Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[C:17]2[CH:25]=[C:24]([Cl:26])[N:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(N(CC)CC)C.CNC>CC(O)C>[Cl:26][C:24]1[N:23]=[CH:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:12][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][CH:13]=3)[C:17]=2[CH:25]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Agent: CNC
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Clc1cc2c(Nc3ccc(Oc4ccccc4)cc3)ncnc2cn1

Procedure:
6-Chloro-4-(4-phenoxyanilino)pyrido[3,4-d]pyrimidine was prepared by the reaction of 4-phenoxyaniline and 4,6-dichloropyrido[3,4-d]pyrimidine in 2-propanol according to Procedure A, with triethylamine present to give the free base of the product directly. Reaction of this product with dimethylamine (33% aqueous solution) according to Procedure C gave the title compound: δH (CDCl3) 9.00 (1H,s), 8.54 (1H,s), 7.70 (2H, d), 7.00-7.44 (5H,m), 7.13 (2H,d), 6.38 (1H,s), 3.22 (6H,s); m/z (M+1)+358.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
A suspension of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 1.76 g, 6.05 mmol), 1-(benzyloxy)-4-isocyanatobenzene (1.50 g, 6.66 mmol) and triethylamine (2.11 mL, 15.1 mmol) in THF (15 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide N-[4-(benzyloxy)phenyl]-4-(2-tert-butylphenyl)piperazine-1-carboxamide (2.65 g, 99%) as a off white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]1[S:12][CH2:11][CH2:10][CH2:9][S:8]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C1COCC1>[CH3:6][C:7]1([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[S:12][CH2:11][CH2:10][CH2:9][S:8]1
Reactant: BrCCCCOCCCc1ccc(N2CCCC2)cc1
Reactant: CC1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(CCCCOCCCc2ccc(N3CCCC3)cc2)SCCCS1
Reaction time: 2 h
Yield: 45.5 %

Procedure:
n-Butyllithium (1.5M in hexane, 12 ml) was added over 5 min to a stirred solution of 2-methyl-1,3-dithiane (2.4 g) in dry THF (30 ml) at 70° under nitrogen. The yellow solution was then stirred at -30° to -20° for 2 h, cooled to -78° and treated with a solution of the product of stage (iii) (6.1 g) in THF (25 ml). The solution was stirred at room temperature overnight, the solvent was evaporated and the residue was purified by FCC (hexane→System D 9:1) to give the title compound as a pale yellow oil (3.2 g) T.l.c. (System D 9:1) Rf 0.18.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])#[N:12].[OH-].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:11]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:11]#[N:12])=[O:7])#[N:12]
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: Cc1ccc(NC#N)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: Cc1ccc(N(C#N)C(=O)CCCCC(=O)N(C#N)c2ccc(C)cc2C)c(C)c1

Procedure:
A solution of 10.07 g (0.055 mol) of adipyl chloride in 30 ml of acetone is added dropwise to 14.6 g (0.1 mol) of N-cyano-2,4-dimethylaniline in 60 ml of 2N NaOH (0.12 mol) at 10°-26° C. in the course of 40 minutes, while cooling and stirring rapidly, and the reaction mixture is then stirred for another 2 hours and 15 minutes at 15°-25° C. 50 ml of chloroform are then added, the mixture is stirred for 10 minutes, the two phases are separated, the organic phase is dried with anhydrous sodium sulfate, the suspension is filtered with suction and the filtrate is concentrated on a rotary evaporator at 40° C. in vacuo. The residue is recrystallised from 113 ml of ethyl acetate to give 18.7 g (93.0% of theory) of a colourless, crystalline compound with a melting point of 120°-122.2° C.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:26](N1C=CN=C1)([N:28]1C=CN=[CH:29]1)=O.CNC.O>CN(C)C=O>[CH3:26][N:28]([CH3:29])[C:23](=[O:25])[CH2:22][CH2:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH:11]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
3-[2-(2-Oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Dimethylamine (2.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 8.9 g (83% yield) of N,N-dimethyl-3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:25][OH:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:25]([CH:17]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ONC1CCCCCCC1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCCCCC1
Yield: 47.1 %

Procedure:
A solution of 4benzyloxybenzaldehyde (12.7 g, 0.060 mol), N-cyclooctylhydroxylamine (10.0 g, 0.070 mol) and a catalytic amount of HCl in methanol (300 mL) was refluxed for 56 hours with molecular sieves in a soxhlet for water removal. The reaction mixture was concentrated and dry flash columned on silica with hexanes/ethyl acetate to give the title compound as a pale yellow powder, (9.53 g, 47.0% yield), m.p. 107.5° C. (Rf =0.46 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant). The N-cyclooctylhydroxylamine precursor was obtained by sodium cyanoborohydride reduction of cyclooctanone oxime in acetic acid/tetrahydrofuran.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([NH:11]C(OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19]1([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[OH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:11][CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH2:2][N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:26])[CH2:32][CH2:31]1
Reactant: OC(c1ccccc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(CCBr)c1ccccc1
Product: NC(CCN1CCC(C(O)c2ccccc2)CC1)c1ccccc1

Procedure:
The procedure given in Example 2 except for the formation of salts was followed using 3-bromo-1-(tert-butoxycarbonyl)amino-1-phenyl propane and phenyl-piperidin-4-yl-methanol as reactants, instead of d-1-bromo-2-(tert-butoxycarbonyl)amino-3-phenyl propane and hexamethyleneimine to give [1-(3-Amino-3-phenyl-propyl)-piperidin-4-yl]-phenyl-methanol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][CH2:43]O.[Cl:45][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]2[C:55]=1[C:54](=[O:56])[NH:53][N:52]=[CH:51]2.Cl>C1COCC1>[Cl:45][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]2[C:55]=1[C:54](=[O:56])[N:53]([CH2:43][CH2:42][C:33]1[CH:34]=[CH:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:32]=1)[N:52]=[CH:51]2
Reactant: OCCc1ccc2ccccc2n1
Reactant: O=c1[nH]ncc2cccc(Cl)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2c(Cl)cccc2cnn1CCc1ccc2ccccc2n1
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (9.00 g, 34.3 mmol) in THF (100 mL), DEAD (5.44 mL, 34.3 mmol) was added at 0° C. After stirring for 15 min, 2-(quinolin-2-yl)ethanol from Example a1 (2.97 g, 17.17 mmol) was added. After another 15 min, 8-chlorophthalazin-1(2H)-one (3.1 g, 17.17 mmol) was added. The mixture was stirred overnight at room temperature; LC-MS indicated complete conversion to the product. 1 N HCl was added (pH=4). The mixture was extracted with EtOAc (3×50 mL), the EtOAc layers were discarded. The aqueous layer was neutralized by aq.NaHCO3 and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was suspended in EtOAc. The solid was filtered through a Büchner funnel. The purity of the title product was 95%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[CH:11]=1)=[CH:8][CH:7]=[C:6]([CH3:13])[N:5]=2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:10]1[C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: Cc1ccc2c(=O)cc(C)[nH]c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)cc(C)nc2n1

Procedure:
The product from Example 14a (500 mg, 2.87 mmol) was reacted with 10 mL of POCl3 for 2 h following the procedure from Example 1d giving the title compound, which was used without purification.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][CH:9]=2)[N:4]=1.CC[OH:20]>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[CH:11]=[CH:12][C:3]=1[CH:2]=[O:20]
Reactant: CCO
Reactant: BrC(Br)c1ccc2ccc3ccccc3c2n1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2ccc3ccccc3c2n1

Procedure:
To a mixture of 2-(dibromomethyl)benzo[h]quinoline (52 mg, 0.148 mmol) in EtOH (2 mL) and THF (1 mL) was added a solution of AgNO3 (75 mg, 0.444 mmol) in H2O (1 mL). The mixture was stirred at reflux for 2 h. The solid was filtered off and the organic solvent was removed under reduced pressure. DCM (5 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (5 mL×2). The combined organic layers were washed with brine (2 mL) and dried by anhydrous Na2SO4. The organic layer was concentrated to give benzo[h]quinoline-2-carbaldehyde (30 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)c2ccc3oc4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)cc1
Yield: 33 %

Procedure:
The product of Example 29, step B and sodium 4-methylbenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 90:10 to 50:50 hexane/ethyl acetate) provided tert-butyl 8-(4-methylphenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (65 mg, 33%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.07 (br s, 1H), 7.86-7.78 (m, 3H), 7.49 (d, J=8.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 4.57 (br s, 2H), 3.88-3.78 (m, 2H), 2.90-2.82 (m, 2H), 2.38 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@:11]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37]Br>CN(C)C=O>[CH2:3]([N:10]1[C@@H:15]2[C@@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@:11]1([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@H:12]([O:25][CH2:37][C:36]1[CH:39]=[C:40]([C:42]([F:44])([F:45])[F:43])[CH:41]=[C:34]([C:33]([F:32])([F:46])[F:47])[CH:35]=1)[CH2:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reaction time: 20 h
Yield: 121.2 %

Procedure:
Sodium hydride (60% in oil, 110 mg, 2.75 mmol) was added to a stirred mixture of (1R*,2R*,5S*,6S*)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 21a; 670 mg, 1.1 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (1 ml, 5.45 mmol) in N,N-dimethylformamide (5 ml) at room temperature. The reaction mixture was stirred for 20 hours, quenched with saturated aqueous NH4Cl and extracted into a 1:1 mixture of iso-hexane:diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-5%) to give the title compound (826 mg, 78%).
Reaction SMILES: [OH:1]CC1C=C(O)C=CC=1.[C:10]([O:13][C:14]1[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:16](Cl)=[O:17])(=[O:12])[CH3:11]>[Na+].[OH-].ClCCl>[C:10]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:1])=[O:17])(=[O:12])[CH3:11]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: OCc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
3-hydroxymethylphenol (25.25 g, 0.2 moles) is dissolved in a 5% hydroxide sodium solution (160 ml). To the so obtained solution an acetylsalicylic acid chloride solution (40.4 g, 0.2 moles) in dichloromethane (50 ml) is added at roam temperature, under stirring. The mixture is maintained at room temperature under stirring for 2 hours and then extracted with dichloromethane (2×100 ml). The organic phase is separated, anhydrified with sodium sulphate and the solvent evaporated under vacuum. The residue is crystallized from a mixture of ethyl acetate and hexane. 3-hydroxymethylphenyl ester of the 2-acetoxybenzoic acid (45.8 g, 0.16 moles, yield 80%) is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:46])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:43]=3)=[C:18]([O:44][CH3:45])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:36])([F:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:46])=[CH:17][C:18]=4[O:44][CH3:45])=[N:43][C:27]2=3)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of 0.090 g (0.14 mmole) of 4-[4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-250) 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.060 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-piperidin-4-yl-benzamide (I-251).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:14][CH2:13][C:12]2[C:15]([O:25][CH3:26])=[C:16]([O:23][CH3:24])[C:17]([O:21][CH3:22])=[C:18]([O:19][CH3:20])[C:11]=2[CH2:10][CH2:9]1)(=O)=O.[I-:27].[Na+].CC(C)=O>O>[I:27][CH2:6][CH2:7][CH:8]1[CH2:14][CH2:13][C:12]2[C:15]([O:25][CH3:26])=[C:16]([O:23][CH3:24])[C:17]([O:21][CH3:22])=[C:18]([O:19][CH3:20])[C:11]=2[CH2:10][CH2:9]1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOS(C)(=O)=O)CC2
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Yield: 97.5 %

Procedure:
The mixture of 2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethyl methanesulfonate (3.12 g), sodium iodide (3.61 g), and acetone (40 ml) was heated under reflux for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium sulfite, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (3.29 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14]([C:16]([NH:21]C(=O)OC(C)(C)C)([CH3:20])[CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[C:16]([CH3:20])([NH2:21])[CH:17]([CH3:18])[CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(NC(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(N)C(C)C)CC1
Yield: 99 %

Procedure:
2,2,2-trifluoro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}carbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.524 g, 99%). 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), trifluoroaceticanhydirde (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2,2-trifluoro-N-({-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}acetamide (0.036 g, 61%) as an oil. ES-LCMS m/z 656 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:30])=[O:29])=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Yield: 41 %

Procedure:
4(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4 -carboxylic acid ethyl ester (5.8 g, 10 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98° C.; MS: 559.6 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[NH:32][CH2:31][CH2:30][O:29][CH3:28])[CH:19]=[CH:18][N:17]=1
Reactant: COCCN
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (1.5 g, 3.68 mmol) and cesium carbonate (2.5 g, 7.67 mmol) in 2-methoxyethan-1-amine (15 mL) was stirred under nitrogen for 3 days at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified on a C18 column (acetonitrile/water, 5:95-80:20) to give 0.55 g (39%) of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine as a yellow solid. LC-MS: m/z=+363 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O-:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:15]([O-])(O)=O.[Na+]>CO>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)[O-])s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C)s1
Temperature: 83 °C
Yield: 67 %

Procedure:
5-Methyl-2-thiophene carboxylate (2.0 g, 14.1 mmol, Aldrich, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA) was carefully dissolved in 50 ml methanol and 15 ml conc. sulfuric acid at room temperature under an inert atmosphere. The reaction mixture was refluxed at 83° C. for 5 hours. After the reaction mixture was allowed to cool to room temperature, it was poured into a beaker containing 200 ml of ice. This aqueous mixture was neutralized to pH 7 with solid NaHCO3. This liquid was poured into a separatory funnel and extracted 2×200 ml CH2Cl2. The combined organics were dried over MgSO4, filtered, and stripped to provide the title compound of this Preparation (2.2 g, 67% yield) as a brown oil. 1H NMR (CDCl3): δ 7.61 (1H, d J=4), 6.77 (1H, d, J=4), 3.84 (3H, s), 2.52 (3H, s).