Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[C:21]([N:23](C)C)=O>O.[C-]#N.[Zn+2].[C-]#N.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>[C:21]([C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)#[N:23]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1cc2c([nH]1)CCC2c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(3-bromophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.103 g, 0.32 mmol) was combined with zinc cyanide (0.046 g, 0.39 mmol) and dissolved in dimethyl acetamide (3 mL). Then the solution was evacuated and back-flushed with N2 four times and sparged with N2 for an additional 5-10 min. Tetrakis(triphenylphosphine)palladium(0) (0.091 g, 0.08 mmol) was added and the reaction placed in a preheated (85° C.) heating block and stirred for 2 hour. The reaction was then cooled to room temperature and diluted with aqueous H2O (40 mL) and extracted three times with ethyl acetate. The organic layer was washed once with brine, then dried over Na2SO4. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane afforded the title compound. 0.021 g. LCMS-MS (ESI+) 289.2 (M+Na).
Reaction SMILES: [CH3:1][C@@:2]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=1.[Br-].[Li+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[OH:10][C:8]1[CH:9]=[C:4]([CH2:3][C@@:2]([CH3:1])([C:12]([O:14][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])[NH2:15])[CH:5]=[CH:6][C:7]=1[OH:11]
Reactant: C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: BrCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 85 %

Procedure:
In a manner similar to that described in Example I, 1.05 grams (0.005 mole) of α-methyldopa, 0.88 gram (0.010 mole) of lithium bromide, 0.5 gram of powdered 4A sieves, 0.98 gram (0.0057 mole) of benzyl bromide and 5.0 grams of N-methylpyrrolidinone were stirred for 65 hours at 25° C. At the end of this period, high pressure liquid chromatographic assay showed an 85 percent yield of the desired benzyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate product.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18](CO)=[CH:17][CH:16]=1)[C:3]([N:5]([CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)=[O:4].[ClH:23].CCCCCC.[CH:30]([Cl:33])(Cl)Cl>>[CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([CH2:30][Cl:33])=[CH:17][CH:16]=1)[C:3]([N:5]([CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:23])=[CH:8][CH:7]=1)=[O:4]
Reactant: CN(C(=O)N(C)c1ccc(CO)cc1)c1ccc(CO)cc1
Reactant: Cl
Reactant: ClC(Cl)Cl
Solvent: CCCCCC
Product: CN(C(=O)N(C)c1ccc(CCl)cc1)c1ccc(CCl)cc1

Procedure:
A solution of 10 g N,N'-dimethyl-N,N'-bis(p-hydroxymethylphenyl) urea in 250 ml CHCl3 was stirred vigorously for two hours with 250 ml conc. HCl. The layers were separated, and the organic phase was washed with dilute HCl, dried, and stripped to give a yellow oil. Trituration with hexane caused the product to crystallize. Filtration, washing with hexane, and air drying gave 3.5 g of a fluffy-white crystalline solid which was pure by TLC, m.p. 72°-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CCO
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.8 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), ethanol (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml ethanol. The cis to trans ratio is 82 to 85/18 to 15. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.80 to 0.82%].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].Cl.[C:16]1([CH:22]2[O:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:25][NH:24][C:23]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:30]2[CH2:29][CH2:28][C:26]3([CH2:25][NH:24][C:23](=[O:33])[CH:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:27]3)[CH2:32][CH2:31]2)=[O:11])=[CH:7][C:6]=1[CH3:14])([CH3:2])[CH3:3]
Reactant: O=C1NCC2(CCNCC2)OC1c1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCC3(CC2)CNC(=O)C(c2ccccc2)O3)ccc1OC(C)C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
To 4-isopropoxy-3-methyl-benzoic acid (114 mg, 0.59 mmol), 4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one hydrochloride salt (166 mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol) in DMF (0.5 mL) was added diisopropylethylamine (228 mg, 307 μL, 1.76 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo, diluted with methanol and purified by prep LCMS (1-99% ACN/H2O, 5 mM HCl modifier) to give 3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one (100 mg, 40%) as a yellow foam. ESI-MS m/z calc. 422.2. Found 423.5 (M+1)+; Retention time: 1.61 minutes (3 min run).
Reaction SMILES: [CH2:1]([C:4]([O:15][CH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([O:23][CH2:24][O:25][CH3:26])[CH2:18]1)([CH2:12][CH:13]=[CH2:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])C=C.CCCCCCC.C(OCC)(=O)C>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:26][O:25][CH2:24][O:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([CH2:16][O:15][C:4]2([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:1][CH2:14][CH2:13][CH2:12]2)[CH2:18]1
Reactant: C=CCC(CC=C)(OC[C@H]1CCC[C@@H](OCOC)C1)C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: COCO[C@@H]1CCC[C@H](COC2(C(=O)OC(C)(C)C)CCCC2)C1
Temperature: 40 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
140 mg of tert-butyl 2-allyl-2-(cis-3-methoxymethoxycyclohexylmethoxy)pent-4-enoate are dissolved in 5 ml of dichloromethane, 10 mg of Grubbs catalyst (Cl2(Cy3P)2Ru═CHPh) are added under an Ar atmosphere and the mixture is stirred at 40° C. for 48 h. 10 ml of heptane/ethyl acetate (3/1) are added and the solution is filtered through silica gel. This gives 100 mg of tert-butyl 1-(cis-3-methoxymethoxy-cyclohexylmethoxy)cyclopent-3-enecarboxylate as a brown oil. This is dissolved in 2 ml of MeOH, degassed and saturated with Ar. 30 mg of Pd/C (10%) are then added, and the mixture is degassed again. The solution is saturated with hydrogen and stirred at room temperature overnight. Dilution with 20 ml of ethyl acetate and filtration through Celite give 100 mg of crude tert-butyl 1-(cis-3-methoxymethoxycyclohexylmethoxy)cyclopentane-carboxylate. This is taken up in 2 ml of tetrahydrofuran, 0.5 ml of HCl (conc.) is added and the mixture is stirred at room temperature overnight. The solution is neutralized with saturated NaHCO3 solution and extracted three times with ethyl acetate. The organic phases are dried over MgSO4 and concentrated. Chromatography of the residue on silica gel (heptane/ethyl acetate 10/1->1/1) gives 57 mg of tert-butyl 1-(cis-3-hydroxycyclohexylmethoxy)cyclopentanecarboxylate as a yellow oil. For the next step, this is used in crude form.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35][N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:40])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (77 mg, 0.3 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (112 mg, 0.36 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (61 mg).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][O:15][C:14]2=[O:26])=[O:12])=CC=1)([O-])=O.C(OC(=O)[N:33]([CH:40]1[CH2:45][CH2:44][C:43]([C:52]#[N:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(C)(C)C.CCCCCC.CCOC(C)=O>C1COCC1>[F:25][C:20]1[CH:19]=[C:18]([CH:17]2[CH2:16][O:15][C:14](=[O:26])[N:13]2[C:11]([N:37]2[CH2:36][CH2:35][CH:34]([NH:33][CH:40]3[CH2:41][CH2:42][C:43]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:52]#[N:53])[CH2:44][CH2:45]3)[CH2:39][CH2:38]2)=[O:12])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N(C1CCNCC1)C1CCC(C#N)(c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC1(c2ccccc2)CCC(NC2CCN(C(=O)N3C(=O)OCC3c3ccc(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (80 mg, 0.21 mmol) in 5 ml of THF was added (4-cyano-4-phenyl-cyclohexyl)-piperidin-4-yl-carbamic acid tert-butyl ester (150 mg, 0.40 mmol) in a portion and the resulting solution was stirred for 12 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow oil, which was subjected to column chromatography (50% Hexane/EtOAc) to provide the tert-butyl ester of the desired product as a colorless oil. The product obtained was dissolved in 5 ml of EtOAc and 1 ml of 1N HCl-Et2O to afford a white solid of the product as the HCl salt: mp 181-192 C; Anal. Calc. For C27H28F2N4O3.1.0HCl requires C, 61.70; H, 5.73; N, 10.28. Found: C, 59.48; H, 5.41; N, 10.34.
Reaction SMILES: [C:1]1([S:7]([N:10](S(C2C=CC=CC=2)(=O)=O)[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.Cl>CO.CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cnc2ccc(N(S(=O)(=O)c3ccccc3)S(=O)(=O)c3ccccc3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1cnc2ccc(NS(=O)(=O)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 6-[bis(phenylsulfonyl)amino]quinoline-3-carboxylate (0.29 g, 0.601 mmol) in methanol (2.4 mL) was added a 1 M solution of sodium hydroxide in H2O (2.4 mL, 2.4 mmol). N,N-dimethylformamide (1 mL) was added to aid solubility and the resulting suspension was stirred at room temperature for 48 h. The reaction was then warmed to 60° C. and stirred for 96 h. A solution of hydrochloric acid (1.0 M in water) was added until pH=7. The mixture was extracted with ethyl acetate three times. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure and used as obtained (Int-12, 0.201 g, 61%). LC-MS: (FA) ES+ 329.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][CH3:16])[C:9]=1[O:10]COC)[CH:5]=[O:6].[C:17]([Cu])#[N:18].CCOC(C)=O>CN(C=O)C>[CH2:15]([O:14][C:8]1[C:9]([OH:10])=[C:2]([CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1)[C:17]#[N:18])[CH3:16]
Reactant: CCOc1cc(C=O)cc(Br)c1OCOC
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(C#N)c1O
Temperature: 180 °C
Yield: 49.8 %

Procedure:
A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg, 2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180° C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of the starting material was consumed. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the 3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9](N)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][N:7]2[N:8]=1
Reactant: Br
Reactant: Nc1nc2cccc(Br)n2n1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1nc2ccccn2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
2-Bromo-[1,2,4]triazolo[1,5-a]pyridine. A suspension of [1,2,4]triazolo[1,5-a]pyridin-2-amine (0.500 g, 3.73 mmol, obtained from pyridin-2-amine following an analogous procedure as the one described for 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine) in 48% HBr (5 mL) was cooled to 0° C. and slowly treated with a solution of sodium nitrite (0.386 g, 5.59 mmol) in water (2 mL) resulting in a dark brown suspension with brown gas evolution. The mixture was stirred for 1 h. A dark purple solution of copper(I) bromide (0.642 g, 4.47 mmol) in 48% HBr (2 mL) was added and the reaction mixture was stirred overnight at room temperature. The purple suspension was poured into water (15 mL) and the resulting yellow-orange suspension was collected and dried to give an orange solid which was further purified by column chromatography (eluting with 100% dicholomethane) to afford 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (0.455 g, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.96 (dt, 1H), 7.81-7.91 (m, 1H), 7.68-7.79 (m, 1H), 7.27 (td, J=1.37, 6.93 Hz, 1H); MS (ESI) m/z 197.9 [M]+and 200.1 [M+2]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].CN(C)C=O>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:21][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(C#N)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(-c3nnn[nH]3)cc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 3.4 g of 4-methyl-N-[4-(4-cyanophenoxy)butyl]benzenesulfonamlde (Example 53), 1.3 g of sodium azide, 1.5 g of ammonium chloride, and 25 ml of dimethylformamide is stirred at 120°-130° C. (oil bath) for 16 hours. The reaction mixture is added to 200 ml of water and the resultant solution then acidified to pH 4-5 with acetic acid. The precipitate that forms is collected, washed with water, dried and recrystallized from boiling ethanol. Cooling gives the pure compound, m.p. 180°-182° C.; yield, 2.4 g.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH:16]1[CH2:18][CH2:17]1.O.O.[Cl:21][Sn]Cl>O.Cl.CC(O)=O>[ClH:21].[CH:16]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:7]=2[NH:6][NH2:1])[C:11]([OH:13])=[O:12])[CH2:17][CH2:18]1
Reactant: Nc1ccc(C(=O)O)cc1C1CC1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NNc1ccc(C(=O)O)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
A solution of 0.38 g of NaNO2 in 4.5 ml of water is added slowly to a solution, cooled to -5° C., of 0.95 g of the product obtained in step C in 22 ml of concentrated HCl and 21 ml of AcOH, and the mixture is stirred for 1 h 15 min at 0° C. It is cooled to -10° C., and a solution of 3.76 g of SnCl2.2H2O in 8 ml of concentrated HCl is added slowly. After 4 hours of stirring at RT, the mixture is filtered, and the residue is washed with 2 ml of concentrated HCl and dried under vacuum to obtain 1 g of expected product.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>C(#N)C.C(OCC)(=O)C>[C:3]1([C@@H:2]([NH:9][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: C[C@H](N)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (S)-α-methylbenzylamine (3.87 mL, 0.03 mol) in acetonitrile (50 mL) was added diisopropylethylamine (5.23 mL, 0.03 mol), followed by methyl bromoacetate (2.84 mL, 0.03 mol). The reaction was stirred under nitrogen, at room temperature, overnight. The solution was concentrated and the residue partitioned between ethyl acetate and saturated NaHCO3. The aqueous layer was separated, and the product extracted three times with ethyl acetate. The ethyl acetate solutions were combined, washed three times with brine, dried over MgSO4, and concentrated to give a light yellow liquid. Chromatography was carried out on silica gel, using ethyl acetate as eluent, to give a colorless liquid; 4.97 g (86% yield). MS-APCI: M+1=194.2.
Reaction SMILES: [ClH:1].Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:48](=O)([O:57]C1C=CC([N+]([O-])=O)=CC=1)[O:49][CH:50]([O:53][C:54](=[O:56])[CH3:55])[CH2:51][CH3:52]>CN(C)C=O>[ClH:1].[C:54]([O:53][CH:50]([O:49][C:48]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:57])[CH2:51][CH3:52])(=[O:56])[CH3:55]
Reactant: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Reactant: CCC(OC(C)=O)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(CC)OC(C)=O)CC3)CC2=O)cc1

Procedure:
The title compound was prepared in a yield of 115 mg (100%) as a free base from 101 mg of ethyl 4-[[2-oxo-4-(piperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in the same manner as in Example 8 except that N,N-dimethylformamide, proton sponge and 1-acetoxypropyl 4-nitrophenyl carbonate were used in an amount of 2 ml, 101 mg and 82.8 mg, respectively.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:24]([CH:31]4[CH2:33][CH2:32]4)[CH2:25][C:26]([O:28]CC)=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:12][C:11]=2[C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO.C1COCC1>[C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:24]([CH:31]4[CH2:33][CH2:32]4)[CH2:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:12][C:11]=2[C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(C)(C)C)o3)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2-c2nnc(C(C)(C)C)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of ethyl 3-(3-(((2-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)-3-cyclopropylpropanoate (115 mg) in methanol (1.0 mL) and THF (1.0 mL) was added 1N aqueous sodium hydroxide solution (0.60 mL), and the mixture was stirred at room temperature for 2 hr. Water and 1N hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (62 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[CH:14]1[CH:19]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:15]=1.[C:33]([O-])([O-])=O.[K+].[K+].N#N>COCCOC.CC(=O)OCC.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>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH:11]=[C:14]([CH3:19])[CH3:15])[N:8]=[C:7]([CH3:33])[CH:6]=1)[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1cc(C)nc(C=C(C)C)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of 2-chloro-6-methylisonicotinic acid ethyl ester (9.92 g, 49.7 mmol), 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (13.0 g, 49.7 mmol, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971), and PPh3 (1.39 g, 8.60 mmol) in DME (120 mL), a solution of 2 M aq. K2CO3 (40 mL) is added. The mixture is degassed and flushed with N2 before Pd(PPh3)4 (580 mg, 0.793 mmol) is added. The mixture is stirred at 100° C. for 20 h before it is cooled to rt, diluted with EA and washed with sat. aq. NaHCO3 (2×200 mL). The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 15:1 to give 2-methyl-6-(2-methyl-propenyl)-isonicotinic acid ethyl ester (9.90 g) as a yellow oil; LC-MS: tR=0.44 min, 1H NMR (CDCl3): δ 1.43 (m, 3 H), 1.98 (s, 3 H), 2.09 (s, 3 H), 2.63 (s, 3 H), 4.34-4.46 (m, 2 H), 6.39 (s, 1 H), 7.50 (s, 1 H), 7.56 (s, 1 H).