Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:32]=[CH:31][C:18]2[N:19]([CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:20]([CH2:22]Cl)=[N:21][C:17]=2[CH:16]=1>>[Cl:14][C:15]1[CH:32]=[CH:31][C:18]2[N:19]([CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:20]([CH2:22][N:7]3[C:8]4=[CH:9][N:10]=[CH:11][CH:12]=[C:13]4[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6]3)=[N:21][C:17]=2[CH:16]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1c[nH]c2cnccc12
Product: CS(=O)(=O)CCCn1c(Cn2cc(S(C)(=O)=O)c3ccncc32)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 3-(methylsulfonyl)-1H-pyrrolo[2,3-c]pyridine and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:25][CH:26]=[CH2:27])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:24])C.[CH3:29][NH2:30]>>[CH2:25]([C:6]12[C:15]3[CH:14]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]1([OH:24])[N:30]([CH3:29])[C:4](=[O:3])[CH2:5]2)[CH:26]=[CH2:27]
Reactant: CN
Reactant: C=CCC1(CC(=O)OCC)C(=O)CCc2ccc(OCc3ccccc3)cc21
Product: C=CCC12CC(=O)N(C)C1(O)CCc1ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 6.30 g (167 mmol) ethyl-1-allyl-7-benzyloxy-2-oxo-1,2,3,4-tetrahydro-1-naphthaleneacetate (IXc), 31.0 g methylamine and 200 ml 1:1 ethanol-dioxane was stirred at room temperature for 3 days. The reaction mixture was concentrated by evaporation of the solvent (35°-40° C.) to half the volume and diluted with 200 ml ether to provide a crystalline product which was collected to give 51.0 g (86%) Xc, m.p. 188°-190°; IR (Nujol), 3250, (broad), 1665, 1615, 1505 cm-1.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:41]=[CH:40][C:31]([CH2:32][N:33]3[C:37](=[O:38])[NH:36][C:35](=[O:39])[O:34]3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[O:38]=[C:37]1[NH:36][C:35](=[O:39])[O:34][N:33]1[CH2:32][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:5][CH2:6][C@@H:7]([C:9]3[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=3)[OH:8])[CH2:23][CH2:24]2)=[CH:41][CH:40]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(Cn3oc(=O)[nH]c3=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(Cn4oc(=O)[nH]c4=O)cc3)CC2)ccc1O
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
Acetic acid (0.09 mL, 1.6 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (197 mg, 0.8 mmol) (which was obtained in Example 10), 2-[4-(4-oxo-1-piperidinyl)benzyl]-1,2,4-oxadiazolidine-3,5-dione (231 mg, 0.8 mmol) (which was obtained in Example 55), and DMF(5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (203 mg, 0.96 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 4/1) to produce an off-white solid (296 mg, 71% yield); mp 193–195° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58–1.62 (m, 2H), 1.96–2.07 (m, 2H), 2.60–2.70 (m, 2H), 2.86–3.17 (m, 6H), 3.72–3.8 (m, 2H), 4.28 (s, 2H), 2.70–2.74 (m, 1H), 6.83–6.87 (m, 3H), 7.03–7.13 (m, 3H), 7.23 (m, 1H), 8.60 (brs, 2H); MS (ES) m/z: 518 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[C:27]1([CH2:33][CH2:34][C:35](=[NH:37])[NH2:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[O-].[Na+].CO.C(OCC)(=O)C>CO.O>[CH2:22]([C:21]1[N:37]=[C:35]([CH2:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:36][C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: N=C(N)CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CCc2ccccc2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (0.70 g) and 3-phenylpropanimidamide (0.63 g) in methanol (10 mL) was added 28% sodium methoxide-methanol solution (1.7 mL), and the mixture was stirred at room temperature for 24 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.71 g, 79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[O:23]1[CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]1>CC(O)C>[CH3:9][C:6]1([CH3:8])[CH2:7][C:2]([CH3:22])([CH3:1])[CH2:3][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH:25]([OH:23])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21]2)[CH2:5]1
Reactant: CCCCC1CO1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Solvent: CC(C)O
Product: CCCCC(O)CN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (120 mg, 0.399 mmol) produced in Example (8b), 1,2-epoxyhexane (240 mg, 2.39 mmol) and 2-propanol (0.8 mL) was stirred for 18 hours at an external temperature of 80° C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 116 mg of 1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}hexan-2-ol as a light yellow solid. This compound (12 mg, 0.030 mmol) was dissolved in diethyl ether and a 4N solution of hydrogen chloride in ethyl acetate (0.0083 mL, 0.033 mmol) was added. The mixed solution was concentrated under reduced pressure and the obtained solid residue was washed with a diethyl ether-heptane mixed solvent and then dried under reduced pressure to give 10 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:18].[K+]>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([OH:18])[C:11]([Cl:15])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: [OH-]
Agent: [K+]
Product: CC(C)(C)OC(=O)Nc1cc(O)c(Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
In analogy to Example 63A, tert-butyl(3,4,5-trichlorophenyl)carbamate from Example 66A (3.98 g, 13.4 mmol) was reacted with potassium hydroxide (1.77 g, 26.8 mmol). The reaction mixture was heated to 80° C. overnight and subsequently to 90° C. for 3 h. The product was isolated by preparative HPLC to yield 760 mg (20%).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][CH2:8][O:9][C:10]([CH:12]1[C:18]([CH3:19])=[CH:17][C:15](=[O:16])[CH2:14][CH2:13]1)=[O:11].Cl.Cl[CH2:22][C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[CH2:8]([O:9][C:10]([CH:12]1[CH2:13][CH2:14][C:15](=[O:16])[C:17]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:36][CH:37]=2)=[C:18]1[CH3:19])=[O:11])[CH3:7]
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)C1CCC(=O)C(Cc2ccc(OCCN3CCCCC3)cc2)=C1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of KOtBu (1.0 M in tBuOH, 10.7 mL) at 25 cC was added Hagemann's ester (1.0 mL, 5.324 mmol). The mixture was stirred for 10 min at 25° C. and then to the mixture was added 1-[2-(4-chloromethyl-phenoxy)ethyl]piperidine hydrochloride (1.54 g, 5.324 mmol). The mixture was refluxed for 3 h. The tBuOH was distilled off, then the reaction mixture was diluted with water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The organic extracts were acidified with 1N HCl (100 mL). The layers were separated and the diethyl ether layer was discarded. The aqueous layer was then basicified to pH 11 with 10% NaOH (aq) and extracted with diethyl ether to yield 2-methyl-4-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-2-enecarboxylic acid ethyl ester as dark amber oil.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]2[C:6]=1/[C:7](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:8](=[O:17])[NH:9]2.[Cl-].[NH4+]>O.CO.[Zn]>[NH2:14][C:13]1[C:5]([C:4]#[C:3][CH2:2][OH:1])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])/[C:7]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CCO)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#CCO)c21

Procedure:
Using Method L above, (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (63 mg, 0.19 mmol) (from Example 30 above) was reduced with zinc (0.11 g, 1.67 mmol) and ammonium chloride (22.4 mg, 0.42 mmol) in 10% water in methanol (10 mL) with heating at reflux for 2 h to give (Z)-5-amino-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H -indol-2-one. (Yield 18 mg, 40%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]1(C2(C(Cl)=O)CCCCC2)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]1([C:2]2([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1(c2ccccc2)CCCCC1
Reactant: CC1(C(=O)Nc2ccccc2[N+](=O)[O-])CCCCC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1[N+](=O)[O-])C1(c2ccccc2)CCCCC1
Yield: 91 %

Procedure:
This compound was prepared following the procedure described for compound 39A in example 39, except that 1-phenylcyclohexanecarbonyl chloride (J. Am. Chem. Soc. 68, 2345-7 (1946)) was used in place of 1-methylcyclohexanecarbonyl chloride, toluene in place of CH2Cl2, DIPEA in place of triethylamine and reaction mixture was refluxed for 15 h. The crude was purified by flash chromatography (petroleum ether-EtOAc 98:2). Yield 91%.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:25]([O:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.CN(C=O)C.O.C(OCC)(=O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]([O:30][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CCCCCOc1cccc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(C(=O)c2ccc(F)c3ccccc23)c2ccccc12
Temperature: 4 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
A stirred solution of 4-fluoro-1-naphthoic acid (0.5 g, 2.63 mmol) in anhydrous DCM (10 mL) is treated at room temperature with oxalyl chloride (0.52 g, 4.1 mmol) followed by a few drops of anhydrous DMF. Once bubbling subsided, the clear solution is cooled to 4° C. in an ice bath, and aluminium chloride (0.7 g, 5.25 mmol) is added in one portion. After stirring at 4° C. for 20 min, 1-pentyloxy-naphthalene (0.563 g, 2.63 mmol) is added, and the reaction mixture is allowed to warm gradually to ambient temperature overnight. The reaction mixture is distributed between ethyl acetate (50 mL) and water (250 mL) and extracted. The aqueous phase is additionally washed with fresh ethyl acetate (2×50 mL). The combined organic phases are dried (anhydrous MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel using a Biotage apparatus (Dyax Corp.) and cyclohexane:ethyl acetate (9:1) as eluant to give the desired product (0.996 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-])[C:6]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:9][CH2:8]2.[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>>[C:29]([O:32][C:4]1[N:5]=[C:6]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:11](=[O:13])[C:12]=2[C:3]=1[O:2][CH3:1])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN2CCc3c(c(OC)c[n+]([O-])c3C(=O)N(C)C)C2=O)cc1
Product: COc1ccc(CN2CCc3c(C(=O)N(C)C)nc(OC(C)=O)c(OC)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide 2-oxide (10.3 g) was dissolved in 30 ml acetic anhydride and transferred to a 50 mL heavy walled pressure flask and sealed. The reaction was heated in a 100° C. oil bath overnight. The reaction was concentrated in vacuo. The remaining oil was dissolved in 5 mL EtOAc and purified on an Isco automated system affixed with a Biotage Flash 40 (L) (120 g silica) cartridge eluted with 0-10% MeOH in EtOAc over 20 minutes and hold at 10% for 40 minutes. The product eluted pure by HPLC/MS and NMR.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]2[NH:21][CH2:20][C@@H:19]3[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:18]3[C:17]=2[CH:16]=1>>[CH3:26][O:25][C:23]1[C:22]2[NH:21][CH2:20][C@@H:19]3[CH2:27][NH:28][CH2:29][C@@H:18]3[C:17]=2[CH:16]=[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:13])([F:12])[F:1])[CH:24]=1
Reactant: COc1cc(Br)cc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: COc1cc(-c2ccccc2C(F)(F)F)cc2c1NC[C@@H]1CNC[C@H]21

Procedure:
Following the procedures described in Example 12, except that 2-(trifluoromethyl)phenylboronic acid was used instead of phenylboronic acid, (±)-cis-tert-butyl 8-bromo-6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 11, Part A was converted into the title compound of Example 13. 1H NMR (CDCl3): δ 7.73 (d, 1H, J=7.7 Hz), 7.57-7.52 (m, 1H), 7.46-7.40 (m, 1H), 7.36 (d, 1H, J=7.4 Hz), 6.68 (s, 1H), 6.66 (s, 1H), 4.51 (broad s, 1H), 3.85 (s, 3H), 3.65-3.30 (overlapping m, 5H), 3.15-2.98 (m, 2H), 2.78-2.68 (m, 1H). LRMS (ES)+: 349.3 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1>C(O)(=O)C.[Rh]>[NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: [Rh]
Solvent: CC(=O)O
Product: O=C(O)C1CCNC2CCCCC21
Yield: 88.8 %

Procedure:
A solution of 4-quinoline carboxylic acid (1.5 g., 8.6 mmoles) in acetic acid (30 ml) containing 5% Rh/Al2O3 (400 mg) was reduced (4.2 kg, 85° C.) in a steel bomb for 15 hours. After cooling, the catalyst was filtered and the solvent was evaporated to dryness. The residue was triturated with EtOH/Et2O (50/50), filtered and washed with a minimum of Et2O to give pure 4-decahydroquinoline carboxylic acid (1.4 g, 90%) as white crystals, mp >300° C., see Burckhardt, Helferick, L. Wissel, J. Prak. Chim. 39 (1966). An analytical sample of its hydrochloride salt was recrystalized in acetonitrile/water. (Found: C 54.19; H 8.62; N 6.33. Calc. for C10H18ClNO2 : C 54.66 H 8.26; N 6.38). 1H NMR 400 MHz (H2O) δ=1.3-1.5 (4H, m) 1.67-1.76 (1H,m) 1.82-2.04 (5H, m) 2.29-2.4 (1H, m) 2.62-2.7 (1H, d t) 3.01-3.17 (1H, m) 3.46-3.57 (2H,m) 7.89 (1H, broad s, exchangeable D2O) 8.29 (1H broad s, exchangeable D2O).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=[O:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[H][H]>[Pt].C(N(CC)CC)C>[F:1][C:2]([F:12])([F:13])[CH:3]([OH:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CC(C)OC(=O)CC(=O)C(F)(F)F
Agent: [Pt]
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Isopropyl 4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.1 g of 5% Pt/C, 0.01% load) and triethylamine (0.2 g, 0.4 % load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 48.5 g (96% yield) of isopropyl 4,4,4-trifluoro-3-hydroxybutyrate is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[O:28][CH3:29])=[O:16])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:14][C:15](=[O:16])[N:17]([C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[O:28][CH3:29])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)/C=C/c1cccc(F)c1NC(=O)Nc1cc(C(F)(F)F)ccc1OC
Solvent: CC(C)=O
Product: COC(=O)CC1c2cccc(F)c2NC(=O)N1c1cc(C(F)(F)F)ccc1OC
Temperature: 56 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
Methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-phenyl}acrylate (50 g) is suspended in acetone (1.2 l) and treated with 1,8-diazobicyclo[5.4.0]undec-7-ene (3.7 g). The suspension is warmed to reflux (ca. 56° C.) and stirred for 4 h. The resulting clear solution is filtered warm through kieselguhr (5 g). The kieselguhr is rinsed with warm acetone (100 ml). Subsequently, acetone (550 g) is distilled off. The resulting suspension is cooled to 0° C. in the course of 3 h and stirred. The product is filtered off with suction, washed twice with cold acetone (50 ml) and dried at 45° C. overnight in the vacuum drying oven using entraining nitrogen. A total of 44.5 g of methyl {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate are obtained as a solid, corresponding to 89% of theory.
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].Cl>CN(C=O)C.CO>[F:14][C:15]1([F:21])[CH2:20][CH2:19][N:18]([C:2]2[C:11]([CH3:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)c1cnc(F)c(C)c1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(=O)O)cnc1N1CCC(F)(F)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
A mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol), 4,4-difluoropiperidine hydrochloride (4.66 g, 29.6 mmol), and cesium carbonate (13.5 g, 41.4 mmol) in DMF is stirred at 120° C. for 16 hours. After cooling to rt, 1 M aqueous sodium hydroxide solution (50 mL) and MeOH (50 mL) are added to the resulting mixture. After stirring at 60° C. for 3 hours, the mixture is acidified by 2 M hydrochloric acid (pH is around 4), and MeOH is removed in vacuo. The formed white precipitate is collected by filtration to give 1.17 g (39%) of the title compound as white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[CH:27]O)[C:20](=[O:26])[NH:21]2>>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[CH:27][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:14][CH:13]=1)[C:20](=[O:26])[NH:21]2
Reactant: O=C1Nc2cccc(F)c2C1=CO
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Product: O=C1Nc2cccc(F)c2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 77.1 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) to give the named compound as a yellow solid (790 mg, 77.0%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[C:6](=[O:8])=[O:7]>>[C:6](=[O:8])([OH:7])[NH2:1].[NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4]
Reactant: O=C=O
Agent: CC(N)CN
Product: NC(=O)O

Procedure:
Sixty grams fumed silica (sold as "Cab-O-Sil" MS-7 by Cabot Corp.) were agitated in a 1-liter flat bottom reaction kettle under a carbon dioxide atmosphere. The kettle was fitted with a stirrer, a gas inlet and an inlet from a pump. 1,2-Diaminopropane and carbon dioxide were simultaneously added via the pump and gas inlets over a period of 7.5 hrs. while the temperature was kept at 25°-30° C. At the end of this time 211 g. of 1,2-diaminopropane carbamate had been formed.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[F:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:17])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C)cc1F
Yield: 75 %

Procedure:
Sulfuric acid (2 mL) was added to the solution of 2-fluoro-4-methylbenzoic acid (0.848 g; 5.34 mmol) in methanol (30 mL). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure to give 0.672 g (75%) of methyl 2-fluoro-4-methylbenzoate as a solid.