Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.Cl[C:11]1[N:16]=[C:15]2[NH:17][N:18]=[CH:19][C:14]2=[CH:13][N:12]=1>>[NH:17]1[C:15]2=[N:16][C:11]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=3)=[N:12][CH:13]=[C:14]2[CH:19]=[N:18]1
Reactant: Nc1cnn(CCO)c1
Reactant: Clc1ncc2cn[nH]c2n1
Product: OCCn1cc(Nc2ncc3cn[nH]c3n2)cn1

Procedure:
The title compound was made following Procedure D (Step i) using 2-(4-amino-1H-pyrazol-1-yl)ethanol and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine to form 2-(4-((1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol. This was followed by Procedure D (Step ii) using 4-(3-(bromomethyl)-2,4-difluorophenyl)morpholine. 1H NMR (d6-DMSO) δ 9.86 (s, 1H), 8.88 (s, 1H), 8.17 (br s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.14-6.97 (m, 2H), 5.56 (s, 2H), 4.88 (t, 1H), 4.18-4.09 (m, 2H), 3.77-3.73 (m, 2H), 3.70 (t, 4H), 2.92 (t, 4H); LC-MS method B, (ES+) 457.2, RT=6.98 min.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2].[CH2:25]([Li])[CH2:26][CH2:27]C.IC(C)C>O1CCCC1>[CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=[C:6]([N:15]([CH:26]([CH3:27])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: COc1ccc(Nc2cc3c(c(C(C)C)c2C)OCC3(C)C)cc1
Solvent: CC(C)I
Solvent: C1CCOC1
Product: COc1ccc(N(c2cc3c(c(C(C)C)c2C)OCC3(C)C)C(C)C)cc1
Yield: 7 %

Procedure:
Following general procedure L and using 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.6 g, 2.7 mmol), 1.6M solution of n-butyllithium in hexanes (2.2 mL, 3.5 mmol) and 2-iodopropane (0.9 g, 5.4 mmol) in 10mL of anhydrous tetrahydrofuran, the title compound (0.077 g, 7%) was obtained as a brown oil after separation from recovered 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.2 g) by preparative normal phase HPLC using 4% ethyl acetate in hexanes as the mobile phase. 1H NMR (300 MHz, CDCl3): δ 6.75 (d, 2H, J=9.2 Hz), 6.62 (s, 1H), 6.38 (d, 2H, J=9.2 Hz),4.25-4.11 (m, 3H), 3.73 (s, 3H), 3.19 (heptet, 1H, J=7.0 Hz), 2.06 (s, 3H), 1.33 (d, 6H, J=7.0 Hz), 1.27 (s, 6H), 1.11 (br m, 6H).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[Cl:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([CH3:38])[C:28]=1[CH:39]=O>C1COCC1>[CH2:12]([O:14][C:15](=[O:25])[CH:16]=[CH:39][C:28]1[N:29]([CH3:38])[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:31][C:27]=1[Cl:26])[CH3:13]
Reactant: Cn1c(-c2ccccc2)nc(Cl)c1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1c(Cl)nc(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.72 ml of a 1.6 M solution of n-butyllithium in n-hexane (4.4 mmol) were added at 0° C. to a solution of 1.219 g (5.4 mmol) of diethylphosphonoacetic acid ethyl ester in 30 ml of dry THF. After stirring at 0° C. for 30 min, 0.8 g (3.8 mmol) of 5-chloro-3-methyl-2-phenyl-3H-imidazole-4-carbaldehyde in 10 ml of THF were added. The reaction mixture was allowed to stand overnight and then concentrated. The residue was taken up in 100 ml of ethyl acetate, and the solution washed three times with 30 ml each of a sodium hydrogencarbonate solution, dried with magnesium sulfate and evaporated. The obtained crude 3-(5-chloro-3-methyl-2-phenyl-3H-imidazol-4-yl)-acrylic acid ethyl ester was stirred in 5.4 ml of 1 N sodium hydroxide solution and 20 ml of tert-butanol at room temperature for 24 h. After concentration, 10 ml of water were added, and the mixture was acidified to pH=5 with hydrochloric acid. The mixture was stirred for 1 h, and the precipitated product was filtered off with suction and dried.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[Na].[CH2:10]([OH:13])[CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][O:13][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: ClCc1cnccn1
Reactant: OCCO
Agent: [Na]
Product: OCCOCc1cnccn1

Procedure:
2-Chloromethylpyrazine is reacted with the sodium salt of ethylene glycol to give 2-(2-hydroxyethoxymethyl)pyrazine which is treated with thionyl chloride to give 2-(2-chloroethoxymethyl)pyrazine. Using this intermediate to place of 4-(3-chloropropoxy)methylimidazole in the procedure of Example 22 gives the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:35])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:35][C:21]([CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH2:25][CH2:24]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc3c(c2)OCO3)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 18.4 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.40 g), tetrahydrofuran (2 ml) and magnesium (30 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(3,4-methylene-dioxyphenyl)cyclopropane (Example 22) (0.32 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 5:95) to afford 1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (82 mg, 19%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:12]4[S:13][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][N:11]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.088 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (THF/hexane) to yielded the title compound as a light brown solid (0.03 g, 14%). MS (ISN) 485.2 [(M−H)−]; mp 263° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([NH2:15])[N:12]=[N:13][CH:14]=1.[Br:16]N1C(=O)CCC1=O>>[Br:16][C:14]1[N:13]=[N:12][C:11]([NH2:15])=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Nc1nncc(-c2ccc(F)cc2F)n1
Reactant: O=C1CCC(=O)N1Br
Product: Nc1nnc(Br)c(-c2ccc(F)cc2F)n1
Yield: 21.6 %

Procedure:
6-Bromo-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.13 g, 21%) was prepared from 5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.45 g, 2.1 mmol) and N-bromosuccinimide (0.49 g, 2.80 mmol) according to the general procedure of Preparation 3.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:38][C:39]([C:41]1[N:42]=[CH:43][N:44]([CH3:46])[CH:45]=1)=[O:40])=[O:4].O1CCCC1.[OH-].[K+]>CO>[CH3:47][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:38][C:39]([C:41]1[N:42]=[CH:43][N:44]([CH3:46])[CH:45]=1)=[O:40])=[O:4]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Reaction time: 2 h
Yield: 20.2 %

Procedure:
1-Methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-amide (0.092 mmol) was dissolved in methanol (0.25 mL) and tetrahydrofuran (0.25 mL) and 50% w/v aqueous potassium hydroxide (0.1 mL) was added at 0° C. After 2 hours, the reaction was quenched by addition of acetic acid (0.5 mL). The mixture was redissolved in tetrahydrofuran and the insoluble salts were removed by filtration. The crude material was purified by preparative HPLC to afford 1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-amide (9.2 mg, 20.2%, 2 steps).
Reaction SMILES: O.O.O.O.O.O.[Cl-:7].[Cl-:8].[Ni+2:9].[CH:10]1[CH:15]=[C:14]([S:16]([O-:19])(=[O:18])=[O:17])[CH:13]=[C:12]([P:20]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([O-:40])(=[O:39])=[O:38])[CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([O-:30])(=[O:29])=[O:28])[CH:22]=2)[CH:11]=1.[Na+:41].[Na+].[Na+]>O>[Cl:7][Ni:9][Cl:8].[CH:35]1[CH:34]=[C:33]([S:37]([O-:40])(=[O:39])=[O:38])[CH:32]=[C:31]([P:20]([C:12]2[CH:11]=[CH:10][CH:15]=[C:14]([S:16]([O-:19])(=[O:17])=[O:18])[CH:13]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([O-:30])(=[O:29])=[O:28])[CH:22]=2)[CH:36]=1.[Na+:41].[Na+:41].[Na+:41]
Reactant: [Cl-]
Reactant: [Ni+2]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [Na+]
Solvent: O
Product: Cl[Ni]Cl

Procedure:
Nickel chloridehexahydrate (0.05 mols) was reacted with tppts (0.12 mols) in water sufficient to dissolve and formed complex was precipitated by ethanol
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: CCI
Reactant: Oc1ccc(OC(F)(F)F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(OC(F)(F)F)c(Br)c1
Yield: 125 %

Procedure:
To a solution of the 3-bromo-4-trifluoromethoxyphenol (1.0 g, 2.48 mmol) in acetone (30 ml) was added ethyl iodide (0.795 ml, 9.94 mmol) followed by potassium carbonate (1.37 g, 9.94 mmol) and the reaction was heated to reflux for 12 hrs. The reaction mixture was cooled then filtered and concentrated in vacuo. Dichloromethane (20 ml) and water (20 ml) were added and the solution was filtered through a phase separation cartridge. The organic layer was collected, and evaporated in vacuo to afford crude title compound as a colourless oil (884 mg, 80%). Material was taken on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([N:10]2[C:21]3[C:13](=[CH:14][N:15]=[C:16]4[C:20]=3[CH:19]=[CH:18][N:17]4S(C3C=CC=CC=3)(=O)=O)[N:12]=[N:11]2)[CH2:6]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:1][O:2][C:3](=[O:31])[NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([N:10]2[C:21]3[C:13](=[CH:14][N:15]=[C:16]4[C:20]=3[CH:19]=[CH:18][NH:17]4)[N:12]=[N:11]2)[CH2:6]1
Reactant: COC(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
A solution of racemic trans [3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid methyl ester (171 mg, 380 μmol) in methanol (2 mL) and THF (1 mL) was treated with a 1M sodium hydroxide solution (2 mL) and stirred at ambient temperature for 1.5 hours. Dilute HCl was added and the mixture purified by Isolute® SCX-2 column (gradient: methanol to 2M NH3 in methanol solution). The residue obtained was purified further by column chromatography on silica gel (gradient: 50% ethyl acetate in cyclohexane then 0-10% methanol in ethyl acetate). The product was further purified by a diethyl ether/cyclohexane trituration to afford 48 mg (41%) of racemic trans [3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid methyl ester as a white solid. LCMS (Method A, ESI): RT=2.92 min, m+H=301.3; 1H NMR (400 MHz, DMSO) δ: 12.35 (s, 1H), 8.99 (s, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 7.03 (d, 1H), 5.66 (m, 1H), 4.28 (m, 1H), 3.55 (s, 3H), 2.50 (m, 2H), 2.23 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([OH:7])=O.[NH2:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]([OH:33])=[O:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([NH:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]([OH:33])=[O:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:7]
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1cccc(O)c1
Yield: 38.6 %

Procedure:
2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.33 g.) and 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3 g.) were reacted according to similar manners to those of Examples 1(b), 2(b), 3(b) and 6(b) to give powder of 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.447 g.).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][C:24]=4[CH:31]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.C([O:59][C:60](=[O:64])[CH2:61][NH:62][CH3:63])C>>[CH3:34][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([N:62]([CH2:61][C:60]([OH:64])=[O:59])[CH3:63])=[O:30])=[CH:25][C:24]=4[CH:31]=3)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33]
Reactant: CCOC(=O)CNC
Reactant: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)N(C)CC(=O)O)cc2c1

Procedure:
A solution of 5-{1-[4-(3,3-Dimethyl-2-oxo-cyclohexyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (244 mg, 0.527 mmol) (from example 73A), EDC (151 mg, 0.791 mmol), HOBT (75 mg, 0.554 mmol), triethylamine (0.3 ml, 2.1 mmol), and sarcosine ethyl ester hydrochloride (105 mg, 0.685 mmol) were reacted followed by base hydrolysis as in Example 74 to yield (48 mg, 30%) MS (ES) m/e: 532.3 (M−1)
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25]([C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:25]([C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:42])=[O:41])(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCCCCCCCCCN
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7 ml of anhydrous triethylamine are added to 5.3 g of ethyl 11-aminoundecanoate hydrochloride in 30 ml of anhydrous methylene chloride and, after stirring for one hour at ambient temperature, 6.3 g of 2-benzoyl-4-chlorobenzenesulphonyl chloride are added dropwise. After stirring for 12 hours, the reaction medium is evaporated to dryness under vacuum, taken up with water and extracted with ethyl acetate. The organic phase which is washed with water until the washings are free of Cl- ions is dried over sodium sulphate and evaporated to dryness under vacuum.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC=C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.8 %

Procedure:
In THF (14.0 ml)/methanol (14.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-2-butenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.70 g). To the solution was added 1N sodium hydroxide (7.0 ml), and the mixture was stirred at room temperature for 24 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=6/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-2-butenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.46 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][C:8]1([OH:25])[CH2:11][N:10]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH:12]([N:10]1[CH2:9][C:8]([CH2:7][NH:6][C:3](=[O:4])[CH2:2][Cl:1])([OH:25])[CH2:11]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (0.846 mL) was added dropwise over 30 minutes to a vigorously stirred mixture of 3-(aminomethyl)-1-benzhydrylazetidin-3-ol (example 33, step c) (2.1 g) in ethyl acetate (100 mL) and potassium carbonate (3.03 g) in water (100 mL) at 0° C. The mixture was stirred for a further 30 minutes at 0° C. and then extracted with ethyl acetate, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.6 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[Cl:14].[N-:16]=[N+:17]=[N-:18].[Na+].O>CS(C)=O>[N:16]([CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[Cl:14])=[N+:17]=[N-:18]
Reactant: Nc1nc(Cl)c2ncn(CCCCl)c2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCn1cnc2c(Cl)nc(N)nc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
N9-(3-Chloropropyl)-2-amino-6-chlorpurine (21, 2.56 g, 10.40 mmol) and sodium azide (811 mg, 12.48 mmol) are dissolved in 25 mL DMSO and stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture is poured into 150 mL of water and extracted with CH2Cl2. The combined organic phases are washed with water, dried over MgSO4 and evaporated in vacuo. The residue is purified by flash column chromatography (dichloromethane/methanol 50:1 to 10:1) to yield the title compound as a colorless solid (650 mg, 2.57 mmol, 24%). 1H-NMR (400 MHz, DMSO-d6): δ=8.12 (s, 1H, H-8), 6.89 (s, 2H, NH2), 4.10 (t, J=6.8, 2H, CH2), 3.38 (t, J=6.8, 2H, CH2), 2.05 (m, 2H, CH2) ppm. MS (ESI) m/z 253.0 [M+H]+.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:2][CH2:3][C:4]#[CH:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O>[C:13]([N:6]([C:7]1[N:8]=[CH:9][CH:10]=[CH:11][N:12]=1)[CH2:1][CH2:2][CH2:3][C:4]#[CH:5])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCCCNc1ncccn1
Agent: O=S(=O)(O)O
Product: C#CCCCN(C(C)=O)c1ncccn1
Temperature: 90 °C

Procedure:
A mixture of 2-(pent-4-ynylamino)pyrimidine (4.25 g, 26.4 mmol) and concentrated sulfuric acid (5 drops) in acetic anhydride (100 mL) was heated to 90° C. for 16 h. The mixture was cooled and partitioned between water and methylene chloride. The organic layer was dried (Na2SO4), filtered through a pad of silica and evaporated in vacuo to give the title compound:
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.CCN(CC)CC.[C]=O.[CH3:27][CH2:28][O:29][C:30](C)=[O:31]>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:28]([O:29][C:30]([C:2]1[C:3]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:5]=[N:6][CH:7]=1)=[O:31])[CH3:27]
Reactant: CCOC(C)=O
Reactant: Fc1ccc(-n2ncc3c(Br)cncc32)cc1
Agent: [Fe+2]
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine (3.5 g, 12 mmol), Et3N (3.5 mL, 25 mmol), Pd[PhCN]2Cl2 (105 mg, 0.273 mmol), and dppf (418 mg, 0.754 mmol) in absolute ethanol (90 mL) was placed in a sealed bomb with stirring and placed under 15 bars of carbon monoxide and warmed to 140° C. for 4 hours. The mixture was then cooled to room temperature, returned to atmospheric pressure and opened. The reaction was monitored by TLC (EtOAc-hexanes 4:6 and EtOAc) indicating the starting material was consumed. The reaction was diluted with water (300 mL) and the solid was collected by filtration washing with water. The filtrate was diluted with water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (2×100 mL). The still moist filter cake was dissolved in EtOAc and combined with the extracted organic layers, dried over magnesium sulfate, treated with activated carbon) and filtered through a pad of diatomaceous earth and a layer of silica gel. The material from the pad was dissolved in dichloromethane and passed through a pad of silica gel eluting with dichloromethane to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid ethyl ester.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][CH:18]([CH:22]([CH3:26])[C:23]([OH:25])=O)[C:19]([OH:21])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:19](=[O:21])[CH:18]([CH3:17])[CH:22]([CH3:26])[C:23]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16])=[O:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C(=O)O)C(C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Yield: 67.9 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 600 mg (4.1 mmol) 2,3-dimethylsuccinic acid afforded, after flash chromatography (EtOAc), 1.45 g (69%) of the title compound as a colorless oil.