Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])=[C:11](I)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])=[C:11]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(-c2ccc(Cl)c(Cl)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(Cl)c(Cl)c2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [2-(3,4-dichloro-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 105) was reacted with pyridine-3-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 484.3 (MH+, 2Cl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8]C)[C:5]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:4]([CH3:21])[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[OH-].[Na+]>CCOC(C)=O>[F:20][C:16]1[CH:15]=[C:14]([CH2:13][NH:12][C:10]([C:5]2[C:6]([OH:8])=[N:7][C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:3][C:4]=2[CH3:21])=[O:11])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)nc(O)c1C(=O)NCc1cccc(F)c1
Temperature: 120 °C
Yield: 45.5 %

Procedure:
A mixture of 1.37 g (4.4 mmol) 6-Chloro-N-[(3-Fluorophenyl)-methyl]-2-methoxy-4-methyl-pyridine-3-carboxylic acid amide and 2.9 ml (33.2 mmol) morpholine was heated in the microwave to 120° C. for 30 min. The RM was then diluted with EtOAc (50 ml) and a 1M aq. NaOH sol. (20 ml) was added. The precipitate formed was filtered off to give 715 mg (2.0 mmol, 47%) N-[(3-Fluorophenyl)-methyl]-2-hydroxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide. The organic layer was separated from the filtrate, washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 397 mg (1.1 mmol, 25%) N-[(3-Fluorophenyl)-methyl]-2-methoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 19). [M+H]+ 360.2.
Reaction SMILES: [C:1]1(CC=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15]C=CC=1.C[OH:19]>[Pd]>[C:1]1([NH:17][C:10]([CH:11]2[CH2:16][CH2:15]2)=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: NCc1ccccc1
Reactant: O=CCc1ccccc1
Agent: [Pd]
Product: O=C(Nc1ccccc1)C1CC1

Procedure:
Phenylacetaldehyde (0.091 mL, 0.780 mmol) was added to N-benzylamine 86 (0.055 g, 0.156 mmol) dissolved in MeOH (5.2 mL, 0.03M). 10% Pd/C (0.0557 g) was added, and the mixture was shaken under 40 psi H2 until the consumption of H2 ceased and the reaction was judged complete by TLC. The crude reaction mixture was passed through a column of Celite, concentrated in vacuo, and purified by flash column chromatography (50:48:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain pure 4-phenethyl-1,4-ozazepan-2-ylmethyl)-N-phenylcyclopropanamide (87). 1H NMR (CDCl3) 7.47 (2H, m), 7.37–7.26 (5H, m), 7.24–7.17 (3H, m), 3.94–3.80 (3H, m), 3.69 (1H, broad dd, J=13.3, 7.8 Hz), 3.62 (1H, ddd, J=11.7, 6.2, 5.3 Hz), 2.96–2.86 (2H, m), 2.77 (4H, s), 2.67 (1H, ddd, J=12.8, 8.9, 4.1 Hz), 2.50 (1H, dd, J=8.9, 6.7 Hz) 2.0–1.74 (2H, m), 1.42–1.28 (1H, m), 1.04 (2H, dtd, J=7.8, 3.4, 1.1 Hz), 0.67–0.60 (2H, m) ppm. 13C NMR (CDCl3) 173.79, 143.39, 140.46, 129.52, 128.82, 128.61, 128.44, 127.53, 126.05, 76.41, 67.15, 60.06, 59.53, 53.90, 52.09, 34.21, 30.28, 12.92, 8.71, 8.50 ppm. LRMS: 378.80.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[N:23]O)[C:14]=2[CH:13]=[CH:12][CH:11]=1>[Ni].C(O)C.O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([NH2:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccccc2[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4ccccc4[nH]3)cccc21
Yield: 87.4 %

Procedure:
Carry out the procedure as in Example 6, starting from 1.57 g of 4-(1H-benzimidazol-2-yl)-fluoren-9-one oxime (Z,E), obtained in Example 68, and 5.6 mg of Raney Nickel in 80 ml of ethanol and 80 ml of tetrahydrofuran for 4 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 1.31 g of 4-(1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a white powder, with the following characteristics:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][C:24]([CH3:28])([CH3:27])CN.[CH3:29][N:30](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:21][O:22][CH2:23][C:24]([N:30]([CH3:29])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:27])[CH3:28]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COCC(C)(C)CN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)N(C)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3-methoxy-2,2-dimethylpropan-1-amine (CAN 1177316-77-6) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=384.5 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccccc2OCCOC2CCCCO2)cc1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 2-benzyloxyphenol (3.00 g, 15.0 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% in oil) (719 mg, 18.0 mmol) under ice-cooling, and the mixture was stirred at 30 min. 2-(2-Bromoethoxy)tetrahydropyran (2.72 ml, 18.0 mmol) was added to the reaction mixture and the mixture was stirred at 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 2-[2-(2-benzyloxyphenoxy)ethoxy]tetrahydropyran (4.90 g). The obtained compound was used for Step 2 without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1.[N:19]([C:22]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:23]=1[C:24](OCC)=[O:25])=[C:20]=[S:21]>O1CCCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:1]3[C:24](=[O:25])[C:23]4[C:22](=[CH:32][C:31]([O:33][CH2:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:30][CH:29]=4)[NH:19][C:20]3=[S:21])[CH2:5][CH2:6]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1N=C=S
Reactant: NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=S)[nH]c3cc(OCc4ccccc4)ccc3c2=O)CC1
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a stirred mixture of 6.25 parts of [1-(2-aminoethyl)-4-piperidinyl](4-fluorophenyl)methanone and 135 parts of tetrahydrofuran was added dropwise a solution of 7.5 parts of ethyl 2-isothiocyanato-4-(phenylmethoxy)benzoate in 45 parts of tetrahydrofuran. Upon completion, stirring was continued for 4 hours at room temperature and for 30 minutes at reflux temperature. After cooling, the product was filtered off and crystallized from a mixture of N,N-dimethylformamide and water. The product was filtered off and dried, yielding 3.8 parts (29%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-(phenylmethoxy)-2-thioxo-4(1H)-quinazolinone; 236.0° C. (dec.) (6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[S:43](Cl)(=[O:45])=[O:44].O>ClCCl>[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[S:43]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:10]2[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:29][CH:28]=1)(=[O:45])=[O:44]
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)c2cccs2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (100 mg, 0.22 mmol) and triethylamine (0.31 ml, 2.25 mmol) in dichloromethane (2.5 ml) were cooled to −78° C. 2-Thiophenesulfonyl chloride (287 mg, 1.57 mmol) dissolved in dichloromethane (2.5 ml) was carefully added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase washed with water and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (110 mg, 83%) as a solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@@H:5]([NH:23][C@H:24]1[C:33]2[C:28](=[C:29]([O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O=S(Cl)Cl>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([C@H:5]3[CH2:4][CH2:3][CH2:2][N:23]3[C@H:24]3[C:33]4[C:28](=[C:29]([O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of (1R)-1-[[(1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (2.6 g) in CH2Cl2 (50 ml) was added SOCl2 (3 ml). After being stirred for 12 hours, the solvent was removed. The residue was dissolved in N,N-dimethylformamide (DMF) (15 ml) and K2CO3 (2 g) was added to the solution. After being stirred for 4 hours at the room temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.22 g).
Reaction SMILES: [C:1]1([CH2:17][C:18]([OH:20])=O)[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH3:21]>>[C:1]1([CH2:17][C:18]([NH2:21])=[O:20])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: N
Product: NC(=O)Cc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
Under the stated conditions, the ester of anthraquinone-acetic acid reacts with the NH3 to form, directly, the 1-aza-2-hydroxybenzanthrone, without the necessity of isolating the intermediate product 1-anthraquinone acetamide.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21](F)=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[CH2:13][CH2:12]1)=[O:9])#[N:2].C(OC1C=C(C=O)C=C(OCC)C=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[C:8]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([O:28][CH2:29][CH3:30])[C:21]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)=[C:22]([O:24][CH2:25][CH3:26])[CH:23]=2)[CH2:15][CH2:16]1)=[O:9])#[N:2]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC#N)c3)CC2)cc(OCC)c1F
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC#N)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 3-cyanomethoxy-5-methoxy-N-piperidin-4-yl-benzamide (example 245) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 562.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Br)[CH:7]=1)C.BrN1[C:20](=[O:21])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CO.C[O-].[Na+].C(OCC)(=O)C>[CH3:1][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:21][CH3:20])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(CBr)c1
Agent: C[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl(3-(bromomethyl)phenyl)acetate (1.78 g) in carbon tetrachloride (80 ml), 1.78 g of N-bromosuccinimide and 100 mg of benzoyl peroxide were added, and the reaction solution was heated overnight at reflux. The reaction solution was cooled, then the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-10:90)) to afford a crude product. To a solution of the crude product (304 mg) in methanol (1 ml), 0.3 ml of sodium methoxide (25% methanol solution) was added, and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution and a saturated saline solution sequentially, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., ethyl acetate/hexane (20:80)) to afford the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:33]5[CH2:34][CH2:35][CH2:36][C@H:32]5[CH3:31])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CC1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@H]5C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (600 mg, 1.35 mmol) in dimethyl sulfoxide (10 mL) was added of 20 drops of acetic acid and 2-methylpyrrolidine (1.37 mL, 13.5 mmol). The resulting mixture was stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride (2.86 g, 13.5 mmol). The reaction was stirred at room temperature overnight then purified by Gilson Preparatory HPLC. This compound was then separated to give the title compound as 98.6% chirally pure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]4)[CH:15]=3)[N:10]=[CH:9]2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[C:33]([C:35](Cl)=[O:36])[CH:32]=[CH:31][N:30]=1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N:19]5[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]5)[CH:15]=4)[N:10]=[CH:9]3)[CH:7]=2)=[O:36])[CH:32]=[CH:31][N:30]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described in Example 5, 3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-one was reacted with 2-chloropyridine-4-carbonyl chloride to give the title compound; NMR Spectrum: (DMSOd6) 1.84-1.96 (m, 2H), 2.06 (s, 3H), 2.29 (s, 3H), 2.42-2.49 (m, 2H), 2.62-2.68 (m, 2H), 3.53 (t, 2H), 3.58-3.64 (m, 2H), 7.22 (d, 1H), 7.34 (m, 1H), 7.44 (m, 1H), 7.58 (d, 1H), 7.73-7.78 (m, 2H), 7.82-7.86 (m, 1H), 7.96-7.98 (m, 2H), 8.50-8.62 (m, 1H), 10.68 (s, 1H); Mass Spectrum: M+H+ 503 & 505.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:5]1[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(OC)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) was mixed with trimethyl orthoformate (4 mL, 36.10 mmol) and p-toluenesulfonic acid (5 mg). The reaction was stirred at room temperature for 3 h and then quenched by adding excess of sodium bicarbonate solid and stirred for 1 h. The solid was removed by filtration and the filtrate was concentrated to yield 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100%). A mixture of 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 4.31 mmol), cesium carbonate (1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladium tetrakis(triphenyl) phosphine (0.25 g, 0.216 mmol) in toluene (60 mL) and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C. for 28 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), concentrated to afford a solid residue. Purification by column chromatography left 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60%). A solution of 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20 mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at room temperature for 2 h. The reaction mixture was then neutralized with 1 N sodium bicarbonate aqueous to pH 9 and extracted with DCM (3×100 mL), to afford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na].C(O)(=O)C>C(#N)C.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][NH:14]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(C)CN=C(c2ccc3c(c2)OCO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CNC(c2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.8 %

Procedure:
To a solution of 5-(1,3-benzodioxol-5-yl)-3,3-dimethyl-3,4-dihydro-2H-pyrrole (363 mg, 1.673 mmol) in acetonitrile (35 mL) add sodium triacetoxyborohydride (390 mg, 1.84 mmol) and stir at room temperature for two days. Then add more sodium triaxetoxyborohydride (390 mg, 1.84 mmol) and acetic acid and stir for 3 h. Add more add sodium triaxetoxyborohydride (390 mg, 1.84 mmol). After 0.5 h dissolve the reaction by adding methanol and load onto an ion-exchange SCX-2 (25 g), wash with methanol and then extract with ammonia in methanol. Concentrate under reduced pressure the basic solution, to afford 289 mg (79%) of the title compound. MS: 220 [M+H]+; 1H NMR (300 MHz, CDCl3): δ 6.90 (s, 1H), 6.72-6.75 (m, 1H), 6.72-6.75 (m, 1H), 5.91 (s, 2H), 4.20-4.25 (m, 1H), 2.68-2.72 (m, 1H), 2.75-2.79 (m, 1H), 1.72-1.98 (m, 2H), 1.45-1.1.53 (m, 1H), 1.10-1.18 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 0.844 g (4 mmol) of 4-chlorobenzenesulphonyl chloride in 5 ml of dichloromethane is added dropwise to a solution of 0.857 g (4 mmol) of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, 0.99 ml (6 mmol) of diisopropylethylamine and 0.024 g (0.2 mmol) of 4-dimethylaminopyridine in 9 ml of dichloromethane. The mixture is stirred at ambient temperature overnight. The organic phase is washed with 10 ml of water and then 4 ml of a 1N aqueous hydrochloric acid solution, 2 times 14 ml of water, 2 times 14 ml of a 1N aqueous sodium hydroxide solution, 3 times 14 ml of water and 14 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness in order to obtain 1.371 g (3.52 mmol) of product in the form of an orange paste used as is in the following stage.