Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:4]=[CH:3][CH:2]=1.CN1C2C(=CC=C3C=CC=CC3=2)C=C[CH:17]1[OH:30].[CH2:31]1[CH2:37][S:34](=[O:36])(=[O:35])[O:33][CH2:32]1.CI>>[CH3:17][O:30][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]2=[C:10]2[C:5]=1[CH:4]=[CH:3][CH2:2][N:1]2[CH2:32][CH2:31][CH2:37][S:34]([OH:33])(=[O:36])=[O:35]
Reactant: c1ccc2c(c1)ccc1cccnc12
Reactant: O=S1(=O)CCCO1
Reactant: CN1c2c(ccc3ccccc23)C=CC1O
Solvent: CI
Product: COc1cc2ccccc2c2c1C=CCN2CCCS(=O)(=O)O

Procedure:
Compound 13 wae synthesized according to the procedure outlined above in Example 3 for the synthesis of the N-methyl-hydroxy benzoquinoline derivative 15. Compound 13 was then allylated according to the general amino group alkylation procedure described above in Example 3, this time using 1,3-propane sultone as the alkylating agent rather than MeI, to give a 5-methoxybenzoquinoline-N-propanesulfonic acid intermediate 16 (1HNMR: CD3OD d 7.94 (d, 1 H, J=8.7 Hz), 7.65 (d, 1 H, J=8.4 Hz), 7.32 (t, 1 H), 7.27 (t, 1 H), 6.85 (s, 1 H), 4.89 (s, 3 H), 3.20 (m, 2 H), 3.08 (bt, 2 H, J=6 Hz), 2.91 (m, 2 H), 2.72 (t, 2 H, J =6.6 Hz), 2.33 (m, 2 H), 1.89 (m, 2 H). Subsequent methoxy group deprotection of compound 16 by the general boron tribromide procedure described above in Example 1 resulted in the 3-(5-hydroxybenzoquinolin-1-yl) propanesulfonic acid 17.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:34])[C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[BH4-]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]([OH:34])[C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: [BH4-]
Agent: [Na]
Solvent: CO
Product: O=C(N1CCc2ccc(C(O)Cn3ccc(OCc4ccccc4)cc3=O)cc2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.20 g (2.48 mmol) 4-benzyloxy-1-{2-oxo-2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (example 22.1) in 10 mL MeOH is added 94 mg (2.48 mmol) sodium-borohydride and the mixture is stirred 2 h at RT. The solvent is evaporated, the residue is taken up in EtOAc and water. The layers are separated, the organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via chromatography (silica gel; EE/MeOH 8:2).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[C:5]=1[CH3:13])([O-])=O.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH3:16][N:17]([CH:19]=[CH:13][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1)[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccccc1
Yield: 139.3 %

Procedure:
A mixture solution of 2,6-dinitrotoluene (18.2 g, 0.1 mol) and N,N-dimethylformamide dimethylacetal (28 mL, d=0.89, 0.2 mol) in anhydrous DMF (80 mL) was refluxed for 5 h. The mixture was then evaporated to concentrate to a reddish-black oil. After run flash column using CH2Cl2:MeOH (10:1) as eluent to give a red crystalline solid intermediate, 2,6-dinitro-trans-{circumflex over (α)}-dimethylaminostyrene (20.5 g, yield 86%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH2:6][C@@H:5]1[CH2:14][C:15]1[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1.Cl[CH2:30][C:31]1[S:32][C:33]2[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=2[N:35]=1.O>CN(C=O)C>[F:41][C:37]1[C:38]([F:40])=[CH:39][C:33]2[S:32][C:31]([CH2:30][O:13][C:10]3[CH:11]=[C:12]4[C:7]([CH2:6][CH:5]([CH2:14][C:15]5[CH:16]=[C:17]([NH:21][S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=5)[CH:4]4[OH:3])=[CH:8][CH:9]=3)=[N:35][C:34]=2[CH:36]=1
Reactant: Fc1cc2nc(CCl)sc2cc1F
Reactant: O=S(=O)(Nc1cccc(C[C@H]2Cc3ccc(O)cc3[C@H]2O)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cccc(CC2Cc3ccc(OCc4nc5cc(F)c(F)cc5s4)cc3C2O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 127.4 %

Procedure:
382 mg (9.54 mmol) of sodium hydride, 60% oil dispersion, were added in one portion to a room temperature solution of 1.76 g (4.54 mmol) of the product of Example 56 in 30 mL of anhydrous DMF. After 20 minutes, a room temperature solution of 1.40 g (6.36 mmol) of 2-chloromethyl-5,6-difluorobenzothiazole in 10 mL of anhydrous DMF was added over 15-20 minutes. After stirring 18 hours at room temperature, the reaction mixture was poured into 500 mL H2O, acidified to pH 1, and extracted two times with 300 mL ethyl acetate. The ethyl acetate extracts were combined, washed three times with 150 mL H2O, one time with 100 mL brine, and dried over Na2SO4. Filtration, concentration and drying gave 3.3 g of a brown oil, which was purified by silica gel chromatography (15% to 25% ethyl acetate in CH2Cl2) to afford 1.52 g of the title product as an off-white solid. 59% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].CCOC(C)=O.CO>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH:15][C:25](=[O:26])[C:24]4[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)cn2c1
Yield: 79.6 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.20 g, 0.897 mmol) and 4-nitrobenzoyl chloride (0.166 g, 0.897 mmol) in dry pyridine (13 ml) to give the title compound (0.266 g, 80%) as a pale yellow solid after work-up and flash chromatography (1:1 EtOAc/MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:1]([O:3][C:4](=[O:24])[C:5]([N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: C#CCCCCCCCCCC
Reactant: CCOC(=O)C(=O)N(Cc1ccc(F)cc1)Cc1ccc(Br)cc1
Product: CCCCCCCCCCC#Cc1ccc(CN(Cc2ccc(F)cc2)C(=O)C(=O)OCC)cc1
Yield: 23 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl[(4-bromobenzyl)(4-fluorobenzyl)amino](oxo)acetate and 1-dodecyne gave the title compound as a pale yellow oil (23%). 1H NMR (CDCl3, 300 MHz) δ 7.39 (m, 2H), 7.25-7.00 (m, 6H), 4.45 (s, 1H), 4.44 (s, 1H), 4.36 (m, 2H), 4.30 (s, 1H), 4.28 (s, 1H), 2.42 (t, 2H, J=7.1 Hz), 1.62 (m, 2H), 1.46 (m, 2H), 1.37-1.25 (m, 15H), 0.89 (t, 3H, J=6.6 Hz). M+(LC/MS(ESI)): 480.3. HPLC (Condition A), Rt: 6.28 min (HPLC purity: 99.8%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cc(F)cc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Sodium hydroxide (40 mg) was added to a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D137) (287 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E97) (147 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.61 (2H, t), 2.96 (2H, t), 4.87-4.93 (1H, m), 7.35 (1H, s), 7.46 (1H, d), 7.65-7.70 (2H, m), 8.21 (1H, d), 8.39 (1H, d), 10.96 (1H, s), 12.12 (1H, br s); δF (DMSO-d6, 376 MHz): −124.9; MS (ES): C22H19ClFN3O4 requires 443; found 444.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH:5]1[C:4]2[C:9](=[N:10][C:11]3[C:16]([C:3]=2[CH2:2][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: BrCc1c2ccccc2nc2ccccc12
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1c2ccccc2nc2ccccc12)OCC
Temperature: 25 °C
Yield: 94 %

Procedure:
The mixture of 10 (1.5 g, 5.5 mmol) and triethyl phosphite (2 mL) was heated to reflux for 4 h. After cooling down to room temperature, the excess triethyl phosphite was removed under vacuum to afford 11 (1.7 g) in 94% yield. NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.8 Hz, 2H), 8.17 (d, J=8.8 Hz, 2H), 7.72 (t, J=7.2 Hz, 2H), 7.54 (t, J=7.2 Hz, 2H), 4.13 (d, J=24 Hz, 2H), 3.92-3.77 (m, 4H), 1.04 (t, J=7.2 Hz, 6H). 13C NMR (400 MHz, CDCl3) δ 148.4, 148.3, 135.8, 135.7, 129.9, 129.8, 125.8, 125.3, 125.2, 124.9, 124.8, 62.4, 27.5, 26.1, 16.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][CH2:15][CH:16]=O)([O-])=O>[C].[Pd].C(O)C>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:13][CH:12]=1)[NH:1][C:15]([CH3:16])=[CH:14]2)=[O:9]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(CCC=O)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc2[nH]c(C)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To an ethanol (10 ml) solution of methyl 4-nitro-3-(oxopropyl)benzoate (13.0 g), added is palladium-carbon (5%, 2.6 g) in a nitrogen atmosphere. This is purged with hydrogen, and further stirred at room temperature for 3 hours and then at 60° C. for 19 hours. The solid is removed through filtration, and the filtrate is concentrated. The resulting oily product is crystallized from toluene. The crystal formed is collected and dried to obtain 5-(methoxycarbonyl)-2-methylindole (8.42 g).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=1)[C:15]([CH3:40])([CH3:39])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:25]=[C:26]([C:30]3[CH:31]=[CH:32][C:33]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=3)[CH:27]=[CH:28][CH:29]=1)[C:15]([CH3:40])([CH3:39])[CH2:14]2
Reactant: NS(=O)(=O)C1CC1
Reactant: CN(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)NS(=O)(=O)C4CC4)CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a suspension of 60% sodium hydride (91 mg, 2.2 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (280 mg, 2.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 0.23 mmol) and 1,1′-carbonyldiimidazole (94 mg, 0.58 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (49 mg, 40%) as a white solid: LC/MS m/e calcd for C29H32ClN3O3S (M+H)+: 539.11, observed: 538.1.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[CH3:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:8][C:9]=2[CH:14]=1
Reactant: Cc1ccc(O)c(N=Cc2ccccc2)c1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 2-benzylideneamino-4-methylphenol 54 (1.34g, 6.3 mmol) and manganese (III) acetate dihydrate (3.4 g, 12.7 mmol) in toluene (65 ml) was heated at reflux under an atmosphere of N2 for 1 hr and cooled to room temperature. The mixture was filtered to remove the insoluble manganese salts. The filtrate was evaporated under reduced pressure. The residue was taken up in methylene chloride and purified by filtration to yield 1.23 g 5-methyl-2-phenylbenzoxazole 55.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:29][NH2:30]>CO.CC(O)=O.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:30][CH3:29])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CN
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reaction time: 3 h

Procedure:
To a solution of 5-fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 76.1., 0.60 g) in MeOH (5.0 ml), AcOH (0.92 ml), tetrahydrofuran (2.0 ml) and methyl amine (2 M in THF, 3.2 ml) was added portion wise Na(CN)BH3 (202 mg) and stirring was continued at 22° C. for 3 h. The mixture was evaporated and the residue partitioned between 1 N aqueous HCl and dichlormethane. The pH of the aqueous layer was adjusted to 11 using NaOH, extracted with dichloromethane, dried and evaporated to give 5-fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless oil. MS: 391.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.[CH3:25][O:26][C:27](=[O:35])C1C=CC(Cl)=NC=1>>[CH3:25][O:26][C:27](=[O:35])[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Clc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
6-(2-Phenylchroman-6-yloxy) nicotinic acid methyl ester was prepared as described for 5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine in Example 61, but replacing 2,5-dichloropyridine with 6-chloronicotinic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ: 8.70 (d, 1H, J 2.4 Hz), 8.29 (dd, 1H, J 8.6, 2.4 Hz), 7.47-7.32 (m, 5H), 7.07 (d, 1H, J 8.6 Hz), 6.96-6.88 (m, 3H), 5.14 (d, 1H, J 10.0 Hz), 3.85 (s, 3H), 2.97 (m, 1H), 2.74 (m, 1H), 2.18 (m, 1H), 2.01 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[NH:44]1[C@H:48]([C:49]([OH:51])=[O:50])[CH2:47][CH:46]=[N:45]1>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([N:44]2[C@H:48]([C:49]([OH:51])=[O:50])[CH2:47][CH:46]=[N:45]2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@@H]1CC=NN1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a 1000 ml round bottom flask under N2 was added (2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (Tetrahedron, 2001, 57(36), 7675-7683) (38.1 g, 149 mmol) in acetonitrile (650 mL) at 0° C., followed by N-methylmorpholine (82 mL, 744 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (53.7 g, 164 mmol). The solution was stirred at the same temperature for 2 hours and then (5S)-4,5-dihydro-1H-pyrazole-5-carboxylic acid, hydrochloride (22.4 g, 149 mmol) was added. The solution was allowed to warm up to room temperature and stirring continued overnight. LCMS showed that the reaction was complete. The acetonitrile was removed under reduced pressure, and the residue was taken up in DCM (500 mL) and neutralized by the addition of 2 N HCl. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash automated silica gel chromatography (0-5% methanol containing 1% formic acid/DCM) to provide (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (27.7 g, 79 mmol, 53% yield) as a clear oil. LCMS: [M+H]+: 353.4.
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([CH2:10]P(=O)(OCC)OCC)#[N:9].[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[C:29]([CH:44]=O)=[CH:30][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:32][CH:33]=1>O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[CH:30][C:29]=1[CH:44]=[CH:10][C:8]#[N:9]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=CC#N)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a mixture of sodium hydride (60%, 133 mg) and THF (20 mL) was added diethyl cyanomethylphosphonate (0.54 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the reaction mixture was added 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carbaldehyde (1.03 g) obtained in Example 93, step 2, and the mixture was stirred at 50° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([Si:18]([O:8][CH:1]1[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: OC1CCC=CCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC=CCC1)(c1ccccc1)c1ccccc1

Procedure:
A solution of the product of Example 8B (1.57 g, 14.05 mmoles), imidazole (1.43 g, 21.08 mmoles), and Tert-butyl-chlorodiphenylsilane (4.76 gm, 17.4 mmoles) in N,N-dimethylformamide (10 mL) was stirred for five hours at 23° C. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine (25 mL), dried with MgSO4, filtered, and solvent evaporated in vacuo. The crude product was purified by flash column chromatography (hexanes:ethyl acetate 100:0 to 90:10) to provide the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[NH2:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[NH:18][C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=2)[N:7]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: Nc1ccncc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(-c2nc3cnccc3[nH]2)n1
Temperature: 120 °C
Reaction time: 48 h
Yield: 18.2 %

Procedure:
6-Chloropyridine-2-carboxylic acid (2.00 g, 12.7 mmol), 3,4-diaminopyridine (1.52 g, 14.0 mmol) and DIPEA (2.43 mL, 14.0 mmol) were dissolved in DMF (20 mL) and HBTU (5.29 g, 14.0 mmol) was added. The reaction mixture was stirred for 48 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 (2×100 mL), water (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography, dissolved in AcOH and heated at 120° C. for 50 min. The solvent was removed in vacuo and the residue was suspended in 1 M aq Na2CO3 (50 mL) and extracted with EtOAc (5×50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography and recrystallisation from MeOH to give the title compound (534 mg, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]#[N:13])=[N:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2.[OH-:16].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]([NH2:13])=[O:16])=[N:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(Cl)c(C#N)c2n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(C(N)=O)c2n1
Yield: 64 %

Procedure:
3-Chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile (5.0 g, 22.8 mmol, 1.0 eq) is suspended in a 10% sodium hydroxide aqueous solution (125 mL) and the resulting mixture is heated to reflux for 30 minutes. The reaction mixture is then extracted with ethyl acetate (3×100 mL) and the pH is adjusted to 3-4 by the addition of a 3N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:1 to 4:1, v/v) to afford 3-chloro-6-methoxy-[1,5]naphthyridine-4-carboxylic acid amide as an off-white solid (3.44 g, 64% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7]1)[CH3:2].C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([N:6]1[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[N:8]=[CH:7]1)=[CH:19][N:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCOC(=O)Cn1cnc(C(F)(F)F)c1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1cnc(C(F)(F)F)c1

Procedure:
38.0 g (170.8 mmol) of the compound from Example 32A and 58.5 ml (50.3 g, 341.6 mmol) dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For working up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried in vacuo.