Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:29]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccc(C(=O)c2ccccc2)c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc(C(=O)c2ccccc2)c1
Yield: 56.2 %

Procedure:
Using the method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.2 g, 0.78 mmol) was reacted with 3-benzoylbenzoyl chloride (0.18 g, 0.73 mmol) to provide 0.19 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-benzoylbenzamide as a white crystalline solid, m.p. 103-105° C. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (t, J=6.0 Hz, 1H), 8.22 (s, 1H), 8.16 (broad s, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 0.1H), 7.85 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.70 (t, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 2H), 7.40 (t, J=8.0 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 6.67 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.32 (q, J=6.0 Hz, 2H), 1.91 (quintet, J=7.0 Hz, 2H), 1.59 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 463.2022 (463.2008 calcd for C28H25N5O2).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1>>[Br:22][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1OC(F)(F)F
Product: N#Cc1ccc(CBr)c(OC(F)(F)F)c1

Procedure:
4-Methyl-3-Trifluoromethoxybenzonitrile is brominated with NBS according to Example 1A to give 4-bromomethyl-3-trifluoromethoxybenzonitrile. 1H NMR (400 MHz, CDCl3) δ (ppm) 4.51 (s, 2H), 7.55 (br s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[CH:10])[O:6][CH2:5][CH2:4][O:3]1.[Cl:11][CH2:12][CH2:13][CH2:14]Br.ClCCCI.[NH2-].[Li+].N>>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:14][CH2:13][CH2:12][Cl:11])[O:6][CH2:5][CH2:4][O:3]1
Reactant: ClCCCBr
Reactant: C#CCCC1(C)OCCO1
Agent: ClCCCI
Agent: N
Agent: [Li+]
Product: CC1(CCC#CCCCCl)OCCO1

Procedure:
In a preferred embodiment of the process, 2-methyl-2-(3-butynyl)-1,3-dioxolane is reacted with 1-chloro-3-bromo-propane or 1-chloro-3-iodo-propane, in the presence of lithium amide in liquid ammonia to obtain 2-methyl-2-(7-chloro-3-heptynyl)-1,3-dioxolane. Conversion of the latter to the nitrile, 2-methyl-2-(7-cyano-3-heptynyl)-1,3-dioxolane, is accomplished by reaction with sodium cyanide in ethanol under reflux. The nitrile is then hydrolyzed in sodium hydroxide to obtain the desired 9-oxo-5-decynoic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[N:14][C:13]=1[CH:27]=C.O.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O.O>[CH:27]([C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)[S:16][C:12]=1[C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:29])[CH3:30])[CH:11]=[CH:10][N:9]=1)=[O:33]
Reactant: C=Cc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1nccn1COCC[Si](C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(C=O)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
N-{4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-vinyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.650 g, 1.47 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL) at ambient temperature and 0.157 M osmium tetraoxide in water (93 uL, 0.014 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Sodium metaperiodate (0.661 g, 3.09 mmol) was then added in portions over 20 minutes and the mixture was stirred at room temperature overnight. Solids were removed by filtration and washed with THF (2×50 mL) and ethyl acetate (2×5 mL). The filtrate was extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Crude material was purified by silica gel chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.25 g, 38%). LCMS: (FA) ES+, 444. 1H NMR (400 MHz, CDCl3) δ: 8.75 (s, 1H), 10.21 (s, 1H), 8.41 (d, J=5.18 Hz, 1H), 8.20-8.07 (m, 1H), 7.76 (dd, J=5.21, 1.58 Hz, 1H), 7.30 (dd, J=2.87, 1.21 Hz, 2H), 5.32 (s, 2H), 3.50-3.33 (m, 2H), 2.26 (s, 3H), 0.93-0.78 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [OH:1][C:2]([C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17]3[N:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=3[CH2:15][N:14]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:13]=2[CH:41]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].O=C(C1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(OC(F)(F)F)=CC=3)(=O)=O)C=2C=1)C(OCC)=O.C[Mg+].[Br-].[NH4+].[Cl-].C([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC=CC=1>[OH:1][C:2]([C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17]3[N:19]=[C:20]([C:23]([F:25])([F:26])[F:24])[CH:21]=[CH:22][C:16]=3[CH2:15][N:14]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:40])[F:39])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:13]=2[CH:41]=1)([CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: CCOC(=O)C(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: C[Mg+]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)(C(=O)O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-hydroxy-2-[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]propanoate To a solution of ethyl oxo[6-{[4-(trifluoro-methoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]acetate (103 mg, 0.175 mmol, Example 510) in THF was added a solution of MeMgBr (0.25 ml, 0.35 mmol) in toluene (1.4 M) and the solution was stirred for 30 min. at 0° C. The LC-MS showed the reaction was almost complete. The solution was poured into aqueous NH4Cl to quench the reaction, and the pH was adjusted to 7-8 with 1N aqueous NaHCO3. The mixture was partitioned between 20 mL of CH2Cl2 and 5 mL of water, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried over Na2SO4, and the solvent was evaporated under reduced pressure to give the title compound as white solid; Mass Spectrum: m/e=606 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH3:49][N:50]1[CH:54]=[CH:53][C:52]([NH2:55])=[N:51]1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:55][C:52]2[CH:53]=[CH:54][N:50]([CH3:49])[N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 47.7 %

Procedure:
Triphenylphosphine (1.190 g, 4.54 mmol) was dissolved in methylene chloride (40 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (914 mg, 5.14 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 1.00 g, 3.02 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for 30 min. After such time, 1-methyl-1H-pyrazol-3-ylamine (441 mg, 4.54 mmol) and pyridine (740 μL, 4.53 mmol) were added and it was stirred at 25° C. for 16 h. The reaction was then diluted with water (30 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) followed by reverse phase preparative HPLC purification (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole (590 mg, 48%) as a white solid: ESI-LRMS m/e calcd for C19H24ClN3O3S [M+] 409.1. found 410.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.96-1.18 (m, 2H, CH2), 1.35-1.86 (m, 8H, 4×CH2), 2.10-2.21 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.57 (t, J=7.6 Hz, 1H, CH), 3.73 (s, 3H, NCH3), 6.59 (d, J=2.3 Hz, 1H, Ar), 7.21 (d, J=2.3 Hz, 1H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.50 (d, Jm=1.7 Hz, 1H, Ar), 7.96 (d, Jo=8.2 Hz, 1H, Ar), 8.82 (s, 1H, NH).
Reaction SMILES: [CH3:1]N1C(=O)N(C)CC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH:28]=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].[I-].C[S+](C)C>CS(C)=O.C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH:28]1[O:29][CH2:1]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN1CCN(C)C1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: C[S+](C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Temperature: -13 °C
Reaction time: 1 h

Procedure:
DMI (350 ml) was added to a THF solution (1M, 350 ml) of sodium bis(trimethylsilyl)amide. After cooling the mixture to -13° C., a solution of N-(tert-butoxycarbonyl)-L-prolinal (57.71 g) and trimethylsulfonium iodide (73.9 g) in DMSO (350 ml) was dropwise added, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water and extracted with toluene. The extract was washed with 10% citric acid, a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give a mixture (52.74 g) of two diastereomers of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH3:12]>>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([NH2:12])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: N
Product: Nc1cccc(C(F)(F)F)n1
Temperature: 170 °C

Procedure:
A mixture of 2-chloro-6-trifluoromethylpyridine (20.0 g), cuprous chloride (0.2 g) and ammonia (specific gravity 0.88, 75 ml) was heated at 170° C. in a pressure vessel for 18 hours. After cooling to ambient temperature, the mixture was extracted with dichloromethane (300 ml). The organic extract was dried and evaporated to give 6-trifluoromethylpyridin-2-amine, m.p. 74°-79° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:6]2[S:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.O>CN(C=O)C>[CH3:1][S:2][C:5]1[C:6]2[S:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: Clc1ncnc2ccsc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncnc2ccsc12
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Sodium thiomethoxide (9.1 g) was added to a solution of 4-chlorothieno[3,2-d]pyrimidine (WO9849899, example 3A; WO9924440, example 1C) (17.0 g) in DMF (100 mL). After stirring for 90 minutes the mixture was poured into water (400 mL), extracted into EtOAc, washed with water, dried (MgSO4), and the solvent removed. Purification by flash chromatography on silica eluting with DCM:EtOAc (4:1) gave the title compound as a pale yellow solid (16.5 g, 69%);
Reaction SMILES: C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1CCCO1.FC(F)(F)S(O[C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][CH:59]=[C:60]([C:65]3[CH:70]=[C:69]([N:71]4[CH:76]=[CH:75][C:74](=[O:77])[NH:73][C:72]4=[O:78])[CH:68]=[C:67]([C:79]([CH3:82])([CH3:81])[CH3:80])[C:66]=3[O:83][CH3:84])[CH:61]=2)[CH:56]=1)(=O)=O.[CH3:87][S:88]([NH2:91])(=[O:90])=[O:89]>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].C(OCC)(=O)C>[C:79]([C:67]1[C:66]([O:83][CH3:84])=[C:65]([C:60]2[CH:61]=[C:62]3[C:57](=[CH:58][CH:59]=2)[CH:56]=[C:55]([NH:91][S:88]([CH3:87])(=[O:90])=[O:89])[CH:64]=[CH:63]3)[CH:70]=[C:69]([N:71]2[CH:76]=[CH:75][C:74](=[O:77])[NH:73][C:72]2=[O:78])[CH:68]=1)([CH3:82])([CH3:81])[CH3:80]
Reactant: CS(N)(=O)=O
Reactant: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.0042 g, 4.56 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0053 g, 12.0 μmol) and milled potassium phosphate tribasic (0.213 g, 1.003 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (1.9 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl trifluoromethanesulfonate (0.5 g, 0.912 mmol, Example 3-6, compound (5e)), methanesulfonamide (0.104 g, 1.094 mmol) and ethyl acetate (5.7 mL) were added to the 40-mL reaction vial. The temperature of the closed vial and its contents was raised to 90° C. and stirred for 14 hours. HPLC analysis of the reaction mixture showed that the product was formed in 91 area % at 210 nm.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[K+].[C:13]([OH:17])(=[O:16])[CH:14]=O.O.[K].Cl>O>[ClH:1].[ClH:1].[NH:10]1[C:6]2[CH2:5][CH2:4][NH:3][CH:14]([C:13]([OH:17])=[O:16])[C:7]=2[N:8]=[CH:9]1
Reactant: O=CC(=O)O
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: O
Product: O=C(O)C1NCCc2[nH]cnc21
Temperature: 90 °C

Procedure:
25.00 g (0.135 moles) of histamine dihydrochloride were dissolved in 125 ml of water; 26.92 g (0.40 moles) of 85% potassium hydroxide were then added to the cooled solution. A solution of 12.51 g (0.136 moles) of monohydrate glyoxylic acid and 9.00 g (0.136 moles) of 85% potassium hydroxyde in 125 ml of water was dropped into the first one and the reaction mixture heated at 90° C., 6 hours, cooled, treated with conc. HCl and concentrated in vacuo to dryness.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(Cl)ncc1N
Solvent: CC(=O)O
Product: CC(=O)Nc1cnc(Cl)nc1C
Yield: 86.8 %

Procedure:
A solution of 2-chloro-4-methylpyrimidin-5-amine (10 g, 68.26 mmol, 1.00 equiv, 98%) and acetic anhydride (14.3 g, 137.27 mmol, 2.01 equiv, 98%) in acetic acid (50 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to give 11 g (82%) of N-(2-chloro-4-methylpyrimidin-5-yl)acetamide as an off-white solid
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])[N:2]=1.S(=O)(=O)(O)O.[OH-].[NH4+].[CH2:26](O)[CH3:27]>>[CH2:26]([O:17][C:16](=[O:18])[CH:15]=[CH:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH3:27]
Reactant: CCO
Reactant: O=C(O)C=Cc1cc2c(cn1)[nH]c1ccccc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)C=Cc1cc2c(cn1)[nH]c1ccccc12
Temperature: 0 °C

Procedure:
A mixture of 2.3 g of 3-(3-beta-carbolinyl)-acrylic-acid, 70 ml of 99% ethanol, and 10 ml of concentrated sulfuric acid is boiled at the reflux for 5 h. After cooling, the reaction mixture is placed in an ice mixture of 100 g of ice and 40 ml of concentrated ammonium hydroxide. The reaction mixture is filtered off. 2.2 g of ethyl-3-(3-beta-carbolinyl)-acrylate with a m.p. of 132°-134° C. is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:3]1=2.O.NN>C(O)C.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:3]2[N:2]([CH3:1])[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[CH:10]=1
Reactant: CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1C(=O)CCCc2cc(N)ccc21
Temperature: 25 °C

Procedure:
1-Methyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (185 mg, 0.84 mmol) was dissolved in ethanol (3.5 ml). 10% palladium on carbon (50 mg) and hydrazine hydrate (1 ml) were then added, and the mixture was heated to reflux for 2 hours. After cooling to room temperature, the mixture was then filtered through Celite and concentrated to give 7-Amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one as a clear oil, 166 mg. 1H NMR (400 MHz, DMSO-d6) δ 6.92-6.97 (m, 1H), 6.42-6.50 (m, 1H), 6.40 (s, 1H), 5.13 (s, 2H), 3.10 (s, 3H), 1.90-2.16 (m, 6H); MS (m/e) 221 (M+1).
Reaction SMILES: O1CCCC1.Br[C:7]1[C:8](=[O:35])[N:9]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:24][CH:23]=2)[N:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.CCCCCC.C([Li])CCC.CO>C(OCC)(=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][C:12]2[CH:11]=[N:10][N:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)=[CH:26][CH:27]=3)[C:8](=[O:35])[CH:7]=2)=[CH:20][CH:19]=1
Reactant: O=c1c(Br)c(OCc2ccc(F)cc2)cnn1-c1ccc(OC2CCCCO2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: O=c1cc(OCc2ccc(F)cc2)cnn1-c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a tetrahydrofuran solution (1 mL) of 4-bromo-5-(4-fluorobenzyloxy)-2-{4-[(2-tetrahydropyranyl)oxy]phenyl}-2H-pyridazin-3-one (136 mg, 0.29 mmol), 2.66 N n-butyl lithium hexane-solution (0.13 mL, 0.35 mmol) was added at −78° C. and stirred for 30 minutes. Methanol was added to the reaction liquid, warmed up to room temperature and ethyl acetate was added. Thus obtained organic layer was washed with 5% aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; ethyl acetate:hexane=1:1) to provide the title compound (74.2 mg, 65.3%).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[N:32]=[C:31]([O:36][CH3:37])[CH:30]=[CH:29][C:28]=2[CH:27]1[C:38]([OH:40])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:41][C:42]1[CH:43]=[C:44]([CH:46]=[C:47]([F:53])[C:48]=1[Si:49]([CH3:52])([CH3:51])[CH3:50])[NH2:45].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:53][C:47]1[CH:46]=[C:44]([NH:45][C:38]([CH:27]2[N:26]([C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])[CH2:35][CH2:34][C:33]3[N:32]=[C:31]([O:36][CH3:37])[CH:30]=[CH:29][C:28]2=3)=[O:40])[CH:43]=[C:42]([F:41])[C:48]=1[Si:49]([CH3:50])([CH3:51])[CH3:52]
Reactant: C[Si](C)(C)c1c(F)cc(N)cc1F
Reactant: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
T3P (3.84 mL, 6.45 mmol) was added to a solution of 6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylic acid (1.326 g, 4.3 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (0.866 g, 4.30 mmol), DIEA (3.74 mL, 21.50 mmol) and DMAP (0.578 g, 4.73 mmol) in ethyl acetate (31 mL) at room temperature, and the mixture was stirred at 65° C. for 15 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with 10% aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitate was washed with cooled hexane to give tert-butyl 5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.69 g, 3.44 mmol, 80%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:27]=1)[C:7]([NH:9][C:10]1[C:11]([C:23]([O:25]C)=[O:24])=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:13][CH:14]=1)=[O:8].[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:27]=1)[C:7]([NH:9][C:10]1[C:11]([C:23]([OH:25])=[O:24])=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:13][CH:14]=1)=[O:8]
Reactant: COC(=O)c1c(NC(=O)c2cc(F)ccc2O)csc1-c1ccc(C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2scc(NC(=O)c3cc(F)ccc3O)c2C(=O)O)c(F)c1
Yield: 65 %

Procedure:
Ester 385 (61 mg, 151 μmol) and lithium hydroxide (21.7 mg, 907 μmol) in tetrahydrofuran:methanol:water (3:2:1, 0.8 mL) was stirred at 60° C. for 2 h. The mixture was cooled, quenched with 2 M HCl (0.7 mL) and diluted with water (2 mL). The precipitate that formed was filtered and washed with methanol:water (1:2, 1 mL) and dichloromethane (1 mL) to provide 386 (38.2 mg, 65%) as a solid: LRESIMS m/z 390.1 [M+H]+, calcd. for C19H14F2N1O4S1 390.1.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH:18]=[O:19])=[C:9]([CH:17]=1)[O:10][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].[BH4-].[Na+].Cl>CO>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:18][OH:19])=[C:9]([CH:17]=1)[O:10][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1C=O
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: COC(=O)C(C)Oc1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To a solution of 0.10 g (0.018 mole) of sodium methoxide in 20 mL of methanol that had been cooled to 5° C. was added a solution of 8.0 g of methyl 2-(5-chloro-2-formylphenoxy)propionate in 20 mL of methanol. While the temperature was maintained between 0° C. and 5° C., to this mixture was added 0.50 g (0.013 mole) of sodium borohydride. This addition required 10 minutes, during which gas was evolved. The yellow solution was allowed to warm up to room temperature, where it was stirred for four hours. At the end of this period the reaction mixture was poured into 100 mL of 0.25N hydrochloric acid. This mixture was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving a yellow oil as a residue. This oil was placed on a silica gel column and eluted with methylene chloride/ethyl acetate (95/5). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 4.42 g of methyl 2-(5-chloro-2-hydroxymethylphenoxy)propionate was isolated as an orange oil, which subsequently solidified, m.p. 51°-52° C.