Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=[C:10]([O:23][CH3:24])[CH:9]=1.[CH:26]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:38][CH:39]([CH3:41])[CH3:40])[CH:37]=1)[CH:33]=O)([CH3:28])[CH3:27].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([O:23][CH3:24])[CH:11]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:33][C:32]3[CH:35]=[C:36]([O:38][CH:39]([CH3:41])[CH3:40])[CH:37]=[C:30]([O:29][CH:26]([CH3:28])[CH3:27])[CH:31]=3)[CH2:20][CH2:21]2)[CH:13]=1
Reactant: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCN(Cc3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 4-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-butyric acid methyl ester (example 168b) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless oil. MS: 557.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:18]([C:26](Cl)=[O:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CC(OC)(C)C>[CH3:7][N:6]1[C:2]([NH:1][C:26](=[O:27])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][C:4]([CH3:8])=[N:5]1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(Cl)C(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(NC(=O)C(=O)c2ccccc2)n(C)n1
Reaction time: 18 h
Yield: 48.2 %

Procedure:
To a solution of 5-amino-1,3-dimethylpyrazole (2.00 g, 18.0 mmol) in THF (20 mL) was added at ambient temperature N,N-diisopropyl ethyl amine (4.62 mL, 27.0 mmol) and over a period of 5 min benzoylformic acid chloride (which might be prepared according to Synlett (11) 1763-1765, 1999, 3.64 g, 21.6 mmol) and the reaction mixture was stirred for 18 h at this temperature. It was diluted with TBME (50 mL) and washed twice with water (50 mL) and brine (50 mL). The combined aqueous layers were extracted with TBME (50 mL) and the combined organic layers were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (2.11 g, 48%) as a light brown oil. MS m/e: 244.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>Cl.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(-c2nc(CSc3ccc(C)cc3)c(C)o2)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(SCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A mixture of methyl 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoate (3.1 g, 8.78 mmol, 1.00 equiv) in 6N hydrochloric acid (90 mL) was stirred overnight at 90° C. The reaction mixture was diluted with 150 mL of water and extracted with 3×150 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.2 g (74%) of 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoic acid as a white solid. LC-MS: (ES, m/z):
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:25]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OC1N=C(NC2C=CC(C3N=C(N4CCOC[C@@H]4C)C4CCNCC=4N=3)=CC=2)C=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.CI>CN(C=O)C.O>[CH3:32][N:29]1[CH2:30][CH2:31][C:25]2[C:24]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])=[N:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:21][CH:20]=3)=[N:27][C:26]=2[CH2:28]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(C)C2
Agent: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCNC2
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(=O)[nH]3)cc2)nc2c1CCN(C)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Step 1—Synthesis of (S)-6-(benzyloxy)-N-(4-(7-methyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine (mt): (S)-6-(benzyloxy)-N-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyridin-2-amine (ms) (100 mg, 0.2 mmol) was dissolved in DMF (2 mL) and DIPEA (159 μL, 0.9 mmol)). To this solution was added MeI (14 μL, 0.2 mmol) at rt. The resulting solution was stirred at rt for 4 hrs. It was diluted with H2O, extracted with EtOAc (2×10 mL). The combined organics were washed with brine, dried over Magnesium sulfate, filtered, concentrated in vacuo to afford 100 mg (100%) of the title compound mt. LC-MS: m/z=+524 (M+H)+.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:23]3[CH:24]=[CH:19][N:20]=[C:21]([NH:25][CH:26]4[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]4)[N:22]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2ccc(Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(Cl)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-chloro-1H-indole (prepared by TBDMS protection of 6-chloro-1H-indole using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 650 mg (77%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH2:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:17]([C:24]1[CH:25]=[CH:26][C:27]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:28][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCc1ccccc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Temperature: 90 °C

Procedure:
First, 4-cyanobenzoyl chloride (25 g, 0.15 mole) is added dropwise over 15 minutes with vigorous stirring to aluminum chloride (24.2 g, 0.18 mole) in heptylbenzene (300 ml). The mixture is heated (90° C. for 30 minutes) and then mixed with ice (1 kg) and concentrated hydrochloric acid (100 ml). The resulting suspension is extracted with ether (5×100 ml). The extract is washed with 2N sodium hydroxide (2×100 ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is triturated with hexane (3×100 ml). The hexane solutions are combined, filtered, concentrated and chromatographed on silica gel to give 4'-n-heptyl-4-cyano-benzophenone (14.4 g). This product is heated under reflux in a mixture of 75% sulfuric acid (100 ml) and acetic acid (75 ml) for 30 minutes. The reaction mixture is cooled, diluted with water (200 ml) and filtered. The insoluble solid is recrystallized from aqueous ethanol to give 4-(4-n-heptylbenzoyl)benzoic acid (12.7 g) as cream colored crystals, m.p. 181° C.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][NH2:19]>C(O)C>[CH3:17][N:18]1[C:14](=[O:16])[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19]1
Reactant: CNN
Reactant: O=C(c1ccccc1)c1ccsc1C(=O)O
Solvent: CCO
Product: Cn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
A solution of 31.2 g (0.134 mol) of 3-benzoyl-2-thiophenecarboxylic acid in 400 mL of ethanol was treated with 9.3 (0.2 mol) of methylhydrazine at room temperature for 18 hours, refluxed 3 hours, cooled and 30.7 g of the product filtered off, mp 174-175.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([CH3:22])=[O:21])[CH2:18][N:17](CC4C=CC=CC=4)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:31]([O:33][CH3:34])=[O:32]>ClC(Cl)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([CH3:22])=[O:21])[CH2:18][N:17]([C:31]([O:33][CH3:34])=[O:32])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cl
Reactant: COc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2C(C)=O)cc1OC1CCCC1
Solvent: CC(Cl)Cl
Product: COC(=O)N1C[C@@H](C(C)=O)[C@H](c2ccc(OC)c(OC3CCCC3)c2)C1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methylcarbonyl-1-(phenylmethyl)pyrrolidine (703 mg, 1.78 mmol) in 3.5 mL of dichloroethane in a thick-walled glass sealable tube was added methyl chloroformate (336 mg, 3.56 mmol). The tube was sealed and the resulting solution was heated to 80° C. for 8 hr. After cooling to room temperature, the solution was concentrated. Silica gel chromatography of the residue (6:3:1, hexanes:ethyl acetate:CH2Cl2) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-1-methoxycarbonyl-4-(methylcarbonyl)pyrrolidine as a viscous oil (350 mg, 54%). Anal. Calcd for C20H27NO5 : C, 66.46; H, 7.53; N, 3.88. Found: C, 66.24; H, 7.60; N, 3.79.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[NH:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.N1C=CC=CC=1CCl>C(Cl)(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCNCCNCCN1
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: c1ccc(CN2CCNCCNCCNCC2)nc1
Reaction time: 0.5 h

Procedure:
A 2-picolyl chloride solution in chloroform was prepared by basifying 3 mL of an aqueous solution of 1.03 g (6.3 mmol) of 2-picolyl chloride hydrochloride to pH>14 and extracting into chloroform. To a stirred chloroform solution of 2.03 g (11.8 mmol) of 1,4,7,10-tetraazacyclododecane was added 10 mL of the prepared 2-picolyl chloride solution in chloroform in one portion. After stirring at temperature for 30 min, the reaction mixture was concentrated in vacuo to give a residue which was chromatographed on sffica gel (column, 2.5×20 cm), eluting with CHCl3 :CH3OH: NH4OH (10:4:1), Rf =0.29 on SiO2 plate. After concentration of eluent, the monoalkylated product was isolated a as thick pale yellow liquid, which upon standing solidified to give 1.17 g of an off-white powder (72%, based on 2-picolyl chloride), and further characterized by:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:9][C:10](=[O:20])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[NH2:19])[CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([N:9]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[NH:19][C:23]1=[O:24])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCC[C@H](NC(=O)c1cc(OC)ccc1N)C(=O)OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2ccc(OC)cc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 136 %

Procedure:
To a solution of (S)-2-(2-amino-5-methoxy-benzoylamino)-hexanoic acid methyl ester (410 mg, 1.39 mmol) in THF (30 mL) is added trichloromethyl chloroformate (200 mg, 1.01 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated to give (S)-2-(6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (440 mg, 98%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH2:39])[CH2:37][CH3:38]>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:39][CH2:36][CH2:37][CH3:38])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 100 mg (0.19 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 30 μl (0.37 mmol) of n-propylamine were stirred in 2.5 ml of THF for 2 h. The reaction mixture was then purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 67 mg (64% of theory) of the target compound.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[CH3:12][N:13]1[N:17]=[N:16][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:14]1.C(N(CC)CC)C.CN(C)C=O>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:12][N:13]1[N:17]=[N:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:2]#[C:1][C:3]3([OH:11])[CH:8]4[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]4)[CH2:4]3)=[CH:22][CH:23]=2)=[N:14]1
Reactant: Cn1nnc(-c2ccc(Br)cc2)n1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (0.3 g), 2-methyl-5-(4-bromophenyl)tetrazole (0.48 g), bis(triphenylphosphine)-palladium (II) chloride (70 mg), copper (I) iodide (35 mg), triethylamine (1 ml) and dimethylformamide (2 ml) was stirred at 70° C. for 2 hours. The mixture was diluted with dichloromethane (4 ml) and filtered down a short column of silica (Varian Bond-sluts S1 silica) eluting with a gradient of 0:100 (v/v) to 100:0 (v/v) methanol/dichloromethane. The appropriate organic fractions were combined, washed with saturated aqueous sodium carbonate (3×30 ml), dried (Na2CO3) and evaporated to give 3-[2-(4-[2-methyl-tetrazol-5-yl]phenyl)ethynyl]-3-hydroxyquinuclidine (260 mg) as a solid, m.p. 228°-230° C.; microanalysis, found: C, 65.9; H, 6.1; N, 22.2%; C17H19N5O requires: C, 66.0; H, 6.2; N, 22.6%; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.7(4H,m), 2.8-3.2(2H,m), 4.4(3H,s), 5.6(1H,s), 7.6(2H,m), 8.05(2H,m); m/z 310(M+H).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C(O)(C)(C)C>C(O)(C)C>[C@H:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(C)O
Product: O[C@@H]1CCCc2ccccc21
Temperature: 60 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
General procedure for hydrogenation: Hydrogenation of 28 illustrates the typical reaction procedure: To a mixture of 1-tetralone, 28, (10.0 g, 66.4 mmol) and RuCl2[(2R,2′R,3S,3′S)-MeO-BIBOP](amqui), 27, (1.0 mg, 0.001 mmol, 0.002 mol %) was added isopropanol (40 mL) and a 1 M solution of t-BuOK in tert-butanol (1.33 mL, 1.33 mmol, 0.02 equiv). The autoclave reactor was first purged with nitrogen, then with hydrogen, and then the reaction mixture was stirred at 60° C. under 400 psi of hydrogen for 20 h. After venting the hydrogen gas, the solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography with ethyl acetate/hexane (0-50%) as eluent to give (R)-1,2,3,4-tetrahydro-1-naphthol, 29, (colorless oil, 9.6 g, 98% yield, 96:4 er). The er of 1,2,3,4-tetrahydro-1-naphthol was determined by HPLC analysis: column, Chiralcel OJ-3, 4.6×150 mm; eluent, heptane/isopropanol (95:5); flow rate, 1 mL/min; column temperature, 25° C.; retention time (tR) of (R)-1,2,3,4-tetrahydro-1-naphthol, 7.45 min (95.8%); tR of (S)-1,2,3,4-tetrahydro-1-naphthol, 5.75 min (4.2%). [α]D=−31.2 (c=2.0, MeOH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][P:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)(=[O:8])[CH2:4][CH2:3]1.[F:16][C:17]([F:23])([F:22])[S:18](N)(=[O:20])=[O:19]>CN(C=O)C>[F:16][C:17]([F:23])([F:22])[S:18]([O:15][C:12]1[CH:13]=[CH:14][C:9]([P:5]2(=[O:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:10][CH:11]=1)(=[O:20])=[O:19]
Reactant: CN1CCP(=O)(c2ccc(O)cc2)CC1
Reactant: NS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCP(=O)(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(1-Methyl-4-oxido-1,4-azaphosphinan-4-yl)phenol (0.50 g, 2.22 mmol) was made 0.5 M in DMF and N-Phenyl-bis(trifluorometanesulfonamide (1.19 g, 3.33 mmol) was added, followed by TEA (0.62 mL, 4.44 mmol). The mixture was stirred at ambient temperature for 16 h then the precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was purified by HPLC (20-95% MeCN in water w/0.025% TFA). Pure fractions were identified, combined and concentrated in vacuo. The residue was taken up in EtOAc and washed with saturated aqueous sodium bicarbonate (1×) then dried (MgSO4) and concentrated in vacuo to afford the requisite product as a freebase. MS: cal'd 358 (MH+), exp 358 (MH
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:21]([O:20][C:14](=[O:19])[CH2:15][CH:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)[CH3:18])[CH3:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (1 g, 5.37 mmol), ethyl acetoacetate (883 μl, 6.98 mmol) in DCM (30 ml) was stirred for 30 min at rt under nitrogen, then (2.4 g, 10.74 mmol) NaBH(OAc)3 was added. The reaction mixture was stirred at rt overnight, quenched by addition of water, stirred for 15 min and slowly diluted with a saturated aqueous solution of sodium bicarbonate (pH around 8-9). The reaction mixture was shaken for 1 h. After separation, the aqueous layer was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (Snap 50 g cartridge, MeOH/DCM: 0/100 to 5/95 over 20 CV, not UV active) to afford the desired product 513 (1.03 g, 3.43 mmol, 63% yield) as a colorless sticky oil. MS (m/z): 301.4 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=1
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(F)c2Cl)CC1
Temperature: 80 °C
Yield: 52.2 %

Procedure:
A mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (2, 1.18 g, 3.56 mmol), 2-chloro-3-fluorophenyl boronic acid (0.621 g, 3.56 mmol), Pd(PPh3)4 (0.411 g, 0.356 mmol) and 2 M Na2CO3 (20 mL) in DME (50 mL) was heated at 80° C. for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4×50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4-(2-chloro-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (12) as a clear oil (0.579 g, 52%): 1H NMR (300 MHz, DMSO-d6) δ 7.43-7.31 (m, 2H), 7.16-7.10 (m, 1H), 5.81-5.72 (m, 1H), 4.03-3.93 (m, 2H), 3.53 (t, J=5.7 Hz, 2H), 2.41-2.31 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[C:10](F)=[N:11][CH:12]=[C:13]([I:15])[CH:14]=1>C1COCC1>[Br:8][C:9]1[C:10]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[N:11][CH:12]=[C:13]([I:15])[CH:14]=1
Reactant: Fc1ncc(I)cc1Br
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cc(I)cnc1OCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in mineral oil, 4.32 g) in THF (300 mL) was added cyclopropylmethanol (5.83 g) at 0° C. and the mixture was stirred for 30 min at 0° C. A solution of 3-bromo-2-fluoro-5-iodopyridine (16.3 g) in THF (50 mL) was added to the suspension at 0° C. The suspension was allowed to warm to r.t. and stirred for 18 h. The suspension was poured into ice water and then extracted with EA (200 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by SGC (eluent: PE) to give the subtitle compound. MS ESI+: m/z=354 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(OCC)(=O)NN.[C:14](Cl)([Cl:16])=[O:15]>C(OCC)(=O)C>[CH3:6][O:5][C:1]([NH:2][NH:3][C:14]([Cl:16])=[O:15])=[O:4]
Reactant: COC(=O)NN
Reactant: O=C(Cl)Cl
Agent: CCOC(=O)NN
Solvent: CCOC(C)=O
Product: COC(=O)NNC(=O)Cl
Yield: 91.8 %

Procedure:
Example 1 was repeated but substituting methyl carbazate (50 g, 0.55 mole) for the ethyl carbazate and using phosgene (75 ml, 1.13 mole) in dry ethyl acetate as solvent. Solvent was removed under reduced pressure at a bath temperature <60° C. and the product was re-dissolved in ethyl acetate, filtered to remove insoluble material and recovered by evaporation of the solvent in vacuo, giving 2-methoxycarbonylhydrazinecarbonyl chloride (77 g, 92%) mp 55°-58° C. The ir spectrum was similar to that of 2-ethoxycarbonylhydrazinecarbonyl chloride.