Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([Mg]Cl)[CH2:11][CH2:12][CH3:13].O.Cl.CCOCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCCC[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 3-chlorobenzaldehyde (1.4 g, 10 mmol) in THF (10 mL) was cooled to −10° C., then 2.0 M n-butylmagnesium chloride (10 mL) was added. The reaction was allowed to warm to RT under N2 overnight. Next day the reaction was cooled to 0−5° C., water (5 mL) was added, followed by 2N HCl—Et2O partition. The organic layer was washed with brine, then dried over Na2SO4. After filtration and concentration the crude material was purified by chromatography using 9/1 hex/EtOAc. Recovered 1.25 g (63%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1C=CC=CC=1.O>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CCOC(=O)C(C)CCCCCBr
Reactant: CCCCCC(CCCNS(C)(=O)=O)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCC(CCCN(CCCCCC(C)C(=O)OCC)S(C)(=O)=O)OC1CCCCO1
Reaction time: 1 h

Procedure:
A stirred suspension of sodium hydride (57%) (5.0 g., excess) in a solvent mixture of benzene (75 ml.) and dimethylformamide (75 ml.) is treated, over 30 minutes, with N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamide (Example N, Step 4) (32.1 g., 0.1 mole) dissolved in benzene (20 ml.). Stirring is continued for one hour. Then ethyl 7-bromo-2-methylheptanoate (Example L, Step 4) (25.3 g., 0.1 mole) is added dropwise, and the reaction is heated on the steam bath for 6 hours. The cooled reaction mixture is poured into water (400 ml.) and extracted with ethyl acetate (2× 200 ml.). The organic fractions are combined, washed with brine, then dried over sodium sulfate. The solvents are removed in vacuo to give ethyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamido}-2-methylheptanoate as a pale yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])(C)[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].C1CCN2C(=NCCC2)CC1.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>C(#N)C>[CH2:1]([C:3]1[C:8]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[CH:12]([CH3:15])[O:13]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:37][CH2:36][C:35]([O:39][CH2:40][CH3:41])=[O:38])[CH2:20][CH2:19]1)[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCN1CCC(c2cccc(B3OC(C)C(C)(C)O3)c2CC)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (80 mg, 0.186 mmol) and DBU (0.034 mL, 0.224 mmol) in Acetonitrile (8 mL) was added ethyl 2-propenoate (57 mg, 0.499 mmol). The solution was sealed and stirred at 80° C. for 2 h. The solution was evaporated in vacuo to afford ethyl 3-{4-[2-ethyl-3-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinyl}propanoate (D123) (46 mg). MS (ES): C24H38BNO4 requires 415.3. found 416.3 (M+H+).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].COP([O-])OC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]=[C:45]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:44]=[C:45]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].[CH:1]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCCCCCC
Agent: [Pd+2]
Agent: C=C(CCCCCC)P(=O)(OCC)OCC
Agent: CC(=O)[O-]
Product: CCCCCCC=CP(=O)(OCC)OCC

Procedure:
A mixture of 5 mmol of 1-octyne, 5 mmol of dimethylphosphite and 0.025 mmol of palladium acetate and 1,3-bis(diphenylphosphino)propane (1.5 equivalents based on the palladium acetate) was reacted at 100° C. for 6 hours in the atmosphere of nitrogen. The proton NMR analysis of the resulting reaction mixture revealed that an isomeric mixture of (a) dimethyl 1-octen-2-yl-phosphonate and (b) dimethyl 1-octen-1-yl-phosphonate was obtained with a yield of 100% and that the weight ratio of the former phosphonate (a) to the latter phosphonate (b) was 98:2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:13]([CH2:23][O:24]CC3C=CC(OC)=CC=3)=[N:12][C:11]=2[CH:34]([CH3:36])[CH3:35])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:13]([CH2:23][OH:24])=[N:12][C:11]=2[CH:34]([CH3:36])[CH3:35])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CCc2ccccn2)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)c1nc(CO)n(CCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To 1.43 g of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1-(2-(2-pyridyl)ethyl)-1H-imidazole was added 20 ml of ethanol and 40 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:1) to give 571 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-hydroxymethyl-1-(2-(2-pyridyl)ethyl)-1H-imidazole (112a) (yield 51%). 1H-NMR (CDCl3 -TMS) δ ppm: 1.29(d,J=6.8 Hz,6H), 3.15(m,3H), 4.52 (m,2H), 4.76(s,2H), 6.87(d,2H), 6.80-7.40(m,3H), 7.60(m,1H),8.50(m,1H); Elementary analysis (C20H21Cl2N3OS); Calc. (%): C,56.87;H,5.01;N,9.95;Cl,16.79;S,7.59; Found (%): C,56.58;H,5.13;N,9.90;Cl,16.65;S,7.53.
Reaction SMILES: [N:1]#[N:2].C(O[C:11]([NH:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:12])C1C=CC=CC=1.[CH2:42]([O:49][C:50]([NH:52][C@H:53](C(O)=O)[CH2:54][C:55](=[O:57])[NH2:56])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(O)C.[Pd]>[N:1]#[N:2].[CH2:42]([O:49][C:50]([NH:52][C@H:53]([C:11]([NH:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:33][CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:23])[CH3:24])=[O:12])[CH2:54][C:55](=[O:57])[NH2:56])=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)[C@H](O)C[C@@]2(C(N)=O)CCCN2C(C)(C)C)cc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)[C@H](O)C[C@@]2(C(N)=O)CCCN2C(C)(C)C)cc1
Yield: 31.1 %

Procedure:
A solution of 1.58 g of N2 -[3(S)-(benzyloxyformamido)-4-(4-tert.butoxyphenyl)-2(R)-hydroxybutyl]-N1 -tert.butyl-L-prolinamide in 200 ml of ethanol was hydrogenated over 100 mg of 10% palladium-on-carbon for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to give an oil which was coupled with 0.74 g of N-(benzyloxycarbonyl)-L-asparagine in a manner analogous to that described in Example 1. The crude product was chromatographed on a column of silica gel using 10% methanol in dichloromethane for the elution. There was obtained 0.59 g of N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-4-(4-tert.butoxyphenyl)-2(R)-hydroxybutyl]-N1 -tert.butyl-L-prolinamide as a white solid; MS: m/e 654 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29]([S:33](=[O:52])(=[O:51])[N:34]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[C:35]3[S:39][N:38]=[CH:37][N:36]=3)=[CH:28][C:27]=2[F:53])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=3[CH:24]=2)[CH:7]=1.C(N(CC)CC)C.[C:61](Cl)(=[O:63])[CH3:62]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:61]([N:16]([C:13]1[C:12]2[CH:24]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][C:26]3[CH:31]=[C:30]([F:32])[C:29]([S:33](=[O:52])(=[O:51])[N:34]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=4[O:49][CH3:50])[C:35]4[S:39][N:38]=[CH:37][N:36]=4)=[CH:28][C:27]=3[F:53])[CH:9]=[CH:10][C:11]=2[O:15][N:14]=1)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])(=[O:63])[CH3:62]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(NC(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(C)=O)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of tert-butyl (5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate (0.20 g, 0.25 mmol), triethylamine (105 μL, 0.75 mmol) and 4-(dimethylamino)pyridine (0.030 g, 0.25 mmol) in dichloromethane (20 mL) at 0° C. was treated with acetyl chloride (36 μL, 0.5 mmol). The resulting solution was stirred for 1 h. The reaction mixture was diluted with ethyl acetate (70 mL), washed with saturated ammonium chloride (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford tert-butyl acetyl(5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate as a colourless solid in 35% yield (0.05 g): 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.68-7.63 (, m, 1H), 7.63-7.58 (m, 1H), 7.56-7.54 (m, 1H), 7.50-7.45 (m, 2H), 7.42-7.38 (m, 1H), 7.15-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.33-6.25 (m, 2H),6.19-6.17 (m, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 2.67 (s, 3H), 1.31 (s, 9H); MS (ES+) m/z 727.5 (M−100), 729.7 (M−100).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[NH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[C:7](=[O:12])[C@@H:6]([CH3:13])[NH:5][C:4]=2[N:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C[C@H]1Nc2nc(Cl)ncc2NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1Nc2nc(Cl)ncc2N(c2cccc(C#N)c2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
To a stirred solution of (7R)-2-chloro-7-methyl-7,8-dihydropteridin-6(5H)-one (4.2 g, 21.15 mmol) in dichloromethane (350 mL) was added triethylamine (29.61 ml, 211.5 mmol), cupric acetate (7.69 g, 42.30 mmol) and 3-cyanophenyl boronic acid (6.62 g, 42.30 mmol) followed by 4 Å molecular sieves (2.0 g). The reaction mixture was stirred for 24 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (Yield: 39%). 1HNMR (300 MHz, CDCl3): δ 1.66 (d, J=6.9 Hz, 3H), 4.55 (q, J=5.1 Hz, 1H), 5.98 (br s 1H), 7.16 (s, 1H), 7.50-7.53 (m, 1H), 7.59-7.68 (m, 1H), 7.72 (t, J=7.8 Hz, 1H) and 7.81-7.83 (m, 1H).
Reaction SMILES: N1[C:5]([C:6]2[N:16]=[CH:15][C:9]3[N:10]=[CH:11][NH:12][C:13](=[O:14])[C:8]=3[CH:7]=2)=[N:4][N:3]=N1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[CH3:18][C:17]1[O:19][C:5]([C:6]2[N:16]=[CH:15][C:9]3[N:10]=[CH:11][NH:12][C:13](=[O:14])[C:8]=3[CH:7]=2)=[N:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]cnc2cnc(-c3nnn[nH]3)cc12
Product: Cc1nnc(-c2cc3c(=O)[nH]cnc3cn2)o1

Procedure:
6-(1,2,3,4-Tetrazol-5-yl)-pyrido[3,4-d]pyrimidin-4-one (1.4 g) in acetic anhydride (10 ml) was heated at reflux under N2 for 2.5 hours. The cooled mixture was absorbed onto silica and purified by chromatography to give the title compound 90.14 g) as a beige solid; δH [2H6]DMSO 13.0(1H,bs), 9.30 (1H,s), 8.66 (1H,s), 8.47 (1H,s) 2.75 (3H,s); m/z (M+1+)230.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:21])=[CH:7][C:8]([CH:12]([CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)O)=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)(Cl)Cl>[C:1]([C:5]1[C:6]([OH:21])=[CH:7][C:8]2[CH2:12][C:14]3([O:11][C:9]=2[CH:10]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(O)c(C(O)C2CCCCCC2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To 0.66 g of 5-t-butyl-2-(cycloheptylhydroxymethyl) benzene-1,4-diol dissolved in 20 ml of chloroform was added 0.44 g of p-toluenesulfonic acid monohydrate and the mixture was stirred at room temperature for a whole day and night. After the reaction mixture was poured into water and extracted with chloroform, the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10% ethyl acetate) to give 0.27 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a white solid (yield 43%).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[C:12]=12>C(O)C>[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([N:26]=[CH:1][C:2]4[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=4[OH:4])=[CH:22][CH:21]=3)[C:12]=12
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N=Cc4ccccc4O)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Salicylaldehyde (0.063 g, 0.000513 mol) and tert-butyl 4-[4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (0.200 g, 0.000489 mol) were combined in absolute ethanol (5 mL) and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate which was used without further purification. Trimethylsulfoxonium iodide (0.269 g, 0.00122 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and a 60% dispersion of sodium hydride in parafine (0.049 g, 0.00122 mol) was added at once. After 10 min., the solution of tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (70 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. The crude compound was dissolved in ethyl acetate (5 mL) and treated with a 4N aqueous solution of hydrochloric acid (1.5 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile—0.1M ammonium acetate over 25 min, 21 mL/min) to yield 3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.038 g, 0.000078 mol) as a white solid
Reaction SMILES: C(#N)C=C.CO[CH2:7][O:8][CH3:9].COC1C=C(C=C(OC)C=1OC)C=O.C1N2CCN(CC2)C1.C(OC)=O.O[CH:37]([C:42]1[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=1)[C:38](=C)[C:39]#[N:40]>CO>[CH3:53][O:52][C:44]1[CH:43]=[C:42]([CH:37]=[C:38]([CH2:7][O:8][CH3:9])[C:39]#[N:40])[CH:47]=[C:46]([O:48][CH3:49])[C:45]=1[O:50][CH3:51]
Reactant: COCOC
Reactant: C=C(C#N)C(O)c1cc(OC)c(OC)c(OC)c1
Agent: C1CN2CCN1CC2
Agent: COc1cc(C=O)cc(OC)c1OC
Solvent: C=CC#N
Solvent: CO
Solvent: COC=O
Product: COCC(C#N)=Cc1cc(OC)c(OC)c(OC)c1
Reaction time: 25 h

Procedure:
55 ml of acrylonitrile, 50 ml of dimethoxymethane, 100 g of 3,4,5-trimethoxybenzaldehyde and 30 g of DABCO are introduced into a 500 ml reactor fitted with a stirrer. After stirring for 25 hours, 50 g of methyl formate and 100 ml of methanol are added and the mixture is stirred at room temperature for more than 24 hours until the 3-hydroxy-2-methylene-3-(3,4,5-trimethoxyphenyl)propionitrile has disappeared; the 3-(3,4,5-trimethoxyphenyl)-2-methoxymethylacrylonitrile formed is isolated or reacted with sodium methylate, after removal of the volatile reactants and solvents, to give the acetal of the formula III.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].Cl.[CH3:14][N:15]([CH2:17][C:18]1[O:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)[CH3:16]>C(O)C>[C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][S:8][CH2:22][C:21]1[O:24][C:18]([CH2:17][N:15]([CH3:16])[CH3:14])=[CH:19][CH:20]=1)#[N:2]
Reactant: C#CCNC(=NCCS)NC#N
Reactant: CN(C)Cc1ccc(CCl)o1
Agent: Cl
Solvent: CCO
Product: C#CCNC(=NCCSCc1ccc(CN(C)C)o1)NC#N

Procedure:
A solution of N-cyano-N'-(2-propyn-1-yl)-N"-(2-mercaptoethyl)guanidine [prepared according to the procedure described in U.S. Pat. No. 4,112,234] in ethanol is reacted with an ethanol solution of about an equimolar amount of 5-dimethylaminomethylfurfuryl chloride hydrochloride and about two equivalents of base, and the title product is thereby produced.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:25])[C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[CH:10]=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:8]=1>O.C1COCC1>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([N:13]3[CH:17]=[N:16][N:15]=[N:14]3)[CH:10]=2)[C:6]([OH:25])=[O:5])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2cnnn2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3cnnn3)c2)nc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of LiOH hydrate (82 mg, 1.94 mmol) in H2O (7 mL) was added dropwise to a suspension of 3-(5-methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester (440 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6˜7. The resulting precipitate was collected and dried to afford 3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid as a yellow solid (390 mg, 93%). MS (M+H)=282.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][O:16][C:17](=[O:48])[CH:18]([NH2:47])[CH2:19][S:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:39]4[O:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:38]=4[CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>O.C(Cl)Cl>[CH3:15][O:16][C:17](=[O:48])[CH:18]([NH:47][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:2]=1[F:1])[CH2:19][S:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[C:39]4[O:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:38]=4[CH:37]=[CH:36][CH:35]=3)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)C(N)CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Fluoro-5-trifluoromethylbenzoic acid (49 mg, 0.24 mmol) was added to a stirred solution of methyl-2-amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate (92 mg, 0.2 mmol), EDCI (58 mg, 0.3 mmol) and triethylamine (404 mg, 0.56 mL, 0.4 mmol) in anhyd methylene chloride (5 mL). The reaction mixture was stirred at room temperature for 4-6 h (TLC control) and then diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined organic extract were washed with water, sat'd aq NaCl, dried over anhydrous MgSO41 filtered and concentrated in vacuo. Purification by flash column chromatography (30% ethyl acetate in heptane) afforded the title compound has a white solid (117 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:16]([O-:20])(=[O:19])[CH2:17][CH3:18].[Na+]>C(OC(=O)CC)(=O)CC>[CH3:18][C:17](=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1)[C:16]([OH:20])=[O:19]
Reactant: CCC(=O)[O-]
Reactant: O=Cc1ccc(Sc2ccccn2)cc1
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Product: CC(=Cc1ccc(Sc2ccccn2)cc1)C(=O)O
Reaction time: 5 h

Procedure:
A mixture of 6 g of 4-(2-pyridylthio)benzaldehyde, 6 g of sodium propionate and 30 ml of propionic anhydride was stirred for 5 hours at a temperature of 150° to 155° C. and then concentrated under reduced pressure. Water was added to the mixture which was then heated. The mixture was allowed to stand to precipitate crystals and the resulting crystals were separated by filtration, washed with water and dried to obtain 2-methyl-3-[4-(2-pyridylthio)phenyl]propenoic acid. The product was dissolved in 30 ml of methanol, and a small amount of methanolic hydrogen chloride was added to the solution, followed by refluxing for 1 hour. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of methanol and ethyl acetate to obtain 2.6 g (30% yield) of methyl 2-methyl-3-[4-(2-pyridylthio)phenyl]propenoate hydrochloride as colorless needles having a melting point of 130°-133° C.