Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)C.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:31]=[C:30]([C:19]2[CH:18]=[CH:17][C:16]([F:22])=[C:15]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[O:6][CH2:5][C:4]([OH:3])=[O:24])=[O:23])[CH:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C(O)COc1cccc(NC(=O)c2cc(-c3cccc(Cl)c3)ccc2F)c1

Procedure:
The phenyl bromide (139) (50 mg, 0.13 mmol) was coupled to 3-chloro-phenylboronic acid (20 mg, 0.13 mmol) using Method E. During this reaction, hydrolysis occurred and the residue was extracted using Work-up E1. The crude product was then triturated with TBME (2 ml), DCM (2 ml), and recrystallised from a hot 10% EtOH in H2O mixture to give the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]([NH2:29])=[O:28])=[O:25])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH3:20][S:17]([O:16][C@H:14]1[CH2:15][NH:11][C@H:12]([CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]([NH2:29])=[O:28])=[O:25])[CH2:13]1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)O[C@H]1CN[C@H](COCC(=O)NC(N)=O)C1

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (3.00 g) in a mixture of methanol (30 ml) and tetrahydrofuran (60 ml) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 5 hours in the presence of 20% palladium hydroxide on carbon (1 g). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine. To a solution of the compound obtained above in a mixture of tetrahydrofuran (20 ml) and water (20 ml) was dropwise added a solution of allyl chloroformate (0.82 ml) in tetrahydrofuran (2 ml) under ice-cooling with stirring, keeping the pH between 9-10 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 1 hour and extracted with ethyl acetate (50 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (15 g) and eluted with a mixture of methanol and chloroform (2:98 v/v) to give (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (1.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19].C(Cl)Cl>N1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:22][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.8 %

Procedure:
2.0 g of 4-chlorobenzenesulfonic acid chloride are added to a solution of 3.8 g of 5-chloro-2-aminobenzoic acid [4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] in 8.6 ml of pyridine at 0° C. After the reaction mixture has been stirred for 16 hours at room temperature, 300 ml of methylene chloride are added and the resulting solution is then washed with 100 ml each of 1N HCl, H2O, saturated NaHCO3 solution and saturated NaCl solution. The organic phase is then dried with MgSO4 and concentrated by evaporation. The crude product obtained is purified by stirring in diethyl ether. In this manner 3.8 g of 5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid [4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] are obtained in the form of white crystals (m.p. 191°-193° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[C:12]([C:23](OC)=[O:24])[CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.ClC1[N:37]=[C:36](O)[C:35]2[C:30](=[C:31]([C:42](OC)=O)C=[C:33]([N+:39]([O-])=O)[CH:34]=2)N=1.FC1C=CC(N)=CC=1>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[C:23]([OH:24])[C:12]3[C:11](=[C:16]([C:17]([NH:39][CH2:33][CH2:34][C:35]4[CH:36]=[N:37][CH:42]=[CH:31][CH:30]=4)=[O:19])[CH:15]=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c(O)nc(Cl)nc12
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)cc3)nc12
Agent: Nc1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: O=C(NCCc1cccnc1)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)cc3)nc12
Temperature: 25 °C

Procedure:
Methyl 2-(4-fluorophenyl)amino-4-hydroxy-6-nitroquinazoline-8-carboxylate. A solution of methyl 2-chloro-4-hydroxy-6-nitroquinazoline-8-carboxylate (1.50 g) and 4-fluoroaniline (1.76 g) in N-methylpyrrolidone (30 mL) was heated to 100° C. for 1 h. After cooling to room temperature, the reaction was cooled to 0° C. and a precipitate formed. The precipitate was isolated by filtration and washed with water (100 mL), 1M HCl (100 mL), and water (100 mL). The resulting material was dried to afford the title compound as a yellow solid (1.89 g). 1H NMR (300 MHz, DMSO-d6 (w/TFA (50 uL)): 8.80 (d, J=2.6 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 7.85 (dd, J=8.4, 5.3 Hz, 2H), 7.24 (t, J=8.7 Hz, 2H), 3.97 (s, 3H). HPLC (Method F): 6.71 min. MS (APCI+): m/z 359.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) solution of (5-bromo-3-pyridinyl)acetic acid (1.00 g, 4.63 mmol) in diethyl ether (17 mL) and methanol (11 mL) was added a solution of (trimethylsilyl)diazomethane in diethyl ether (2.0 M, 4.6 ml, 9.3 mmol). The reaction was warmed to room temperature and then quenched by the dropwise addition of acetic acid. Once gas evolution ceased, the solution was concentrated under reduced pressure. The resulting material was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (20-80% ethyl acetate in hexanes) provided the title compound: LCMS m/z 231.66 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 7.01 (s, 1H), 6.88 (s, 1H), 6.45 (s, 1H), 2.21 (s, 2H), 2.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][C:18](=[O:20])[CH2:19][CH:12]2[CH2:13]OC3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:21](OCC)=[O:22].[O-][CH2:27][CH3:28].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:27][CH2:28][CH2:13][CH:12]2[C:19](=[CH:21][OH:22])[C:18](=[O:20])[CH2:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: O=C1CC2COCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (170 mg, 0.54 mmol) in THF/ethanol (3 mL, 1/1, v/v) was added ethyl formate (400 mg, 5.4 mmol) followed by sodium ethoxide (0.61 mL of 21% solution in ethanol). The resulting mixture was heated to 60° C. for 30 minutes after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NH4Cl solution (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 9-(4-chloro-benzenesulfonyl)-2-hydroxymethylene-9-aza-bicyclo[3.3.1]nonan-3-one as a yellow solid. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=1.651 min, Method [1], MS (ESI) 344.0 (M+H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3([CH3:28])[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.C(OC(N1CCC(C)(C(O)=O)CC1)=O)(C)(C)C.[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(Cl)(=O)C(Cl)=O.[NH:58]1[C:62](C2C=C(N)C=CC=2)=[N:61]N=N1>ClC(Cl)C.CN(C=O)C>[NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3([CH3:28])[CH2:20][CH2:19][N:18]([C:21]4[C:50]5[C:48]([CH3:49])=[CH:47][NH:46][C:51]=5[N:58]=[CH:62][N:61]=4)[CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1
Reactant: c1ccncc1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(-c3nnn[nH]3)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(-c5nnn[nH]5)c4)CC3)c12
Reaction time: 0.67 h
Yield: 70 %

Procedure:
Preparation of tert-butyl 4-(3-(1H-tetrazol-5-yl) phenylcarbamoyl)-4-methylpiperidine-1-carboxylate. To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (100 mg, 0.41 mmol) in dichloroethane (2.0 mL) were added DMF (2 drops) and pyridine (0.13 g, 1.6 mmol), followed by oxalyl chloride (57 mg, 0.45 mmol). The mixture was stirred for 40 minutes, and 3-(1H-tetrazol-5-yl)-phenylamine was added. The mixture was stirred for 2 hours, and a pink precipitate formed. The mixture was filtered, and the filtrate was washed with 1.0 N aq. HCl and brine, dried over MgSO4, and concentrated to give the title compound in 70% yield. MS (ES+) [M+H]+=387.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17](Cl)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:34])[CH3:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([N:38]3[CH2:39][CH2:40][N:35]([CH:32]([CH3:34])[CH3:33])[CH2:36][CH2:37]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC(C)N1CCNCC1
Product: COc1ccccc1Oc1c(Cl)nc(N2CCN(C(C)C)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure described in Synthesis Example 2 was repeated by use of 4-t-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (5) and 1-isopropylpiperazine, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:16]=2)[N:13]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>ClCCl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH:28]3[CH:27]=[CH:26][N:25]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:24]=[CH:29]3)=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[N:16]=2)[N:13]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccnnc1
Reactant: Fc1ccc(-c2cn3nc(Cl)ccc3n2)cc1
Solvent: ClCCl
Product: CCOC(=O)N1C=CC(c2c(-c3ccc(F)cc3)nc3ccc(Cl)nn23)C=N1
Temperature: 10 °C

Procedure:
2.90 ml (30.3 mmol) of ethyl chloroformate are added, dropwise in 30 minutes, to a solution of 3.00 g (12.1 mmol) of 6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (CAS: 244081-70-7) and 4.40 ml (60.6 mmol) of pyridazine in 40 ml of dichloromethane at 10° C. The medium is stirred at 10° C. for a further hour and then left to stir for 3 hours. It is then poured into ice-cold water and the product is extracted with ethyl acetate.
Reaction SMILES: CN(C=O)C.CS([O:10][CH2:11][C:12]1[O:16][N:15]=[C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[CH:13]=1)(=O)=O.[CH3:38][O:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47].C([O-])([O-])=O.[K+].[K+]>O>[F:35][C:23]([F:36])([C:24]1([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[CH:13]=[C:12]([CH2:11][O:10][C:42]2[CH:43]=[C:44]([O:48][CH3:49])[C:45]([O:46][CH3:47])=[C:40]([O:39][CH3:38])[CH:41]=2)[O:16][N:15]=1)=[O:37]
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCc2cc([C@@H]3CCCN3C(=O)C(F)(F)C3(O)CC(C)(C)CC(C)(C)C3)no2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a DMF (1.0 mL) solution of the compound (20.8 mg) obtained in Example 3-(5) and 3,4,5-trimethoxyphenol (16.0 mg), K2CO3 (24.0 mg) was added and the mixture was stirred at room temperature for 30 minutes, then at 50° C. for 2 hours. The reaction mixture was added to water (20 mL) and the organic layer extracted with AcOEt (20 mL×2) was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by PTLC(NH-form) to give the titled compound (20.5 mg, colorless amorphous.)
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH:12]1[C:27]([OH:29])=O)=[O:10])C1C=CC=CC=1.B.C1COCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[O:10]=[C:9]1[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[CH2:27][O:29]1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN2C(=O)OCC2C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
1,4-Di((benzyloxy)carbonyl)piperazine-2-carboxylic acid (18.9 g, 47.4 mmol) was dissolved in THF (200 mL), and borane-THF complex (1.0 M solution in THF, 100 mL, 100 mmol) was added over about 15 min. Upon complete addition, the reaction mixture was heated to 50° C. After 3 h, the reaction mixture was allowed to cool to rt and was slowly quenched by the dropwise addition of MeOH. After gas evolution ceased, the reaction mixture was heated to 50° C. for 1 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The material was dissolved in EtOH (200 mL) and K2CO3 (6.9 g, 49.9 mmol) was added. The reaction mixture was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure, diluted with H2O (200 mL) and extracted with EtOAc (3×200 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chomatography (10 to 40% EtOAc in Hexanes gradient) to give 10.26 g (78%) of the desired product as a white solid. An additional 0.452 g (3%) of the desired product was isolated from impure chomatography fractions by recrystallization from methyl tert-butyl ether. LC-MS: RT=7.848 min; [M+Na]+=299.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)-sulfonyl](methyl)amino]acetate (0.331 g, 0.736 mmol in methanol/THF was added 1.23 mL (3.5 eq) of a 1.0N solution of LiOH and the reaction was stirred at room temp overnight. The solvent was removed in vacuo and the residue was suspended in water, adjusted to pH to 3 with 2N HCl. The resulting solid was rinsed with ether and dried in vacuo to afford 0.27 g (89%) of [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetic acid. Electrospray Mass Spec 392.1 (M+H)+
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:18]=[N:19][N:20](C3CCCCO3)[N:21]=2)=[CH:7][CH:6]=1)C.C(O)C.Cl>O>[NH:21]1[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=2)=[N:18][N:19]=[N:20]1
Reactant: CCOC(OCC)c1ccc(-c2ccccc2-c2nnn(C3CCCCO3)n2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To 5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydropyran-2-yl)-2H-tetrazole (0.408 g; 1.00 mmol) are added 94% ethanol (2.5 mL) and a 2N aqueous solution of hydrochloric acid (0.5 mL; 1.0 mmol). The resulting solution is heated to 45° C. for 3 hours. After the addition of water (about 2 mL) the mixture is allowed to cool down to room temperature and then stirred at 0 to 5° C. for 30 minutes. The resulting suspension is filtered and the solids are washed with a small amount of water, dried in vacuo at 40° C. to afford 2′-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde as white, crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:17]1([N:22]2[C:26]([NH2:27])=[C:25]([C:28]([NH2:30])=[O:29])[C:24]([CH2:31][CH3:32])=[N:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.C1C=CC=CC=1.O>[Pd].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCC>[CH:17]1([N:22]2[C:26]3=[N:27][C:6]([C:5]4[CH:8]=[CH:9][C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:11][C:4]=4[O:3][CH2:1][CH3:2])=[N:30][C:28](=[O:29])[C:25]3=[C:24]([CH2:31][CH3:32])[NH:23]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOc1cc(N(CC)CC)ccc1C=O
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Solvent: c1ccccc1
Product: CCOc1cc(N(CC)CC)ccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Yield: 15.8 %

Procedure:
A mixture of 2-ethoxy-4-(diethylamino)benzaldehyde (7.87 g, 35.56 mmol), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.95 g, 17.78 mmol), p-toluenesulfonic acid monohydrate (0.05 g), 10% palladium on carbon (0.11 g) and benzene (150 ml) was refluxed overnight with the azeotropic removal of water. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was combined with that from a similar experimental run, and dissolved in CH2Cl2, and loaded onto a silica gel column. Elution of the column with ether/hexane (60/40) afforded a green foam which was titurated with refluxing hexane, and cooled and the product, as pale yellow needles, was collected by filtration to afford 1.19 g (8%) of 1-cyclopentyl-3-ethyl-6-[2-ethoxy-4-(diethylamino)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 138-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.[C:11](#[N:14])[CH:12]=[CH2:13].C1N2CCN(CC2)C1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[C:12]([C:11]#[N:14])[CH2:13][O:10]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Br)cc1O
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: N#CC1=Cc2ccc(Br)cc2OC1

Procedure:
A mixture of 4-bromo-2-hydroxybenzaldehyde (20 g), acrylonitrile (26.4 g) and DABCO (0.78 g) was heated at reflux for 8 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was concentrated and the residue was filtered through silica gel. The 7-bromo-2H-chromene-3-carbonitrile thus obtained (7.5 g) was boiled at reflux with sodium hydroxide solution (10.2 g of sodium hydroxide in 100 ml of water) for 8 hours. The cooled reaction mixture was washed with methyl tert-butyl ether, acidified with hydrochloric acid and extracted with ethyl acetate. Concentration of the organic phase gave 7-bromo-2H-chromene-3-carboxylic acid. This acid (3.0 g) was heated to 85° C. with DPPA (3.2 g), triethylamine (1.6 ml) and toluene (30 ml) for 12 hours. Then hydrochloric acid (6 N) was added and the mixture was heated to reflux for 2 hours. The cooled reaction mixture was extracted with ethyl acetate and the organic phase was concentrated. The product was thus obtained with the molecular weight of 227.06 (C9H7BrO2); MS (ESI): 227 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][N:15]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:30])[OH:26])=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCOc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCOc1cnc(F)c(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred solution of diisopropylamine (Aldrich, 3.03 mL, 21.2 mmol) in THF (30 mL) in 250 mL round-bottomed flask, nBuLi (Aldrich, 2.5 M in hexanes, 8.12 mL, 20.3 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was cooled to −78° C. and 2-fluoro-5-(2-methoxyethoxy)pyridine (1.58 g, 9.23 mmol) in a total of 5 mL THF was added slowly. The orange mixture was stirred at that temperature for 30 min then triisopropyl borate (Aldrich, 4.72 mL, 20.3 mmol) in a total of 5 mL of THF was added slowly. The mixture was stirred at −78° C. for 10 min, then the cold bath was removed and the mixture was stirred at room temperature for 1 h. 1N NaOH (about 70 mL) was added and the layers were separated. The aqueous phase was washed with EtOAc (50 mL) and acidified to about pH 5 with 5 N HCl. The aq phase was extracted with EtOAc (4×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-fluoro-5-(2-methoxyethoxy)pyridin-3-ylboronic acid (1.76 g, 89% yield) as a pale yellow residue. This material was used without further purification.
Reaction SMILES: C(N(CC)CC)C.N1([C:13]2[CH2:14][CH2:15][S:16][CH2:17][CH:18]=2)CCCC1.Br[CH2:20][CH:21]([CH2:27]Br)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(O)(=[O:31])C>C(#N)C>[CH2:25]([O:24][C:22]([CH:21]1[CH2:27][CH:14]2[C:13](=[O:31])[CH:18]([CH2:17][S:16][CH2:15]2)[CH2:20]1)=[O:23])[CH3:26]
Reactant: C1=C(N2CCCC2)CCSC1
Reactant: CC(=O)O
Reactant: CCOC(=O)C(CBr)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC2CSCC(C1)C2=O

Procedure:
A mixture of triethylamine (10.1 ml, 72 mmol) and 3,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran (12.9 g, 76 mmol, prepared according to a procedure described in Tetrahedron Asymmetry 1997, 1811-1820) in anhydrous acetonitrile (55 ml) was heated to reflux, then ethyl 3-bromo-2-(bromomethyl)propionate (14.6 g, 53 mmol) in dry acetonitrile (42 ml) was added dropwise over a period of 45 min. The resulting reaction mixture was refluxed for another 1.5 hours, then cooled to room temperature before a 10% aqueous acetic acid solution (5.2 ml) was added. The mixture was then refluxed for 1 hour and evaporated to dryness. Brine was added to the residue, the aqueous phase was extracted with ethyl acetate, the combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to yield 9-oxo-3-thia-bicyclo[3.3.1]nonane-7-carboxylic acid ethyl ester as a brown oil (15.5 g).