Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18]CC)=O)(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[Cl:34][C:35]1[N:40]=[C:39](/[CH:41]=[C:16](/[C:15]2[CH:14]=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:11])=[O:10])[CH:23]=[CH:22][CH:21]=2)\[OH:18])[CH:38]=[CH:37][N:36]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a stirring solution of ethyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}benzoate (47.9 g, 140 mmol) in 100 mL anhydrous THF at 0° C. was added 1M LiHMDS in THF (421 mL, 421 mmol). A solution of 2-chloro-4-methylpyrimidine (19.9 g, 154 mmol) in 100 mL of anhydrous THF was added to the reaction mixture over 30 min and warmed to rt. The reaction mixture was quenched with 50 mL of MeOH and concentrated to a black solid under vacuum. The residue was partitioned between DCM and 10% NaHSO4. The aqueous and suspended solids were extracted 2× with DCM and the combined organic extracts were filtered through a pad of Celite, concentrated, and passed through a short silica gel column (elution with THF) to provide 57 g (96%) of the title compound of Step B. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.03-11.34 (m, 1H), 8.49-8.91 (m, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.65-7.76 (m, 2H), 7.55-7.63 (m, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.35-7.47 (m, 1H), 7.22-7.34 (m, 2H), 6.43 (s, 1H), and 4.60 (s, 1H); ES-LCMS m/z 423.93 (M+H).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.N1C=CC=CC=1.[C:47]([OH:50])(=[O:49])[CH3:48]>>[C:47]([O:50][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2)(=[O:49])[CH3:48]
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-(6-hydroxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.0 g), pyridine (4 ml) and anhydrous acetic acid (4 ml) was stirred at room temperature for 14 h. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. The solution was dried and concentrated. The residue was crystallized from ethyl acetate-diisopropyl ether to give the titled compound (0.6 g) as a colorless powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(OCC)(=O)C.C(Cl)Cl>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)[CH2:15][CH2:16]2)=[CH:17][CH:18]=1
Reactant: C(=C1CCNCC1)c1ccc(C2=NCCO2)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
120 mg (0.5 mmol) of 4-[4-(2-oxazolin-2-yl)benzylidene]piperidine and 75 mg (0.75 mmol) of triethylamine in 3 ml of ethyl acetate and 2 ml of methylene chloride are cooled to -5° to -10° C. and 104.3 mg (0.5 mmol) of 4-trifluoromethylbenzoyl chloride are added. The mixture is stirred at ambient temperature for 1.5 hours, diluted with ethyl acetate, washed successively with water, 2N sodium hydroxide solution and saturated saline solution, dried and evaporated down. 115 mg (56% of theory) of the title compound of melting point 142° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]([Cl:16])[C:6]=2[N:7]=1.C(N(C(C)C)C(C)C)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]2[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]([Cl:16])[C:6]=2[N:7]=1
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(Cl)c2nc(Cl)nc(Cl)c2n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)c2nc(Cl)nc(N3CCCCC3)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
To a solution of methyl 2,4,8-trichloropyrido[3,2-d]pyrimidine-6-carboxylate (4.65 g; 15.9 mmol; 1 eq.) (Intermediate 1.3) in acetonitrile (140 mL) was added N-ethyldiisopropyl amine (4 mL; 23.8 mmol; 1.5 eq.). The mixture was cooled down to 0° C. A solution of piperidine (1.57 mL; 15.9 mmol; 1 eq.) in acetonitrile (20 mL) was added dropwise. The mixture was stirred 15 min at 0° C. The mixture was partly concentrated and the precipitate was filtered, washed with MeOH and dried under vacuum to afford methyl 2,8-dichloro-4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carboxylate (Intermediate 1.4) (3.98 g; 73%) as a pink solid in 98.8% HPLC purity; Amount: 3.98 g; Yield: 73%; Formula: C14H14O2Cl2N4; 1H NMR (DMSO-d6) δ 1.71 (sl, 6H), 3.92 (s, 3H), 4.01 (sl, 2H), 4.82 (sl, 2H), 8.42 (s, 1H); LC-MS: M/Z ESI: Rt (min) 2.02; 341.02, 342.89 (M+1); HPLC (H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=4.27; 98.84.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cn1
Product: CCOC(=O)c1ccc(N)nc1

Procedure:
To a suspension of 1.3 g (9.4 mmol) 6-aminonicotinic acid in 100 mL of ethanol, was bubbled in dry hydrochloric acid at 0 C, then the solution was refluxed until all the solids dissolved. The solvents were removed under reduced pressure, the residue dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine and concentrated to afford 1.37 g of a white solid, m/e=166(M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: ClCCCCBr
Reactant: c1ccc2[nH]nnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCCn1nnc2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Benzotriazole (11.9 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3, and eluted with dichlormethane to produce 17.0 g of 1-(4-chlorobutyl)-1H-benzotriazole, with a yield of 81.0%.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27](O)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:4][CH2:3][CH2:2]1.[CH:30]1([C:33]2[N:34]=[C:35]([NH2:38])[S:36][CH:37]=2)[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([NH:38][C:35]2[S:36][CH:37]=[C:33]([CH:30]4[CH2:32][CH2:31]4)[N:34]=2)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1nc(C2CC2)cs1
Reactant: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(C2CC2)cs1)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 10 (200 mg, 0.476 mmol) with 4-cyclopropyl-1,3-thiazol-2-amine (73 mg, 0.523 mmol) in the presence of EDCI hydrochloride (182 mg, 0.952 mmol) and DMAP (53 mg, 0.476 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 120 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.80-0.86 (m, 2H), 0.88-0.96 (m, 2H), 1.23-1.29 (m, 1H), 1.85-1.94 (m, 4H), 2.00-2.10 (m, 2H), 2.72-2.80 (m, 1H), 3.98 (d, J=6.6 Hz, 2H), 6.36 (s, 1H), 6.58 (t, J=75.3 Hz, 1H), 6.95 (d, J=4.5 Hz, 1H), 7.00-7.10 (m, 2H), 7.48-7.53 (m, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.82 (d, J=15.6 Hz, 1H), 8.24-8.30 (m, 1H); APCI-MS (m/z) 543.31 (MH)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:16]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a stirred solution of 4-fluorobenzaldehyde (5 g, 40.28 mmol) and phenol (3.8 g, 44.42 mmol) in DMF (50 mL) was added K2CO3 (11.13 g, 80.57 mmol) and the resulting mixture was stirred at 110° C. overnight. The mixture was filtered, the filtrate was diluted with cold water and the product was extracted with EtOAc. The organic layer was washed with 5% aqueous NaOH solution, saturated brine solution and dried over sodium sulphate. The organic layer was then concentrated under reduced pressure to afford 7.7 g (96.5% yield) of 4-phenoxy benzaldehyde as a pale brown oil. 1H NMR: (CDCl3) δ 9.9 (s, 1H), 7.8 (d, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.0 (t, 4H).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:6][C:5](=[O:18])[C:4]=2[CH:3]=1>C1(B2N3CCC[C@H]3C(C3C=CC=CC=3)(C3C=CC=CC=3)O2)C=CC=CC=1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:6][C@@H:5]([OH:18])[C:4]=2[CH:3]=1
Reactant: COCCCN1CC(=O)c2cc(Cl)sc2S1(=O)=O
Agent: c1ccc(B2OC(c3ccccc3)(c3ccccc3)[C@@H]3CCCN23)cc1
Product: COCCCN1C[C@@H](O)c2cc(Cl)sc2S1(=O)=O

Procedure:
Starting with 9.3 g of ketone 6 and following the same procedure as mentioned in Example 5 except using a stock solution of 1M (S)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole as catalyst led to 1, 4.9 g (52%) yield, ee=65%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1
Product: CC(=O)Nc1ccc(Br)cc1
Yield: 96 %

Procedure:
A solution of 4-bromoaniline (10 g, 58.13 mmol) in acetic anhydride (50 mL) was stirred for 20 minutes at room temperature, and then collected by filtration to give N-(4-bromophenyl)acetamide (12 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1C
Product: Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1C
Yield: 18.9 %

Procedure:
582 mg (2.76 mmol) of 3,4-dimethylbenzenesulfonylisocyanate and 473 mg (2.76 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 190 mg of the above-identified compound (yield 18.9%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 2.33 (6H,s), 7.12 (1H,s), 7.23 (1H,d), 7.43 (1H,d), 7.84-7.91 (3H,m), 11.64 (1H,br).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[C:4]([C:20]#[N:21])[CH:3]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[Cl:42]>CO.O.C(OCC)(=O)C.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:35][C:36]1[CH:37]=[C:38]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)=[C:4]([C:20]#[N:21])[CH:3]=2)[CH:39]=[CH:40][C:41]=1[Cl:42]
Reactant: CCOC(=O)c1ccc(Nc2ccc(Br)cc2C#N)cc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
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: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2ccc(-c3ccc(Cl)c(Cl)c3)cc2C#N)cc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a suspension of ethyl 4-(4-bromo-2-cyanophenylamino)benzoate (6.33 g, 18.34 mmol), tetrakis(triphenylphosphine)palladium(0) (0.438 g, 0.379 mmol), toluene (60 mL), and 2 M aqueous sodium carbonate (20.81 mL, 41.6 mmol) under nitrogen were added a solution of 3,4-dichlorophenylboronic acid (4.76 g, 24.94 mmol) in MeOH (18 mL) at rt. The resulting reaction mixture was heated at reflux temperature for 4 h. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and ethyl acetate (250 mL). The aqueous phase was extracted with ethyl acetate (100 ml ×2), and the combined organic phase was washed with water (100 ml ×2), diluted (5%) aqueous ammonia (100 mL), and brine (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude material was suspended in dichloromethane and the solid was collected by filtration, and washed with DCM (5 ml ×2) to afford 5.33 g of ethyl 4-(3′,4′-dichloro-3-cyanobiphenyl-4-ylamino)benzoate. MS (ESI) m/z 411.0 (M+H). 1H NMR (CDCl3) δ ppm 8.04 (2H, d, J=8.55 Hz), 7.73 (1H, d, J=1.83 Hz), 7.58-7.66 (2H, m), 7.51 (1H, d, J=8.55 Hz), 7.46 (1H, d, J=8.85 Hz), 7.34 (1H, dd, J=8.24, 2.14 Hz), 7.20 (2H, d, J=8.55 Hz), 6.61 (1H, s), 4.37 (2H, q, J=7.12 Hz), 1.39 (3H, t, J=7.17 Hz).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12]C(=O)[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:9](=[O:26])[C:8]=2[CH:27]=1>O>[Cl:3][C:4]1[CH:27]=[C:8]([C:9]([NH:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:26])[C:7]([OH:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCCCCCn1c(=O)oc2ccc(Cl)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 98 °C
Reaction time: 4 h
Yield: 76.9 %

Procedure:
400 L of purified water, USP and 45.4 kg NaOH pellets were charged to a 200 gallon glass-lined reactor and the agitator was set to 100-125 RPM. 123.5 kg of the ethyl 8-(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dionyl)octanoate wet cake was charged to the reactor. The charging port was closed. Cooling water applied to the condenser and the valve reactor overheads were set for atmospheric distillation. The reactor contents were heated to 98° C. and conversion monitored by HPLC. Initially (approximately 40 minutes) the reactor refluxed at 68° C., however, as the ethanol was removed (over 3 hours) by distillation the reactor temperature rose to 98° C. The starting material disappeared, as determined by HPLC, at approximately 4 hours. The reactor contents were cooled to 27° C. 150 L of purified water and USP were charged to an adjacent 200 gallon glass-lined reactor and the agitator was set to 100-125 RPM. 104 L of concentrated (12M) hydrochloric acid was charged to the reactor and cooled to 24° C. The saponified reaction mixture was slowly (over 5 hours) charged to the 200-gallon glass-lined reactor. The material (45 L and 45 L) was split into 2 reactors (200 gallons each) because of carbon dioxide evolution. The product precipitated out of solution. The reaction mixture was adjusted to a pH of 2.0-4.0 with 50% NaOH solution (2 L water, 2 kg NaOH). The reactor contents were cooled to 9-15° C. The intermediate crystallized out of solution over approximately 9 hours. The reactor slurry was centrifuged to isolate the intermediate. 50 L of purified water and USP were charged to a 200-gallon glass-lined reactor and this rinse was used to wash the centrifuge wet cake. The wet cake was unloaded into double polyethylene bags placed inside a plastic drum. The N-(5-chlorosalicyloyl)-8-aminocaprylic acid was dried under vacuum (27″ Hg) at 68° C. for 38 hours. The dry cake was unloaded into double polyethylene bags placed inside a 55-gallon, steel unlined, open-head drums with a desiccant bag placed on top. The dried isolated yield was 81 kg of N-(5-chlorosalicyloyl)-8-aminocaprylic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[NH2:25][CH2:26][CH2:27][CH2:28][S:29]([OH:32])(=[O:31])=[O:30].CS(C)=O.C(N(CC)CC)C>CCOCC.CO.CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:25][CH2:26][CH2:27][CH2:28][S:29]([OH:32])(=[O:31])=[O:30])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCS(=O)(=O)O
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CO
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.127 g (0.9111 mmol) of 3-amino-1-propane sulfonic acid were placed into a 10 ml round bottom flask with 2 ml of dimethylsulfoxide and a magnetic stirring bar. To this solution was added 0.100 g (0.988 mmol) of triethylamine and the solution immediately turned green. The solution was stirred at room temperature for five hours. Dimethylsulfoxide was removed in vacuo with gentle heating. 9 ml of acetone was added and the solution was triturated with methanol until homogeneous. No precipitate had formed. The solution was transferred to a 50 ml round bottom flask with 10 ml acetone and 5 ml methanol. Ether was added until just before the cloud point and the flask was placed into freezer overnight (<0° C.).
Reaction SMILES: P.[CH3:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)C>O>[CH3:2][CH:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(C)=O
Agent: P
Solvent: O
Solvent: CCO
Product: CCCCCCC(C)O
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
Into a 3 ounce glass pressure bottle are placed 173 milligrams of [Rh(norbornadiene) (iso-propylmethylphenylphosphine)2 ]BF4 ([α]D25 = +11.0° for the phosphine), 8.2 grams of 2-octanone, 5 ml absolute ethanol, and 0.12 ml water. The bottle is flushed and filled with hydrogen as in Example 1 to 43 psig hydrogen. The bottle is warmed to 75°C and the contents stirred for 3.5 hours. The reaction mass is distilled to afford almost pure 2-octanol, [α]D25 = +0.15°, optical purity = 1.5%.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14](Br)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[Cl:24]>>[CH2:1]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[C:23]([Cl:24])[CH:22]=3)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCCCCc1cc(Br)c2ncccc2c1
Product: CCCCCc1cc(-c2ccc(Cl)c(Cl)c2)c2ncccc2c1

Procedure:
6-pentyl-8-bromoquinoline and 3,4-dichlorobenzene boronic acid can be combined to form 6-pentyl-8-(3,4-dichlorophenyl)quinoline,
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[O:12][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A solution of methyl 5-iodosalicylate (2.00 g, 7.20 mmol) in DMF (20 mL) was treated with imidazole (1.22 g, 18.0 mmol) then chlorotriisopropylsilane (1.85 mL, 8.60 mmol). The mixture was stirred at RT for 18 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with a 10% aqueous citric acid solution, 1N aqueous NaOH solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% EtOAc in cyclohexane, to give the title compound as a colorless oil (2.88 g, 92%). LCMS (Method 3): Rt 5.72 min, m/z 435 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([CH2:14][OH:15])=[CH:9][C:8]=2[F:16])=[CH:4][C:3]=1[F:19].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([CH2:14][O:15][C:21]3[CH:31]=[C:25]4[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23](=[O:32])[N:22]=3)=[CH:9][C:8]=2[F:16])=[CH:4][C:3]=1[F:19]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(Cl)c(F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(Cl)c(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(4-chloro-3-fluorophenoxy)-3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:13](N)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:19].N([O-])=O.[Na+]>[Cu]Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccnc2N)CC1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CCOC(=O)[C@H]1CC[C@H](c2cccnc2Cl)CC1
Reaction time: 2 h

Procedure:
To a solution of trans-4-(2-amino-pyridin-3-yl)-cyclohexanecarboxylic acid ethyl ester (0.21 g, 0.86 mmol) in concentrated hydrochloric acid (3.7 ml, 43 mmol) was added solid sodium nitrite (1.49 g, 21.5 mmol) at 0-5° C. The cooling bath was removed and copper(I) chloride (3.58 g, 36.2 mmol) was added at room temperature. After stirring for 2 h the mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic layer was collected. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.093 g, 44%) as yellow oil. MS m/e: 268 ([M+H]+)