Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:11]([N+:17]([O-])=O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O1CCOCC1.[Fe]>[NH2:17][C:11]1[N:10]=[CH:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NS(=O)(=O)c1c([N+](=O)[O-])ncn1Cc1ccccc1
Agent: [Fe]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Nc1ncn(Cc2ccccc2)c1S(N)(=O)=O
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A solution of the product of Example 312E (434 mg, 1.54 mmol) in acetic acid (4.3 mL) and dioxane (4.3 mL) was reacted with iron powder (343 mg, 6.15 mmol) at 50° C. for 3 hours. The reaction mixture was cooled to 25° C., filtered through a pad of celite® (diatomaceous earth) and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (2×) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel using a gradient of methanol in dichloromethane (0-5%) to give the title compound (180 mg, 46%). MS (ESI+) m/z 253 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.24 (s, 2H), 7.22-7.39 (m, 5H), 7.43 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[C:3](=[O:5])[CH3:4].[I-].[CH3:17][S+](C)(C)=O.[H-].[Na+]>>[CH3:1][C:2]1([C:3](=[O:5])[CH3:4])[CH2:17][CH:6]1[CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14]
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)C(C)=CCC1CC=C(C)C1(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CC(=O)C1(C)CC1CC1CC=C(C)C1(C)C
Yield: 44.6 %

Procedure:
11.3 g (55 mmol) of 3-methyl-5-(2,2,3-trimethylcyclopent-3-enyl)-pent-3-en-2-one was cyclopropanated with 14.1 g (63 mmol) of trimethylsulfoxonium iodide and 3.08 g (64 mmol) of 50% oil suspension of sodium hydride according to Example 11a giving 5.4 g (45% yield) of 1-[1-methyl-2-(2,2,3-trimethylcyclopent-3-enylmethyl)cyclopropyl]ethanone.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>ClCCl.O>[CH2:23]([O:22][C:20]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a suspension of (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (17.0 g: 100 mmole) in dichloromethane (200 ml), triethylamine (29.2 ml: 210 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 5 minutes at room temperature, mixed dropwise with a solution of allyl chloroformate (11.2 ml: 100 mmole) in dichloromethane (20 ml), stirred for 1 hour at room temperature, and diluted with water (250 ml). The organic layer is taken, successively washed with water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (21.82 g) as oil. To a solution of this product in dichloromethane (100 ml), triethylamine (16.7 ml: 120 mmole) and methanesulfonylchloride (9.2 ml: 120 mmole) are added in a nitrogen atmosphere under ice cooling, and the mixture is stirred for 10 minutes. The reaction mixture is successively washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (toluene-ethyl acetate) to give (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (27.62 g) as oil. Yield: 90%.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH2:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH:21][C:10]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=1)=[O:12]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1cccc(-c2ccccc2)c1

Procedure:
Using preparation method 1, 3-phenylbenzoic acid (125 mg, 0.63 mmol) was reacted with 3,4-dichlorobenzylamine (123 mg, 0.7 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100%. White crystals were obtained (111 mg, 50%). NMR 1H (ppm, CDCl3): 8.00 (s, 1H), 7.73 (dd, J3=7.7 Hz, J4=1.6 Hz, 2H), 7.59 (d, J3=7.3 Hz, 2H), 7.50 (t, J3=7.7 Hz, 1H), 7.46-7.34 (m, 6H), 7.19 (dd, J3=8.2 Hz, J4=1.8 Hz, 1H), 6.54 (br. s, 1H), 4.61 (d, J3=5.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][C@@H:21]([NH2:23])[CH2:20][CH2:19][C@H:18]2[CH3:24])[N:3]=1.[C:25]([O-:28])(O)=[O:26].[Na+]>C1COCC1.O>[C:8]1([CH2:6][O:28][C:25](=[O:26])[NH:23][C@H:21]2[CH2:20][CH2:19][C@@H:18]([CH3:24])[N:17]([C:4]3[CH:5]=[C:6]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:22]2)[CH:15]=[CH:14][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: C[C@@H]1CC[C@H](N)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-{2-amino-6-[(2R,5S)-5-amino-2-methyl-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (170 mg, 0.426 mmol) in THF (4 mL) was added saturated aqueous NaHCO3 (2 mL) followed by phenylmethyl chloridocarbonate (0.07 mL, 0.47 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with 3 mL of water and then extracted with EtOAc (3×30 mL). The organic was then washed with brine, dried over MgSO4, filtered and concentrated. The resulting yellow oil was purified on a Biotage SNAP 10 g column with gradient of 0 to 50% EtOAc in hexane over 30 minutes to afford the title compound (57 mg) as a yellow oil. LC-MS (ES) m/z=327 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3C=CC=CC=3)=[C:31]([NH:43][CH:44]=[O:45])[CH:30]=2)[OH:28])=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:48]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:36]([OH:48])(=[O:35])[CH3:37].[C:36]([OH:48])(=[O:35])[CH3:37].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:43][CH:44]=[O:45])[CH:30]=2)[OH:28])=[CH:19][CH:20]=1
Reactant: CO
Reactant: O=CNc1cc([C@@H](O)CNCCCCc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: NCCCCc1ccc(CCCCNC[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of [4-(4-{4-[2-(4-benzyloxy-3-formylaminophenyl)-2-(R)-hydroxyethylamino]butyl}phenyl)butyl]carbamic acid benzyl ester (8) (84 mg, 0.14 mmol), palladium dihydroxide (28 mg, 10% Pd(OH)2 on carbon, 50% wet), three drops of acetic acid, methanol (5 mL), and dichloromethane (5 mL) was stirred at rt for 16 h under atmospheric hydrogen pressure. The catalyst was filtered through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 11 as a yellow solid (69 mg, 99%): 1H NMR (500 MHz, CD3OD) δ 1.68 (m, 8H), 1.93 (s, 6H), 2.63 (m, 4H), 2.91 (m, 2H), 3.08 (m, 4H), 4.83 (m, 1H), 6.88 (d, 1H), 7.05 (d, 1H), 7.11 (s, 4H), 8.10 (s, 1H), 8.30 (s, 1H); m/z (ESI) 400 [C23H33N3O3+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=2)=[CH:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].O>CS(C)=O>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][CH2:37][CH2:36][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=1)[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)C=Cc1ccc(CNCCc2c[nH]c3ccccc23)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C=Cc1ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc2c[nH]c3ccccc23)cc1
Temperature: 52.5 °C
Yield: 97.6 %

Procedure:
To a stirred solution of 2 (2.82 g, 8.44 mmol) and diisopropylethylamine (2.21 mL, 12.66 mmol) in anhydrous DMSO (22 mL) at room temperature under nitrogen was added (2-bromo-ethoxy)-tert-butyl-dimethylsilane (2.17 mL, 10.12 mmol). The reaction mixture was heated at 50-55° C. for 24 h, poured into water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (AcOEt/CH2Cl2, 15/85, plus a few drops of NH4OH) to afford the title compound 3 (4.06 g, 8.24 mmol, 97% yield) as a dark orange oil.
Reaction SMILES: [OH:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[S:4][N:3]=1.[P:16](Cl)([O:20][CH3:21])([O:18][CH3:19])=[S:17]>>[CH3:19][O:18][P:16]([O:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[S:4][N:3]=1)([O:20][CH3:21])=[S:17]
Reactant: Oc1nsc(SCc2ccc(Cl)cc2)n1
Reactant: COP(=S)(Cl)OC
Product: COP(=S)(OC)Oc1nsc(SCc2ccc(Cl)cc2)n1

Procedure:
Using the procedure of Step B of Example 1, 3-hydroxy -5-p-chlorobenzylthio-1,2,4-thiadiazole and dimethyl chlorothiophosphate were reacted to obtain 3-(dimethoxythiophosphoryloxy)-5-p-chlorobenzylthio-1,2,4-thiadiazole with a refractive index of nD20 = 1.605 and Rf = 0.35.
Reaction SMILES: [Br:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)C.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:12]([O-:15])(=[O:14])=[O:13].[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: CCCCCC(Br)Br
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCBr
Temperature: 25 °C

Procedure:
To a stirred mixture of dibromohexane (81.0 g), ethanol (120 ml) and water (50 ml) is added dropwise an aqueous solution (50 ml) of sodium sulfite (12.5 g) under reflux over 2 hours. After additional refluxing for 2 hours, the reaction mixture is allowed to cool and unreacted dibromohexane is removed and then the resulting solution is concentrated under reduced pressure. 95% Ethanol (200 ml) is added and the mixture is allowed to cool at room temperature overnight and precipitated crystals are collected by filtration to give the title compound as colorless prisms. The filtrate is concentrated and is allowed to cool overnight and precipitated crystals are collected by filtration to give additional title compound.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:14]=1[NH2:15].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:14]=1[NH:15][C:46]([NH:45][C:43](=[O:44])[C:37]1[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=1[F:35])=[S:47]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-difluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (42 mg, yield 53%).
Reaction SMILES: [C:1]1([NH:7][S:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[O:10]=[S:8]1(=[O:9])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20][N:11]1[C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Nc1ccccc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCN(c2ccccc2)S1(=O)=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 35.8 %

Procedure:
To a solution of tert-butyl N-phenylsulfamoylcarbamate (2.0 g, 7.35 mmol) and 1,4-dibromobutane (1.6 g, 7.35 mmol) in acetone (30 mL) was added Cs2CO3 (7.2 g, 22.05 mmol) and the mixture was stirred at 60° C. for 48 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford tert-butyl 1,1-dioxo-7-phenyl-1λ6,2,7-thiadiazepane-2-carboxylate as a yellow oil (860 mg, 39%). LCMS (ESI): m/z=271.1 [M−56+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][C@H:15]([CH3:19])[NH:14]1>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:17]2[CH2:16][C@H:15]([CH3:19])[NH:14][C@H:13]([CH3:12])[CH2:18]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and (2R,6S)-2,6-dimethylpiperazine using a method similar to that described for D21 in Description 21A. MS (ES): MH+ 250.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][C:15]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Br-]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:16][C:15]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Reactant: OCc1cccnc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCc2cccnc2)cc1-c1ccccc1

Procedure:
To a solution in DMF of 3-pyridinemethanol (0.59 mL) was added sodium hydride (60% in mineral oil, 0.19 g), and the mixture was stirred until gas evolution ceased. A solution of 2-phenyl-4-bromomethylbenzoic acid methyl ester (0.98 g) in DMF was then added and the reaction mixture was stirred until the bromide was consumed. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried, and concentrated. The residue was purified by chromatography on silica gel (1:1 ethyl acetate-hexanes) to give [4-(3-pyridylmethyloxymethyl)-2-phenylbenzoic acid methyl ester (0.58 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:11][C:10]1[C:2]([NH:1][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(NC2CCCCC2)c(Cl)cc1C(=O)O
Reaction time: 1 h
Yield: 12.8 %

Procedure:
In a stream of argon, 3.08 g of 4-amino-5-chloro-2-methoxybenzoic acid and 1.00 g of cyclohexanone were added to 30 ml of acetic acid at room temperature, 4.30 g of sodium triacetoxyborohydride was added in small portions to the above solution, and then the resulting mixture was stirred for 1 hour. After completion of the reaction, the solvent was evaporated and the resulting residue was mixed with water, extracted with chloroform and then washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1-50:1) to give 0.37 g of 5-chloro-4-cyclohexylamino-2-methoxybenzoic acid.
Reaction SMILES: [C:1]([O:5]CC)(=[O:4])[CH:2]=O.C([NH:10][C:11]([CH2:22][C:23]([CH3:25])=[CH2:24])(C(OCC)=O)[C:12]([O:14]CC)=[O:13])=O.O>C(Cl)Cl>[NH2:10][CH:11]([CH2:22][C:23](=[CH2:24])[CH2:25][CH2:2][C:1]([OH:5])=[O:4])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C=O
Reactant: C=C(C)CC(NC=O)(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Solvent: O
Product: C=C(CCC(=O)O)CC(N)C(=O)O
Temperature: -20 °C
Reaction time: 1 h
Yield: 228.4 %

Procedure:
A solution of 26.5 g of ethyl glyoxylate in 180 ml of methylene chloride was added dropwise over 10 minutes to a solution of 84 g of ferric chloride in 180 ml of methylene chloride and after stirring for one hour, the mixture was cooled to -20° C. A solution of 34 g of the product of Step A in 180 ml of methylene chloride was added dropwise over 20 minutes and the mixture was stirred for one hour at -20° C. and then was poured into 300 ml of iced water. The mixture was extracted with methylene chloride and the organic phase was washed with 2N hydrochloric acid, then with aqueous sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 56.5 g of the expected product melting at 68° C. after purification by chromatography on silica and elution with a 6-4 ethyl acetate-cyclohexane mixture.
Reaction SMILES: [C:1]1([S:7]([C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][N:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=CC(C#C)=CN=1>>[C:1]1([S:7]([C:10]2[N:11]([CH3:16])[C:12]([C:18]#[CH:23])=[CH:13][N:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccc(Cl)nc1
Reactant: Cn1c(I)cnc1S(=O)(=O)c1ccccc1
Product: C#Cc1cnc(S(=O)(=O)c2ccccc2)n1C

Procedure:
2-benzenesulfonyl-5-ethynyl-1-methyl-1H-imidazole was prepared from 2-benzenesulfonyl-5-iodo-1-methyl-1H-imidazole in the same manner as 2-chloro-5-ethynyl pyridine (Example 1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([N:18]3[CH:22]=[C:21]([C:23]4[C:24]5[CH:31]=[CH:30][NH:29][C:25]=5[N:26]=[CH:27][N:28]=4)[CH:20]=[N:19]3)[CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)[C:3]=1[CH3:32].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:33]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([N:18]3[CH:22]=[C:21]([C:23]4[C:24]5[CH:31]=[CH:30][NH:29][C:25]=5[N:26]=[CH:27][N:28]=4)[CH:20]=[N:19]3)[CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)[C:3]=1[CH3:32])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccccc1
Reactant: Cc1c(Cl)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Product: Cc1c(Nc2ccccc2)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Yield: 35.2 %

Procedure:
A solution of 3-[1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.0081 g, 0.018 mmol) in Aniline (95 uL, 1.0 mmol) was heated at 180° C. for 2.5 hours. The reaction was purified by preparative-LCMS (pH 10) to give 3.2 mg white solid (35% yield). 1H NMR (400 MHz, DMSO): δ 12.05 (1H, br); 8.77 (1H, s); 8.61 (1H, s); 8.58 (1H, s); 8.15 (1H, s); 8.1 (1H, s); 7.55 (1H, d); 7.53 (2H, m); 7.2 (2H, t); 6.92 (1H, d); 6.9 (1H, m); 4.57 (1H, m); 3.6 (1H, m); 3.45 (1H, m); 3.27 (2H, m); 2.7 (1H, m); 2.58 (1H, m); 2.02 (1H, m); 1.98 (3H, s); 1.85 (1H, m); 1.3 (2H, m); 1.01 (1H, m). LCMS (M+1): 505.
Reaction SMILES: [Cl:1][C:2]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([NH:19][CH3:20])=O)[CH:13]=[CH:14][CH:15]=1.Cl>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:21][CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH:19][CH3:20])[CH:11]=1
Reactant: CNC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CNCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a stirring solution of 2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-acetamide (101 mg, 0.17 mmol) (Intermediate 3 above) in anhydrous THF (10 mL) was added BH3 THF (0.34 ml, 1 M solution in THF). The resulting solution was then heated to reflux for 1.5 hours. Aqeous HCl (0.34 ml. 6 M) was then added to the reaction and the mixture was heated at reflux for 30 min. After cooling to RT, the reaction mixture was concentrated in vacuo and extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (silica gel 60, EM science) using 5% MeOH:dichloro-methane as eluent. The free base was dissolved in dichloromethane, 1 eq. of HCl (1M in Et2O) was added, and the mixture was evaporated to afford the title compound as a white solid (52 mg, 50%). MS(ES) m/e 581.4 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[F:25])=[O:17]>O1CCCC1>[F:13][C:14]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2F)c(F)c1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(Cc2nnnn2C)c2ccc(C)cc2F)c(F)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,5-dimethyltetrazole (4.6 g, 4.7 mmoles) in tetrahydrofuran (40 mL) at -50° C. was added butyl lithium solution (21.4 mL of a 2.2 M solution, 4.7 mmoles). After stirring for 10 minutes, a solution of 2,2'-difluoro-4,4'-dimethylbenzophenone in tetrahydrofuran (15 mL) was added. The solution was stirred for 2.5 hours during which time it was allowed to warm to -10° C. The reaction was quenched by adding 1N hydrochloric acid. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic fractions were dried (MgSO4) was evaporated. The residue was triturated with diethyl ether and crystallized from isopropyl acetate to give 8.0 g of the title compound; m.p.=150°-151° C. MS: M+ =344.