Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][N:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:22]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)c1cc2c([nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC(OCC)OCC)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (1.44 g, 60.2 mmol) in N,N-dimethylformamide (DMF)(30 mL) was slowly added 195a (5.80 g, 30.1 mmol) at 0° C. The resulting mixture was stirred at room temperature for 0.5 h, followed by the addition of 2-bromo-1,1-diethoxyethane (11.9 g, 60.2 mmol). The reaction was heated at 70° C. for 30 h and quenched with water (100 mL). The mixture was then extracted with ethyl acetate (3×100 mL). The combined organic phase was concentrated under reduced pressure and the residue was purified with silica-gel column chromatography eluting with 40:1 petroleum ether/ethyl acetate to 195b (4.7 g, 51%). MS-ESI: [M-EtOH+H]+ 264. 1H NMR (500 MHz, DMSO-d6) δ 6.65 (s, 1H), 4.59 (t, J=5.0 Hz, 1H), 4.17-4.16 (m, 4H), 3.59-3.57 (m, 2H), 3.27-3.26 (m, 2H), 2.61 (t, J=6.0 Hz, 2H), 2.51 (t, J=6.0 Hz, 2H), 1.73-1.71 (m, 2H), 1.63-1.61 (m, 2H), 1.25 (t, J=7.0 Hz, 3H), 1.02 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1C(N)=CS[CH:6]=1)=[O:4].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C(OC)(=O)C=C>>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][S:13][CH2:12][C:11]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CS
Reactant: COC(=O)c1cscc1N
Solvent: C=CC(=O)OC
Product: COC(=O)CCSCC(=O)OC

Procedure:
Compounds of structure (II) were prepared by using 4-amino-thiophene-3-carboxylic acid methyl ester, as depicted by formula (21), as a starting material. To make this compound, methyl thioglycolate was reacted with methyl acrylate to yield intermediate 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester, depicted by formula (18), which was cyclized to 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (19). This intermediate was reacted with hydroxylamine hydrochloride to yield 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (20), which yielded 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride, depicted by formula (21), as shown in Scheme 10.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[CH2:6])[CH3:2].C([O-])(O)=O.[Na+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:6][S:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: C=C(COC1CCOCC1)C(=O)OCC
Reactant: SCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(COC1CCOCC1)CSCc1ccccc1
Yield: 36.8 %

Procedure:
A suspension of 2-(tetrahydro-pyran-4-yloxymethyl)-acrylic acid ethyl ester (2.2 g, 10.2 mmol) in ethanol (100 ml) was treated with a solution of NaHCO3 (0.86 g, 10.2 mmol) in water ml (10 ml) and benzyl mercaptan (1.21 ml, 10.2 mmol) at room temperature overnight. Ethanol evaporated off under reduced pressure, crude partitioned between ethyl acetate and water, organic layer separated and purified by mplc eluting with 1:9 to 2:8 v/v ethyl acetate-heptane mixture to give the title compound as pale yellow oil (1.27 g). MS: 339 (MH+); LCMS (Protocol B) retention time 4.3 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1>S(Cl)(Cl)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:17]2[CH2:22][CH2:21][S:20][CH2:19][CH2:18]2)=[O:9])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: C1CSCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Nitro-5-(trifluoromethyl)benzoic acid (2.96 g, 12.6 mmol) was allowed to reflux in thionyl chloride (6 mL) for 6 h. The resulting solution was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting solid was taken up in CH2Cl2 (20 mL) and iPr2Net (2.6 mL, 15.1 mmol) and thiomorpholine (1.4 mL, 13.8 mmol) was added. The reaction was stirred at RT for 1 h and then diluted with CH2Cl2 (50 mL). The organic layer was washed with aq. HCl (1M, 25 mL), 9% aq. Na2CO3 (25 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (3-nitro-5-(trifluoromethyl)phenyl)(thiomorpholino)-methanone.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:23](O)=[O:24])[CH2:22][O:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:49][C:50]1[CH:51]=[C:52]([F:72])[C:53]([C:66]2[N:70]=[C:69]([CH3:71])[O:68][N:67]=2)=[C:54]([C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[C@@H:61]([NH2:65])[CH2:60][CH2:59]3)[CH:55]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]3([C:23](=[O:24])[NH:65][C@@H:61]4[C:62]5[C:58](=[CH:57][C:56]([C:54]6[CH:55]=[C:50]([Cl:49])[CH:51]=[C:52]([F:72])[C:53]=6[C:66]6[N:70]=[C:69]([CH3:71])[O:68][N:67]=6)=[CH:64][CH:63]=5)[CH2:59][CH2:60]4)[CH2:22][O:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3N)no1
Reactant: O=C(NC1(C(=O)O)COC1)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)COC2)no1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carboxylic acid (1.70 g, 5.01 mmol) in dry DMF (50.0 ml) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.60 g, 8.35 mmol) and 1-hydroxybenzotriazole hydrate (0.95 g, 6.20 mmol) at room temperature. The resulting colorless solution was stirred for 10 min before a solution of (S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylamine (1.64 g, 4.77 mmol, intermediate A-11) in dry DMF (2.0 ml) was added. This mixture was stirred at room temperature for 20 h. Then water was added, the pH was adjusted to 9 with sat. K2CO3 solution and the mixture was extracted twice with MeCl2. The combined organic layers were washed with water and brine, dried with MgSO4 and evaporated. The remaining light brown foam was purified by chromatography (silica gel; MeCl2/MeOH 100:0 to 98:2%) and the title compound was obtained as off white foam (3.17 g, 100%). MS: 665.2 (MH+, 1Cl).
Reaction SMILES: [CH3:1][CH:2]1[C:5]([CH3:7])([CH3:6])[C:4]2([CH2:11][CH2:10][N:9]([C:12]([O:14]C(C)(C)C)=O)[CH2:8]2)[O:3]1.CC1(C)C2(CCN(C(OC(C)(C)C)=O)C2)OCC1.C(O)(C(F)(F)F)=O.CN(C)C=O.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2(C(O)=O)[CH2:58][CH2:57]2)=[CH:52][CH:51]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2([C:12]([N:9]3[CH2:10][CH2:11][C:4]4([O:3][CH2:1][CH2:2][C:5]4([CH3:6])[CH3:7])[CH2:8]3)=[O:14])[CH2:58][CH2:57]2)=[CH:52][CH:51]=1
Reactant: CC1OC2(CCN(C(=O)OC(C)(C)C)C2)C1(C)C
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCC2(C1)OCCC2(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CCOC12CCN(C(=O)C1(c3ccc(Cl)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2,3,3-trimethyl-1-oxa-6-azaspiro[3.4]octane-6-carboxylate (25.0 mg, 0.0000979 mol) and tert-butyl 4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (25.0 mg, 0.0000979 mol) was treated with 1 mL of TFA at rt for 30 min. The volatiles were removed in-vacuo and the resultant TFA salt was used directly in next step. To a mixture of the above made TFA salt in N,N-dimethylformamide (0.50 mL, 0.0064 mol) were added 1-(4-chlorophenyl)cyclopropanecarboxylic acid (38.5 mg, 0.000196 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (104 mg, 0.000235 mol), followed by N,N-diisopropylethylamine (0.0853 mL, 0.000490 mol). The mixture was stirred at rt for 2 h and then the product was isolated and purified by RP-HPLC. LCMS (M+H) 334.2.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:28])[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[C:6](=[O:22])[N:5]1[CH2:23][CH2:24][CH2:25][CH2:26][OH:27].[CH3:29]I.O>CN(C)C=O>[CH3:3][C:4]1([CH3:28])[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:11]=2)[C:6](=[O:22])[N:5]1[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:29]
Reactant: CI
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Reaction time: 0.33 h

Procedure:
50 mg of sodium hydride were added in several lots to 370 mg of the product of Example 58 in solution in 3 ml of dimethylformamide and the mixture was stirred for 20 minutes. 0.06 ml of methyl iodide were added and the mixture was stirred for one hour. A further 50 mg of sodium hydride were added and then after 20 minutes, 0.06 ml of methyl iodide were added. The reaction medium was poured into water and extracted with ether. The extracts were washed with water, dried and the solvent was evaporated. The residue was chromatographed on silica (eluant: methylene chloride-acetone 98-2) to obtain 135 mg of the expected product melting at 80°-81° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH2:20])=[O:19])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](C(C)C)[C:6]=2[N:17]=1.Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].BrC(C)C>>[NH2:1][C:2]1[C:3]([C:18]([NH2:20])=[O:19])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:6]=2[N:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Solvent: CC(C)Br
Product: CC(C)(C)[Si](C)(C)OCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21

Procedure:
2-Amino-9-(2-(tert-butyldimethylsilyloxy)ethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (xxv-a) was prepared following the procedure detailed in the synthesis of 13 substituting (2-bromoethoxy)(tert-butyl)dimethylsilane for 2-bromopropane. The crude silane was used in the following step without further purification. NH4OAc QC conditions. M+H=385.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=1)[CH:7]=[C:6]([C:19]([O:21]CC)=[O:20])[C:5]2=[O:24].[CH2:25]([NH:27][C:28](=[O:48])[NH:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[C:32]([C:39]2[S:40][CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[N:43]=2)[CH:31]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:25]([NH:27][C:28](=[O:48])[NH:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][N:11]=2)[N:8]([CH2:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]3=[O:24])=[C:32]([C:39]2[S:40][CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[N:43]=2)[CH:31]=1)[CH3:26]
Reactant: CCOC(=O)c1cn(Cc2cnn(C)c2)c2cnc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn(Cc4cnn(C)c4)c3cn2)cn1
Temperature: 60 °C
Reaction time: 9 h
Yield: 15 %

Procedure:
To a solution of palladium (II) acetate (22.95 mg, 0.10 mmol, 0.1 equiv.) and 1,1′-bis(di-t-butylphosphino)ferrocene (48.5 mg, 0.10 mmol, 0.1 equiv.) in acetonitrile (3 mL) was added ethyl 6-bromo-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 52, 400 mg, 1.02 mmol, 1 equiv.), followed by 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (WO2009106885, 372 mg, 1.03 mmol, 1.01 equiv.) and a solution of potassium carbonate (212 mg, 1.53 mmol, 1.5 equiv.) in water (1 mL). The reaction mixture was stirred at 60° C. for 9 h. The reaction mixture was concentrated under reduced pressure and resuspended in 1,4-dioxane (3 mL). 2 M Lithium Hydroxide (1.02 mL) was added, and the reaction mixture as stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with water. 1 N HCl was added until pH 3-4 was reached. The precipitate was washed with water and hexanes and dried. The compound was purified (silica gel chromatography) and concentrated to provide 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid (90.7 mg, 15%). Calcd for C26H21F3N8O4S [M+H]+: 599.16. H1NMR (d6-DMSO) δ 14.42 (s, 1H), 9.54 (s, 1H), 9.52 (s, 1H), 9.25 (s, 1H), 8.55 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.58 (t, 1H), 7.53 (s, 1H), 5.75 (s, 2H), 3.76 (s, 3H), 3.26-3.17 (m, 2H), 1.11 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH:16][C:17]([NH:19]C(=O)C1C=CC=CC=1)=[S:18].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH:16][C:17]([NH2:19])=[S:18]
Reactant: COc1ccnc(-c2ccc(F)c(NC(=S)NC(=O)c3ccccc3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccnc(-c2ccc(F)c(NC(N)=S)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a suspension of N-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)-N′-benzoylthiourea (0.32 g) in methanol (3 ml) was added an aqueous sodium hydroxide solution (1N, 1 ml) dropwise. The mixture was stirred at ambient temperature for 4 hours, and the pH was adjusted to 8.0 with 1N hydrochloric acid. The precipitate was triturated with water, collected by filtration, washed with water and dried under reduced pressure to give N-(2-fluoro-5-(4-methoxypyridin-2-yl)-phenyl)thiourea (216 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([S:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(OCc4cccc(F)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (85 mg, 0.41 mmol) was reacted with 4-[2-amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol (141 mg, 0.41 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (95 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.36 Hz, 3H) 1.85 (sext, J=7.72 Hz, 2H) 3.00 (dd, J=7.36 Hz, 2H) 5.16 (s, 2H) 6.27 (d, J=7.35 Hz, 1H) 6.66 (d, J=8.83 Hz, 2H) 7.09-7.34 (m, 7H) 7.43 (m, J=6.25 Hz, 1H) 7.83 (d, J=8.83 Hz, 1H) 8.40 (d, J=6.99 Hz, 1H) 9.03 (d, J=8.83 Hz, 1H) 9.80 (s, 1H) 11.04 (br s, 1H) 14.45 (br s, 1H); MS (ESI+) m/z, 512 (M+H−TFA)+; (ESI−) m/z, 510 (M−H−TFA)−.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[C:12]([O:20][CH3:21])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 32.19 g (0.101 mol) of methyl 4-(t-butyldimethylsilyl-oxymethyl)-2-methoxybenzoate (prepared as described in Preparation 39) in 50 ml of tetrahydrofuran was added dropwise to an ice-cooled suspension of 3.51 g (92.5 mmol) of lithium aluminum hydride in 250 ml of tetrahydrofuran over a period of 30 minutes. The resulting mixture was then stirred at the same temperature for 1 hour and then at room temperature for 40 minutes. At the end of this time, the reaction mixture was again cooled with ice, and 3.5 ml of water were added to the mixture to terminate the reaction. 3.5 ml of a 15% w/v aqueous solution of sodium hydroxide and 10.5 ml of water were then added, with stirring, to the mixture. Anhydrous magnesium sulfate was added, and the reaction mixture was filtered. The filtrate was freed from the solvent by distillation under reduced pressure, to give 29.30 g (a quantitative yield) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:12]1[CH:14]([CH2:15][O:16][CH3:17])[CH2:13]1>>[CH2:1]([N:8]1[CH2:9][CH2:10][O:12][CH:14]([CH2:15][O:16][CH3:17])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: COCC1CO1
Product: COCC1CN(Cc2ccccc2)CCO1
Temperature: 50 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
N-Benzylethanolamine (459 g) is mixed with 1,2-epoxy-3-methoxypropane (422 g) and the mixture is stirred at 50° C. for 16 hours and thereafter the excess 1,2-epoxy-3-methoxypropane is distilled off under reduced pressure. The residue is dissolved in 1,4-dioxane (3 liters) and thereto are added powdery potassium hydroxide (692.5 g) and tris(3,6-dioxaheptyl)amine (11.4 g). To the mixture is added dropwise with stirring a solution of p-toluenesulfonyl chloride (809.4 g) in 1,4-dioxane (2 liters) over a period of 1.5 hour, during which the temperature of the reaction mixture raises and the solvent is refluxed. After the dropwise addition, the mixture is stirred for 2 hours, and the undissolved materials are filtered off and washed with ethyl acetate. The filtrate and the washing liquid are combined and distilled under reduced pressure to remove the solvent. To the residue are added water (600 ml) and conc. hydrochloric acid (300 ml) to make acidic. The aqueous layer is washed with ethyl acetate, made strongly basic by adding sodium hydroxide (160 g) under ice cooling and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The obtained residue is distilled under reduced pressure to give the title compound (391.3 g) as colorless liquid.
Reaction SMILES: COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl[C:31]1[CH:32]=[N:33][C:34]2[C:35](=[O:44])[NH:36][CH:37]([O:42][CH3:43])[CH:38]([F:41])[C:39]=2[CH:40]=1.[CH3:45][N:46](C=O)C>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:41][CH:38]1[CH:37]([O:42][CH3:43])[NH:36][C:35](=[O:44])[C:34]2[N:33]=[CH:32][C:31]([C:45]#[N:46])=[CH:40][C:39]1=2
Reactant: CN(C)C=O
Reactant: COC1NC(=O)c2ncc(Cl)cc2C1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC1NC(=O)c2ncc(C#N)cc2C1F
Temperature: 110 °C
Yield: 72.8 %

Procedure:
A pressure bottle was charged with Pd2 dba3 (1.032 g, 1.127 mmol), S-Phos (1.157 g, 2.82 mmol), ZnCN2 (2.482 g, 21.14 mmol), 3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one (3.25 g, 14.09 mmol) and DMF (70.5 ml). The bottle was purged with argon and sealed, and the reaction mixture was heated at 110° C. for 1 h. Upon cooling to RT the crude reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated. The crude solids were triturated with DCM, filtered, washed with DCM and air-dried. 5-fluoro-6-methoxy-8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (2.27 g, 10.26 mmol, 72.8% yield) was isolated as an off white solid. LC/MS (ESI+) m/z=222.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>[Pd]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCOC(=O)C=Cc1ccc(Oc2ccc(C(=Cc3cc(OC)cc(OC)c3)C(=O)O)cc2)cc1
Agent: [Pd]
Product: CCOC(=O)CCc1ccc(Oc2ccc(C(Cc3cc(OC)cc(OC)c3)C(=O)O)cc2)cc1
Reaction time: 15 h

Procedure:
3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2-ethoxycarbonylvinyl)-phenoxy]-phenyl}-acrylic acid (4, 2.37 g, 5.0 mmol) was dissolved in a mixture of ethanol-dioxane (2:1, 150 mL), and palladium charcoal (10%, 500 mg) was added. The mixture was stirred under hydrogen for 15 hr. Catalyst was then removed by filtration, and solvent was evaporated under reduced pressure to yield 3-(3,5-dimethoxy-phenyl)-2-{4-[4-(2-ethoxycarbonylethyl)-phenoxy]-phenyl}-propionic acid (18) quantitatively. Urea (0.21 g, 3.58 mmol) was dissolved in sodium ethoxide (2.7 M, 2.2 mL, 5.92 mmol) at 80° C. under argon, and to this a solution of 18 (1.13 g, 2.37 mmol) in anhydrous ethanol (15 mL) was added and heated at this temperature for 13 hr. Ethanol was evaporated under reduced pressure, water (20 mL) was added, acidified to pH 1 by 5% aqueous HCl and extracted with ethyl acetate (50 mL). The organic layer was washed with water (2×25 mL), brine (2×20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (3:7) containing acetic acid (1%), followed by recrystallization from ethanol. Yield: 256 mg, 22.8%.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH2:10][OH:11])[C:3]=2[F:12])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CO)c(F)c1Br
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CO)c(F)c1-c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Into a 100 mL round bottom flask was added (3-bromo-2-fluoro-4-methoxy-phenyl)-methanol (I-31, 1.04 g, 4.0 mmol), 3-chlorophenylboronic acid (0.76 g, 4.8 mmol), Pd(PPh3)4 (0.45 g, 0.41 mmol), Na2CO3 (6 mL, 2M aq), toluene, (32 mL), and EtOH (11 mL). The reaction was degassed with N2, then stirred at 80° C. for 24 hours. Water was added and the product was extracted with ethyl acetate. The combined organics were concentrated and filtered through a SiO2 plug eluting with 50% ethyl acetate/hexanes. The solid was triturated with ether and filtered. The filtrate was concentrated and triturated with ether and filtered. The filter cakes were combined and purified by flash column chromatography eluting with 20% acetone/hexanes to give (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 0.79 g, 67%) as a white solid.