Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[I-].[K+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>CO.C1C=CC=CC=1.O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:15]([C:20]2[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1
Reactant: COC(=O)C(Br)c1ccc(I)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2.38 g of sodium methylate in 80 ml of methanol is added 6.42 g of 4-chlorophenol and a few crystals of potassium iodide. After 1/2 hour of stirring a solution of 14.2 g of methyl α-bromo-α-(p-iodophenyl)acetate in 6 ml of benzene is added. The mixture is refluxed overnight. After cooling to room temperature, the mixture is added to 200 ml of water and extracted with two 50 ml portions of chloroform. The combined organic layers are washed with 50 ml of 5% NaOH, 50 ml of H2O, 50 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent affords the product as a white solid, mp 122°-125° C. A portion is recrystallized from petroleum ether to yield white crystals, mp 126°-127° C.
Reaction SMILES: FC1C=CC(C[O:7][C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH2:21])[N:15]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=CC=1>C(O)C.[Pd]>[C:22]1([CH:20]([C:16]2[N:15]=[C:14]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:8]=3[OH:7])[CH:19]=[CH:18][CH:17]=2)[CH3:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=C(c1ccccc1)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccc(F)cc2)n1
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccccc1)c1cccc(-c2cccc(-c3ccccc3)c2O)n1
Reaction time: 18 h
Yield: 87 %

Procedure:
Compound 10 (1.5 g, 3.3 mmol, 1.0 equiv) was dissolved in ethanol (50 mL) and 10% palladium (50% aqueous) on carbon (0.2 g) was added. The material was shaken on a Parr hydrogenator under a hydrogen atmosphere (30 psi) for 18 hr. The reaction was filtered through a bed of Celite and rinsed with dichloromethane (100 mL). The product was absorbed onto silica gel (4 g) by concentration under reduced pressure. This material was purified on a silica gel column (30 g) by eluting with heptanes (200 mL), ethyl acetate (2%) in heptanes (200 mL), ethyl acetate (3%) in heptanes (200 mL) and ethyl acetate (4%) in heptanes (100 mL). The desired product was isolated pure in 87% yield (1.0 g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:22])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1.C(Cl)Cl>[C:23]([O:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:22])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3[C@@H](O)CC(=O)[C@@]3(C)CC[C@@H]12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@H]12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
168 g of 15α-hydroxy-4-androstene-3,17-dione in 250 ml of pyridine and 125 ml of acetic anhydride are heated on a steam bath. After 90 minutes, the reaction mixture is stirred into ice/water. The thus-precipitated product is suctioned off, taken up in methylene chloride, washed with water, and dried over sodium sulfate. After recrystallization from ethyl acetate, 120 g of 15α-acetoxy-4-androstene-3,17-dione is obtained, mp 145° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]=[CH:9][CH2:10]Cl)=[O:4].C([O:19][AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)/[CH:8]=[CH:9]/[CH2:10][OH:19])=[O:4]
Reactant: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Reactant: COC(=O)c1cccc(C=CCCl)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/CO)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-Methoxycarbonylcinnamyl chloride (24 g) was dissolved in dry tetrahedrofuran and then this solution added to lithium tri-tert-butoxyaluminohydride (63.5 g) dissolved in tetrahydrofuran (250 ml) at -78° C. The resultant clear solution was stirred at -78° C. for 30 minutes then it was added to ice and 2M hydrochloric acid (750 ml). The two phase mixtures was extracted 4 times with dichloromethane. After drying the dichloromethane was evaporated to yield the title compound as a pale yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[C:15]([NH2:34])=[N:16][CH:17]=[C:18]([C:20]2[C:21]([CH2:31][O:32][CH3:33])=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:34][C:15]1[N:16]=[CH:17][C:18]([C:20]2[C:21]([CH2:31][O:32][CH3:33])=[N:22][N:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][OH:4])[CH2:29][CH2:30]3)[CH:24]=2)=[CH:19][C:14]=1[C:6]1[O:5][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: OCCBr
Reactant: COCc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nn(C2CCN(CCO)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2-Bromoethanol (0.051 ml) was added to a stirred suspension of 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-piperidin-4-ylpyrazol-4-yl]pyridin-2-amine] (145 mg) and potassium carbonate (124 mg) in DMF (2 ml) at 100° C. The mixture was stirred at 100° C. for 15 hours. The reaction mixture was then purified by preparative HPLC using a Waters OBD reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to afford the title compound as (90 mg) as a solid.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=2[CH:8]=O)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([NH2:36])[C:28]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=2)=[CH:21][N:20]=1.OOS([O-])=O.[K+]>O>[C:32]([N:31]1[C:28]2[CH:29]=[CH:30][C:25]([C:22]3[CH:21]=[N:20][C:19]([NH2:18])=[N:24][CH:23]=3)=[CH:26][C:27]=2[N:36]=[C:8]1[C:7]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:6]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: O=Cc1cc(C(F)(F)F)ccc1-n1cccn1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CC(C)(C)n1c(-c2cc(C(F)(F)F)ccc2-n2cccn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 60 °C
Yield: 22 %

Procedure:
A 6 mL aliquot of 2-pyrazol-1-yl-5-trifluoromethyl-benzaldehyde from the above reaction is filtered (in DMF, 50% pure by LC-MS, calculated mass based on purity is 98 mg, 0.41 mmol). The crude aldehyde is treated with 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol). Oxone (239 mg, 0.39 mmol) is added as a water solution (1 mL). The resulting mixture is warmed to 60° C. for 2 hours and cooled to room temperature, poured into water and extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (12 g silica gel, 0-6% MeOH/CH2Cl2) follows by mass triggered HPLC (CH3CN/H2O) affords the title compound (40 mg, 22%). LCMS (ESMS): m/z 478.20 (M++1)
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]2[CH2:12][C@@H:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:14](C(OC(C)(C)C)=O)[C@H:8]2[CH2:7]1)=[O:5].C(O)(C(F)(F)F)=O.CCOC(C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]2[CH2:12][C@@H:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:14][C@H:8]2[CH2:7]1)=[O:5]
Reactant: CCOC(=O)[C@@H]1C[C@@H]2CCN(C(=O)CC(C)C)C[C@@H]2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@@H]2CCN(C(=O)CC(C)C)C[C@@H]2N1
Reaction time: 1 h

Procedure:
A solution was made of 1-tert-butyl 2-ethyl rel-(2S,3aS,7aR)-6-(3-methyl butanoyl)octahydro-1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate obtained under step a) (0.335 mmol) in DCM (2.5 mL), to which TFA (2.5 mL) was added. The reaction was left to stir for 1 hour after which time it was checked by TLC (60% EtOAc in heptanes). If the reaction had not gone to completion after this time it was left stirring and checked after every additional ½. Generally this took 2 hours. When the reaction had gone to completion the TFA/DCM was removed in vacuo before being placed on a high vacuum line for 2 hours. The product was used in the next step with no further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:18][C:19]1[CH:24]=[C:23]([Br:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC([O-])(C)C.[K+]>CN1C(=O)CCC1>[Br:25][C:23]1[CH:24]=[C:19]([CH3:18])[C:20]([O:27][C:2]2[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:3]=2[C:4]([NH2:6])=[O:5])=[C:21]([CH3:26])[CH:22]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C(N)=O
Temperature: 160 °C

Procedure:
To a mixture of 2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinamide and 2,6-dimethyl-4-bromo-phenol in NMP was added t-BuOK. The resulting mixture was heated in a 160° C. oil bath overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated, then purified through silica gel Biotage to give the title compound. 1H NMR(CDCl3) d 9.69(d,1H), 7.89(brs,1H), 7.20(s,2H), 6.13(s,1H), 5.5(brs,1H), 3.3(m,1H), 2.10(s,3H), 2.09(s,6H), 1.6(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH2:29]([N:35]=[C:36]=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:36]([NH:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:37])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CCCCCCN=C=O
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 171 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and n-hexyl isocyanate (1.41 g; 10 mmole). Recrystallization from ethanol provided the title compound (4.00 g; 83% yield) as colorless crystals, m.p. 214°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])=[C:6]([CH:16]=1)[CH2:7][NH:8]C(=O)OC(C)(C)C.Cl.O1CCOCC1>C(OCC)(=O)C>[ClH:1].[NH2:8][CH2:7][C:6]1[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1N1CCCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCc1cc(Cl)ccc1N1CCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
(Step 3) To a solution (83 ml) of t-butyl [5-chloro-2-(2-oxopyrrolidin-1-yl)benzyl]carbamate obtained in Step 2 (2.70 g) in ethyl acetate was added 4N hydrogen chloride-dioxane solution (7.27 ml) at 0° C., and the mixture was stirred overnight at room temperature. The purified white crystals were collected by filtration, and washed with ethyl acetate to give 1-[2-(aminomethyl)-4-chlorophenyl]pyrrolidin-2-one hydrochloride (1.20 g).
Reaction SMILES: [Cl:1][Pt:2][Cl:3].[NH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].C(O)C.OO.[OH2:16]>>[OH:16][Pt:2]([OH:10])([Cl:3])[Cl:1].[NH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9]
Reactant: Cl[Pt]Cl
Reactant: O
Agent: CC(=O)CCCN
Agent: OO
Solvent: CCO
Product: O[Pt](O)(Cl)Cl

Procedure:
Thirty-eight grams (0.099 moles) of cis ammino-5-aminopentan-2-one dichloro platinum (II) were suspended in 350 ml of water. Five milliliters of ethanol were added to wet the solid. Next 49 ml of a 30% solution of hydrogen peroxide (0.49 moles) was added with stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3′-chloroacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract was concentrated in vacuo and the desired product, as a 1:1 mixture of E- and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether. The purified oil solidified on standing at room temperature
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13](=O)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(C)(C(O)=O)C1)=O)(C)(C)C.C(N(CC)CC)C.O.[NH2:39][NH2:40]>CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13](=[N:39][NH2:40])[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)C1(C)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CC(C)(C(=O)O)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=NN)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of 3-acetyl-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (prepared from 1-(tert-butoxycarbonyl)-3-methylazetidine-3-carboxylic acid using the similar procedure detailed in Preparation #4, Steps A-B, 0.10 g, 0.47 mmol) and triethylamine (0.5 mL, 3.8 mmol) in EtOH (2 mL) was added aqueous hydrazine hydrate (85%, 0.117 g, 2.34 mmol) and the solution was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature and poured into water. The mixture was extracted with DCM (3×15 mL) and the combined organic phase was washed with brine (10 mL) and concentrated in vacuo to give 3-(1-hydrazono-ethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.076 g, 71%), which was used directly in the next step without further purification. TLC: Rf=0.15 (eluting with 50% EtOAc in petroleum ether).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[NH:13]1[CH:17]=[N:16][C:15]([SH:18])=[N:14]1.C(N(CC)CC)C>C(O)C>[NH:13]1[CH:17]=[N:16][C:15]([S:18][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])=[N:14]1
Reactant: N#Cc1cccc(OCCCl)c1
Reactant: Sc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cccc(OCCSc2nc[nH]n2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
A solution of 3-[(2-chloroethyl)oxy]benzonitrile obtained in Reference Example 1 (11.3 g, 62.3 mmol), 1H-1,2,4-triazole-3-thiol (6.00 g, 59.3 mmol) and triethylamine (8.40 mL, 62.3 mmol) in ethanol (50 mL) was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as a white powder (14.4 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:13]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-bromophenylacetate (3.0 g, 12.3 mmol) and potassium tert-butoxide (1.38 g, 12.3 mmol) were combined in DMF (35 mL). Benzyl bromide (2.1 g, 12.3 mmol) was added and the reaction was stirred at room temperature for 1 hour. Aqueous workup provided the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:28][S:29]([O-:31])=[O:30].[Na+].CNCCNC.CCOC(C)=O>CS(C)=O.[Cl-].[NH4+].FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[CH3:28][S:29]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:31])=[O:30]
Reactant: O=C(NCc1ccc(Br)nc1)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: CS(=O)[O-]
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 110 °C

Procedure:
To a microwave tube charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (6-bromopyridin-3-ylmethyl)-amide (62 mg, 0.15 mmol) in DMSO (1 mL) was added copper (II) trifluoromethanesulfonate (53 mg, 0.15 mmol), sodium methanesulfinate (24 mg, 0.24 mmol) and N,N′dimethylethylene diamine (47 μL, 0.44 mmol). The mixture was warmed at 110° C. for 45 minutes in the microwave. The reaction was monitored by TLC (EtOAc). The reaction was the diluted with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (4×7 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3×7 mL), brine (7 mL), aqueous K2CO3 (7 mL), brine (7 mL), dried over magnesium sulfate, filtered and concentrated. The solid was triturated with ether to afford the title compound.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>CN(C)C=O>[NH:19]1[CH:20]=[C:16]([CH2:15][C:7]([CH3:10])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])[N:17]=[CH:18]1
Reactant: CC(C#N)c1ccccc1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)(Cc1c[nH]cn1)c1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
As described in Example 1, 5.82 g. of 2-phenylpropanenitrile, 2.04 g. of 50% sodium hydride, and 3.06 g. of 4-chloromethylimidazole hydrochloride were reacted in 40 ml. of dimethylformamide. The mixture was stirred for 5 hours at 100° C., and for 16 hours at ambient temperature. The solvent was then evaporated away under vacuum, and the residue was worked up as described in Example 1 to obtain 0.4 g. of crude free base. The product was purified by preparative thin layer chromatography on silica gel with ethyl acetate as the eluant. The purified product was converted to 0.11 g. of the hydrochloride salt of the desired product, m.p. 187°-189° C.
Reaction SMILES: [CH2:1](I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([N:22]([S:31]([NH:34][CH3:35])(=[O:33])=[O:32])[C@H:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C=O)C>[CH2:15]([N:22]([S:31]([NH:34][CH2:35][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])=[O:32])[C@H:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ICc1ccccc1
Reactant: CNS(=O)(=O)N(Cc1ccccc1)[C@@H](C(=O)OC)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C(C)C)N(Cc1ccccc1)S(=O)(=O)NCCc1ccccc1
Reaction time: 96 h
Yield: 60 %

Procedure:
Benzyl iodide (280 mg, 1.28 mmol) and anhydrous potassium carbonate (440 mg, 3.2 mmol) were added to a solution of methyl 2-(R)-[benzyl-(methylaminosulfonyl)amino]-3-methylbutyrate (200 mg, 0.64 mmol), [prepared as described in Step 1 above] in DMF (3 ml) at RT. After 96 h, 1 M HCl was added and the product was extracted into ethyl acetate. The organic layer was washed with dilute sodium thiosulfate and brine and dried over MgSO4. The organics were removed in vacuo and the residue was chromatographed (PTLC, SiO2, 20% ethyl acetate/hexane) to give methyl 2-(R)-[benzyl-(benzylmethylaminosulfonyl)amino]-3-methylbutyrate as a colorless oil (60%).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[F:21][C:15]1[CH:14]=[C:13]([C:5]2([C:3]([OH:4])=[O:2])[N:9]3[CH:10]=[N:11][CH:12]=[C:8]3[CH2:7][CH2:6]2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COC(=O)C1(c2ccc(OC)c(F)c2)CCc2cncn21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(C(=O)O)CCc3cncn32)cc1F
Reaction time: 1 h

Procedure:
5-(3-fluoro-4-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester (0.530 g, 1.82 mmol) is dissolved in THF/water (20 mL) (3:2) and to the solution is added LiOH (0.230 g, 9.58 mmol). After 1 h, the solution is brought to pH 4-5 with 1 M HCl and then evaporated to dryness to give 5-(3-fluoro-4-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid that is used without further purification. MS (ESI) m/z 277.2 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[NH:14][C:13](=[O:23])[C@@:12]([CH3:27])([CH2:24][S:25][CH3:26])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31]>O>[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:14]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:13](=[O:23])[C@@:12]([CH3:27])([CH2:24][S:25][CH3:26])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CSC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(CSC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
NaH (0.076 g, 1.900 mmol) was added to a solution of (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylthiomethyl)piperidin-2-one (Example 88, step E) (0.150 g, 0.380 mmol) in 3-bromopentane (1.42 mL, 11.41 mmol) at rt under nitrogen. The reaction mixture was heated at 120° C. for 24 hours, cooled to rt, diluted with water and extracted with DCM three times. The organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a yellow oil. Purification using a 24 g SiO2 column and eluting with 15% EtOAc/hexanes provided the title compound as a colorless syrup.