Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15].C(#N)C.[Br:22]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>O>[CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([Br:22])[CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15]
Reactant: CCC(C)COc1ccccc1OCC(C)CC
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCC(C)COc1ccc(Br)cc1OCC(C)CC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1,2-Bis(2-methylbutyloxy)benzene (338 g, 1.35 mol) together with 2.5 l of acetonitrile was placed in a reaction vessel, cooled to 0° C. and admixed with 264 g (1.48 mol) of N-bromosuccinimide. The mixture was warmed to RT and stirred for another 90 minutes. After taking off the acetonitrile, the residue was admixed with toluene and water and the phases were separated. After shaking the aqueous phase with toluene and drying the organic phase over Na2SO4, the toluene was taken off. The crude product was purified by double fractional distillation under reduced pressure. This gave the product as a colorless oil (145° C., 1.3 mbar): 275 g (62%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[C:29]1([O:28][C:26](=[O:27])[NH:11][CH2:10][C:8]2[N:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)c1cc(CNC(=O)Oc2ccccc2)n(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
To a solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (5 g, 0.018 mol) in DMF (25 ml, 5 times), potassium carbonate (9.16 g, 0.066 mol, 3.5 eq) was added and cooled the contents to 0° C. Then phenyl chloroformate (3.28 g (2.65 ml), 0.02 mol, 1.1 eq) was added drop wise for 15 min and the overall reaction mixture was stirred for another 15 min at 0° C. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.3). On completion of the reaction, reaction contents were filtered, filtrate was diluted with cold water (100 ml) and the product extracted with ethyl acetate (3×25 ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. Crude obtained was purified by column chromatography (silica gel, 10% ethyl acetate/hexane) to yield the required product as a white solid (3.2 g, 45% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)([O-])=O.[S]>O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [S]
Solvent: O
Product: CC(C)(C)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 1,3-dinitro-4-tert-butylbenzene (10.0 g) in H2O (56 ml) was heated to reflux. A mixture of Na2S (21.42 g) and sulfur (2.85 g) in H2O (34 ml) was added over 1 h via an addition funnel. The reaction maintained at reflux for 1.5 h then cooled to RT and extracted with EtOAc. The organic extracts were combined and washed with H2O, brine, dried over MgSO4 and concentrated in vacuo to afford 4-tert-butyl-3-nitro-phenylamine which was used as is without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[CH3:15][NH:16][CH3:17].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:16]([CH3:17])[CH3:15])=[O:8])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(I)cc(C(=O)N(C)C)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 5-iodo-isophthalic acid monomethyl ester (3.00 g, 9.8 mmol) in N,N-Dimethylformamide (80 ml) was added dimethyl amine(2M solution in Tetrahydrofuran, 9.8 m, 79.61 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 3.72 g, 9.8 mmol), and finally di-iso-propyl ethyl amine (5.1 ml, 29.41 mmol), this mixture was stirred at room temperature over night. The solvent was stripped under reduced pressure and the crude purifies by silica gel chromatography to give afford 5-Iodo-N,N-dimethyl-isophthalamic acid methyl ester (2.46 g, 75%). MS: m/z 333.1 (M+H+).
Reaction SMILES: [C:1]1([C@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.CC1CCCO1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].Cl>O>[C:1]1([C@H:7]([O:9][C:23](=[O:24])[O:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)c1ccccc1
Agent: Cl
Solvent: CC1CCCO1
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A mixture of (R)-1-phenyl-ethanol (60.6 g, 0.496 mol), pyridine (42.5 mL, 0.526 mol) and 2-methyl-tetrahydrofuran (600 mL) was cooled to 0° C. and p-nitrophenyl chloroformate (100 g, 0.496 mol) was added over 15 min keeping the internal temperature below 5° C. The reaction mixture was warmed to room temperature and stirred for 2 h. To the reaction mixture was added 1.0 M HCl in water (300 mL). Layers were separated. The organic layer was washed with 1N HCl (300 mL) and brine (300 mL), filtered, concentrated to dryness by rotary evaporation, and dried under vacuum to give the title compound (140 g) as a clear yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:26])[N:13]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:26])[N:13]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[C:10](=[N:32][NH:31][C:28]([NH2:30])=[NH:29])[CH2:9]1
Reactant: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 154.3 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.25 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.16 ml), water (0.16 ml) and ethanol (15 ml) was refluxed for 8 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 154) (0.24 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:16])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])C>C1COCC1>[CH3:16][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH2:4][OH:3]
Reactant: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of the product from Example 194A (12.32 g, 55.2 mmole) in anhydrous THF (300 mL) at room temperature under nitrogen was added dropwise via cannulae 1M BH3 in THF (200 mL) over ten and one half minutes. On completion of the addition the flask was equipped with a condenser and the mixture heated under nitrogen to reflux in an oil bath for ten hours before cooling to room temperature. The reaction was quenched by the cautious drop wise addition of methanol (60 mL). The resulting mixture was concentrated to an oil which was then dissolved in ethyl acetate (150 mL) and treated with 1N HCl and allowed to stir at room temperature for one hour. The resulting organic phase was washed with brine (4×50 mL), dried over MgSO4, filtered and concentrated. The residue was taken up in toluene (25 mL) and re-concentrated. The oily solid was suspended in hexane (50 mL) and collected by vacuum filtration. The cake was washed with hexane (50 mL) then dried under vacuum to provide the title compound (9.55 g, 89% yield) as a light orange solid. MS (DCI+) m/z @ 213.1 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([CH3:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1C=C(C(O)=O)N2C=CC=CC=12>>[CH3:18][C:10]1[C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][C:16]=2[N:8]([CH2:1][C:2]2[CH:7]=[N:19][C:5]([CH3:6])=[CH:4][CH:3]=2)[N:9]=1
Reactant: Cc1nn(Cc2ccccc2)c2cccc(N)c12
Reactant: O=C(O)c1cnc2ccccn12
Product: Cc1ccc(Cn2nc(C)c3c(N)cccc32)cn1
Yield: 11 %

Procedure:
Prepared according to the method of Example 80, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-3-methyl-1H-indazol-4-amine with imidazo[1,2-a]pyridine-3-carboxylic acid and 3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine (8 mg, 11% yield). MS (APCI) m/z=397 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.CN([C:45]([O:49][N:50]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CO[NH3+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:28])[NH:50][O:49][CH3:45])([CH2:25][CH3:26])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CO[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-ethyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.084 mmol) prepared in Example 18, HATU (65 mg, 0.17 mmol) and DIPEA (66 mg, 0.54 mmol) in THF (1 mL) was added o-methylhydroxylamine hydrochloride (22 mg, 0.25 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (12 mg).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH3:13][CH:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15].[C@H:22]1([NH:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH2:42])[CH:38]=3)[N:33]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C@H:22]1([NH:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH:42][C:1]([N:19]4[CH2:20][CH2:21][N:16]([CH:14]([CH3:15])[CH3:13])[CH2:17][CH2:18]4)=[O:12])[CH:38]=3)[N:33]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(C(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate (44 mg, 0.16 mmol), commercially available 1-(2-propyl)-piperazine (47 mg, 0.363 mmol) and (R)—N2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol); obtained as a white solid (32 mg, 21%); MS: m/e=430.4 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[C:11](=O)([O-])[O-:12].[Na+].[Na+].Cl>O.CC(C)=O>[OH:6][CH:5]([C@H:3]1[O:4][C:11](=[O:12])[NH:1][CH2:2]1)[CH:7]([OH:8])[CH2:9][OH:10]
Reactant: O=C([O-])[O-]
Reactant: NC[C@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1NC[C@@H](C(O)C(O)CO)O1
Reaction time: 8 h
Yield: 28.2 %

Procedure:
1-Amino-1-deoxy-D-ribitol (2.1 g, 0.014 mole prepared from D-ribose as described by Wolfron et. al. J. Org. Chemi. 23, 571 [1958]) was dissolved in water (30 ml), and sodium carbonate (2.9 g, 28 mole) and a solution of p-nitrophenyl-chloroformate (3.2 g, 0.016 mole) in acetone (10 ml) were added at 0° C. The solution was stirred and allowed to stand at room temperature overnight. The solution was acidified with 5N hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase was evaporated and the residue extracted with ethanol. Chromatography on silica eluting with a gradient of chloroform and ethanol gave 5-(S)-(1',2',3'-trihydroxypropyl)-1,3-oxazolidin-2-one (0.7 g) an an oil.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[NH2:9][CH:10]=[C:11]([CH3:14])[CH:12]=O.C(N(CC)CC)C>Cl.C([O-])(=O)C.[NH2+]1CCCCC1>[CH3:14][C:11]1[CH:10]=[N:9][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:12]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(C=O)=CN
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cnc2c(c1)C(=O)CCC2
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.7 %

Procedure:
A mixture of cyclohexane-1,3-dione (22.4 g., 0.2 mol.), 3-amino-2-methylacrolein (17 g., 0.2 mol.), triethylamine (10 ml.) and piperidinium acetate (0.25 g.) was heated with stirring in an oil bath at 120° C for 24 hours. The cooled reaction mixture was dissolved in 2N HCl (50 ml.) and extracted with ethyl acetate (3 × 50 ml.) and the organic extracts discarded. The aqueous solution was adjusted to pH 10 with sodium carbonate and extracted with chloroform (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo. The residual oil was distilled to give the title compound as a colourless oil (17 g., 52%) b.p. 79°/0.2 mm Hg which solidified.
Reaction SMILES: [Li][CH2:2]CCC.CC(C)=O.C(=O)=O.[CH:13]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]2[O:21][CH2:22][O:23][C:15]=2[CH:14]=1.CI.Cl>C1COCC1>[CH3:2][C:17]1[C:16]2[O:21][CH2:22][O:23][C:15]=2[CH:14]=[CH:13][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [Li]CCCC
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C=O)ccc2c1OCO2
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
n-BuLi (2.5 M in THF, 26.4 mL, 66 mmol) was added dropwise to a solution of N,N,N′-(trimethyl)ethylenediamine (8.6 mL, 6.79 g, 66.4 mmol) in THF (120 mL) at −78° C. (acetone-dry ice bath). After 15 min, piperonal (9.0 g, 60 mmol) was added, the mixture was stirred for 15 min, and n-BuLi (2.5 M in THF, 72 mL, 180 mmol) was added via syringe. After the reaction mixture was stirred for 1 h at −78° C., CH3I (22.4 mL, 50.92 g, 360 mmol) was added at −78° C. The mixture was stirred for 2 h at room temperature, poured into cold stirred 10% hydrochloric acid (prepared with 100 mL concentrated hydrochloric acid and 360 mL water), extracted with CHCl3 (400 mL×3), washed with brine (400 mL), dried (Na2SO4), filtered and concentrated to give the crude product. Purification by preparative flash chromatography (SiO2, EtOAc-hexane 10:1) gave the white crystalline product (6.71 g, 68.1%): mp 70-71° C. 1H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.04 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>C(OCC)C.O>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[OH:4]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)Nc1ccc(C(O)CBr)cc1
Reaction time: 0.25 h
Yield: 18.9 %

Procedure:
To a solution of N-[4-(2-bromoacetyl)phenyl]acetamide (2.1 g, 0.0082 mol, in 30 mL of methanol) was introduced solid NaBH4 (1.0 g, 0.026 mol) at 0° C. and stirred at that temperature for 15 minutes. The mixture was diluted with diethyl ether (20 mL) and water (20 mL). The ether phase was separated and the aqueous phase was extracted with diethyl ether. The ether phases were combined and washed with brine, dried. Purification on a silica gel column gave the title compound as a white solid (0.40 g).
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([N:26]=[C:27]=[O:28])=[CH:18][CH:17]=1.[CH3:29]I>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([N:26]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[N:3]([CH3:29])[C:27]2=[O:28])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)c2ccccc12
Reactant: CI
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3ccccc23)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
Step 2 To a suspension of sodium hydride (1.23 g) in N,N-dimethylformamide (70 ml) was added dropwise a solution of ethyl 3-amino4,4,4-trifluorocrotonate (5.6 g) in toluene (50 ml) at 0° C. under nitrogen atmosphere. After 30 minutes, a solution of 4-chloronaphthyl isocyanate (28 mmol) in a mixed solvent of N,N-dimethylformamide (30 ml) and toluene (50 ml) was added dropwise at same temperature. The resulting solution was stirred for 2 hours at ambient temperature, and then methyl iodide (8 g) was added. After 12 hours, the reaction mixture was partitioned with water(200 ml) and a mixed solvent of ethyl acetate-hexane (1:1, 300 ml). The organic phase was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and obtained solid was washed with hot ethyl acetate to give 3-(4-chloronaphthalen-1-yl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidindione (6.6 g) as a brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:32])[C:18]([OH:31])([C:23]3[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:33])[CH:12]=2)=[CH:7][C:6]=1[F:34])=[O:4].Cl.[OH-].[Na+]>O1CCOCC1.O1CCCC1.CO>[Cl:33][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:34])[CH:7]=2)[CH:16]=[CH:15][C:14]=1[CH:17]([CH3:32])[C:18]([OH:31])([C:23]1[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=1)[C:19]([F:22])([F:21])[F:20]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: CC(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F

Procedure:
In analogy to Example 175, step 6, 3′-chloro-3-fluoro-4′-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-4-carboxylic acid methyl ester (Example 176) was treated first with aqueous HCl in dioxane, followed by aqueous NaOH in tetrahydrofuran/methanol to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=468.1 [M−H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[Cl:12][S:13]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:11])([CH3:1])[CH2:6][C:5]=2[CH:7]=1)(=[O:15])=[O:14]
Reactant: CC1(C)Cc2ccccc2O1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)Cc2cc(S(=O)(=O)Cl)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a stirred solution of 22.2 g (0.15 mole) of 2,3-dihydro-2,2-dimethylbenzofuran in 190 mL of chloroform was added dropwise 20 mL (0.3 mole) of chlorosulfonic acid. After complete addition, the reaction mixture was stirred at room temperature for two hours. The reaction mixture was poured into a separatory funnel with ice water and shaken. The organic layer was separated from the aqueous phase and dried over anhydrous magnesium sulfate. The dried organic phase was filtered and the filtrate was evaporated under reduced pressure to leave 14.5 g of 5-chlorosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran as a solid (mp 75°-77° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](O)=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:27]4[CH:28]=[CH:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5ccccc5n4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=49:49:3) to yield the title compound.
Reaction SMILES: C(OC([N:8]=[C:9]1[N:13]([CH2:14][C:15](O)=O)[N:12]=[C:11]([CH2:18][O:19][CH3:20])[S:10]1)=O)(C)(C)C.C(N(CC)CC)C.P(Cl)(Cl)([Cl:30])=O.O>C(#N)C>[Cl:30][C:15]1[N:8]=[C:9]2[N:13]([CH:14]=1)[N:12]=[C:11]([CH2:18][O:19][CH3:20])[S:10]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nn(CC(=O)O)c(=NC(=O)OC(C)(C)C)s1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COCc1nn2cc(Cl)nc2s1
Temperature: 80 °C
Yield: 35.6 %

Procedure:
To {2-[(tert-butoxycarbonyl)imino]-5-(methoxymethyl)-1,3,4-thiadiazol-3(2H)-yl}acetic acid a33 (418 g, 1.378 mol, 1 eq) in acetonitrile (2.51) at room temperature, are successively and slowly added triethyl amine (278.9 g, 2.756 mol, 2 eq), then phosphorous oxychloride (633.9 g, 4.134 mol, 3 eq). The reaction mixture is heated at 80° C. for one hour. After reaction completion, water (2.2 l) is slowly and carefully added at 50° C. The reaction mixture is extracted with dichloromethane (2×1.21), the combined organic layers are washed by a NaOH/NaCl aqueous solution (1.4 l of saturated NaCl solution+400 ml 2N NaOH), dried over MgSO4, filtered and condensed under reduced pressure. The residue is recrystallized from acetonitrile/water (1/1) to afford 99.8 g of pure 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole a35.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:12]3[N:13]=[C:14]([SH:16])[S:15][C:11]=3[CH2:10][C:9]=2[CH:8]=1)C.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:28][CH2:29][S:16][C:14]2[S:15][C:11]3[CH2:10][C:9]4[CH:8]=[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])[CH:19]=[CH:18][C:17]=4[C:12]=3[N:13]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)Cc1sc(S)nc1-2
Product: O=C(O)COc1ccc2c(c1)Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 42 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-6-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize-the title compound. Yield 42%.