Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][CH2:13]O.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([C:7]([O:9][CH2:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCC1
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.4 %

Procedure:
To a mixture of cyclohexanecarboxylic acid (1.28 g, 10 mmol), 2-(trimethylsilyl)ethanol (1.3 g, 11 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.11 g, 11 mmol) in dichloromethane was added 4-dimethylaminopyridine (123 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 3 d. It was partitioned between ethyl acetate and 2N HCl. The organic phase was washed with brine, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuuo. The residue was purified by flash chromatograph on silica gel (eluting with 0-20% ethyl acetate in hexane) to provide the title compound as a colorless oil (1.7 g, 75% yield).
Reaction SMILES: C([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23])(=O)C1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[OH:9][C:10]1([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH3:24])[CH:27]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23]
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: COc1cccc(CCl)c1
Product: CCCN1C(=O)C(O)(Cc2cccc(OC)c2)c2cc(C)ccc21

Procedure:
This compound was made in an analogous fashion to 11-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 5-methyl-2-oxo-1-propylindolin-3-yl benzoate and 3-methoxy benzyl chloride (purchased from Fisher Scientific). 1H NMR δ 7.12 (s, 1H), 7.04 (m, 2H), 6.69 (d, 1H), 6.55 (t, 2H), 6.43 (s, 1H), 3.61 (m, 4H), 3.29 (m, 2H), 3.16 (d, 1H), 2.89 (bs, OH), 2.32 (s, 3H), 1.39 (m, 2H), 0.74 (t, 3H). Calculated mass for C20H23NO3, 325.17. Observed 348.1 (M+Na).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:20]=[C:16]([C:17](O)=[O:18])[C:15]([NH2:21])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:20]=[C:16]2[C:15](=[CH:14][CH:13]=1)[N:21]=[C:2]1[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]1[C:17]2=[O:18]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Product: O=c1c2cc(Cl)ccc2nc2[nH]c3ccccc3n12

Procedure:
2-Chlorobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 5-chloroanthranilic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][C:23]1([CH3:45])[C:27]([C:28]2[CH:33]=[C:32]([CH2:34]O)[CH:31]=[CH:30][C:29]=2[C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[CH:26][CH2:25][CH2:24]1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:34][C:32]1[CH:31]=[CH:30][C:29]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[C:28]([C:27]2[C:23]([CH3:45])([CH3:22])[CH2:24][CH2:25][CH:26]=2)[CH:33]=1
Reactant: BrBr
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)c(-c2ccc(CBr)cc2C2=CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (0.13 g, 0.51 mmol) in DCM (1.0 mL), was slowly added bromine (0.081 g, 0.51 mmol, 0.25 mL, 2M in CCl4) at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes and then a mixture of compound T1.7 (0.15 g, 0.46 mmol) and anhydrous pyridine (0.041 mL, 0.51 mmol) in DCM (3.0 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. DCM (80 mL) was added, and the mixture was washed with water (20×2 mL), and dried over Na2SO4. The solvent was removed under reduced pressure to provide product T1.8. 1H NMR (400 MHz, CDCl3) δ ppm. 7.16-7.29 (m, 3H), 6.88 (t, 1H), 6.72 (m, 2H), 5.45 (s, 1H), 4.46 (s, 2H), 3.68 (s, 3H), 2.16-2.19 (m, 2H), 1.59 (t, 2H), 0.78 (s, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[O:19])[CH:17]=[CH2:18])=[CH:8]1>C(OCC)(=O)C>[N:1]1([CH2:18][CH2:17][C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH3:6])[CH:8]=2)=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)c1cn(C)c2ccccc12
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)CCn2ccnc2)c2ccccc21
Reaction time: 18 h
Yield: 59 %

Procedure:
Imidazole (0.433 g) was added to a solution of 1-(1-methyl-1H-indol-3-yl)-1-prop-2-enone (0.393 g) in ethyl acetate (12 ml) and the mixture was stirred and heated at reflux for 2.25 h. The mixture was cooled and allowed to stand for 18 h at room temperature. The resulting precipitate was filtered off, washed with ethyl acetate (2 ml) and ether (10 ml) and dried to give the title compound (0.317 g), m.p. 121°-123°; λmax (EtOH) 245.5 nm (ε14,080), λinf 248 nm (ε13,750), λinf 258 nm (ε9,400), λmax 304 nm (ε14,000).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7])[N:3]=[CH:2]1.Cl>O1CCOCC1>[S:1]1[CH:5]=[C:4]([C:6]([NH:8][NH2:9])=[O:7])[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cscn1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)c1cscn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,1-Dimethylethyl 2-(1,3-thiazol-4-ylcarbonyl)hydrazinecarboxylate (I64) (1.378 g, 5.66 mmol) was dissolved in 1,4-dioxane (15 mL) and to this was added 4M HCl in 1,4-dioxane (14.16 mL, 56.6 mmol). The solution was then stirred at room temperature for 18 hours. The solvent was then evaporated in vacuo and the remaining residue was loaded onto an SCX cartridge and washed with methanol before being eluted with 2M NH3 in DCM. The solution was then evaporated in vacuo to yield the product in 0.784 g.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)[CH3:2].[C:21]1([CH3:29])[C:22]([C:27]#N)=[CH:23][CH:24]=[CH:25][CH:26]=1>C(O)(=O)C.[Ni]>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][CH2:29][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:12][CH:13]=2)[N:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)[CH3:2]
Reactant: Cc1ccccc1C#N
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [Ni]
Solvent: CC(=O)O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2ccccc2C)cc1
Reaction time: 7.5 h
Yield: 85 %

Procedure:
A slurry of Raney Ni (200 mg, 50% in water) was added to a solution 5-ethyl-3-(3-pyridyl)-1-(4′-aminophenyl)pyrazole (500 mg, 1.89 mmol) and o-tolunitrile (0.27 mL, 1.2 equiv.) in glacial acetic acid (20 mL), and the mixture was stirred under hydrogen at 40 psi for 7.5 h. The reaction mixture was filtered through diatomaceous earth, diluted with water, extracted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. Chromatography on silica gel (hexane/ethyl acetate=1:1) gave the title compound (595 mg, 85%). 1H-NMR (CDCl3): 1.30 (t, J=7.5 Hz, 3H), 2.42 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.95-4.25 (bs, 1H), 4.36 (s, 2H), 6.58 (s, 1H), 6.72 (d, J=8.7 Hz, 1H), 7.21-7.41 (m, 6H), 8.21 (dd, J=1.6, 6.3 Hz, 1H), 8.56 (d, J=4.1 Hz, 1H), 9.10 (d, J=1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[C:13]3[NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:35]C(=O)OC(C)(C)C)([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:35][C:32]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:4]4[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:23][CH2:24]2)=[O:21])=[CH:31][CH:30]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 32.1 %

Procedure:
Following general procedure A-2, tert-butyl 2-{4-[6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]phenyl}propan-2-ylcarbamate (0.140 mmol) was reacted with TFA (2 mL) to afford the desired product (22 mg, 32% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-I) δ 9.38 (s, 1H), 8.26 (dd, J=8.9, 1.9 Hz, 1H), 8.12 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.0, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.30 (t, J=1.9 Hz, 1H), 7.10-7.03 (m, 1H), 2.84-2.76 (m, 1H), 1.79 (s, 6H), 1.19-1.12 (m, 4H).; ESI MS m/z 490 [C28H25ClFN3O2+H]+; HPLC>99% (AUC), tR=10.80 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[N+:14]([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14]
Reactant: O=[N+]([O-])/C=C/c1ccc(C(F)(F)F)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 42.1 %

Procedure:
(E)-2-chloro-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene (160 mg, 0.636 mmol) was diluted with THF (1 mL), placed under nitrogen and cooled to 0° C. LAH (2544 μL, 2.54 mmol) was added dropwise and the reaction was stirred for 5 hours warming to ambient temperature. The reaction was cooled to 0° C. and quenched with 100 μL of water, 100 μL of 15% NaOH and 300 μL water. After stirring for 1 hour, ethyl acetate and MgSO4 was added. The reaction mixture was filtered and concentrated to yield 2-(2-chloro-4-(trifluoromethyl)phenyl)ethanamine (60 mg, 0.268 mmol, 42.2% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:16][C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:17]
Reactant: O=C(O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of 1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid (0.75 g, 3.17 mmol) in methanol (20 ml) was cooled to 0° C. Thionyl chloride (0.71 ml, 9.51 mmol) was added dropwise and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and then diluted with dichloromethane. The organic layer was washed with bicarbonate solution, water and dried. Evaporation to dryness yielded 1-(4-nitrophenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.58 g, 73%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([OH:19])=O)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.CS(C)=O>[F:1][C:2]1[C:3]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:19])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3[nH]2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3[nH]2)cn1
Temperature: 45 °C

Procedure:
To a solution of 2-(4-(5-fluoro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (Example 65B) (75 mg, 0.181 mmol) in N,N-dimethylformamide (1.0 mL) was added methanesulfonamide (20.7 mg, 0.218 mmol), 4-dimethylaminopyridine (66.5 mg, 0.544 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (52.2 mg, 0.272 mmol). The solution was heated to 45° C. for 4 hours. The reaction was cooled to room temperature and diluted with dimethyl sulfoxide (1 mL). The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 um column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 12.30-12.18 (m, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.22 (d, J=3.6 Hz, 1H), 8.16 (s, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.67 (s, 1H), 5.10 (s, 2H), 3.29 (s, 3H), 2.64-2.56 (m, 2H), 2.46-2.32 (m, 2H), 2.05-1.87 (m, 2H); MS ESI(+) m/z 490.9 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19]([SH:22])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:18][CH:17]=2)[C:8](=[O:9])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Product: CC(C)(C)OC(=O)CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cn1

Procedure:
3-Cyclopentyl-2-(6-mercaptopyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 66, 94 mg, 283 μmol) was alkylated with tert-butyl bromoacetate (55 mg, 283 μmol), using the procedure described in EXAMPLE 72, to give tert-butyl {5-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)ethyl]pyridin-2-ylsulfanyl}acetate: m/z (ES+)=448.3 [M+H]+. Step 2: Oxidation of this thioether, employing the protocol described in EXAMPLE 35, provided tert-butyl {5-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]pyridine-2-sulfonyl}acetate: δH (CDCl3): 1.05-1.20 (m, 2H), 1.25 (s, 9H), 1.45-1.85 (m, 7H), 1.90-2.00 (m, 1H), 2.30-2.40 (m, 1H), 3.90-4.00 (m, 1H), 4.30-4.45 (m, 2H), 7.10 (d, 1H), 7.55 (d, 1H), 8.05 (d, 1H), 8.10 (dd, 1H), 8.70 (d, 1H). Step 3: A solution of this compound (48 mg, 100 μmol) in CH2Cl2-TFA (1:3, 4 mL) was stirred at 20° C. for 2 h. Ths solvents were evaporated, then the remainder was treated with saturated aqueous NaHCO3 (5 mL). The resulting solution was acidified with 2M HCl to pH 2, then the mixture was extracted with EtOAc (10 mL+5 mL). The organic layer was concentrated and chromatographed (MeOH—CH2Cl2-AcOH, 2:18:1) to furnish the title compound: RTA=3.37 min; m/z (ES+)=424.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([CH3:14])[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1C
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1C
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a solution of 4-bromo-N-methoxy-2,N-dimethyl-benzamide (886 mg, 3.43 mmol) in anhydrous tetrahydrofuran (20 mL) at −60° C. under an atmosphere of nitrogen was added 3.0 M methylmagnesium chloride in tetrahydrofuran (1.26 mL, 3.78 mmol) via syringe. The reaction was stirred for 20 minutes at −60° C., then at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added, the mixture was poured into a separatory funnel and extracted with diethyl ether (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(4-bromo-2-methyl-phenyl)-ethanone (700 mg, 96%). HR-MS: calcd for C30H29BrN4O4 [M+H+] 589.1445. Found 589.1445.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH3:2].[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[CH2:1]([C:3]1[O:4][C:5]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:15])=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCNC
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 89.8 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoic acid (117 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (128 mg, 90%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[N:7]=[N:6]1.[OH-].[Na+].Cl>O>[F:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]=[N:6]1
Reactant: COC(=O)c1cn(Cc2c(F)cccc2F)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
A mixture of Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate. (50 gms) and a solution of sodium hydroxide (11.76 gms in 100 ml water) were stirred at room temperature contents till it becomes clear. Hydrochloric acid (30 ml ) in DM water (70 ml) was charged to above reaction mass. Adjusted the PH of the reaction till 2-3 by adding the hydrochloric acid solution at 25-30° C. After the completion, reaction mass was filtered and dried the material at 65° C.-70° C. for 15 hours. Yield: 40 gms
Reaction SMILES: [CH:1]([P:3](=[O:8])([O-:7])[O:4][CH2:5][CH3:6])=[CH2:2].C(OCC)(OCC)O[CH2:11][CH3:12].C(OCC)(=O)C>C(O)C>[CH:1]([P:3](=[O:7])([O:8][CH2:11][CH3:12])[O:4][CH2:5][CH3:6])=[CH2:2]
Reactant: CCOC(OCC)OCC
Reactant: C=CP(=O)([O-])OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=CP(=O)(OCC)OCC
Temperature: 150 °C
Yield: 83.6 %

Procedure:
25 g of vinylphosphonic acid and 70 g of diethyl 2-acetoxyethanephosphonate were heated with stirring to 180° C. 252 g of diethyl 2-acetoxyethanephosphonate were then slowly added dropwise over 14 hours while the temperature gradually increased to 200° C. and ethyl acetate distilled off. The mixture was then stirred for 9 hours at 190° C. 190 g of crude monoethyl vinylphosphonate were obtained. Distillation produced 128 g of ethyl acetate and additionally 8 g of light ends which were trapped in a cold trap downstream from the apparatus. 95 g of the crude monoethyl vinylphosphonate and 124 g of triethyl orthoformate were refluxed for 8 hours at about 75° C. The temperature was then gradually increased in the course of 5.5 hours to 150° C. while ethyl acetate and ethanol distilled off. A further 100 g of triethyl orthoformate were then added at room temperature and the mixture was gradually heated again to 150° C. while light ends distilled off. A cold trap downstream from the apparatus collected less that 1 g. The mixture was then distilled and 96.5 g of diethyl vinylphosphonate were obtained. This corresponded to a yield of about 70%, relative to the amount of vinylphosphonic acid and diethyl 2-acetoxyethanephosphonate started with. During the reaction with the orthoester, about 160 g distilled off which contained 28 percent of ethanol and about 10 percent of diethyl ether in addition to about 60 percent of ethyl formate.
Reaction SMILES: [O:1]=[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]2[C:4]([C:5]([N+:17]([O-])=O)=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[H][H]>[Pd].O1CCCC1>[O:1]=[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]2[C:4]([C:5]([NH2:17])=[CH:6][CH:7]=[CH:8]2)=[N:3]1
Reactant: O=C1N=c2c([N+](=O)[O-])cccc2=C1c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1=NC(=O)C=2c1ccccc1
Reaction time: 18 h

Procedure:
Two and one half grams of 2-oxo-3-phenyl-7-nitroindole were dissolved in 200 ml. of THF (tetrahydrofuran). Two grams of 5% palladium-on-carbon were added and the mixture placed in a low pressure hydrogenation apparatus at 60 psi of hydrogen. After 18 hours, the theoretical amount of hydrogen had been absorbed. The hydrogenation mixture was filtered to remove the catalyst and the filtrate was evaporated to dryness in vacuo. The residue containing the 2-oxo-3-phenyl-7-aminoindole formed in the above hydrogenation melted at 226°-30° C. after recrystallization from methanol; yield = 1.5 g.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([CH:11]2[C:16]3=[N:17][NH:18][C:19](=[O:24])[C:20]4[CH:21]=[CH:22][CH:23]=[C:14]([C:15]=43)[NH:13][CH:12]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=[CH:9][CH:10]=1)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:14]3[NH:13][CH:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[CH:4]=[O:3])[C:16]([C:15]=23)=[N:17][NH:18]1
Reactant: CCOC(OCC)c1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.8 %

Procedure:
A mixture of 9-(3-(diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (90 mg, 0.20 mmol) in 3N hydrochloric acid (12 mL) was stirred at room temperature for 20 hr. Then the mixture was adjusted to pH=8 with potassium carbonate. The resulting suspension was extracted with ethyl acetate to give 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (66 mg, yield 88%) as a light yellow solid. LC-MS (ESI) m/z: 368(M+1)+.
Reaction SMILES: C([O:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[N:12]([CH3:21])[C:11](=[O:22])[C:10]=1[C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[N:12]([CH3:21])[C:11](=[O:22])[C:10]=1[C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31]
Reactant: CON1CCC2(CC1)C(OCc1ccccc1)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Reaction time: 22 h

Procedure:
To a solution of 4-benzyloxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (22.6 g, 53.7 mmol) in methanol (226 ml) and water (22.6 ml) in a Parr shaker type hydrogenator was added 5% Pd/C (22.6 g). After hydrogenation under 4 bars H2 at 36° C. for 22 hours, the reaction mixture was filtered and concentrated. The residue was diluted with ethyl acetate and extracted with saturated aqueous sodium carbonate under ice cooling. The organic layer was discarded, the aqueous alkaline phase acidified with cooling to pH 5-6 with an aqueous HCl solution and thoroughly extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Yield: 13.0 g of 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a solid, mp 239-241° C. The spectral data were identical to those described above under preparation example 1, step 1.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=[O:4]>CO>[CH3:1][CH:2]([CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][OH:4]
Reactant: CC(C=O)COC(C)(C)C
Solvent: CO
Product: CC(CO)COC(C)(C)C
Yield: 88 %

Procedure:
This compound was prepared from 2-methyl-3-tert.-butoxypropanal by the method described in Example 7. Yield: 88%; boiling point 71° C./15 mbar; scent: methanol-like, floral.