Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH:22]=[O:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:24][Mg]Br.CCOCC>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([CH:22]([OH:23])[CH3:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine-4-carbaldehyde (described in Example 1, Step 3) (0.20 g, 0.60 mmol) was dissolved in tetrahydrofuran (6.00 mL) and was cooled to −78° C., then 3.0 M methylmagnesium bromide in ether (0.30 mL, 0.90 mmol) was added. The reaction was stirred at −78° C. for 1 hour at which time LCMS analysis showed that it was mostly done. The reaction was quenched with sat. NH4Cl and was and partitioned between water and EtOAc, the phases were separated and the aqueous phase was washed with additional EtOAc. The combined organic phase was washed with water, then sat. NaCl, dried over MgSO4 and filtered and then the solvent removed in vacuo to leave the crude product. The crude material used in the next reaction without purification. MS: 371 (M+Na+), 349 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20]I)[CH3:18]>CN1CCCC1=O>[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCCCC(CC)CI
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCC(CC)COc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 43 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added 4-nitrophenol (27.14 grams, 0.195 moles), potassium carbonate (51.13 grams, 0.370 moles), 2-ethylhexyl iodide (45.63, 0.185 moles) in 1-methyl-pyrrolidin-2-one(180 ml). The contents of the flask were heated at 100° C. for 3 hours; cooled to room temperature; partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×100 ml). The ethyl acetate extract was washed with a 1 N sodium hydroxide solution (4×75 ml), brine (3×100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 29.9 grams of crude product as a yellow oil. Excess 2-ethylhexyl iodide was removed from the product using Kugelrohr distillation apparatus to afford 20 grams of pure product as a yellow oil. 1H NMR (CDCl3) δ 8.2(d, 2H), 6.95(d, 2H), 3.95(d, 2H), 1.75(heptet, 1H), 1.2-1.6(m, 8H), 0.85-1.0(m, 6H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[N:24]=1>>[CH3:30][O:29][C:25]1[N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(Cl)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: COc1cccc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-6-methoxy-pyridine. MS (ESI): mass calculated for C23H23N3O2S, 405.52; m/z found 406.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.56-7.47 (m, 1H), 7.46-7.30 (m, 4H), 7.25-7.12 (m, 2H), 7.09-6.90 (m, 1H), 6.01 (d, J=7.6, 1H), 5.77 (br s, 1H), 3.85 (s, 3H), 3.71-2.59 (m, 10H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18]O>>[CH3:18][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: CO
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 90.9 %

Procedure:
A total of 181.5 g (0.825 mol) of 3,5-diphenylpyrazole and 791 g (24.7 mol) of methanol was used. A total of 175.8 g (91%) of 1-methyl- 3,5-diphenylpyrazole was obtained. The holdup of the bubble column was not taken into account.
Reaction SMILES: [CH3:1][C@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@@H:15]1[CH2:14][C@H:13]1[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:12]1[CH2:11][CH2:10][C:9](=[O:20])[CH2:8]3)[CH2:3]2.CCC(C)[BH-](C(C)CC)C(C)CC.[K+].[OH-].[Na+].OO>C1COCC1>[OH:20][C@H:9]1[CH2:8][C@H:7]2[C@@H:12]([C@@H:13]3[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@@:2]2([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16][C@@H:15]2[CH2:14]3)[CH2:11][CH2:10]1
Reactant: C[C@@]12C[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@]12C[C@@H]3CC[C@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of compound 38 (570 mg, 2.1 mmoL) in THF (20 mL) was added K-selectride (2.6 mmol, 2.6 mL, 1.0 M in THF) at −78° C. After 3 h, aqueous 10% NaOH (30 mL) and 30% H2O2 (20 mL) were added at −78° C. After addition, the reaction was warmed up to room temperature for 1 h. The product was extracted into EtOAc (50 mL×3), and the combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 39 (456 mg, 80%) as a white solid: mp 143-145° C., [α]D25 −41.0 (c 0.19, CHCl3); 1H NMR (CDCl3) δ 3.95-3.90 (m, 1H), 0.75 (s, 3H); 13C NMR (CDCl3) δ 220.8, 65.8, 48.1, 47.5, 46.9, 45.4, 40.2, 39.1, 37.8, 35.8, 35.4, 33.8, 33.7, 32.5, 28.1, 23.8, 23.1, 13.3; IR νmax 3422, 1737 cm−1; Anal. Calcd for (C18H25O2): C, 78.21; H, 10.21. Found: C, 78.29; H, 10.43.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:21]1([N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[N:17]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(COc2ccc(Nc3ccn(-c4ccccc4)n3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Yield: 55.7 %

Procedure:
A suspension of N-(4-benzyloxyphenyl)-1-phenyl-1-H-pyrazol-3-amine (3.17 g) in ethanol (600 ml) was hydrogenated at atmospheric pressure over 10% palladium on carbon until hydrogen uptake ceased. The reaction mixture was filtered and solvent was evaporated. The resulting solid was recrystallised from ether: petroleum ether to give the title compound (1.3 g) mp 147°-148°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:14][C:15]#[N:16]>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([CH2:14][C:15]#[N:16])[CH2:11][CH2:12]1
Reactant: N#CCBr
Reactant: C1COC(CN2CCNCC2)C1
Product: N#CCN1CCN(CC2CCCO2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(Tetrahydro-furan-2-ylmethyl)-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=210.2.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].N[CH2:35][C@@H](O)C.CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: C[C@H](O)CN
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 57 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (S)-(+)-1-amino-2-propanol (0.16 mL 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (387.8 mg, 57%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=1.6 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.92 (m, 1H), 3.32 (m, 2H), 2.19 (s, 3H), 1.18 (d, 3H, J=6.4 Hz); ES-HRMS m/z 508.0661 (M+H C22H21BrF2N3O4 requires 508.0678).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[C:29]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=3)[CH:25]=[CH:24][CH:23]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:4][CH:3]=1.I[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[C:29]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=3)[CH:25]=[CH:24][CH:23]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: Cc1ccc(N(c2cccc(N)c2)c2ccc3ccc4cccc5ccc2c3c45)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N(c2ccc(C)cc2)c2cccc(N(c3ccc(C)cc3)c3ccc4ccc5cccc6ccc3c4c56)c2)cc1
Reaction time: 10 h

Procedure:
A mixture of 2.79 g (7.00 mmol) of N-(4-methylphenyl)-N-(3-aminophenyl)-1-pyrenylamine synthesized in Synthesis Example 2, 15.3 g (70.0 mmol) of 4-iodotoluene, 3.87 g of potassium carbonate, and 0.44 g of copper powder was subjected to azeotropic dehydration in a stream of nitrogen, using an ester tube, with stirring, at 209° to 212° C. for 10 hours.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:51])[C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]5[N:33]=[CH:34][C:35]6[N:41]([CH3:42])[C:40](=[O:43])[C:39]([F:45])([F:44])[CH2:38][N:37]([CH:46]7[CH2:49][CH2:48][CH2:47]7)[C:36]=6[N:50]=5)=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]3[N:33]=[CH:34][C:35]4[N:41]([CH3:42])[C:40](=[O:43])[C:39]([F:44])([F:45])[CH2:38][N:37]([CH:46]5[CH2:47][CH2:48][CH2:49]5)[C:36]=4[N:50]=3)=[CH:27][CH:26]=2)=[O:51])[CH2:20][CH2:19]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)N4CCC(NC(=O)OCC5c6ccccc6-c6ccccc65)CC4)cc3)ncc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)N4CCC(N)CC4)cc3)ncc21
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A mixture of 0.220 g (0.31 mmole) of {1-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoyl]-piperidin-4-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester, 1 mL of piperidine and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 0.038 g of 2-[4-(4-amino-piperidine-1-carbonyl)-phenylamino]-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-15).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]([OH:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](I)[CH2:31][CH2:32][CH3:33]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:27])[C:16]([O:26][CH2:30][CH2:31][CH2:32][CH3:33])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCI
Reactant: CC(C)C(O)(C(=O)NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCOC(C(=O)NC1CCN(Cc2ccccc2)CC1)(c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-benzyl-4-piperidinyl)-2-hydroxy-3-methyl-2-phenylbutanamide (20.0 g) in DMF (200 ml) was added sodium hydride (9.0 g). The resulting mixture was stirred at room temperature for one hour, followed by the dropwise addition of butyl iodide (8.3 ml) and a solution of tetra-n-butylammonium iodide (1.8 g) in DMF (30 ml) under ice cooling. Two hours later, butyl iodide (8.3 ml) and a solution of tetra-n-butylammonium iodide (1.8 g) in DMF (30 ml) were added dropwise again over 15 minutes under ice cooling, followed by stirring overnight at room temperature. The reaction mixture was poured into ice water (500 ml). The mixture was extracted with ethyl acetate (300 ml×2) to separate the organic layer. The organic layer so obtained was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed under pressure. To the residue, 100 ml of ether and 100 ml of hexane were added. After the starting materials so precipitated were filtered off, the solvent was removed under reduced pressure. The residue was purified by a silica gel column to obtain the invention compound (Compound No. 4, 6.50 g, 28.2%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1CO
Reaction time: 22 h
Yield: 98.9 %

Procedure:
Palladium on carbon (10 wt. %, 10 mg) was added to a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (110 mg, 0.41 mmol) in MeOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 22 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 110 mg (99%) of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1COCC1>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12](=[O:13])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
To a stirred solution of acetonitrile (2.0 mL, 38.2 mmol) in THF (50 mL) at −78° C. was added nBuLi (1.81 M in hexane, 16 mL, 28.7 mmol). The resulting slurry was kept at −78° C. for 15 min and 2,4-dichlorobenzoyl chloride (2.0 g, 9.55 mmol) was added dropwise to the acetonitrile anion. After 40 min, the reaction was quenched by addition of saturated NH4Cl (30 mL). THF was removed under reduced pressure and the suspension was filtered. The solid was washed with H2O (100 mL) and dried to give 3-(2,4-dichlorophenyl)-3-oxopropanenitrile (2.0 g, 98%, >95% purity) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]2[CH2:43][CH:42]3[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH:37]2[CH2:43][CH:42]3[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(Cc1ccc(OC2CC3CCC(C2)N3C)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(Cc1ccc(OC2CC3CCC(C2)N3C)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
To a solution of pivalic acid 6-{2-{ethyl[4-(8-methyl-8-azabicyclo[3.2.1 ]oct-3-yloxy)benzyl]amino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) in ethanol (1 ml) was added an aqueous solution of 1N sodium hydroxide (0.2 ml), and the solution was stirred for 1.5 hours at 60° C. The solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (12 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].Cl[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:17][CH2:16][CH2:15][C:14]#[CH:13])[C:5]#[N:6]
Reactant: C#CCCCCl
Reactant: Cc1cc(C#N)cc(C)c1O
Product: C#CCCCOc1c(C)cc(C#N)cc1C
Yield: 99.4 %

Procedure:
Following the procedure of Example 1c and using 14.7 g (100 mmol) of 3,5-dimethyl-4-hydroxybenzonitrile and substituting 5-chloro-1-pentyne (12.7 mL, 120 mmol) for the product of Example 1b, there was obtained a red-brown oil which was purified by chromatography (Silica Gel 60, 15% ethyl acetate in hexanes) to give pure title compound (21.2 g, 99.4%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[Cl:42][CH2:43][C:44](Cl)=[O:45]>[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:44](=[O:45])[CH2:43][Cl:42])[C@@H:28]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCl
Reactant: C=CCOC(=O)C(N1C(=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)[C@H]1S)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Ag]
Product: C=CCOC(=O)C(N1C(=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)[C@H]1SC(=O)CCl)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In a manner analogous to that described in Example 7, 30 g of the silver salt of 2-[(3S,4R)-3-(tert.-butyl-dimethyl-silyloxymethyl)-4-mercapto-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are reacted with 5.04 ml of chloroacetyl chloride to form the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[CH3:14]C1C(=O)NC(=O)NN=1.CC1N=NC(O[Si](C)(C)C)=NC=1O[Si](C)(C)C.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[C:8]([CH3:14])=[N:7]1
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Reactant: Cc1n[nH]c(=O)[nH]c1=O
Agent: Cc1nnc(O[Si](C)(C)C)nc1O[Si](C)(C)C
Agent: ClCCCCBr
Product: Cc1nn(CCCCCl)c(=O)[nH]c1=O

Procedure:
2-(4-Chloro-butyl)-6-methyl-2H-[1,2,4]triazine-3,5-dione were synthesized as described for the synthesis of 2-(4-Chloro-butyl)-2H-[1,2,4]triazine-3,5-dione starting from 6-methyl-2H-[1,2,4]triazine-3,5-dione which was converted into 6-methyl-3,5-bis-trimethylsilanyloxy-[1,2,4]triazine by the method described in working example 1 and thereafter reacted with 1-bromo-4-chloro-butane according to working example 2.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[NH:32]1[CH2:37][CH2:36][C:35]2([CH2:42][C:41](=[O:43])[C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[O:38]2)[CH2:34][CH2:33]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:17]([N:32]1[CH2:37][CH2:36][C:35]2([CH2:42][C:41](=[O:43])[C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[O:38]2)[CH2:34][CH2:33]1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: O=C1CC2(CCNCC2)Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(Cl)c(Cl)c1)C(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Yield: 44 %

Procedure:
Triethylamine (0.50 mL, 0.36 g, 3.6 mmol) was added to a stirred, cooled (0° C.) mixture of (S)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionic acid (364 mg, 1 mmol), spiro[2H-1-benzopyran-2,4'-piperidin]-4-(3H)-one hydrochloride (U.S. Pat. No. 5,206,240, Example 67A) (254 mg, 1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) in dimethylformamide (5 mL) and the mixture was stirred at room temperature for 2 h. Aqueous sodium hydrogen carbonate (saturated, 20 mL) and water (10 mL) were added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×20 mL), aqueous sodium hydrogen carbonate (saturated, 2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99.5:0.5 increasing to 98:2) to give the title compound as a colorless foam (248 mg, 44%). m/e (ES+) 563 (MH+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C.Cl>O1CCCC1>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[B:28]([OH:33])[OH:29])[CH:18]=1
Reactant: Clc1ccc(OCc2ccccc2)c(-c2ccccc2Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 59.5 %

Procedure:
1.6M butyllithium in hexanes (16.8 ml, 26.88 mmol) was added over 10 minutes to a stirred solution of 2′-bromo-5-chloro-2-[(phenylmethyl)oxy]biphenyl (9.29 g, 25.56 mmol) in tetrahydrofuran (120 ml) at −78° C. under nitrogen. After stirring for 15 minutes triisopropyl borate (9.61 g, 51.12 mmol) was added over 2 minutes and the mixture allowed to warm to room temperature. 2M hydrochloric acid (150 ml) was added with vigorous stirring for 25 minutes and the organic phase was separated, dried (magnesium sulphate) and evaporated. The residue was purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:4) then triturated with iso-hexane to give 5.15 g of white solid.