Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:19])[CH2:17][OH:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[K+].[NH3:22]>>[NH2:22][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:19])[CH2:17][OH:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CC(CO)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [K+]
Agent: [OH-]
Product: CC(CO)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C

Procedure:
R 3-(4-Chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol (1.0 g, 3.6 mmol) and methanolic ammonia (30 mL of 15%) were combined and then heated in a steel bomb at 150° C. The container was allowed to cool to ambient temperature. Excess methanolic potassium hydroxide was added to the reaction mixture which was then concentrated under reduced pressure to decrease the volume. Water was added and then concentration was continued until a solid formed. The solid was isolated by filtration, washed with water and then dried to provide a near white solid. This material was recrystallized from methanol/dichloromethane to provide R 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol as colorless solid, m.p. 258-261° C. Analysis: Calculated for C14H16N4O: %C, 65.61, %H, 6.29; %N, 21.86; Found: %C, 65.50, %H, 6.3, %N, 21.7.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33][CH3:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33][CH3:34])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1SC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Allyl(rac)-4-[4-cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (750 mg, 1.54 mmol; Example 39) was dissolved in THF (10 ml), and morpholine (201 mg, 2.308 mmol) was added. The reaction solution was saturated with argon (argon was bubbled through the solution for 30 min). Tetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) was then added, and the mixture was stirred at RT overnight. Since, by HPLC control, only little conversion could be observed, more tetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) was added, and the mixture was stirred at RT for a further 3 h. The contents of the flask was then filtered through kieselguhr, and the residue was washed with THF. The filtrate was concentrated under reduced pressure and the residue was recrystallized from diethyl ether (15 ml). The crystals were filtered off with suction and dried under high vacuum. This gave 663 mg (96% of theory) of the target compound.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[C:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: OCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 41.6 %

Procedure:
To a solution of 45 g of butane-1,4-diol in 0.25 l of pyridine, cooled to 0° C., were added 139.4 g of triphenylchloromethane and the mixture was stirred at room temperature for 26 h. The precipitate formed was removed by filtration and the filtrate was evaporated in vacuo. The residue was taken up in 0.5 I of ethyl acetate and the solution was washed successively with 200 ml portions of water, 1N hydrochloric acid, water, 5% sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from ethyl acetate/hexane afforded 69.0 g of 4-trityloxy-1-butanol as white crystals of m.p. 73°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(F)cc1
Yield: 7.6 %

Procedure:
A solution of 5-chloropyrimidin-2-one (1.309 g) and 2-chloro-4'-fluoroacetophenone (1.726 g) in triethylamine (2 ml) and ethanol (50 ml) was stirred and heated at reflux for 11/2 hours. After evaporation of solvents, the residue was triturated with water (100 ml). The resulting collected solid was crystallised from ethanol then acetone, but still required purification, by preparative thin-layer chromatography on silica developed in chloroform-ethanol (25:1 v/v), before crystallisation from propan-2-ol to give the title pyrimidinone (204 mg,); 196°-202°; λmaxEtOH 245 nm (ε 17780), 333 nm (ε 2090), λinf 236 nm (ε 15230), 280 nm (ε 980).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH3:19]
Reactant: CCO
Reactant: CC(CCC(=O)O)CCC(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC(C)CCC(=O)O

Procedure:
145 g of crude 4-methylpimelic acid, 68 ml of absolute ethanol and 12 ml of concentrated sulfuric acid were refluxed for 5 hours. The mixture was poured into ice and extracted several times. The combined ether solutions were extracted with saturated NaHCO3 until the development of CO2 was finished. The aqueous extracts were covered with a layer of ether and adjusted while stirring to pH 2 to 3 with diluted sulfuric acid. The ether layer was separated and the aqueous phase was saturated with (NH4)2SO4 and extracted three times with ether.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:26][O:25][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[N:13]=[CH:12][N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]2=[O:24]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCBr
Reactant: C1CCNCC1
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCCCC1
Yield: 83 %

Procedure:
A solution of 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.89 g, 6.78 mmol) in piperidine (100 ml) was heated at 100° C. for 1 hour. After cooling, the volatiles were removed under vacuum. The residue was dissolved in methylene chloride, and washed with saturated ammonium chloride and brine. The organic layer was dried (MgSO4) and the volatiles were removed by evaporation. The residue was dried under vacuum to give 6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.4 g, 83%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[F:17][C:18]1[CH:19]=[C:20]([F:24])[CH:21]=[CH:22][C:23]=1[C:10]([CH:7]1[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]1)=[O:12]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
A stirred solution of 10 g (58.5 mmol) of 1-acetylpiperidine-4-carboxylic acid in anhydrous dichloroethane (35 mL) was treated with 5.1 mL (70.2 mmol) of thionyl chloride in 7 mL of dichloroethane and then heated to 60° C. for 30 min. Another flask containing a suspension of 8.02 mL (81.8 mmol) of 1,3-difluorobenzene and 17.9 g (134 mmol) of aluminum chloride in 55 mL of dichloroethane was prepared, to this was added the previously prepared acid chloride suspension in portions. The resulting suspension was refluxed for 4 h, cooled and then poured over ice and HCl. The acidic solution was extracted with CH2Cl2 (3×300 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The crude product was recrystallized from hexanes to afford 9.5 g (61%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C14H15F2NO2, 267.11; m/z found, 268.1 [M+H]+, 1H NMR (CDCl3, 400 MHz): 7.87 (dt, J=8.41, 6.65 Hz 1H), 6.98 (m, 1H), 6.88 (ddd, J=10.96, 8.61, 2.35 Hz, 1H), 4.55 (m, 1H), 3.87 (m, 1H), 3.32 (dtt, J=10.76, 3.91, 1.37 Hz, 1H), 3.19 (ddd, J=13.89, 11.93, 2.93 Hz, 1H), 2.79 (ddd, J=13.89, 12.24, 2.93 Hz, 1H), 2.10 (s, 3H), 1.95 (br d, J=12.91 Hz, 2H), 1.72 (br m, 1H), 1.56 (br m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22](O)=[O:23].Cl.[CH3:26][O:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[N:7]=[C:6]2[C:22]([N:32]1[CH2:31][CH2:30][C:29]2[C:34](=[CH:35][CH:36]=[CH:37][C:28]=2[O:27][CH3:26])[CH2:33]1)=[O:23]
Reactant: COc1cccc2c1CCNC2
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)N3CCc4c(cccc4OC)C3)c2cc1OC
Yield: 20.2 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 110 (20.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.67 and 2.92 (2t, 2H), 3.51-4.09 (m, 11H), 4.47 and 4.98 (2s, 2H), 6.47-7.28 (m, 4H), 7.38-7.42 (m, 1H), 7.51-7.55 (2s, 1H), 7.59-7.63 (m, 1H), 8.15-8.20 (m, 1H), 8.30-8.35 (m, 1H); 19F (376 MHz, DMSO-d6) 6-113.0; MS (ESI) m/z 474 ([M+H]+).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:11]=3)[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:22]=1
Reactant: CCCCc1nc(=O)c2cc(C(C)(C)O)ccc2[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1nc2ccc(C(C)(C)O)cc2c(=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.37 g of 2-butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone in 115 ml of acetone is added 1.58 g of 4-bromobenzyl bromide and 2.18 g of anhydrous potassium carbonate. The resulting suspension is heated to reflux for 16 hours. The reaction mixture is then allowed to cool to room temperature, filtered and the filtrate is concentrated in vacuo. The residue is purified by HPLC eluting with ethyl acetate/hexanes (1:3) to provide the desired product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[C:26]=1[F:27])(=O)=O.O1CCOCC1.B([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[C:42]([OH:44])=[O:43])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[F:27][C:26]1[C:11]2[C:12]([C:22](=[O:25])[NH:23][CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[C:42]([OH:44])=[O:43]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)c(F)c12
Reactant: COc1ccc(C(=O)O)cc1B(O)O
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3OC)c(F)c12
Temperature: 85 °C
Yield: 35.4 %

Procedure:
To a small sealed tube was added 4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (64.5 mg, 0.111 mmol), dioxane (6 mL), water (1.200 mL), 3-borono-4-methoxybenzoic acid (26.1 mg, 0.133 mmol), cesium carbonate (54.2 mg, 0.167 mmol) and finally Tetrakis(triphenylphosphine)palladium(0) (2.6 mg, 2.2 μmol). The tube was sealed and the reaction mixture heated at 85° C. for twenty hours. The reaction mixture was cooled to room temperature, pushed through a plug of celite and evaporated to a dark oil under a stream of nitrogen. The residue was triturated with 15 mL of ice water then air dried overnight giving 17.2 mgs (35.4% yield) of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxy benzoic acid as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS rt=2.770 min., m/z 438.3 (M+H), 93% purity.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:10][C:11](=[O:21])[C:12]=1[O:13]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[CH:10][C:11](=[O:21])[C:12]=1[OH:13])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccc(Cl)cc2)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CC(C)NC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2ccc(Cl)cc2)n1C
Yield: 50.8 %

Procedure:
6-[(4-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (18-07) (250.0 mg, 50.64%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-07) (600.0 mg, 1.19 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [NH:1]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].O[CH2:14][C:15]1[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=1>>[O:21]=[C:18]1[NH:19][CH:20]=[C:15]([CH2:14][N:1]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:11])[O:3][C:2]2=[O:12])[CH:16]=[CH:17]1
Reactant: O=c1ccc(CO)c[nH]1
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Product: O=c1ccc(Cn2c(=O)oc(=O)c3cccnc32)c[nH]1

Procedure:
May be prepared by a similar procedure as described for preparation 7B, starting from 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (can be prepared as described by Beckwith and Hickman in J. Chem. Soc. (C), 1968 pp 2756-2759) and 5-hydroxymethyl-1H-pyridin-2-one (prepared as described in WO 01/77078 A1).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].[OH-].[K+]>C1COCC1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([NH:4][CH2:5][CH:6]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:22][CH:23]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)C(CNC(C)=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NCC(C(=O)O)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{1-[(acetylamino)methyl]-2-methoxy-2-oxoethyl}benzoate (530 mg, 1.65 mmol) in THF (9 mL) and MeOH (3 mL) was added KOH (1N, 1.98 mL, 1.98 mmol). After stirring at room temperature for 1 h, the mixture was diluted with 0.5 M citric acid and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and concentrated to yield 3-(acetylamino)-2-[4-(tert-butoxycarbonyl)phenyl]propanoic acid as a white powder. MS (ESI) calcd [M+Na]+ 330.1, found 330.1.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([C:13](=[O:24])[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH3:15])[CH:3]=1.[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][CH2:28]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][CH2:28][O:11][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Br:1])=[CH:3][C:4]=1[C:13](=[O:24])[N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:15]
Reactant: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1CC(=O)O
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1CC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
To a solution of DCM (10 mL) containing 2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic acid (427 mg, 1.0 mmol) and 2-trimethylsilylethanol (183 mg, 1.5 mmol), were added DMAP (18.9 mg, 0.15 mmol) and DCC (320 mg, 1.5 mmol). The mixture was stirred at rt for 24 hrs, concentrated, and then directly purified via silica gel column chromatography eluting with ethyl acetate in hexane (20%) to yield {4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic acid 2-trimethylsilanyl-ethyl ester (520 mg). MS: (M−CH2CH2)+487.9/486.0; tR=3.34 min (method 1).
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:42])[CH2:10][N:11]([C:21](=[O:41])[C@H:22]([CH3:40])[NH:23][P:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.[OH-].[Na+]>CC(C)=O.O>[CH2:26]([P:24]([NH:23][C@H:22]([C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:43])=[O:2])=[O:42])=[O:41])[CH3:40])([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN(C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1)C1Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)O)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Dibenzylphosphoryl-L-alanyl-N-(2-indanyl)glycyl-L-proline methylester (0.79 g, 1.2 m mole) was dissolved in acetone (5 ml), and sodium hydroxide (0.15 g, 3.8 m mole) in water (4 ml) solution was added thereto while cooling in the ice bath. The mixture was stirred for 1 hour. To this solution water (100 ml) was added, and thereafter this thus formed solution was washed with ethyl ether (50 ml). the ether washed solution was neutralized with 1N hydrochloric acid, and therefrom the desired product was extracted with ethyl acetate. The thus extracted solution was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily dibenzylphosphoryl-L-alanyl-N-(2-indanyl)glycyl-L-proline (0.77 g, yield: 99.7%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>>[ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(C2(O)CCN(Cc3ccccc3)C2)c1
Agent: Cl
Product: Cc1cccc(C2=CN(Cc3ccccc3)CC2)c1
Yield: 100 %

Procedure:
A mixture of 8 parts of 3-(3-methylphenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride and 150 parts of a hydrochloric acid solution 6N was stirred and refluxed for 3 hours. After cooling, the reacting mixture was evaporated, yielding 7.4 parts (100%) of 2,3-dihydro-4-(3-methylphenyl)-1-(phenylmethyl)-1H-pyrrole hydrochloride as a residue (intermediate 47).
Reaction SMILES: CCCCCC.[H-].[K+].[CH3:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=1[Cl:25]>CN(C)C=O>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([N:12]2[CH:13]=[CH:14][C:10]([CH3:9])=[N:11]2)=[CH:20][C:19]=1[Cl:25]
Reactant: Cc1cc[nH]n1
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1Cl
Temperature: 130 °C
Yield: 82.8 %

Procedure:
Under anhydrous conditions a stirred suspension of hexane washed potassium hydride (0.424 g, 10.6 mmol) in 5 mL of dimethylformamide was treated in one portion with 3-methyl pyrazole (0.85 mL, 10.6 mmol). After the gas evolution ceased, 2-chloro-4-fluorobenzoic acid methyl ester (2.0 g, 10.6 mmol) was added to the clear solution. The mixture was heated at 130° C. for 15 minutes, cooled, and partitioned between ethyl acetate and brine. The organic layer was washed with water and brine, and dried over sodium sulfate. Removal of solvent afforded 2.2 g of a yellow oil consisting of a mixture of 3-methyl and 5-methylpyrazole regioisomers. In addition, about 20% of the acid derived from hydrolysis of the ester was detected by analysis of the NMR spectrum of the crude product. The desired 3-methylpyrazole regioisomer was separated from the 5-methyl isomer of Example 16 by flash chromatography (on silica Merck-60, dichloromethane-hexane 2:1) and was isolated as a white solid (1.55 g).
Reaction SMILES: ClC1C=C(C(F)(F)F)C=C(Cl)C=1N.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](C(CC#N)C(=O)C)(=[O:23])=[O:22])=[CH:17][CH:16]=1.ClC1C=CC(S([C:41]([N:48]=[N:49][C:50]2[C:55]([Cl:56])=[CH:54][C:53]([C:57]([F:60])([F:59])[F:58])=[CH:52][C:51]=2[Cl:61])([CH2:45][C:46]#[N:47])[C:42](=[O:44])[CH3:43])(=O)=O)=CC=1>>[C:42]([C:41]1[C:45]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:46]([NH2:47])[N:49]([C:50]2[C:51]([Cl:61])=[CH:52][C:53]([C:57]([F:58])([F:60])[F:59])=[CH:54][C:55]=2[Cl:56])[N:48]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)C(CC#N)(N=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(=O)C(CC#N)S(=O)(=O)c1ccc(Cl)cc1
Agent: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
A process according to claim 1, comprising reacting the hydrogensulfate diazonium salt of 2,6-dichloro-4-trifluoromethylaniline with 3-(4-chlorophenylsulfonyl)-4-cyanobutan-2-one, and then subjecting the resultant 3-(4-chlorophenylsulfonyl)-3-(2,6-dichloro-4-trifluoromethylphenylazo)-4-cyanobutan-2-one to rearrangement to afford 3-acetyl-5-amino-4-(4-chlorophenyl)sulfonyl-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole.