Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH:15]=[CH2:16])=[CH:13][CH:14]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2]
Reactant: C=Cc1ccc(-c2ccc(OCC)c(F)c2F)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2ccc(CC)[se]2)c(F)c1F

Procedure:
1.50 g (4.77 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)-5-vinylselenophene are hydrogenated in 15 ml of ethyl acetate, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane:EtOAc=5:1). The further purification is carried out by recrystallisation from n-heptane. 2-(4-Ethoxy-2,3-difluorophenyl)-5-ethylselenophene is obtained as a colourless solid (m.p. 52° C.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][C:9]([OH:25])=[C:10]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34](OCC)=[O:35]>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:20][C:21]([F:22])([F:23])[F:24])[C:34](=[O:35])[CH2:33][O:25][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(NCC(F)(F)F)c(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(=O)N3CC(F)(F)F
Yield: 93.8 %

Procedure:
This compound was prepared by General Method 13 from 2-isopropyloxy-7-hydroxy-6-[(2,2,2-trifluoroethyl)amino]-4-(trifluoromethyl)quinoline (1.51 g, 4.10 mmol), K2CO3 (1.16 g, 8.40 mmol) and ethyl bromoacetate (0.719 g, 4.30 mmol) in 16.4 mL DMF to afford 1.57 g (94%) of 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one, a light yellow-brown solid, Rf 0.50 (4:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.57 (broad s, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 5.53 (hept, 1H, J=6.2), 4.79 (s, 2H), 4.71 (q, 2H, J=8.4), 1.41 (d, 6H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]=1[C:31](=[O:34])[CH2:32][Br:33])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Br:1])=[CH:19][C:18]=1[C:31](=[O:34])[CH2:32][Br:33])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(CBr)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
N-bromo succinimide (2.67 g, 0.015 mol) was added to a stirred solution of crude 1-(2,4-Bis-benzyloxyphenyl)-2-bromo-ethanone (ca. 6.16 g, 0.015 mol) in dimethylformamide (50 ml) and the mixture was stirred for 18 h. The mixture was concentrated to dryness, dissolved in dichloromethane (50 mL) and washed with (2×50 ml). The combined organic phases were dried over magnesium sulphate and concentrated to give 1-(2,4-Bis-benzyloxy-5-bromo-phenyl)-2-bromo-ethanone as a white solid, which was used without further purification.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1.[C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)[CH:40]=[CH:41][CH:42]=1)#[N:36]>>[C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)[CH:40]=[CH:41][CH:42]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(C#N)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(C#N)c4)cc3)cc2C1=O
Yield: 86 %

Procedure:
The compound of example 70 was prepared analogous to compound of example 52 by hydrolysis of compound of example 69.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([C:31]2[O:35][N:34]=[C:33]([CH:36]=O)[C:32]=2[C:38]([F:41])([F:40])[F:39])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Br:2][C:1]([Br:5])=[CH:36][C:33]1[C:32]([C:38]([F:39])([F:40])[F:41])=[C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:35][N:34]=1
Reactant: O=Cc1noc(-c2ccccc2)c1C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1c(C=C(Br)Br)noc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of carbon tetrabromide (12.24 g, 36.9 mmol) in dichloromethane (10 mL) at 0° C. was added a solution of triphenylphosphine (4.84 g, 18.5 mmol) in dichloromethane (10 mL), and the resulting mixture was stirred at 0° C. for 5 min. A solution of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde (Intermediate I-13B, 1.59 g, 4.62 mmol) in dichloromethane (10 mL) was added via syringe, and the reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was diluted with dichloromethane and washed with water. A white precipitate formed in the organic and was removed by vacuum filtrating. The filtrate was washed with a saturated aqueous solution of sodium bicarbonate, washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (1%-3%) to give 3-(2,2-dibromovinyl)-5-phenyl-4-(trifluoromethyl)isoxazole (1.21 g, 3.05 mmol, 66.0% yield) as a white solid. The product had an HPLC ret. time=3.10 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=397.9. 1H NMR (500 MHz, CDCl3) δ ppm 7.43 (s, 1H), 7.52-7.56 (m, 2H), 7.56-7.61 (m, 1H), and 7.74 (d, J=7.49 Hz, 2H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][O:8][N:9]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:11]#[N:12].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[Br:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10](=[N:9][O:8][CH3:7])[C:11]#[N:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CON=C(C#N)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CON=C(C#N)c1ccccc1CBr
Reaction time: 8 h
Yield: 76 %

Procedure:
Benzene (80 ml) was added to (-methoxyimino-2-methylphenylacetonitrile (isomer A)(4.0 g, 23 mmol) and N-bromosuccinimide (4.9 g, 28 mmol), and the mixture was heated under reflux for 1 hour in the presence of 2,2'-azobis(isobutyronitrile) (190 mg, 1.2 mmol) as a radical initiator. After allowing the mixture to stand for cooling, n-hexane (100 ml) was added, and the mixture was allowed to stand overnight, and the resulting insoluble materials were filtered off. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-bromomethyl-α-methoxyiminophenyl-acetonitrile (4.4 g, 76%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
N-(3-Methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-methoxybenzylamine using method N. NMR; δH [2H6]—DMSO 9.12,(1H, t), 8.00,(2H, d), 7.90,(1H, dd), 7.76,(1H, d), 7.56-7.51,(3H, m), 7.24,(1H, t), 6.90,(2H, m), 6.83,(1H, dd), 4.48,(2H, d), 3.73,(3H, s), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.34 min, MH+ 414.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:35][N:34]=[N:33][N:32]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[N:35]([CH3:36])[N:34]=[N:33][N:32]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5nnn[nH]5)c4)cc3C2)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: Cn1nnnc1-c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
A suspension of N-(3-tert-butylphenyl)-7-{[2-(1H-tetrazol-5-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.075 g, 0.16 mmol), potassium carbonate (0.11 g, 0.80 mmol), and methyl iodide (0.019 mL, 0.30 mmol) in acetone (8 mL) was allowed to stir at 0° C. for 10 min. The reaction mixture was allowed to warm to rt, diluted with water, and extracted with EtOAc. The organic solution were combined and concentrated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-{[2-(1-methyl-1H-tetrazol-5-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (9.3 mg) I-321 [1H NMR (400 MHz, d6-DMSO, HCOOH salt) δ: 9.94 (s, 1H), 8.67 (d, 1H), 7.63 (t, 1H), 7.57 (d, 1H), 7.49 (d, 1H), 7.27 (d, 1H), 7.18-7.22 (m, 2H), 7.04-7.07 (m, 2H), 6.99-7.02 (m, 1H), 3.31 (s, 3H), 2.73-2.96 (m, 5H), 2.08-2.12 (m, 1H), 1.79-1.83 (m, 1H), and 1.25 (s, 9H), LCMS: (FA) ES+ 484.0, ES− 482.0] and N-(3-tert-butylphenyl)-7-{[2-(2-methyl-2H-tetrazol-5-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (10.6 mg) I-334. [1H NMR (400 MHz, d6-DMSO, HCOOH salt) δ: 9.95 (s, 1H), 8.60 (d, 1H), 7.63 (t, 1H), 7.47-7.50 (m, 2H), 7.18-7.20 (m, 2H), 7.10 (dd, 1H), 7.05-7.07 (m, 2H), 6.98 (d, 1H), 3.31 (s, 3H), 2.74-2.95 (m, 5H), 2.07-2.12 (m, 1H), 1.77-1.82 (m, 1H), and 1.25 (s, 9H), LCMS: (FA) ES+ 484.0, ES− 482.0].
Reaction SMILES: C[O-].[Na+].C(OP([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(OCC)=O)C.[CH2:18](/[C:20](=[CH:23]\[CH3:24])/[CH:21]=O)[CH3:19].O>CO.C1(C)C=CC=CC=1>[CH2:23](/[C:20](=[CH:18]\[CH3:19])/[CH:21]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:24]
Reactant: C/C=C(/C=O)CC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: C/C=C(/C=C/C(=O)OCC)CC
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 12.7 kg (235 mol) of sodium methoxide and 48.0 kg (214 mol) of ethyl diethylphosphonoacetate in 40 l of methanol is added dropwise 20 kg (204 mol) of 2-ethylcrotonaldehyde at 20°-30° C. during 0.5 hour. After stirring for 2 hours at same temperature, the reaction mixture is poured into the solution of 180 l of water and 120 l of toluene. The toluene layer is separated and combined with 50 l toluene extract of aqueous phase, and washed with two 120 l portions of saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent is removed and the residue is distilled under reduced pressure to give ethyl (E,E)-4-ethyl-2,4-hexadienoate (Yield 28.5 kg) (83.1%), b.p. 41°-75° C./5-8 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13]C)=[O:12])[CH2:8][CH2:7][N:6]1[C:15]([O:17][CH3:18])=[O:16].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][N:6]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccccc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccccc1F
Yield: 76.2 %

Procedure:
Dimethyl 2-(2-fluorobenzyl)piperidine-1,4-dicarboxylate (6.16 g, crude) was dissolved in acetonitrile (45 mL) and water (0.9 mL). Lithium bromide (13.84 g, 159.39 mmol) and triethylamine (11.05 mL, 79.69 mmol) were added and the mixture was heated at reflux overnight. Water (90 mL) and MTBE were added. The organic phase was extracted with water (×2). To the pooled aqueous layer was added MTBE and the solution was acidified to pH 1 with 2 M HCl and then extracted with MTBE (×2). The combined organic layer was dried over Na2SO4 and evaporated to give 2-(2-fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.48 g, 76%) as a slightly yellow semisolid. MS m/z 296 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=1.CCN(C(C)C)C(C)C.[CH2:24]([NH:26][C:27]([N:29]1[N:33]=[CH:32][C:31]2([CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30]1)=[NH:28])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:12])(=[O:11])[N:28]=[C:27]([N:29]2[N:33]=[CH:32][C:31]3([CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:30]2)[NH:26][CH2:24][CH3:25])[CH:5]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=NS(=O)(=O)c1cccc(C(=O)OC)c1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 4.07 g 3-chlorosulfonyl-benzoic acid methyl ester in 150 mL DCM were added 17.69 mL (6.0 equiv.) DiPEA and 4.00 g (1.0 equiv.) N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine. The reaction mixture was stirred overnight at room temperature under N2 atmosphere, and extracted with water. The organic phase was dried over Na2SO4 and evaporated, and the residue was purified by automated flash chromatography (EtOAc/PA 1:1) to give 4.80 g (71%) of a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=8 Hz, 3H), 1.62-1.86 (m, 8H), 3.42-3.53 (m, 2H), 3.87 (s, 2H), 3.95 (s, 3H), 6.83 (s, 1H), 6.83-6.95 (broad peak, 1H), 7.56 (t, J=8 Hz, 1H), 8.13-8.18 (m, 2H), 8.61 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[CH3:26])=[C:9]([CH3:28])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BH4-].[Na+]>CO>[OH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17]2[CH:16]=[CH:15][C:14]([CH3:26])=[C:13]([CH:18]=2)[C:12]([NH:11][C:10]2[C:2]([CH3:1])=[C:3]([CH:7]=[CH:8][C:9]=2[CH3:28])[C:4]([OH:6])=[O:5])=[O:27])[CH2:20][CH2:21]1
Reactant: Cc1ccc(N2CCC(=O)CC2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N2CCC(O)CC2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 2,4-dimethyl-3-[[2-methyl-5-(4-oxo-1-piperidyl)-benzoyl]amino]benzoic acid (51 mg, 134.05 μmoles) in methanol (1.34 ml) is added sodium tetrahydroborate (10.14 mg, 268.11 μmoles) and the mixture is stirred at ambient temperature. After 1 hour, the mixture is quenched and adjusted to pH7 with saturated solution of NH4Cl and extracted twice with CHCl3 (3 ml):IPA (1 ml). The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid is re-dissolved in 3:1 CHCl3:IPA and diluted with HCl to pH2 and extracted with 3:1 CHCl3:IPA. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is taken up in MeOH and filtered through cotton plug. The filtrate is concentrated under reduced pressure followed by dissolution in H2O and lyophilized for 12 hours to afford the title compound as an off-white powder (0.04 g, 81.9%). Mass spectrum (m/z): 383.2 (M+1).
Reaction SMILES: [CH:1]([C@@H:14]1[N:19]2[CH2:20][CH2:21][N:22](C(OCC3C=CC=CC=3)=O)[CH2:23][C@@H:18]2[CH2:17][N:16]([CH2:34][C:35]2[CH:40]=[C:39]([N:41]3[C:45]([C:46]([F:49])([F:48])[F:47])=[N:44][N:43]=[N:42]3)[CH:38]=[CH:37][C:36]=2[O:50][CH3:51])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[ClH:59]>O1CCCC1.ClCCl.C(OCC)(=O)C.[Pd]>[ClH:59].[ClH:59].[ClH:59].[CH:1]([C@@H:14]1[N:19]2[CH2:20][CH2:21][NH:22][CH2:23][C@@H:18]2[CH2:17][N:16]([CH2:34][C:35]2[CH:40]=[C:39]([N:41]3[C:45]([C:46]([F:49])([F:48])[F:47])=[N:44][N:43]=[N:42]3)[CH:38]=[CH:37][C:36]=2[O:50][CH3:51])[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@H]2CN(C(=O)OCc3ccccc3)CCN2[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@H]2CNCCN2[C@@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
(4S,9aS)-4-Benzhydryl-8-benzyloxycarbonyl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine (187 mg) was dissolved in tetrahydrofuran (2 ml), and triethylamine (0.0747 ml) was added to it at room temperature. The solution was hydrogenated over 10% palladium-charcoal (50% wet, 40 mg) at room temperature under atmospheric pressure for 2 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give colorless syrup. The resulting residue was purified by column chromatography on silica gel (7 g) using a mixed solvent of dichloromethane and methanol (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a syrup. To a solution of the syrup in dichloromethane (2 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (0.050 ml), and triturated with diisopropyl ether. The precipitate was collected by filtration and dried under reduced pressure for 5 hours at 40° C. to give (4S,9aR)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine trihydrochloride (154 mg) as a colorless powder.
Reaction SMILES: C(Cl)(=O)C.[C:5]([CH:7]([CH:12]([C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])[CH2:13][C:14](OC)=[O:15])[C:8]([O:10][CH3:11])=[O:9])#[N:6].[H][H].C(=O)([O-])[O-].[K+].[K+].C[Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1.C(OCC)C.CO.[Pt](=O)=O.CO>[CH3:11][O:10][C:8]([C@H:7]1[C@H:12]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:13][C:14](=[O:15])[NH:6][CH2:5]1)=[O:9]
Reactant: COC(=O)CC(c1cc(F)c(F)cc1F)C(C#N)C(=O)OC
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CNC(=O)C[C@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 450 mL of methanol at 0° C. was carefully added 30 mL of acetyl chloride and the resulting solution was allowed to stir at ambient temperature for 30 min. The resulting solution was added to 27 g (86 mmol) of dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate from Step B and the reaction mixture was then shaken with 5.0 g of platinum (IV) oxide under 50 psi of hydrogen for 20 h. The mixture was filtered through a pad of Celite and the filter cake washed with methanol and dichloromethane. The combined filtrate and washings were concentrated and then taken up in 400 mL of 1:1 methanol/toluene with potassium carbonate (28 g, 200 mmol). The resulting mixture was heated to reflux for 4 h, then cooled to 0° C. and carefully quenched with 1N hydrochloric acid until the solution was acidic by pH paper. The resulting mixture was then extracted with six 300-mL portions of 3:1 chloroform/isopropyl alcohol and the organic phases combined and washed with saturated aqueous brine (300 mL). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a colorless solid. This crude material was dissolved in 500 mL of 1:1 diethyl ether/methanol and cooled to 0° C. To this solution was added 75 mL (150 mmol) of trimethylsilyldiazomethane solution (2M in hexanes) in portions until a yellow color persisted. After warming to ambient temperature, the solution was stirred an additional 2 h, then concentrated in vacuo. The title compound was collected as a colorless crystalline solid which was used without further purification. LC/MS 288.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].[F:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:28]([NH:27][C:25](=[O:26])[C:24]2[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:23]=2[F:22])=[O:29])[C:10]=1[CH2:11][CH3:12]
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)NC(=O)c2c(F)cccc2F)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 18 h

Procedure:
A solution of the amine of Example 43 (6.5 mg, 20 μmol) in dimethylformamide (250 μL) was treated with 2,6-difluorobenzoylisocyanate (4.0 mg, 22 μmol) and the mixture was shaken for 18 hours. The reaction mixture was filtered and the filtrate was purified by HPLC (Hypersil Thermoquest Luna C8 150×10 mm column; a gradient mobile phase was used, 10:90 (by volume)→95:5 (by volume) acetonitrile:(water, 95% by volume/trifluoroacetic acid, 0.1% by volume/acetonitrile 5%, by volume)).
Reaction SMILES: Cl.[CH:2]1([CH2:5][C:6](=[NH:8])[NH2:7])[CH2:4][CH2:3]1.C[O-].[Na+].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:28](OC)=[O:29])=[CH:22][CH:21]=1)#[N:13]>CO>[CH2:33]([C:32]1[N:8]=[C:6]([CH2:5][CH:2]2[CH2:4][CH2:3]2)[NH:7][C:28](=[O:29])[C:27]=1[CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([C:12]#[N:13])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:25][CH:24]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: N=C(N)CC1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CC2CC2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 75.6 %

Procedure:
A solution of 2-cyclopropylethanimidamide hydrochloride (3.9 g), 28% sodium methoxide (8.7 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (5.0 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (4.3 g, 76%) as a pale-yellow solid.