Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1nc(-c2ccc3c(c2)CCCC3)cs1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1nc(-c2ccc3c(c2)CCCC3)cs1)c1ccccc1
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture consisting consisting of 2-amino-4-(5,6,7,8-tetrahydro-2-naphthyl)thiazole (500 mg), benzoylisothiocyanate (363 mg) and acetone (10 ml) was stirred at 55° to 60° C. for 3 hours and then concentrated under reduced pressure. The residue was treated with ether, and the resultant crystals were recrystallized from chloroform-ethanol to produce 1-benzoyl-3-[4-(5,6,7,8-tetrahydro-2-naphthyl)-2-thiazolyl] thiourea (yield of 583 mg, 68.2%) in the form of colorless prisms. m.p., 181°-182° C.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][N:28]5[CH:32]=[C:31]([CH3:33])[N:30]=[N:29]5)[O:24][C:23]4=[O:34])=[CH:17][C:16]=3[F:35])[CH2:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.Cl.C(OCC)(=O)C>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:10][CH:11]=[C:12]([C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:26][C@H:25]([CH2:27][N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[N:29]4)[O:24][C:23]3=[O:34])=[CH:17][C:16]=2[F:35])[CH2:13][CH2:14]1)=[O:8]
Reactant: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)nn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H](O)CO)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 64 h
Yield: 50.7 %

Procedure:
(5R)-3-[4-(1-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]-5-[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Intermediate 55) (542 mg, 1.08 mmol) was dissolved in tetrahydrofuran (20 ml). A solution of hydrochloric acid (1N, 10 ml) was added and the reaction mixture was stirred at room temperature. After 64 hours, the solution was poured into ethyl acetate the aqueous was extracted with ethyl acetate. The aqueous was basified with a solution of 10% aqueous sodium acetate and re-extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and concentrated under vacuum. Chromatography on silica gel with 10% methanol in ethyl acetate gave 254 mg of the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCCC1

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.133 g, 0.50 mmol) and pyrrolidine (0.210 mL, 2.50 mmol) gives the title compound.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21](OC)[O:22]C)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH:21]=[O:22])[CH3:26])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=CC=C3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: O
Product: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@]21C
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.5 %

Procedure:
In 5 ml of methanol was dissolved 100 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxypregna-5,7-diene, followed by addition of 5 ml of water and 100 mg of copper sulfate. The mixture was stirred in an atmosphere of argon gas at a temperature of 60° C. for 7 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 60 mg of 3β-benzoyloxy-1α-(N-methylcarbamoyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][CH:8](Cl)Cl.C[O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[CH:15][CH:14]=1.[OH-].[NH4+]>C(Cl)Cl.O>[NH:26]1[CH:27]=[C:23]([CH2:22][CH:19]2[C:20]3[C:16](=[CH:15][C:14]([CH:13]=[O:12])=[C:8]([O:7][CH3:6])[CH:21]=3)[CH2:17][CH2:18]2)[N:24]=[CH:25]1
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)C(Cc1c[nH]cn1)CC2
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)CCC2Cc1c[nH]cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tin(IV)chloride (1.60 g) is added dropwise to a stirred solution of dichloromethyl methyl ether (0.68 g) in methylene chloride (12 ml) with ice cooling under a nitrogen atmosphere. The solution is stirred at 0° C. for one hour before adding a solution of 4-(6-methoxyindan-1-ylmethyl)-1H-imidazole (0.60 g) in methylene chloride (4 ml). The resulting mixture is allowed to warm to ambient temperature while being stirred for 4 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. The product is extracted into methylene chloride which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](C1C=CN=CC=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:36]1[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc2nc(-c3ccncc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3cccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-3-yl)quinolin-6-yl)acetic acid (74) was prepared following the procedure for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-4-yl)quinolin-6-yl)acetic acid of Example 73 except that pyridin-3-ylboronic acid was used instead of pyridin-4-ylboronic acid. 1H-NMR: 400 MHz, (CD3CN) δ: 9.49 (s, 1 H), 8.94 (d, J=8.4 Hz, 1 H), 8.79 (s, 1 H), 7.91 (m, 2H), 7.80 (Abq, J=26.2, 8.8 Hz, 2 H), 7.58 (m, 3 H), 7.34 (m, 1 H), 5.25 (s, 1 H), 2.61 (s, 3H), 0.97 (s, 9 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H26ClN2O3: 461.16. found: 461.00.
Reaction SMILES: [C-:1]#[C-:2].[Na+].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25]I)=[CH:19][CH:18]=1>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:1]#[CH:2])=[CH:19][CH:18]=1
Reactant: [C-]#[C-]
Reactant: Fc1ccc(CCCI)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCCCc1ccc(F)cc1
Yield: 62 %

Procedure:
Subsequently, sodium acetylide (18% slurry in xylene) (50 ml) was added to hexamethylphosphoramide (20 ml) with stirring, and to the resulting mixture was furthermore added a solution of 3-(4-fluorophenyl)-1-iodopropane (7.00 g, 26.5 mmol) obtained above in dry dimethylformamide (20 ml) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 2 hours. After stirring, ice-cold water was added to the reaction mixture carefully with stirring under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by flash chromatography on a silica gel column using hexane as the eluent to afford the title compound (2.67 g, yield: 62%) as a colorless oil.
Reaction SMILES: [C:1]([C:9]1[C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:28]>>[C:1]([C:9]1[C:17]([S:18](=[O:20])(=[O:19])[NH2:28])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1C(=O)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Product: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1C(=O)c1ccccc1
Reaction time: 4.5 h

Procedure:
4-Benzoyl-3-n-butoxy-5-chlorosulfonylbenzoic acid (1.5 g) is in portions added to conc. ammonium hydroxide (15 ml) while stirring at 10°-12° C. After additional stirring at room temperature for 16 hours, the mixture is left in a refrigerator for 4-5 hours. The separated ammonium salt is collected by filtration and washed with a small amount of icecold water. After drying, the salt is dissolved in 1 N sodium hydroxide (15 ml) and the solution is dropwise added to icecold 1 N acetic acid (20 ml) while stirring. The separated material is collected by filtration, washed with water and dried in the air. The product is recrystallized from aqueous ethanol, and the thus purified material is dissolved in 1 N NaOH (15 ml). The solution is dropwise added to icecold 1 N acetic acid (18 ml) while stirring. The precipitated material is collected by filtration, washed with water and dried in vacuo in the presence of P2O5, to give 4-benzoyl-3-n-butoxy-5-sulfamylbenzoic acid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH3:20]>>[NH2:20][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Reactant: N
Agent: Cl
Product: NS(=O)(=O)c1ccc2c(C(=O)O)c[nH]c(=O)c2c1
Reaction time: 18 h

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g) was added to 0.880 ammonia (60 ml) and the mixture was stirred for 18 h. Concentrated hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-(aminosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)[CH:22]=2)=[CH:10][CH:9]=1.[CH3:35][N:36]([CH3:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>N1C=CC=CC=1>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:41](=[O:42])[C:40]4[CH:39]=[CH:38][C:37]([N:36]([CH3:35])[CH3:46])=[CH:45][CH:44]=4)=[CH:32][CH:33]=3)[CH:22]=2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(Nc2cc(-c3cccc4c3oc3ccccc34)ncn2)cc1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(Nc3cc(-c4cccc5c4oc4ccccc45)ncn3)cc2)cc1

Procedure:
To a solution of N-(6-dibenzofuran-4-yl-pyrimidin-4-yl)-benzene-1,4-diamine trifluoroacetate (compound A1) (500 mg, 1.1 mmol) in pyridine (10 mL) is added at 10° C. 4-dimethylaminobenzoyl chloride (288 mg, 1.21 mmol) portion wise. After 14 h at ambient temperature the mixture is evaporated and the crude product is purified by crystallization.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].[Cl:9][C:10]1[CH:15]=[C:14](C2C=NN(C3CCCCO3)C=2)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[CH:15]=[C:14]([C:2]2[C:3]([CH3:8])=[N:4][O:5][C:6]=2[CH3:7])[CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(-c2cnn(C3CCCCO3)c2)ccn1
Reactant: Cc1noc(C)c1Br
Product: Cc1noc(C)c1-c1ccnc(Cl)c1

Procedure:
The title compound was prepared from 4-bromo-3,5-dimethylisoxazole generally according to the synthetic procedure described for 2-Chloro-4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyridine. UPLC (Rt)=0.81 min (method N)
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=1)(=[O:18])=[O:19]
Reactant: COC(=O)c1ccc(Oc2cccc(S(C)(=O)=O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1cccc(Oc2ccc(C(=O)O)cc2)c1

Procedure:
A stirred solution of 4-(3-methanesulfonyl-phenoxy)-benzoic acid methyl ester (1.0 mmol) (see Intermediate 12) in 1:1 methanol/tetrahydrofuran (0.15 M), is treated with 2 N sodium hydroxide (3.0 mmol) and heated to reflux for one hour. The reaction is concentrated in vacuo. 1 N Hydrochloric acid and water are added and the mixture extracted with 10% isopropanol/dichloromethane. The organic portion is concentrated in vacuo to yield the desired product. MS (m/e): 291.0 (M−1).
Reaction SMILES: [O:1]([C:8]1[C:9]([OH:18])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([O:18][C:9]3[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:11][N:10]=3)[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: Oc1ncc(C(F)(F)F)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ncc(C(F)(F)F)cc2Oc2ccccc2)c1

Procedure:
The title compound is prepared according to Example 8 by using 3-phenoxy-5-trifluoromethyl-pyridin-2-ol and 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford 32 mg (6%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H24O5NF3 523, found 524 (M+1, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6][CH2:5]1.[BrH:29]>O>[OH2:23].[BrH:29].[BrH:29].[BrH:29].[NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[N:12]=2)[CH2:6][CH2:5]1
Reactant: COc1ccc(Cn2c(NC3CCN(CCN)CC3)nc3ccccc32)cc1
Agent: Br
Solvent: O
Product: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(O)cc2)CC1
Yield: 57 %

Procedure:
A mixture of 7.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-methoxyphenyl)methyl]-1H-benzimidazol-2-amine and 225 parts of a hydrobromic acid solution 48% in water was stirred and heated over week-end. After cooling, the precipitated product was filtered off and dried, yielding 7.3 parts (57%) of 4-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1H-benzimidazol- 1-yl]methyl]phenol trihydrobromide monohydrate; mp.>250° C. (intermediate 139).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=4)[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and 4-trifluoromethoxyphenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4(s, 1H), 8.4(s, 1H), 8.2(m, 1H), 8.05(d, 1H, J=7.2 Hz), 7.9(m, 3H), 7.4-7.7(m, 7H), 7.0(d, 1H, J=10.1 Hz), 4.3(m, 2H), 3.6(m, 4H), 2.9(m, 2H), 2.6(m, 4H).
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)(Cl)Cl>[CH3:29][S:30]([O:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:24]1)(=[O:32])=[O:31]
Reactant: O[C@H]1CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@H]1CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
trans-4-[(Trityloxy)methyl]cyclohexanol (2.72 g, 0.00730 mol) was dissolved in chloroform (30.0 mL) and the mixture was cooled at 0° C. To this mixture was added TEA (1.4 mL, 0.010 mol) and methanesulfonyl chloride (0.68 mL, 0.0088 mol) and the resulting mixture was stirred at 0° C. for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and the concentrated in vacuo. 1H NMR (CDCl3): δ 7.43 (m, 6H), 7.20-7.31 (m, 9H), 4.57 (m, 1H), 3.00 (m, 3H), 2.90 (m, 2H), 2.16 (m, 2H), 1.93 (m, 2H), 1.09-1.60 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C[O-].[Na+].[O:15]([CH2:22][CH2:23][N:24]1[CH:28]=[C:27]([CH:29]=O)[CH:26]=[N:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[O:15]([CH2:22][CH2:23][N:24]1[CH:28]=[C:27](/[CH:29]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])[CH:26]=[N:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1cnn(CCOc2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnn(CCOc2ccccc2)c1
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
Trimethyl phosphonoacetate (20.6 g, 112 mmol) was dissolved in 350 mL THF. A 25% w/w NaOMe solution (25 mL) was then added at room temperature and the resulting mixture was stirred for 30 min. 1-(2-Phenoxyethyl)-1H-pyrazole-4-carbaldehyde (24 g, 111 mmol) dissolved in 150 mL THF was added and the reaction mixture was stirred for 5 h before being quenched with aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography using a gradient of hexane/EtOAc (30:1 to 1:2) to yield (E)-methyl 3-(1-(2-phenoxyethyl)-1H-pyrazol-4-yl)acrylate (22 g, 72.7%).
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[S:4]1[CH:5]=[CH:6][N:7]=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: C[Si](C)(C)c1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
10 g (63.7 mmol) of 2-trimethylsilylthiazole (1) and 435 ml of toluene are placed in a 2-liter round-bottomed flask under argon. The reaction mixture is stirred and cooled using an ice bath, and, when the temperature has reached about 8° C., a solution of 12.2 ml (0.128 mol) of ethyl chloroformate in 500 ml of toluene is added. Once all the solution has been added, the mixture is left for about 10 minutes and then warmed to 25° C. After stirring for 20 hours, 200 ml of aqueous sodium carbonate solution are added and the mixture is stirred for 30 minutes. After separation of the phases by settling, the organic phase is washed with 200 ml of saturated aqueous sodium chloride solution. After drying over magnesium sulfate, the organic phase is concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=200 g; eluent: 60/40 cyclohexane/ethyl acetate). 5.12 g of ethyl 2-thiazolecarboxylate (2) are thus obtained in the form of a greenish liquid that crystallizes. Rf(50/50 cyclohexane/ethyl acetate)=0.52.
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[CH:13]=1>CO>[CH3:20][O:19][CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][CH:3]([C:4](=[O:5])[CH3:6])[C:2]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(C)=O
Reactant: COCc1cccc(CBr)c1
Agent: [Na]
Solvent: CO
Product: COCc1cccc(CC(C(C)=O)C(=O)OC)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 0.34 g (15.1 mmol) of sodium in 8 mL of anhydrous MeOH are added dropwise, at room temperature and under argon, 1.6 mL (15.1 mmol) of methyl acetoacetate. After stirring for 30 minutes, 3.25 g (15.11 mmol) of 1-(bromomethyl)-3-(methoxymethyl)benzene are rapidly added dropwise and the reaction medium is then heated for 2 hours 30 minutes at 70° C. The reaction medium is then concentrated under reduced pressure, and the residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. 3.2 g of methyl 2-[3-(methoxymethyl)benzyl]-3-oxobutanoate are obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH:8]=2)[N:3]=1.[BH4-].[Na+].CC(C)=O>CO>[NH2:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: Cc1cccc(C(O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice bath) solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.246 g, 0.581 mmol, prepared as in Example 15, Step 1) in MeOH (10.0 mL) was added sodium tetrahydroborate (0.044 g, 1.162 mmol) in one portion. The reaction mixture was then allowed to warm to RT and stirred for 17 h (overnight). Additional 4 eq of NaBH4 was added and stirred for 7 h until the conversion was completed, determined by LCMS. Acetone was added to quench the excess NaBH4. The resulted solution was concentrated and dried in vacuum to afford crude (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl) (phenyl)methanol as light yellow solid which was used without further purification.