Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:31])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OCC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Temperature: 7.5 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-hydroxy-hexyl)-phenoxy]-butyric acid ethyl ester (0.85 mmol, 349 mg) and carbon tetrabromide (1.26 mmol, 423 mg) in dichloromethane (10 mL) was added triphenylphosphine (1.07 mmol, 281 mg) at −0° C. The resulting colorless solution was stirred for 3 h at 5-10° C. Then, the solvent was removed under vacuum and the crude was tried to dissolve in a mixture of ethyl acetate and hexanes (1:3, 50 mL). As a result, a cloudy solution containing some precipitate was formed and the cloudy solution was transferred into a separatory funnel and was washed with a mixture of methanol and water (2:1, 150 mL). The aqueous layer was extracted one more time with ethyl acetate and hexanes (1:3, 50 mL). The combined organic extracts were washed with brine solution (100 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a colorless oil which was purified by using a Biotage™ (40M) column chromatography eluting with 10% ethyl acetate in hexanes to obtain the desired 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (350 mg, 87.5%) as a colorless oil: ES(+)-HRMS m/e calculated for C23H35BrO5 (M+Na)+ 493.1560, found 493.1560.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[C:12]1(C)C=CC=CC=1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[CH3:12])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(CO)c(N)n1
Reactant: Cc1ccccc1
Product: CSc1ncc(C(C)=O)c(N)n1
Yield: 72 %

Procedure:
By substituting 1-(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanol (Example 34) for (4-amino-2-methylsulfanyl-pyrimidin-5-yl)-methanol in Example 3 and conducting the reaction at 80° C. in toluene, 3.74 g (72%) of the product as a solid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[Cl-].[Ca+2].[Cl-]>C(O)C.O>[NH2:17][C:15]1[CH:14]=[CH:13][C:3]([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])=[C:2]([Cl:1])[CH:16]=1
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(Oc2ccc(N)cc2Cl)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a solution of 3-(2-chloro-4-nitrophenoxy)benzonitrile (2.0 g) in ethanol/water (9:1, 40 mL) was added calcium chloride (90%, 449 mg), and the mixture was stirred at 100° C. for 10 min. Reduced iron (90%, 2.7 g) was added at room temperature, and the mixture was stirred at 100° C. for 5 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (1.25 g) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:47]1[CH2:52][CH2:51][S:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:47]2[CH2:52][CH2:51][S:50][CH2:49][CH2:48]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: C1CSCCN1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCSCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), thiomorpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][N:43]3[C:46]4[N:52]=[CH:51][CH:50]=[CH:49][C:47]=4[CH:48]=[C:42]3[C:41]=2[N:53]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:37]4[CH:38]=[CH:39][C:40]5[O:45][CH2:44][N:43]6[C:46]7[N:52]=[CH:51][CH:50]=[CH:49][C:47]=7[CH:48]=[C:42]6[C:41]=5[N:53]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(n1)-c1cc3cccnc3n1CO2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5cccnc5n3CO4)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (40 mg, 0.08 mmol), 2-chloro-6H-pyrido[2,3-e]pyrido[3′,2′:4,5]pyrrolo[1,2-c][1,3]oxazine (27 mg, 0.10 mmol) and K3PO4.3H2O (64 mg, 0.24 mmol) in 1,4-dioxane/water (1.5 mL/0.2 mL), Pd2(dba)3 (5 mg), X-Phos (10 mg) were added under N2 protection. After stirred overnight at 80° C., the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloromethane:MeOH=20:1) to provide the product of Compound 48 (30 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 8.34˜8.37 (m, 1H), 8.04 (s, 1H), 7.93˜8.00 (m, 3H), 7.68 (s, 1H), 7.48˜7.56 (m, 2H), 7.17˜7.24 (m, 2H), 7.10˜7.16 (m, 2H), 6.22 (s, 2H), 5.96 (br s, 1H), 3.53 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.76 (s, 3H). MS (M+H)+: 598.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:22])[C@H:17]([CH:19]([CH3:21])[CH3:20])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:22])[C@H:17]([CH:19]([CH3:21])[CH3:20])[NH:18][S:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:39])=[O:38])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 90 %

Procedure:
L-valyl-L-proline benzylester hydrochloride (1.70 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise to the solution. The mixture was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with aqueous 5% sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given and dried over anhydrous magnesium sulfate. The solvent was stilled off under reduced pressure to obtain N-benzenesulfonyl-L-valyl-L-proline benzylester(yield: 2.00 g, 90.0%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13])(=[O:7])[CH3:6]
Reactant: N#Cc1c(CO)cccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetic anhydride (0.84 mL, 8.87 mmol) was added to a solution of 2-(hydroxymethyl)-6-nitrobenzonitrile (Example 207d) (0.31 g, 1.77 mmol), pyridine (0.86 mL, 10.6 mmol), and DMAP (0.22 g, 1.77 mmol) in CH2Cl2 (10 mL), and stirred for 24 h at rt. The mixture was washed once with AcOH (1 M, 20 mL), dried with MgSO4, concentrated, and purified by chromatography on silica using CH2Cl2, to give the title compound in amount of 0.36 g (92%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 5.35 (s, 2H), 7.99 (t, J=8.0 Hz, 1H), 8.06 (dd, J=0.8, 8.0 Hz, 1H), 8.37 (dd, J=0.8, 8.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:48])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:48])[CH2:35][O:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=4)=[O:22])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)N[C@@H](C)COCc1ccc(C(F)(F)F)cc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCc3ccc(C(F)(F)F)cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N-isopropyl-N—[(S)-1-methyl-2-(4-trifluoromethyl-benzyloxy)-ethyl]-amine as described for example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CCOCC>[CH3:9][N:8]([CH3:10])[C:5]1[N:6]=[CH:7][C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN(C)c1ccc(Br)cn1
Solvent: CCOCC
Product: CN(C)c1ccc(C2(O)CCC3(CC2)OCCO3)cn1

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-dimethylamino-pyridine (Indofine) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30](O)=[O:31].CCCP(=O)=O>CC1CCCO1>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1)=[O:31]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 85 °C
Yield: 75.8 %

Procedure:
Pyridine (12.9 mL, 161 mmol) was added to a solution of ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (9.32 g, 40.3 mmol) and 5-bromo-2-chlorobenzoic acid (10.4 g, 44.3 mmol) in 2-methyl-tetrahydrofuran (100 mL). The reaction was heated to 85° C. before the addition of propylphosphonic anhydride (38.5 mL, 60.4 mmol, 50% solution in EtOAc) drop-wise. The reaction was heated at 85° C. for 16 hours before cooling to room temperature. The organic solution was washed with saturated aqueous sodium hydrogen carbonate solution (3×25 mL), saturated brine (30 mL) and concentrated in vacuo. The resulting solid was triturated with TBME (5×50 mL) to afford the title compound (13.7 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: CCCC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Yield: 62 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using butyryl chloride instead of methoxyacetyl chloride, to the title compound (155 mg, 62%) which was obtained as a white solid. MS: m/e=353.3 [M+H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[C:12]([C:35]3[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: C[C@H](CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CSc1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, a mixture of the product from Example 545C (0.98 g, 2 mmol), 4-(methylthio)benzeneboronic acid (0.4 g, 2.4 mmol), K3PO4 (1.2 g, 6 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol), isopropanol (9 mL), and water (1 mL) was stirred at 70° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (30 mL) was added and stirring was continued for 2 hours. The crude black precipitate was collected by filtration then Washed with water (10 mL) and hexane (10 mL). This title intermediate was used without further purification in the following oxidation/deprotection step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-pyridine-2-carbaldehyde (1.0 eq.) in THF:EtOH (1:1; 0.2M) at −78° C. was added NaBH4 (4.0 eq.). The mixture was stirred for 2 h at −78° C., quenched with excess AcOH, poured in aqueous HCl (1M), stirred for 15 min, neutralized to pH=7 with NaOH (1M) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14](Cl)[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CO.CN(C)[CH:31]=[O:32]>O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14]([O:32][CH3:31])[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2oc2c(OCc3ccccc3)cccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(=O)c3cccc(OCc4ccccc4)c3oc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-benzyloxy-3-chloroxanthone (8.5 g.), sodium hydride (3 g.), methanol (20 ml.) and dimethylformamide (100 ml.) is stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is filtered. The residue is recrystallised from isopropanol to give 5-benzyloxy-3-methoxyxanthone, m.p. 158° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H][H]>[Ni].CO.C(OCC)(=O)C.N>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(C#N)cn2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc(CN)cn2)CC1
Yield: 103.8 %

Procedure:
A mixture of 2 g (8 mmol) 6-(4-ethyl-piperazin-1-yl)-nicotinonitrile, 1.3 g Raney Nickel (B113Z, Degussa) in 25 ml methanol, 15 ml ethyl acetate and 5 ml ammonia aq. (ca. 25%) was treated with 1 bar hydrogen at 30-35° C. for 4 h. The mixture was filtered and the residue washed three times with 20 ml ethyl acetate each and the combined organic phases evaporated to dryness to yield 1.83 g (97%) of the title compound as white crystals. (m/e): 261.1 (MH+; 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[C:17]([O:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:22](=[O:30])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:29][CH2:28]2)=[N:5][CH:4]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 58 mL of chloroform, the obtained (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde was dissolved, 2.67 g of tert-butyl(piperidin-4-yl)carbamate and 0.80 g of acetic acid were added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 4.23 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 15 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC. and an eluent of chloroform:methanol=10:1 to obtain 4.36 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (0.151 g, 0.43 mmol), benzylamine (0.05 mL, 0.48 mmol), and sodium cyanoborohydride (0.041 g, 0.65 mmol) were combined in CH2Cl2 (3 mL). Acetic acid (2 drops) was added, and the reaction was stirred overnight at room temperature. The mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated, and the residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([NH2:19])(=[O:18])=[O:17]>O>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]2[C:6](=[O:2])[NH:19][S:16](=[O:18])(=[O:17])[C:8]=2[CH:9]=1)([O-:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Solvent: O
Product: O=C1NS(=O)(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 42 h
Yield: 68 %

Procedure:
To a solution of CrO3 (20.8 g, 208 mmol) in water (150 mL) was slowly added concentrated sulfuric acid (190 mL). To the resulting mixture was added 2-methyl-5-nitrobenzenesulfonamide (10.0 g, 46.3 mmol) and the mixture was stirred at rt for about 42 h. The mixture was filtered and the filter cake was washed with water (100 mL). The solid was dissolved in 10% aqueous NaHCO3, filtered and the filtrate acidified with 2 N HCl (pH=1). The precipitate was collected by filtration and washed with water (2×50 mL) to provide 6-nitro-1,1-dioxo-1,2-dihydro-1lambda*6*-benzo[d]isothiazol-3-one (7.2 g, 68%). 1H NMR (DMSO-d6) δ: 8.42-8.53 (m, 2H), 8.00 (s, 1H), 3.70 (br s, 1H).
Reaction SMILES: Cl.[C@@H:2]12[N:9]([CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])[C@@H:6](CC1)[CH2:5][NH:4][CH2:3]2.[CH3:24][C:25]1[N:30]=[C:29]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)[CH:28]=[CH:27][C:26]=1[CH:36]1[CH2:38][O:37]1>>[OH:12][C@H:11]([C:13]1[CH:21]=[CH:20][C:19]2[C:18](=[O:22])[O:17][CH2:16][C:15]=2[C:14]=1[CH3:23])[CH2:10][N:9]1[CH2:2][CH2:3][N:4]([CH2:38][CH:36]([OH:37])[C:26]2[C:25]([CH3:24])=[N:30][C:29]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:28][CH:27]=2)[CH2:5][CH2:6]1
Reactant: Cc1nc(-n2cnnn2)ccc1C1CO1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Agent: Cl
Product: Cc1nc(-n2cnnn2)ccc1C(O)CN1CCN(C[C@H](O)c2ccc3c(c2C)COC3=O)CC1

Procedure:
5-[(1R)-1-Hydroxy-2-(4-{2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 34 starting from (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) and 6-methyl-5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl) pyridine (INTERMEDIATE 34).