Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:27]=[C:26]([NH2:28])[N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: N=C(N)N
Reactant: COc1ccc(C(=O)CC(=O)c2cccnc2)cc1Cl
Agent: O=C(O)O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(-c2cc(-c3cccnc3)nc(N)n2)cc1Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
4-(3-Chloro-4-methoxy-phenyl)-6-pyridin-3-yl-pyrimidin-2-yl amine was prepared by treateing 1-(3-chloro-4-methoxy-phenyl)-3-pyridin-3-yl-propane-1,3-dione (0.3 g, 1.0 mmol) with guanidine carbonate (0.21 g, 1.1 mmol) in dowtherm (7 mL) at 180° C. for 30 minutes. The mixture was cooled to temperature in the range of 20-40° C. and diluted with petroleum ether (25 mL). The mixture was stirred for 1 hour. The solid was filtered and dried to give the desired product.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)([O:8][Si](CC)(CC)CC)[C:4]([F:7])([F:6])[F:5].[Li][CH2:35][CH2:36][CH2:37][CH3:38].BrCC1CC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCCCCC>[CH:37]1([CH2:38][N:22]([C@H:19]2[CH2:20][CH2:21][C@H:16]([C:3]([OH:8])([C:2]([F:33])([F:1])[F:32])[C:4]([F:7])([F:6])[F:5])[CH2:17][CH2:18]2)[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:35][CH2:36]1
Reactant: [Li]CCCC
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)N(CC1CC1)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: -40 °C

Procedure:
A solution of 500 mg (0.89 mmol) of trans N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide (example 1.3) in 10 mL of THF was cooled to −78° C. and treated dropwise with 0.72 mL of a 1.6 M BuLi solution in hexane. The solution was warmed to −40° C. within 30 min, treated with 0.43 mL (4.45 mmol) of bromomethylcyclopropane, allowed to reach RT and then refluxed overnight. An excess of TBAF was added and the mixture was stirred for an additional hour. Distribution of the crude mixture between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4, evaporation and chromatography on silica gel with CH2Cl2 gave 200 mg (49%) of trans N-cyclopropylmethyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide, as a colorless viscous oil, MS: 460 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1.[CH2:28](B(O)O)[CH2:29][CH2:30][CH3:31]>C1COCC1.O>[CH2:28]([C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCB(O)O
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1ccc(OCC(=O)O)c(C(=O)c2cnn(-c3ccccc3)c2)c1

Procedure:
A solution of ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate (472 mg, 1.1 mmol), 1-butylboronic acid (102 mg, 1.0 mmol) and Pd (dppf)Cl2 (72 mg, 0.05 mmol) in THF (10 mL) and water (1 mL) under argon was refluxed for 24 h. The reaction mixture was extracted with CH2Cl2, the organic phase was filtered through celite and concentrated, and the residue was purified by flash chromatography (SiO2, EtOAc:heptane, 1:10 to 1:1). The purest fraction was concentrated (˜10 mg), and the residue was hydrolysed according to GP3: LC/MS (an 10p8): Rt 2.59 min, m/z 379.1 [M+H]+; 1H NMR (CDCl3): δ 0.88 (t, J=7.5 Hz, 3H), 1.29 (m, 2H), 1.49 (m, 2H), 2.48 (m, 2H), 4.51 (s, 2H), 6.84 (m, 1H), 7.14 (m, 1H), 7.30 (m, 2H), 7.42 (m, 2H), 7.65 (m, 2H), 7.97 (s, 1H), 8.46 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1>CO.[Pd]>[F:15][C:14]1[CH:13]=[CH:12][C:11]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)=[CH:10][C:9]=1[OH:8]
Reactant: Cn1cc(-c2ccc(F)c(OCc3ccccc3)c2)cn1
Agent: [Pd]
Solvent: CO
Product: Cn1cc(-c2ccc(F)c(O)c2)cn1
Yield: 77 %

Procedure:
A solution of 4-(3-benzyloxy-4-fluoro-phenyl)-1-methyl-pyrazole (which may be prepared as described in Description 78) (760 mg, 2.69 mmol) in methanol (15 mL) was hydrogenated through a H-Cube using a 10% Pd/C (70 mm cartridge) at 50° C. with a Flow rate of 1 mL/min. The eluent was concentrated in vacuo and gave 2-fluoro-5-(1-methylpyrazol-4-yl)phenol (419.2 mg, 2.0721 mmol, 77% yield) (D79) as a colourless solid;
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:72])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:70])[C:57]4[CH:62]=[CH:61][CH:60]=[C:59]([O:63][C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=5)[CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:71])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:72])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:70])[C:57]4[CH:62]=[CH:61][CH:60]=[C:59]([O:63][C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=5)[CH:58]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:71])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(Oc5ccccc5)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(Oc5ccccc5)c4)cc3)cc2C1=O
Yield: 83.44 %

Procedure:
The compound of example 148 was prepared analogous to compound of example 98 by hydrolysis of compound of example 147.
Reaction SMILES: C(OC([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][NH:18][CH2:19][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[CH:21]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:36][O:37][C:38]1[C:43]2[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=2[CH:41]=[C:40]([C:49](Cl)=[O:50])[CH:39]=1.FC(F)(F)C(O)=O>ClCCl>[S:24]1[C:20]([CH2:19][N:18]([CH2:17][C@@H:9]2[CH2:10][C@H:11]3[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12]3)[NH:8]2)[C:49]([C:40]2[CH:39]=[C:38]([O:37][CH3:36])[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=3[CH:41]=2)=[O:50])=[CH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]1=2
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Reactant: CC(C)(C)OC(=O)N1[C@H](CNCc2cc3ccccc3s2)C[C@@H]2CCCC[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N(Cc2cc3ccccc3s2)C[C@@H]2C[C@@H]3CCCC[C@@H]3N2)cc2c1OC(C)(C)O2

Procedure:
Experimental conditions analogous to Example 1, from 0.12 (0.31 mmol) of (2S,3aS,7aS)-2-{[(benzo[b]thiophen-2-ylmethyl)-amino]-methyl}-octahydro-indole-1-carboxylic acid tert-butyl ester, 3 mL dichloromethane, 52 μL (0.37 mmol) of triethylamine, and 83 mg (0.34 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride and 0.4 mL trifluoroacetic acid. The compound was purified using reverse phase HPLC, mobile phase with a gradient 15-80% acetonitrile in 50 min, gave 104 mg of the product as the free base as an off-white solid. LC-MSD, m/z for C29H34N2O4S [M+H]+: 507.6. 1H NMR (400 MHz, CDCl3/HCl): δ 1.4-2.0 (m, 8 H), 1.7 (s, 6 H), 2.1-2.2 (m, 1 H), 2.4-2.5 (m, 1 H), 3.2 (bs, 1 H), 3.3-3.4 (m, 1 H), 3.7-3.8 (m, 1 H), 3.8 (s, 3 H), 4.2-4.4 (m, 2 H), 4.9-5.2 (m, 2 H), 6.8 (s, 1 H), 7.1 (s, 1 H), 7.3-7.4 (m, 2 H), 7.7-7.8 (m, 2 H), 7.9 (bs, 1 H), 11.6-11.8 (bs, 1 H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6]>CO.O.O>[Br:19][C:15]1[CH:14]=[C:13]([C:7]2([C:5]([OH:6])=[O:4])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1(c2cccc(Br)c2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 65 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
Lithium hydroxide (0.21 g, 5.01 mmol) is added to a solution of 4-(3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (0.5 g, 1.67 mmol) in methanol/water (8 mL, 3:1) and the reaction mixture is stirred for 5 hours at 65° C. The mixture is diluted with water and the volatiles are removed in vacuo. The aqueous is extracted once with diethyl ether, acidified to pH 2, and extracted twice with ethyl acetate. The combined extracts is dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-(3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid (445 mg) sed in the next step without further purification. LCMS: RT=1.9 minutes; MS: 283 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:17]I>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([O:14][CH3:17])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C2(O)CCOCC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cccc(N)c2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 4-(3-aminophenyl)-4-hydroxytetrahydropyran (630 mg, 3.26 mmol), prepared as in step 3, in dry DMF (13 mL) was added sodium hydride (326 mg of a 60% oil dispersion). The reaction was stirred at ambient temperature for 1 hour and then methyl iodide (0.24 mL, 3.19 mmol) was added neat. The resulting solution was stirred at ambient temperature for 0.5 hour and quenched with saturated aqueous ammonium chloride. The biphasic solution was extracted with ethyl acetate. The organic layer was washed (1×, saturated aqueous ammonium chloride; 2×, brine), dried (MgSO4), and concentrated in vacuo to provide an oil. Chromatography on silica gel with 20% ethyl acetate/hexanes as the eluant provided 4-(3-aminophenyl)-4-methoxytetrahydropyran as a beige solid (510 mg, 76%). mp 99.0°-100.5° C. 1H NMR (300 MHz, CDCl3) δ7.17 (1H, t, J=9 Hz), 6.73- 6.82 (2H, m), 6.62 (1H, ddd, J=9, 2, 1 Hz), 3.85 (2H, td, J=10.5, 10.5, 2.5 Hz), 3.81 (2H, ddd, J=10.5, 9, 3 Hz), 2.99 (3H, s), 1.87-2.07 (4H, m). MS m/e 207 (M)+, 225 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[C:6]([Br:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]([CH2:16]/[CH:17]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=[O:15])[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]([N:12]1[C:3]2[C:2](=[C:7]([O:8][CH3:9])[C:6]([Br:10])=[CH:5][C:4]=2[F:11])[C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16]1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)/C=C\CN(C(C)=O)c1c(F)cc(Br)c(OC)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(C(C)=O)c2c(F)cc(Br)c(OC)c12
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To the solution of 8-7 (20 g, 44.0 mmol) in anhydrous DMF (250 mL) was added Pd(OAc)2 (2.0 g, 8.8 mmol), Bu4NBr (14.3 g, 44.0 mmol) and DIPEA (14.2 g, 110 mmol) under N2. The mixture was stirred at 80° C. for 3 h. TLC showed that the reaction was completed. The mixture was poured into ice water and extracted with ethyl acetate (150 mL×3). The organic layers were combined and were concentrated in vacuo. The residue was purified by flash chromatography (Silica-gel, petroleum ether/ethyl acetate=10:1) to afford 8-8 (13.0 g, 79%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCCc2c(-c3ccc(Cl)cc3)noc2C1
Yield: 80.3 %

Procedure:
2,48 g of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylate were treated with 0.8 g of potassium hydroxide in 2 ml of water and 50 ml of methanol at 20° C. Methanol was removed from the mixture by evaporation and the residue was taken up in water. After washing with diethyl ether, the aqueous alkaline solution was acidified with 2N hydrochloric acid and extracted with diethyl ether. The ethereal extract was dried over magnesium sulfate and evaporated to give 1.9 g of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]-isoxazole-7-carboxylic acid of melting point 215°-217° C. (from methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH:8](=[O:11])[CH2:9][CH3:10].C([N-]C(C)C)(C)C.[Li+]>C(OCC)C>[Br:1][C:2]1[C:3]([CH:8]([OH:11])[CH2:9][CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncnc1
Reactant: CCC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCC(O)c1ncncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To 5-bromopyrimidine (2.39 g, 15.0 mmol) and propionaldehyde (1.05 g, 18.0 mmol) in diethyl ether (80 mL), lithium diisopropylamide (18 mmol) in diethyl ether (20 mL) was gradually added dropwise at 0° C. After the dropwise addition, the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted by adding water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2.5/1) to give a mixture (colorless oil) containing the desired product, which was used for the next step (427 mg, 13% yield). 2-[1-(5-Bromopyrimidin-4-yl)propyl]isoindoline-1,3-dione
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14]([NH:17][C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[CH:20]=2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].[C:43]([OH:46])(=[O:45])[CH3:44]>CN(C)C=O.CO>[C:8]1([S:14]([NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]3[N:25]=[C:44]([C:43]([OH:46])=[O:45])[N:26]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:30][CH:29]=4)[C:21]=3[CH:20]=2)=[O:40])(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc2nc(C(=O)O)n(Cc3ccc(-c4ccccc4)cc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.080 g) and 0.148 g of methyloxalyl chloride were added to a solution of 0.400 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 3 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to obtain crude 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole. This compound was dissolved in 1 ml of acetic acid and 5 ml of methanol, and the mixture was stirred at 60° C. for 15 hours. The reaction solution was neutralized with a potassium hydroxide aqueous solution. The crystals precipitated were separated through filtration, and were dried to give 0.245 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole (229).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]4[C:22]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)=[N:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]4[C:22]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)=[N:21]3)[CH2:16][CH2:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(C2CCNCC2)CC1
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
1-[ 1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (254 mg, 0.446 mmol) was stirred in 25 ml of 10% trifluoroacetic acid in dichloromethane overnight. The solvent was evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromathane. The combined organic layer was washed, dried and evaporated to give 108 mg of 1-[1-(4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate GG) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N+:30]([O-:32])=[O:31])=[CH:22][CH:23]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
To a solution of 0.199 g (1.13 mmol) of 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine in 5 mL of anhydrous dimethylformamide was added 0.050 g (1.25 mmol) of a 60% mineral oil dispersion of sodium hydride. The reaction mixture was magnetically stirred under a nitrogen atmosphere for 30 minutes, at which point 0.365 g (1.25 mmol) of 4-bromomethyl-2'-nitrobiphenyl was added as a solid. The reaction mixture was stirred an additional 1.5 hours at room temperature, then partitioned between ethyl acetate and water. The organic layer was extracted, washed with brine, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 50% ethyl acetate-hexane, which after evaporation of the pure fractions and drying in vacuo afforded 0.340 g (77%) of the product as a tan solid: NMR (CDCl3) δ 1.31 (t, J=10 Hz, 3H), 2.58 (s, 3H), 2.62 (s, 3H), 2.78 (q, J=10 Hz, 2H), 5.48 (s, 2H), 6.88 (s, 1H), 7.14-7.24 (m, 4H), 7.34-7.38 (m, 1H), 7.42-7.48 (m, 1H), 7.54-7.60 (m, 1H), 7.83, (d, J=10 Hz, 1H); MS (FAB) m/e 387 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[Br-].[N+:16]([C:19]1[CH:20]=[C:21]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:18])=[O:17].C[O-].[Na+].C(O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:46][O:45][C:44]1[CH:43]=[CH:42][C:21]([CH:22]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:20][C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(C=Cc2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
3,4,5-Trimethoxybenzaldehyde (5, 54.7 g), (4-methoxy-3-nitrobenzyl)triphenylphosphonium bromide (4, 148.6 g) and 1300 ml of toluene are charged, at 20° C. and under nitrogen, into a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a dropping funnel and a reflux condenser surmounted by a bubble counter. The stirred suspension is cooled to 5° C. using an ice bath and then 63.2 g of a 25% w/w solution of sodium methoxide in methanol are added at 5° C. over 40 minutes. As the addition progresses, the suspension color changes from off-white to yellow and then to brown. The mixture is stirred for 1 hour at 5° C. and the end of the reaction is monitored by HPLC (complete consumption of the aldehyde). Acetic acid (3 g, 0.05 mol) is then added. The suspension is heated to 40° C. and is maintained at 40° C. for 30 minutes. At this temperature, only the salts remain insoluble. The mixture is filtered at 40° C. through a sintered glass filter (No. 3) and the salts are washed on the filter 3 times with 100 ml portions of toluene. The filtrate is returned to a round-bottomed flask with 250 ml of distilled water, and the two-phase mixture is stirred for 20 minutes at 40° C. and then the phases are separated. The toluene phase is washed twice with 250 ml portions of distilled water and then concentrated to dryness on a rotary evaporator. The residue is taken up in 600 ml of isopropanol and 12 ml of toluene at 40° C. The expected product begins to crystallize and the temperature is allowed to return to ambient temperature overnight with slow stirring. The stirred suspension is cooled to and maintained for 1 hour at 5° C., then filtered through a sintered glass filter, and the filter cake is washed twice with 125 ml portions of isopropanol, sucked dry and dried in an oven under vacuum (35° C./30 mmHg/18 hours). A mixture of Z and E isomers (6) and (7) (91.7 g) is obtained with a Z/E ratio of 75/25 (IS IPLC) and a yield of 95%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:18](=[CH:19][CH:20]=1)[C:10]1[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=1[CH2:8]2)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:18](=[CH:19][CH:20]=1)[C:10]1[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=1[CH2:8]2)[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1ccc2c(c1)Cc1c-2[nH]c2ccccc12

Procedure:
A solution of 5,10-dihydro-2-(N-acetylamino)indeno[1,2,b]-indole (0.70 g, 2.8 mM) in dry tetrahydrofuran (50 cm3), under a protective atmosphere of nitrogen, was treated with lithium aluminium hydride (0.40 g, 10.50 mM) during the course of 3 hours. The mixture was then heated to reflux for a further 3 hours, and eventually cooled. Excess reagent was destroyed by the addition of a saturated solution of sodium potassium tartrate (5 cm3) and the organic phase separated. The residual aqueous slurry was extracted with tetrahydrofuran (3×10 cm3) and the extracts and organic phase were combined, filtered through phase transfer paper, and evaporated. This gave the title compound as a pale yellow solid. M.p. 225° C. Yield; 0.47 g, 71%. 1H NMR (CDCl3) δ: 1.23 (3H, t, J=7.0 Hz), 3.09 (2H, q, J=7.0Hz), 3.59 (2H, s), 4.80 (1 H, br.s), 6.56 (1H, d, J=7.5Hz), 6.87 (1H, s), 7.01 (2H, br.m), 7.32-7.48 (3H, br.m), 10.47 (1H, br.s).