Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[CH3:9][S:10][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([C:24](F)=[O:25])=[CH:13][N:12]=1.Cl>CN(C=O)C>[NH2:2][C:1]1[N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]2[N:16]=[C:11]([S:10][CH3:9])[N:12]=[CH:13][C:14]=2[C:24](=[O:25])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSc1ncc(C(=O)F)c(Nc2ccccc2)n1
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)c(C(N)=O)c(N)n(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.0 g (11.96 mmol) of cyanoacetamide in 17 mL of anhydrous DMF, cooled to 0-5°C., is added 0.96 g (23.93 mmol) of 60% NaH. After the addition, the mixture is stirred for 10 minutes at room temperature and then cooled again on an ice-water bath, and a solution of 3.0 g the acid fluoride (11.39 mmol) prepared in step 20.3 in 17 mL of anhydrous DMF is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is cooled on an ice-water bath, and 0.48 g (11.96 mmol) of 60% NaH is added. The reaction mixture is stirred for 5 hours at room temperature and then poured into ice-cold aqueous 0.5 N HCl solution. The precipitate formed is isolated by filtration, rinsed with water, drained by suction and then dried in an oven. 3.44 g of a yellow solid mainly composed of the expected product in non-cyclized form are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH3:35])[CH:29]=[CH:28][C:27]([S:30]([O:33]C)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(#N)C>[S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:35])=[CH:25][CH:26]=1)([O-:33])(=[O:32])=[O:31].[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([O:10][CH2:11][CH2:12][N+:13]([CH3:24])([CH3:15])[CH3:14])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)CCOC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC#N
Product: CC(C)(C)c1cc(C(=O)OCC[N+](C)(C)C)cc(C(C)(C)C)c1O
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A mixture of 16.07 g (50 mmol) of 2-dimethylaminoethyl 3,5-di-tert-butyl-4-hydroxybenzoate, prepared as described in Example 1, 9.31 g (50 mmol) of methyl p-toluenesulfonate and 125 ml of acetonitrile was heated at reflux for 1 hr. The mixture was cooled and filtered. The collected solid was recrystallized from 1 liter of acetonitrile to give 17.15 g (67.56% of theory) of product; mp=233.5°-236.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:4]=1[CH:5]=[CH:6][S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N+:19]([O-])=O)[CH:12]=1)(=[O:9])=[O:8].O.NN>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:4]=1[CH:5]=[CH:6][S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH2:19])[CH:12]=1)(=[O:9])=[O:8]
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c(N)c2)c(OC)c1

Procedure:
2,4,6-trimethoxystyryl-N-(4-methoxy-3-nitrophenyl)sulfonamide (7 mmol) (See, e.g., PCT publication WO03072063) was dissolved in ethanol (55 mL) in a round bottomed flask. Palladium catalyst (5% Pd/C, 275 mg) was added. Hydrazine hydrate (182 mmol) was then added in one portion. The resulting mixture was refluxed for 5 h and the reaction progress was monitored by TLC. When the reaction was complete, the palladium catalyst was removed by filtration and the filtrate was poured into a beaker containing ice cold water. The solution was stirred and a solid precipitate formed. The precipitated material was separated by filtration and dried in vacuum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](C(OC)=O)=[CH:2]1.[H-].[Na+].CI.[CH3:18][N:19]([CH:21]=O)[CH3:20]>O>[CH3:18][N:19]1[C:20]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:2][NH:1][CH3:9])=[CH:21]1
Reactant: CN(C)C=O
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CNCc1cn(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Methyl 1-methyl-1H-indole-3-carboxylate NaH (60% dispersion in mineral oil, 8.56 g, 214.0 mmole) was added portionwise, allowing for gas evolution, to a solution of methyl 1H-indole-3-carboxylate (25.00 g, 142.7 mmole) in DMF (350 mL) at 0° C. When the NaH addition was complete, methyl iodide (44.4 mL, 713.5 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated to afford the title compound (26.00 g, 96%) as an orange solid: MS (ES) m/e 190 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][C:22]4([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][O:25]4)[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:33]C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][C:22]4([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][O:25]4)[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][N:14]([CH3:33])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(c1cn(CC2CCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1′-{[6-chloro-1-(pyrrolidin-3-ylmethyl)-1H-indol-3-yl]carbonyl}-3H-spiro[2-benzofuran-1,4′-piperidine] in MeOH was treated with aq. H2CO (1.5 eq), AcOH (1.1 eq) and stirred for 15 min at room temperature, then treated with NaCNBH3 (1.1 eq) and stirred at room temperature for 1 h. Concentration and purification by preparative HPLC gave the desired product. ES-MS m/e (%): 464.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][CH2:11][CH2:12]1)[C:8](=[O:34])[NH:7]2)=[O:5])C.CO.O[Li].O.Cl>C1COCC1.O>[C:29]([O:28][C:26]([NH:25][C@@H:15]1[C:14](=[O:33])[N:13]2[C@@H:9]([CH2:10][CH2:11][CH2:12]2)[C:8](=[O:34])[NH:7][C@@:6]2([C:4]([OH:5])=[O:3])[C@@H:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N2
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2CCCN2C1=O
Reaction time: 4 h
Yield: 98.5 %

Procedure:
The macrocyclic ester 1e from Step C (1.0 g, 2.1 mmol) was first dissolved in THF (3.0 mL), then methanol (3.0 mL) and water (1.5 mL) were added, followed by addition of LiOH—H2O (3 equiv). The resulted mixture was stirred for 4 h and concentrated to dryness. The residue was first re-dissolved in water (10 mL), then acidified with aqueous HCl (3.0 N, 2.2 mL, 6.6 mmol). The aqueous was extracted with EtOAc (3×15 mL). The combined organic layers was dried with sodium sulfate and concentrated to give the acid product 1f (0.93 g, 99%). MS (ESI+): 450 [M+1] (5) and 350 [M+1−100] (100).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:15][C:16]1[C:21]([CH3:22])=[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)[CH2:25][CH2:24]2)[N:19]=[N:18][C:17]=1[CH2:39][C:40](O)=[O:41].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:15][C:16]1[C:21]([CH3:22])=[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)[CH2:25][CH2:24]2)[N:19]=[N:18][C:17]=1[CH2:39][C:40]([NH:5][NH:4][C:1](=[O:3])[CH3:2])=[O:41]
Reactant: Cc1c(CC(=O)O)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)Cc1nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c(C)c1C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Acetic acid hydrazide (20.6 mg, 0.28 mmol) is added to a round-bottom flask under N2 followed by DMF (5 mL). Diisopropylethylamine (0.25 mL) is added and the reaction is stirred for 30 min. {4,5-Dimethyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazin-3-yl}-acetic acid (110 mg, 0.28 mmol) is added and the reaction is stirred for 1 h. HOBT (42 mg, 0.311 mmol) and HBTU (116.8 mg, 0.31 mmol) are added and the reaction is allowed to stir for 16 h. The crude reaction mixture is purified via flash chromatography on silica gel (0-30% methanol in dichloromethane) to afford the title compound (114 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[N:12][O:13][CH2:14][C:15]([OH:17])=O)[CH2:7][CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:5][C:4]=2[N:3]=1.S(Cl)(Cl)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(Cl)Cl>[N:34]1([C:15](=[O:17])[CH2:14][O:13][N:12]=[C:8]2[CH2:7][CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[CH:10][C:9]2=3)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Nc1ncc2c(n1)CC(c1ccccc1-c1ccccc1)CC2=NOCC(=O)O
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccccc1)CC2=NOCC(=O)N1CCOCC1

Procedure:
The title compound was prepared from (2-amino-7-biphenyl-2-yl-7,8-dihydro-6H-quinazolin-5-ylideneaminooxy)-acetic acid (compound 54) by treating with thionyl chloride followed by amidation using morpholine and triethylamine in DCM.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[N:4][CH:3]=[CH:2]1.[CH3:12][N:13]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].C(N(CC)CC)C.O1C[CH2:42][CH2:41][CH2:40]1>ClCCl.O>[CH:40]1[CH:41]=[CH:42][N:4]2[CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:1]([C:27]([C:26]3[CH:30]=[CH:31][C:23]([N:13]([CH3:12])[C:14](=[O:22])[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH3:21])=[CH:24][CH:25]=3)=[O:28])[CH2:2][C:3]=12
Reactant: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)Cl)cc1
Reactant: C1=CNc2ccccc2C=N1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.27 g of 10,11-dihydro-5H-pyrrolo[2,1-c][(1,4]benzodiazepine, 0.518 g of 4-(N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride, 0.182 g of triethylamine and 7 ml of tetrahydrofuran is stirred at room temperature for 3 hours. To the mixture is added 0.29 g of 4-[N-methyl-N-(2-methylbenzoyl) amino]benzoyl chloride and 0.10 g of triethylamine in 2 ml of dichloromethane and the mixture stirred for 2 days. The mixture is poured into water and extracted with dichloromethane. The extract is washed with water, 1 N HCl, 1 N NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo and the residue crystallized from dichloromethane-hexane to give 0.38 g of crystals, m.p. 168-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(F)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 65 °C
Yield: 69.3 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.52 mmol), NaOH (41 mg, 1.03 mmol), H2O (1 mL) and THF (10 mL) was heated at 65° C. for 1 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to “pH” 2-3 by addition of concentrated aqueous HCl. The white solid was collected by filtration, dried to give the title compound (200 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:25]=4[O:37][C:38]([F:41])([F:40])[F:39])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:47])=O)(C)(C)C.[ClH:48]>O1CCCC1.O1CCOCC1>[ClH:48].[CH3:36][N:33]1[CH2:32][CH2:31][N:30]([C:28]2[CH:27]=[CH:26][C:25]([O:37][C:38]([F:41])([F:39])[F:40])=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:15]4[N:14]([CH2:42][C:43]([F:45])([F:46])[F:44])[C:11]5[CH2:12][CH2:13][NH:8][C:9](=[O:47])[C:10]=5[CH:16]=4)[CH:22]=[CH:21][N:20]=3)[CH:29]=2)[CH2:35][CH2:34]1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3nccc(-c4cc5c(n4CC(F)(F)F)CCN(C(=O)OC(C)(C)C)C5=O)n3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3nccc(-c4cc5c(n4CC(F)(F)F)CCNC5=O)n3)c2)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 2-{2-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-pyrimidin-4-yl}-4-oxo-1-(2,2,2-trifluoro-ethyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (25 mg, 0.037 mmol) in tetrahydrofuran (1 mL), 4M HCl in dioxane (0.4 mL) were added. The solution was stirred at room temperature over night. The solvent was evaporated under vacuo to yield 22 mg (98%) of the title compound as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH2:12])=[C:4](I)[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[CH:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH2:12])=[C:4]([C:22]#[C:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])[CH:3]=1
Reactant: C#Cc1ccccc1Cl
Reactant: Nc1c(I)cc(Cl)cc1C(F)(F)F
Product: Nc1c(C#Cc2ccccc2Cl)cc(Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-iodo-6-trifluoromethyl-phenylamine (1.5 g, 4.67 mmol) and 1-chloro-2-ethynyl-benzene (766 mg, 5.6 mmol). Brown solid (1.05 g, 68%). LC-MS (ESI): 328 (M−H)−.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:9])[CH:3]=1.Cl.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][SH:25])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:9].[ClH:1].[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][S:25][CH2:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCc1cccnc1
Reactant: SCCN1CC=C(c2ccccc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C1=C(c2ccccc2)CCN(CCSCc2cccnc2)C1
Temperature: 80 °C
Yield: 29.1 %

Procedure:
A solution of 3-picolyl chloride hydrochloride (2.50 g) and 3,6-dihydro-4 phenyl-1(2H)-pyridineethanethiol hydrochloride (3.90 g) (Example A) in 100 mL of dimethylformamide is treated with triethylamine (7.4 ml) and the mixture is heated at 80° C. for 8 hours. The solvent is evaporated in vacuo, and the residue is partitioned into chloroform/sodium bicarbonate solution. The organic extract is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography (silica gel; 2% methanol in chloroform) to yield 1.7 g of the title compound as an oil, which is converted into its hydrochloride salt (hydrogen chloride gas in diethyl ether) and recrystallized from ethanol/acetonitrile; mp 218°-220° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3[C@@H](O)[C@@H](O)[C@H](CO)O3)[C:9]=2[N:10]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CS(C)=O>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Agent: Cl
Solvent: CS(C)=O
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of 2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (14 g, 49.47 mmol) in DMSO (50 mL) was added (bromomethyl)benzene (10 g, 59.36 mmol). The mixture was stirred at 50° C. overnight. Then the mixture was cooled to room temperature and HCl (50 mL, 10% w.w) was added and the mixture was stirred at 70° C. for 2 h. The reaction was cooled to room temperature, filtered and the filter cake was washed with water and ethanol and dried under vacuum to give 2-amino-7-benzyl-1H-purin-6(7H)-one (10 g, 74.2% yield) as grey solid. LCMS retention time 0.529 min; LCMS MH+ 242.
Reaction SMILES: C([C:3]1[C:8]([CH3:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11])C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CC(C)=O>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:19][CH2:20][O:21][CH3:22])=[CH:3][C:8]=1[CH3:9]
Reactant: COCCBr
Reactant: CCc1c(O)ccc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc(Cl)c(C)c1

Procedure:
To a solution of ethyl 4-chloro-3-methylphenol (1 eq.) in acetone (0.2 M) was added potassium carbonate (5 eq.) and 1-bromo-2-methoxyethane (1.3 eq.). The resulting suspension was refluxed for 25 h. The insolubles were removed via filtration and the filtrate was concentrated in vacuo to furnish the title compound.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[Mg][CH:23]1CCCC1>>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:23][CH2:4]1
Reactant: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: Br[Mg]C1CCCC1
Product: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCCC2)[nH]1

Procedure:
The title compound was synthesized using standard chemical manipulations and procedures similar to those used for the preparation of compound 152.8 and using bromo(cyclopentyl)magnesium in place of bromo(cyclobutyl)magnesium.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)(=[O:17])=[O:16])[C:11]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[C:10]([O:34][CH3:35])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N([CH:42]([CH3:44])C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1([O:61][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(O)(=O)C>[CH3:35][O:34][C:10]1[C:11]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)(=[O:17])=[O:16])[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([O:1][C:42](=[O:61])[CH3:44])[CH:7]=[CH:6][CH:5]=2)[N:9]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(O)c2)nc1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(OC(C)=O)c2)nc1OC
Reaction time: 12 h

Procedure:
49.5 mg of 5-methyl-pyridine-2-sulfonic acid [2-(3-hydroxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 1, dissolved in acetontrile (3 ml) was treated at RT subsequently with 25.8 mg of n-ethyldiisopropylamine, 53 mg of benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate and, 0.5 h later, with 72 mg of acetic acid. The mixture was stirred for 12 h, partitioned between water and EtOAc. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/EtOAc: 8/1). Combination of the purified fractions and evacuation in vacuo afforded acetic acid 3-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-phenyl ester as a white solid. ISP mass spectrum, m/e 537.2 (M+1 calculated for C26H24N4O7S: 537).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=O)[CH2:9]3)=[CH:4][C:3]=2[O:2]1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8]([N:24]4[CH2:25][CH2:26][N:21]([C:16]5[N:15]=[CH:20][CH:19]=[CH:18][N:17]=5)[CH2:22][CH2:23]4)=[CH:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C1CCc2cc3c(cc2C1)OCO3
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C1=C(N2CCN(c3ncccn3)CC2)CCc2cc3c(cc21)OCO3
Yield: 95.2 %

Procedure:
A solution of 3.8 g of 6,7-methylenedioxy-2-tetralone and 3.3 g of 1-(2-pyrimidinyl) piperazine in 100 ml of anhydrous toluene was boiled for 30 minutes in the presence of 100 mg of p.toluenesulphonic acid, in a Dean and Stark apparatus. When the theoretical quantity of water was collected, the solution was cooled and washed with twice 20 ml of water. The solution was then decanted off, and the solvent was evaporated under reduced pressure. The residue was taken up with petroleum ether, and there were obtained 6.4 g of 1-(6,7-methylenedioxy-3,4-dihydro-2-naphthyl)-4-(2-pyrimidinyl) piperazine, beige crystals melting at 155°-160° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C1C=CC(COC2C=CC(N3CCNCC3)=CC=2)=CC=1.ClCC(Cl)=O.[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][C@H:68]2[CH2:73][CH2:72][C@H:71]([OH:74])[CH2:70][CH2:69]2)=[CH:63][C:62]=1[C:75]([F:78])([F:77])[F:76])([O-:60])=[O:59]>>[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][C@H:68]2[CH2:73][CH2:72][C@H:71]([O:74][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=5)=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[CH2:70][CH2:69]2)=[CH:63][C:62]=1[C:75]([F:76])([F:77])[F:78])([O-:60])=[O:59]
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: O=C(CCl)N1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: FC(F)(F)c1ccc(COc2ccc(N3CCNCC3)cc2)cc1
Agent: O=C(Cl)CCl
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine (also known as 2-chloro-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone) was prepared with a 46% yield from 1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine (prepared in accordance with Example 19) and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-{4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-ethanone was prepared from the 1-chloracetyl-4-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (10% yield). The structure was confirmed using Protocol II-A. Calculated mass=681; observed mass=681; HPLC retention time=4.75 min.