Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[OH:16].O.O.[OH-].[Li+]>CO>[OH:16][C:5]1[CH:6]=[C:7]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CCOCC2)cc1O
Temperature: 80 °C

Procedure:
To a stirred solution of 2-hydroxy-4-morpholin-4-yl-benzoic acid methyl ester (4.6 g; 19.4 mmol) in MeOH (120 mL) was added water (60 mL) and lithium hydroxide hydrate (4.08 g; 97 mmol). The resulting mixture was heated to 80° C. for 15 hours. The resulting mixture then was washed with EtOAc (3×60 mL), and cooled to 0° C. and acidified with 2 N aqueous hydrochloric acid to pH 4. The resulting precipitate was collected on a Buchner funnel with suction, washed with water, and air dried to provide the acid (4.16 g; 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][NH2:36])[N:30]=[CH:29]1>CO>[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][NH:36][C:15]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:4]=3)=[O:10])=[CH:21][CH:20]=2)=[NH:19])[N:30]=[CH:29]1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: NCCCc1c[nH]cn1
Solvent: CO
Product: N=C(NCCCc1c[nH]cn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 3-(1H-imidazol-4-yl)propan-1-amine (27 μl, 0.23 mmol) via procedure W to afford 83 mg of 4-(N-(3-(1H-imidazol-4-yl)propyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 459 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[Cl:13][C:14]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17].C(OCC)C>CN1CCCC1=O>[Cl:13][C:14]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:15]=1[C:16]([NH:18][C:19]([NH:5][C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:20])=[O:17]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
4.0 g (23.8 mmol) of 2-methoxy-5-nitroaniline were dissolved in 10 ml of N-methyl-2-pyrrolidinone, and 5.2 g (23.8 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate were added. Slight warming occurred. After 15 minutes at room temperature, diethyl ether was added, and the resulting precipitate was filtered off with suction. 6.6 g (79%) of the desired product were obtained.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[CH2:1]([CH:3]1[N:12]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCC1Nc2cc(F)ccc2-n2cccc21
Product: CCC1c2cccn2-c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1

Procedure:
4-Ethyl-7-fluoro-5-(4-methoxybenzoyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 17 and p-anisoyl chloride according to the procedure of Example 106, Step 2, mp 39-42° C. MS (ESI) m/z 351; Anal. Calcd for C21H19FN2O2: C, 71.99; H, 5.47; N, 7.99. Found: C, 70.90; H, 5.62; N, 7.65.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:19]1([NH:22][C:23]([C:25]2[S:38][C:28]3=[N:29][C:30](S(C)=O)=[C:31]([Cl:34])[C:32]([CH3:33])=[C:27]3[C:26]=2[NH2:39])=[O:24])[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([NH:22][C:23]([C:25]2[S:38][C:28]3=[N:29][C:30]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:31]([Cl:34])[C:32]([CH3:33])=[C:27]3[C:26]=2[NH2:39])=[O:24])[CH2:21][CH2:20]1
Reactant: OCc1ccccc1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCc2ccccc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
To a solution of benzyl alcohol (0.541 g, 5.00 mmol) in THF (2.5 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(2.50 ml, 2.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 2 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). The mixture is diluted to 100 ml with water and then cooled to 0° C. and stirred. A yellow precipitate is formed. This solid is collected by filtration and purified by flash chromatography (1.5:1 hexane:EtOAc) to give the title compound as a pale yellow solid (0.130 g, 33%). Mass (m/z): 388.2 (M++1), 386.2 (M+−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
To a solution of 2,4-dichloropyrimidine (2.307, 15.49 mmol) and TEA (2.15 mL, 15.49 mmol) in EtOH (19.36 mL) at −10° C. was added (R)-piperidine-3-carboxylic acid (Sigma Aldrich, 2 g, 15.49 mmol). The reaction was allowed to slowly warm to room temperature while stirring. After 20 hours, the reaction was concentrated. The residue was adsorbed onto a plug of silica gel and purified by chromatography through a 100 g silica gel column, eluting with 2% to 10% MeOH in DCM followed by 20% to 50% 5:45:50 folic acid:EtOH:DCM, to provide M4.1 as a white solid in 21% yield. 1H NMR (400 MHz, CD3OD) δ ppm 1.51-1.63 (m, 1H) 1.76-1.91 (m, 2H) 2.09 (dd, J=8.71, 4.40 Hz, 1H) 2.51-2.60 (m, 1H) 3.33-3.51 (m, 3H) 4.01 (br. s., 1H) 6.74 (d, J=6.46 Hz, 1H) 7.96 (d, J=6.26 Hz, 1H); ESI-MS M+H 241.9.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:29][CH:28]2[CH2:30][CH:24]3[CH2:25][CH:26]([CH2:31][CH:22]1[CH2:23]3)[CH2:27]2.Cl>O.C1(C)C=CC=CC=1>[CH:24]12[CH2:30][CH:28]3[CH2:27][CH:26]([CH2:31][CH:22]([N:21]([CH2:20][CH2:19][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:8]#[N:9])[CH2:29]3)[CH2:23]1)[CH2:25]2
Reactant: ClCCN1CC2CC3CC(C2)CC1C3
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(CCN1CC2CC3CC(C2)CC1C3)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 18 parts of α-phenylbenzeneacetonitrile in 140 parts of dry toluene is added, with stirring under nitrogen, approximately 4 parts of a 57% dispersion of sodium hydride in oil. The resultant mixture is heated to 90° and stirred thereat under nitrogen for 3/4 hr. The yellow-green flocculent suspension which eventuates is cooled to around 65°, whereupon 20 parts of 4-(2-chloroethyl)-4-azatricyclo[4.3.1.13,8 ]undecane [preparable by mixing the hydrochloride thereof (U.S. Pat. No. 3,845,038) with excess aqueous sodium carbonate, extracting the mixture with toluene, and consecutively washing the extract with water, drying it over anhydrous sodium sulfate, filtering out the drying agent, and removing the solvent by vacuum distillation] in 85 parts of dry toluene is introduced, with stirring, during 15 minutes. The mixture thus obtained is stirred for 2 hours at 90°-100°. The yellow-orange solution which results is cooled to room temperature, at which point 20 parts of water is stirred in. Aqueous and organic phases are separated, the aqueous phase is extracted with toluene and then discarded, and the extract and organic phases are combined and thereupon consecutively washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is stripped of solvent by vacuum distillation, affording 4-[4-azatricyclo(4.3,1.13,8)undecan-4-yl]-2,2-diphenylbutanenitrile as the residue. The product has the formula ##STR9##
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:35]([O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47]Br)=[CH:41][CH:40]=1)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:24])[CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:41][CH:40]=1)[CH3:36]
Reactant: CCOC(=O)c1ccc(OCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCOC(=O)c1ccc(OCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Yield: 17.1 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (prepared in Example 1A, Step C) (250 mg, 0.719 mmol) was alkylated with NaHMDS (1 M in THF, 0.86 mL, 0.86 mmol) and 4-(2-bromo-ethoxy)-benzoic acid ethyl ester (216 mg, 0.791 mmol). The reaction temperature was maintained at 50° C. over 24 h. Purification by radial chromatography (hexanes to 4:1 hexanes:EtOAc) provided 4-(2-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-ethoxy)-benzoic acid ethyl ester (66.4 mg). 1H NMR (CDCl3) (selected peaks) δ7.96 (m, 2H), 7.29–7.13 (m, 5H), 6.84 (m, 2H), 4.33 (q, 2H), 4.12 (m, 2H), 3.90 (m, 2H), 3.68 (m, 1H), 3.34 (m, 1H), 2.73 (m, 2H), 2.32 (m, 2H), 1.36 (t, 3H), 0.85 (s, 9H), −0.03 (s, 3H), −0.15 (d, 3H).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[CH:15]=1)=[O:28]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Product: CC(F)(F)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(F)cc3Cl)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=410.06.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[CH:9][C:8]2=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].CO.Cl.[C:26](=O)([O:30]CC)[O:27]CC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:26]([OH:30])=[O:27])=[CH:9][C:8]2=[O:18])=[CH:19][CH:20]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Yield: 15 %

Procedure:
A solution of 1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (18.0 g.) in diethyl carbonate (80 ml.) was added to a stirred suspension of sodium hydride (15.4 g.; weighed as a 60% w/w dispersion in oil, but subsequently washed by decantation with light petroleum, b.p. 40°-60° C., to remove the oil) in diethyl carbonate (20 ml.). The mixture was stirred under reflux for 11/2 hours, and formed a thick suspension. This was cooled and treated with a small amount of methanol to destroy any remaining sodium hydride. Dilution with ether (400 ml.) gave a suspension from which the solid was filtered. This was suspended in ethanol (180 ml.) and brought to pH 3 by addition of hydrochloric acid. Water (600 ml.) was added, and the suspension was stirred for 30 minutes before the solid was collected by filtration, washed with water, and well drained. This solid [which comprised diethyl 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylmalonate] was dissolved in ethanol (180 ml.), to which was added aqueous 40% w/v sodium hydroxide (20 ml.), and the mixture was heated under reflux for 4 hours. The cooled mixture was added to water (600 ml.) to give a solution which was brought to pH 3 by addition of concentrated hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, drained, and crystallised from ethanol to give 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid, m.p. 208°-209° C., in 51% overall yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:38])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35].C(N(CC)CC)C>O1CCCC1>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:30]=[C:2]([NH:1][C:31](=[O:38])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])[N:3]=2)[N:6]=1)=[O:29]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (400 mg, 0.967 mmol) in tetrahydrofuran (10 mL) were added dropwise 2,2,2-trichloroethyl chlorocarbonate (159 μL, 1.16 mmol) and triethylamine (202 μL, 1.45 mmol), and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, and the residue was washed with diisopropyl ether and water to give the title compound (436 mg, 76%) as a pale-yellow powder.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>CCOCC>[C:1]([N:5]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=NNC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)=NN(C(=O)c1ccccc1)C(C)(C)C

Procedure:
Acetone tert-butylhydrazone (2.0 g) is admixed with 4.4 g of benzoyl chloride and 15 mL of 10% sodium hydroxide. The mixture is stirred until the benzoyl chloride odor is no longer detectable. The resulting product is then dissolved in ether and dried over magnesium sulfate. Evaporation of the solvent from the mixture leaves acetone N-tert-butyl-N-benzoylhydrazone, b.p. 100°-103° C. This product also is referred to as 1-tert-butyl-2-isopropylidenehydrazide of benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[O:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[O:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1ccc(-c2cccc3c2CCNC3C)o1
Product: Cc1ccc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)o1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[C:13]([CH3:15])[C:10]([C:11]#[N:12])=[C:9]([CH3:16])[CH:8]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl>O1CCCC1>[C:11]([C:10]1[C:13]([CH3:15])=[CH:14][C:7]([B:17]([OH:22])[OH:18])=[CH:8][C:9]=1[CH3:16])#[N:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(Br)cc(C)c1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4.55 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 1.39 g of 4-bromo-2,6-dimethylbenzonitrile in 25 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 20 minutes, 1.88 ml of triisopropyl borate are added. After 45 minutes, 15 ml of 1N aqueous HCl are added to the reaction mixture, which is warmed to room temperature. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1:1) each time. The combined organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remaining oil is mixed with 50 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in the title compound as a beige solid. Rt=3.20.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>O>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reaction time: 2 h

Procedure:
Condensation with Meldrum's acid was carried out according to the method of Bigi et. al. (2001) Tetrahedron Lett. 42:5203-5205. A 2 L pear-shaped flask was charged with 4-hydroxybenzaldehyde (50 g, 409 mmol) and water (400 mL). The flask was placed in a water bath at 75° C., and Meldrum's acid (62 g, 430 mmol) was added as a slurry in 400 mL of water. The reaction mixture was agitated for 2 hours and cooled in an ice bath for 2 hours. The product was collected by filtration and rinsed with cold water. After drying thoroughly, adduct M1.1 was obtained as a fine yellow powder. MS ESI (pos.) m/e: 519.0 (2M+Na). 1H NMR (500 MHz) (DMSO-d6) δ 9.75 (br s, 1H); 8.27 (s, 1H); 8.24 (d, 2H, J=10 Hz); 6.98 (d, 2H, J=10 Hz);.1.76 (s, 6H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:9]=[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[CH2:19]([C:8]1[N:7]=[C:6]([CH2:5][CH2:4][NH2:1])[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:9]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2cc(CCN=[N+]=[N-])nc(Cc3ccccc3)n2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(CCN)nc(Cc3ccccc3)n2)cc1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
To a solution of the product of Step C (0.066 g, 0.2 mmol) in THF (2 mL) was added PPh3 (0.059 g, 2.2 mmol). After 18 h, water was added (0.10 mL) and the mixture was stirred for 48 h. The mixture was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (5-15% EtOAc/hexanes) to give 0.060 g (99%) of the title compound. MS (ESI): exact mass calcd. for C20H21N3, 303.17; m/z found, 304.4 [M+H]+. 1H NMR (CDCl3): 7.98-7.96 (m, 2H), 7.45-7.44 (m, 2H), 7.36 (s, 1H), 7.32-7.28 (m, 4H), 7.23-7.19 (m, 1H), 4.31 (s, 2H), 3.13 (t, J=6.5, 2H), 2.91 (t, J=6.5, 2H), 2.42 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25]CCCCC)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>>[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=CCOCc1ccccc1
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Product: COC(=O)c1cccc(NCCOCc2ccccc2)c1C(=O)OC
Yield: 78 %

Procedure:
Benzyloxyacetaldehyde (5.27 ml, 37.5 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (6:3:1 methylene chloride/hexane/ethyl acetate) to give 7.98 g (78%) of yellow oil: 1H NMR (DMSO-d6) d 7.38–7.26 (m, 5H), 6.89–6.77 (m, 3H), 4.57 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.69 (t, J=5.5 Hz, 2H), 3.38 (q, J=5.4 Hz, 2H).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([N:25]3[CH:29]=[N:28][N:27]=[N:26]3)[CH:22]=[C:21]([C:30](O)=[O:31])[CH:20]=2)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[CH3:50][C@H:51]([NH2:59])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:50][CH:51]([NH:59][C:30]([C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:24]=[C:23]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)[CH:22]=1)=[O:31])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1
Reactant: C[C@H](N)CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3cnnn3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2cc(C(=O)NC(C)CN3CCOCC3)cc(-n3cnnn3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion at 0° C. to a solution of 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid (60.0 mg, 0.214 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000 mmol) in CH2Cl2 (3 mL). After the reaction stirred at 0° C. for 1 hour, (S)-1-Methyl-2-morpholin-4-yl-ethylamine (50.0 mg, 0.230 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to afford 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)-amide as a white solid (70 mg, 81%). MS (M+H)=407.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-methylsulfonylbenzenesulfonyl chloride as described in synthetic METHOD B to give a white solid (20.9 mg) with purity >90%. MS (pos) m/z 405.3.