Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][C:6]([O:22][CH3:23])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC>[CH3:1][N:3]1[CH2:4][CH2:5][C:6]([O:22][CH3:23])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][CH2:8]1
Reactant: COC1(c2ccccc2Cc2ccccc2)CCN(C=O)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COC1(c2ccccc2Cc2ccccc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 4.0 g of 1-formyl-4-methoxy-4-(α-phenyl-2-tolyl)piperidine, of Example 50 b, in 300 ml of anhydrous ether, 0.68 g of 95% lithium aluminum hydride and 100 ml of anhydrous ether is added dropwise the solution of 1-formyl-4-methoxy-4-(α-phenyl-2-tolyl)piperidine, followed by stirring 16 hours at room temperature. The resultant mixture is quenched under N2 with distilled water. The mixture is gravity filtered, the phases are separated and the aqueous phase is further extracted with ether. The combined organic phase is dried (K2CO3), filtered and evaporated to give an oil. The oil is dissolved in ether, cooled and acidified wth ethereal HCl. After 15 minutes of stirring, a crystalline precipitate is collected by suction filtration and dried in vacuo at 40° C. Recrystallization of the filter cake from absolute ethenol affords colorless crystals, mp 238°-239° C. of 1-methyl-4-methoxy-4-(α-phenyl-2-tolyl)piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:25][C:24]([CH3:26])=[C:23]3[C:19]=2[CH2:20][C@H:21]2[C:27]([CH3:29])([CH3:28])[C@H:22]23)=[O:17])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[CH3:30][O-:31].[Na+]>CO>[OH:11][CH:10]([CH2:12][O:31][CH3:30])[CH2:9][O:8][C:7]1[C:6]([CH3:13])=[CH:5][C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:25][C:24]([CH3:26])=[C:23]3[C:19]=2[CH2:20][C@H:21]2[C:27]([CH3:28])([CH3:29])[C@H:22]23)=[O:17])=[CH:3][C:2]=1[CH3:1]
Reactant: C[O-]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC1CO1
Agent: [Na+]
Solvent: CO
Product: COCC(O)COc1c(C)cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc1C

Procedure:
3-[4-(2-Hydroxy-3-methoxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one is prepared by treating 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one with sodium methylate in methanol at 65° C. for 16 h in analogy to the procedure given in Example 99; LC-MS: tR=1.10 min, [M+1]+=443.18.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH2:2][CH3:3].Br[C:20]1(C=CC=[C:26]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[C:35]([CH2:43][CH3:44])=[N:36][O:37][C:38]=3[C:39]=2[CH2:40][CH2:41][CH3:42])[CH2:25]1)OCCC>>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:20][CH2:25][CH2:26][O:30][C:31]1[CH:32]=[CH:33][C:34]2[C:35]([CH2:43][CH3:44])=[N:36][O:37][C:38]=2[C:39]=1[CH2:40][CH2:41][CH3:42])[CH2:2][CH3:3]
Reactant: CCCc1cc(CC(=O)OC)cc(CCC)c1O
Reactant: CCCOC1(Br)C=CC=C(Oc2ccc3c(CC)noc3c2CCC)C1
Product: CCCc1cc(CC(=O)OC)cc(CCC)c1OCCCOc1ccc2c(CC)noc2c1CCC

Procedure:
Using the method of Example 17, Step D, methyl 3,5-dipropyl-4-hydroxyphenylacetate and 1-bromo-3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)phenoxypropane as the starting material, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:21])[C:8](Br)=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[C-:22]#[N:23].[K+].O.C(Cl)Cl>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:21])[C:8]([C:22]#[N:23])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: [C-]#N
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(Br)n1C
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(C#N)n1C
Temperature: 80 °C
Yield: 90 %

Procedure:
Dissolve 5-bromo-3-(4-bromo-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (205 mg, 0.500 mmol, prepared in example E-265) in DMSO (2.5 mL). Add potassium cyanide (325 mg, 5.0 mmol) to the mixture. Heat the mixture at 80° C. for 16 h. Add H2O (30 mL) and methylene chloride (30 mL) into the reaction mixture. Extract with H2O (5×30 mL). Combine the organic layers, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify by flash chromatography (elution with 33% Et2O in hexanes) to provide the title compound (161 mg, 0.450 mmol, 90%). Mass spectrum (m/e): 375.0 (M+18). Rf=0.2 (50% Et2O in hexanes).
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH:6]=[CH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([O-:5])=[O:4]>O1CCOCC1.C(O)C>[N+:3]([CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: O=[N+]([O-])CCc1ccc2ccccc2c1
Yield: 6.7 %

Procedure:
To a suspension of sodium borohydride (4 g) in a mixture of dioxane (85 ml) and ethanol (30 ml) was added dropwise a solution of 2-(2-nitroethenyl)naphthalene (100 g) in dioxane (90 ml) over 30 minutes. The flask was cooled with a cold water bath during addition. Stirring was maintained for an additional 11/2hours. Ice (100 ml) and 50% aqueous acetic acid room temperature, concentrated in vacuo and extracted with methylene chloride. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo to yield an oil which was crystallized from acetic acid to give the title compound (6.79 g) as a yellow solid, m.p. 59°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1.[Cl:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:24]([NH:23][CH2:22][CH2:21][Cl:20])=[O:25])[CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1
Reactant: O=C=NCCCl
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCCN2
Solvent: ClCCl
Product: O=C(NCCCl)N1CCN=C(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
25 Parts of 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine is dissolved in 250 parts by volume of methylene chloride. To this solution 15 parts of 2-chloroethylisocyanate is slowly added with stirring. The resultant mixture is stirred at ambient temperature for about 90 minutes. The resulting dark brown solution is filtered through a layer of activated magnesium silicate, the filtrate dried and treated with charcoal. After removal of charcoal by filtration the solvent is removed from the resultant filtrate to affort an oil. This oil is dissolved in about 100 parts by volume of ether and the resultant solution cooled to give 7-chloro-N-(2-chloroethyl)-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide as crystalline solid melting at about 150°-153° C. This compound is represented by the following formula ##STR19##
Reaction SMILES: ClCC(N1CCN(C2C=CC=CC=2C)CC1)=O.[Cl:18][CH2:19][C:20](Cl)=[O:21].[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Ca+2]>CN(C)C=O.C(C(C)=O)C>[Cl:18][CH2:19][C:20]([N:35]1[CH2:36][CH2:37][N:32]([C:25]2[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=2[CH3:23])[CH2:33][CH2:34]1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)c(N2CCNCC2)c(C)c1
Agent: Cc1ccccc1N1CCN(C(=O)CCl)CC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(N2CCN(C(=O)CCl)CC2)c(C)c1
Yield: 96 %

Procedure:
Compound 52A is prepared according to the procedure described for compound 12A, using the following reactants: chloroacetyl chloride (480 ml, 6.05 mmol); 1-(2,4,6-trimethylphenyl)piperazine (31A) (1.122 g, 5.5 mmol); calcium carbonate (1.65 g, 16.5 mmol); methyl ethyl ketone (25 ml) and dimethylformamide (10 ml) to solubilize the 1-(2,4,6-trimethylphenyl)piperazine).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]#[N:15])[N:12]=2)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1csc(-c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Product: NCCc1csc(-c2ccc(Cl)cc2)n1
Yield: 99.7 %

Procedure:
Borane dimethyl sulfide complex (0.24 mL, 2.5 mmol) was added to a solution of 2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile (150 mg, 0.63 mmol) in dry THF (15 mL) at room temperature. The reaction mixture was refluxed for 0.5 h and then quenched carefully with methanol. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-(2-(4-chlorophenyl)thiazol-4-yl)ethanamine (150 mg, crude) which was used as such for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:89][CH3:90])=[C:7]2[CH2:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:73])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]([CH2:44][C:45]4[C:54]5[C:49](=[C:50]([Br:55])[CH:51]=[CH:52][CH:53]=5)[CH:48]=[CH:47][C:46]=4[O:56][CH3:57])[C:36](=[O:58])[C@@H:35]([NH:59][C:60](=[O:72])[C@@H:61]([N:63](C(OC(C)(C)C)=O)[CH3:64])[CH3:62])[CH2:34]3)=[O:32])=[CH:27][CH:26]=2)[CH2:16][C@H:15]([NH:74][C:75](=[O:87])[C@@H:76]([N:78](C)[C:79](=O)OC(C)(C)C)[CH3:77])[C:14]1=[O:88].[ClH:91]>O1CCOCC1>[ClH:91].[ClH:91].[Br:55][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[C:49]=1[CH:48]=[CH:47][C:46]([O:56][CH3:57])=[C:45]2[CH2:44][N:37]1[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N:33]([C:31](=[O:32])[C:28]2[CH:27]=[CH:26][C:25]([C:24]([N:17]3[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:13]([CH2:12][C:7]4[C:8]5[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=5)[CH:4]=[CH:5][C:6]=4[O:89][CH3:90])[C:14](=[O:88])[C@@H:15]([NH:74][C:75](=[O:87])[C@@H:76]([NH:78][CH3:79])[CH3:77])[CH2:16]3)=[O:73])=[CH:30][CH:29]=2)[CH2:34][C@H:35]([NH:59][C:60](=[O:72])[C@@H:61]([NH:63][CH3:64])[CH3:62])[C:36]1=[O:58]
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5c(Br)cccc45)c4ccccc43)cc2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H]1CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)NC)C(=O)N(Cc4c(OC)ccc5c(Br)cccc45)c4ccccc43)cc2)c2ccccc2N(Cc2c(OC)ccc3c(Br)cccc23)C1=O
Yield: 77.2 %

Procedure:
To a solution of tert-butyl N-[(1S)-2-[[(3S)-5-[(5-bromo-2-methoxy-1-naphthyl)methyl]-1-[4-[(3S)-5-[(5-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (50 mg, 0.037 mmol) in dioxane (1 mL) at 0° C. was added 4 M HCl in dioxane (0.6 mL) dropwise and the cooling bath removed. After 3 h the mixture was evaporated and the residue was triturated with hexane to afford the title compound (35 mg, 77.2%) as a white solid. LC-MS: 1153.2 (M+H).
Reaction SMILES: I.CO[CH:4](OC)[CH2:5][NH:6][C:7]([S:23][CH2:24][CH3:25])=[N:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.Cl.[OH-].[Na+]>>[CH2:24]([S:23][C:7]1[N:8]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:4]=[CH:5][N:6]=1)[CH3:25]
Reactant: CCSC(=NN1CCN(c2ccc(OC)cc2)CC1)NCC(OC)OC
Agent: Cl
Agent: I
Agent: [Na+]
Product: CCSc1nccn1N1CCN(c2ccc(OC)cc2)CC1
Yield: 100 %

Procedure:
A mixture of 9 parts of ethyl N-(2,2-dimethoxyethyl)-N'-[4-(4-methoxyphenyl)-1-piperazinyl]carbamimidothioate monohydroiodide and 100 parts of a hydrochloric acid solution 6N is stirred and refluxed for 1 hour. The reaction mixture is cooled and adjusted to pH 10 with a sodium hydroxide solution 50%. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 1,1'-oxybisbutane (activated charcoal), yielding 6 parts (100%) of 1-[2-(ethylthio)-1H-imidazol-1-yl]-4-(4-methoxyphenyl)piperazine; mp. 111.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[C:17]([NH:20][NH2:21])(=[O:19])[CH3:18]>O1CCCC1>[C:17]([NH:20][NH:21][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)NN
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Solvent: C1CCOC1
Product: COc1cc(C(=O)NNC(C)=O)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (0.438 g, 1.93 mmol) in tetrahydrofuran (10 mL) at room temperature was added 1,1-carbonyldiimidazole (0.343 g, 2.12 mmol) in one portion and the mixture was stirred at room temperature for one hour, then at 70° C. for two hours, whereupon acetic hydrazide (0.157 g, 2.12 mmol) was added. The resulting was stirred at room temperature for thirty minutes, then at 70° C. for two hours. After cooling to room temperature, the mixture was poured onto ice-water (100 mL) and the precipitate was filtered off and washed with water. 3,4-Dimethoxy-5-nitro-benzoic acid N′-acetyl-hydrazide was obtained as a white solid (0.296 g, 54%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:21]Br>CN(C=O)C.C(OCC)(=O)C>[Br:21][C:3]1[CH:4]=[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: BrBr
Reactant: O=S(=O)(Nc1ccc(O)c2ccccc12)c1cccs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cc(Br)c(O)c2ccccc12)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
305.7 mg N-(4-hydroxynaphthalen-1-yl)thiophene-2-sulfonamide (3) was dissolved in 1 ml DMF, to which at 0° C. was added 320 mg Br2 in 1 ml dichloromethylene solution. After stirred at r.t. for 1 h, 558 μl TEA was added at 0° C. The reaction was stirred at r.t. overnight and diluted with ethyl acetate to 50 ml. The organic phase was washed with water and brine. Dried over Na2SO4, the organic phase was filtered and concentrated. The crude product was purified via flash chromatography (Hex/EtOAc gradient) affording an orange-red solid 140 mg (36.4%), m.p.: 128-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1(C)C=CC=C(N2[CH:19]=[N:18][C:17]([C:20]([OH:22])=[O:21])=[N:16]2)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH:19]=[N:18][C:17]([C:20]([OH:22])=[O:21])=[N:16]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: Cc1cccc(-n2cnc(C(=O)O)n2)c1
Product: O=C(O)c1ncn(-c2cccc(Br)c2)n1

Procedure:
This intermediate was prepared from 3-bromoaniline in three steps according to the preparation of 1-m-tolyl-1H-[1,2,4]-triazole-3-carboxylic acid (Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N-:16][CH2:17][C@H:18](O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[O:15][C@@H:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][N:16]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C([N-]C[C@H](O)c1ccccc1)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2ccc(C3=NC[C@H](c4ccccc4)O3)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of 1.24 g of 4'-chlorobiphenyl-4-carbonyl-[2(R)-hydroxy-2-phenylethyl]amide in 20 ml of pyridine is cooled in an ice bath and treated with a solution of 921 mg of methanesulfonic acid anhydride in dichloromethane. The reaction mixture is stirred for additional 16 hours at 5°, ethyl acetate and saturated aqueous sodium hydrogencarbonate are added, the organic layer is separated, dried and concentrated in vacuo. Vacuum flash chromatography on silica gel (toluene/ethyl acetate =3/1) yields the compound as pale yellow crystals; m.p.: 121.5° (recrystallized from ethanol); [α]D20 =+133.5° (c=1.3, methanol);
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([C:14](=[O:22])[CH:15]=[C:16]([OH:21])[C:17]([O:19]C)=[O:18])[C:11](=[O:23])[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[CH:13]=[C:12]([C:14](=[O:22])[CH:15]=[C:16]([OH:21])[C:17]([OH:19])=[O:18])[C:11](=[O:23])[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Yield: 84.3 %

Procedure:
A solution of methyl 4-(1,3-dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-enoate (3a) (757 mg, 1.8 mmol) in dioxane (100 ml) was refluxed with 1N HCl (60 ml) for 4 h. The solution was evaporated to dryness. The resulting solid was recrystalized from hexane and ethyl acetate (3:1) to give 617 mg a pale yellow solid. Yield was 84.2%. Mp. 186-188° C. 1HNMR (DMSO-d6): 8.89 (s, 1H), 7.57 (s, 1H), 7.24-7.36 (m, 10H), 5.16 (s, 2H), 5.02 (s, 2H). 13CNMR (DMSO-d6): 186.1, 169.0, 163.2, 159.9, 151.1, 150.2, 136.5, 135.8, 128.7, 128.4, 128.0, 127.8, 127.6, 127.3, 107.7, 100.9, 52.8, 44.2. FAB-HRMS: [M+H]+ calcd. for C22H19N2O6 407.1243, found 407.1248.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=1.C[O:27][B:28](OC)[O:29]C>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([B:28]([OH:29])[OH:27])[C:10]=2[N:9]=[C:8]1[CH3:11]
Reactant: COB(OC)OC
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1ccccc1Cl
Product: Cc1nc2c(B(O)O)cc(N3CCOCC3)cc2n1Cc1ccccc1Cl

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(2-chlorobenzyl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.2 g, 0.475 mmol) using Method A with trimethylborate to give the product (0.272 g, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.15-3.25 (m, 4H) 3.65-3.82 (m, 4H) 5.75 (s, 2H) 6.82-6.88 (m, 1H) 7.22-7.30 (m, 1H) 7.32-7.40 (m, 2H) 7.56 (dd, J=7.96, 1.14 Hz, 1H) 7.80 (d, J=1.95 Hz, 1H); MS (ES+) 386.0 m/z
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[OH:9][C@H:10]([CH3:43])[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:24]3[CH:25]=[CH:26][NH:27][C:23]=3[N:22]3[N:28]=[CH:29][C:30]([C:31]4[CH:32]=[N:33][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:35][CH:36]=4)=[C:21]3[N:20]=2)[CH2:15][CH2:14]1)=[O:12]>CN(C=O)C>[Cl:8][C:25]1[C:24]2[C:19]([CH:16]3[CH2:15][CH2:14][N:13]([C:11](=[O:12])[C@H:10]([OH:9])[CH3:43])[CH2:18][CH2:17]3)=[N:20][C:21]3[N:22]([N:28]=[CH:29][C:30]=3[C:31]3[CH:32]=[N:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[C:23]=2[NH:27][CH:26]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]cc(Cl)c23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
NCS (3.7 mg, 0.027 mmoL) was added to a solution of (R)-2-hydroxy-1-(4-(3-(6-phenylpyridin-3-yl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-5-yl)piperidin-1-yl)propan-1-one (25, prepared in Example 15) (12.8 mg, 0.027 mmoL) in DMF (1 mL). The mixture was stirred at room temperature for 3 days. Purification by prep-LC afforded (R)-1-(4-(6-chloro-3-(6-phenylpyridin-3-yl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-5-yl)piperidin-1-yl)-2-hydroxypropan-1-one (34): LCMS tR=3.70 Min (10 min run, UV254nm). Mass calculated for, M+500.1, observed 501.5 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][C:4]=1[NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][C:4]=1[NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2cc(-c3ccc(NC(=O)c4ccccc4)c(OC)c3)ccc2c1
Agent: BrB(Br)Br
Product: O=C(Nc1ccc(-c2ccc3cc(O)ccc3c2)cc1O)c1ccccc1

Procedure:
The compound is prepared by reaction of N-[2-methoxy-4-(6-methoxy-2-naphthyl)phenyl]benzamide (49 mg. 0.13 mol, 1 eq) with boron tribromide solution (2.25 ml, 2.25 mmol, 15 eq) according to method G. Purification by preparative thin-layer chromatography with dichloromethane/methanol 95/5 as the eluent yielded the desired product in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:4]=1.[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:23][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:22])([F:1])[F:21])=[N:4]2)=[CH:13][CH:14]=1
Reactant: CNCCc1ccccc1
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CN(CCc1ccccc1)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid and N-methylphenethylamine using a similar procedure to that described for Example 2.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>CCOCC>[CH2:14]([N:16]([CH2:17][CH3:18])[C:11]([C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8])=[O:12])[CH3:15]
Reactant: CCNCC
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Solvent: CCOCC
Product: CCN(CC)C(=O)c1sc(Cl)nc1C(F)(F)F
Yield: 89.4 %

Procedure:
To a well-stirred solution of 4.0 g (0.0160 mole) of the acid chloride of Example 16 in 20 ml. of ether was added dropwise 2.34 g (0.032 mole) of diethylamine in 5 ml. of ether. The insoluble salt was filtered. The ether solution was washed with water, dried and concentrated under reduced pressure. The residue was crystallized from hexane at low temperature to give 4.1 g of the desired product, m.p. 40°-41° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][CH:5]=1.[CH2:11](Br)[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][CH:5]=1)[CH3:12]
Reactant: Cc1cccc(N)n1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCNc1cccc(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 3000 ml dry toluene were added 185 g of 60% sodium hydride. A solution of 500 g of 6-amino-2-picoline and 500 ml of toluene were dropwise added at 60° C. over about 2 hours to the resulting dispersion. Ethyl bromide of 554 g were dropwise added at 70° C. over about 2 hours to the resulting mixture and stirred for additional one hour. The reation mixture was added to 3000 ml of ice water. The organic phase was extracted and the extract was washed two times with water, concentrated and dried. Thus, 632 g of 6-ethylamino-2-picoline were obtained.