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCCCCC.CCOC(C)=O>CCOC(C)=O>[CH2:31]([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([I:21])[CH:15]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(I)c1)C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(I)c1)C(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
(2S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-3-iodo-phenyl)-propionic acid (490 mg. 1.2 mmol) of Step A is stirred in EtOAc (3.6 mL) with DIEA (418 μL, 2.4 mmol) at RT under N2. Benzyl bromide (171 μL, 1.44 mmol) is then added and the reaction mixture is then heated to 90° C. overnight. TLC in 3/1 hexane/EtOAc shows complete consumption of starting material (ninhydrin positive) and the appearance of two higher rf spots. The reaction is cooled to RT, diluted with EtOAc and washed with 1N HCl (2×30 mL) and with saturated NaHCO3 (2×30 mL). The organics are dried (MgSO4), filtered and concentrated to provide a mixture of mono- and dibenzylated products. Flash chromatography (3:1 hexane/EtOAc) affords the title compound, (2S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-3-iodo-phenyl)-propionic acid benzyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CCO>[C:26]([O:25][C:23](=[O:24])[NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=1)[CH2:20][CH3:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCC(Br)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCO
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 90 °C
Yield: 52 %

Procedure:
A reaction mixture of 32 and N-Boc-1,3-diaminopropane (800 μl) in EtOH (10 ml) was heated at 90° C. for 14 h, then cooled to room temperature and purified by preparative HPLC to give 33 (350 mg) at the yield of 52% for two steps. 33 had an analytical HPLC retention time=3.03 min. (Column: YMC S5 Combiscreen 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4) 1H-NMR (400 MHz, CDCl3): δ 7.25–7.41 (m, 5H), 5.80 (d, J=16.41 Hz, 1H), 5.16 (d, J=16.41 Hz, 1H), 5.04 (brs, 1H), 4.66 (t, J=5.82 Hz, 1H), 3.11 (m, 2H), 2.89 (s, 3H), 2.72 (m, 1H), 2.57 (m, 1H), 2.02 (m, 2H), 2.74 (m, 2H), 1.43 (s, 9H), 0.84 (t, J=7.36 Hz, 3H).
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29].C(Br)(Br)[Br:36]>>[Br:36][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
t-Butyinitrite (84 ml, 0.662 mol) was added to a suspension of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole (100 g, 0.221 mol) in bromoform (320 ml). The resulting mixture was heated to 60-70° C. for 3 hours. Another portion of t-butylnitrite (84 ml, 0.662 mol) was added and the mixture stirred at 60-70° C. for a further 2.5 hours. It was then cooled, washed with hexane, hexane-toluene, and then filtered. The solid was washed with pentane and vacuum dried to give 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole as a yellow solid (96.69 g, 79% yield), mp 142° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)[C@@H]1CCCC[C@H]1N>CS(C)=O.[Cu]I>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=c1c2cc(Cc3ccc(-n4cccn4)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Temperature: 130 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.050 g, 0.12 mmol) and pyrazole (0.024 g, 0.36 mmol) in 2 mL of DMSO under an atmosphere of nitrogen was added cesium carbonate (0.24 mL, 1 N aqueous, 0.24 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.012 mmol), and copper(I) iodide (2.3 mg, 0.012 mmol). The mixture was heated at 130° C. for 24 h, cooled to rt, and purified via preparative reverse phase HPLC. The appropriate fractions were concentrated in vacuo. The residue was taken up in saturated aqueous sodium bicarbonate and extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 452.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.01-8.99 (m, 1H), 8.50 (s, 1H), 8.32-8.30 (m, 2H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.69-7.64 (m, 3H), 7.56 (d, J=8.4 Hz, 1H), 6.43 (s, 2H), 4.63 (br s, 1H), 4.09 (br s, 1H), 2.28-2.22 (m, 1H), 2.14-2.00 (m, 1H), 1.94-1.84 (m, 3H), 1.60-1.40 (m, 3H), 1.18-1.10 (m, 1H).