Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:14]([OH:15])=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][Br:10])[CH2:2][CH3:3].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:14]([O:15][CH3:19])=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][Br:10])[CH2:2][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCc1c(OCCCBr)ccc(C(C)=O)c1OC
Yield: 94.2 %

Procedure:
3.15 g (0.01 mole) of 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane was dissolved in 50 ml of dry acetone. To this solution was added 2.75 g (0.02 mole) of anhydrous potassium carbonate and 3 g (0.02 mole) of methyl iodide. After refluxing for four days under an argon atmosphere, the reaction mixture was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with 2% ethyl acetate/toluene to give 3.1 g (94%) of the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: COC(=O)CBr
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure A: Reaction of (5-Aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol, methylbromoacetate and DIPEA in CH2Cl2 gave (4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamino)-acetic acid methyl ester as a white foamy solid. 1H NMR (CDCl3) δ 1.60 (m, 1H), 1.80 (br s, 1H), 1.98 (m, 1H), 2.19 (m, 2H), 2.22 (s 3H), 2.25 (s, 3H), 2.64 (m, 1H), 2.79 (m, 1H), 3.40 (s, 2H), 3.63-3.77 (m, 8H), 3.91 (t, 1H, J=7.5 Hz), 4.15 (m, 2H), 4.36 (d, 1H, J=12.0 Hz), 7.01 (dd, 1H, J=7.5, 3.0 Hz), 7.16 (d, 1H, J=7.5 Hz), 7.21-7.31 (m, 4H), 8.16 (s, 1H), 8.37 (d, 1H, J=3.0 Hz). 3C NMR (CDCl3) δ 18.3, 18.6, 21.1, 22.1, 29.8, 50.4, 52.1, 53.3, 54.4, 54.6, 57.9, 63.0, 121.9, 127.4, 131.4, 131.8, 132.2, 133.8, 134.9, 136.3, 136.9, 139.3, 139.7, 142.6, 146.5, 146.9, 153.7, 157.3, 173.2. HPLC: 98%. ES-MS m/z 489 [M+H]+, 511 [M+Na]+. Anal. Calcd. for C29H36N4O3.0.1 CH2Cl2: C, 70.31; H, 7.34; N, 11.27. Found: C, 70.54; H, 7.48; N, 11.17.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:17]([CH3:28])[S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=2)[CH:10]=[C:9]1[C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[N:32]=[N:31][C:30]=1[O:41]C)=O)(C)(C)C.[OH-].[Na+]>C(O)C>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:17]([CH3:28])[C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[C:9]([C:29]4[C:30](=[O:41])[NH:31][N:32]=[C:33]([C:35]5[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=5)[CH:34]=4)[NH:8]3)=[CH:12][CH:13]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(N(C)S(=O)(=O)c3ccc(C)cc3)cc2n1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc3cc(-c4cc(-c5ccncc5)n[nH]c4=O)[nH]c3c2)cc1
Temperature: 150 °C
Yield: 48.9 %

Procedure:
155 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-[methyl-(toluene-4-sulfonyl)-amino]-indole-1-carboxylic acid tert-butyl ester are dissolved in 2.25 mL ethanol. 1.85 mL 1 N aqueous sodium hydroxide are added. The reaction mixture is heated to 150° C. in a microwave oven for 15 minutes. Purification by HPLC affords 61 mg (39%) 4, N-dimethyl-N-[2-(3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazin-4-yl)-1H-indol-6-yl]-benzenesulfonamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].CO.CO[C:9]([C:11]1[NH:12][C:13]2[CH:14]=[C:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:16]=[C:17]3[C:23](=[O:24])[NH:22][N:21]=[CH:20][C:19]=1[C:18]=23)=[O:10].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:29]([O:28][C:26](=[O:27])[NH:25][C:15]1[CH:16]=[C:17]2[C:23](=[O:24])[NH:22][N:21]=[CH:20][C:19]3=[C:11]([C:9](=[O:10])[NH:1][CH2:2][CH2:3][OH:4])[NH:12][C:13]([CH:14]=1)=[C:18]23)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: NCCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc2c3c(c(C(=O)NCCO)[nH]c3c1)C=NNC2=O
Yield: 39 %

Procedure:
Preparation of example 162 was carried out in a manner analogous to step 5 of Example 147, except that 2-aminoethanol was substituted for methanol, and chromatography was not required. Thus CO was bubbled through a mixture of Intermediate 147(d) from Example 147 (60 mg, 0.16 mmol), triethylamine (0.044 mL, 0.32 mmol), 2-aminoethanol (19 mg, 0.32 mmol), and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (26 mg, 0.032 mmol) in N,N-dimethylformamide (3.0 mL). After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated, and methanol was added. The resulting solids were collected by filtration and washed with methanol, dichloromethane and diethyl ether. After drying under vacuum, the title compound (24 mg, 0.062 mmol) was obtained as a yellow powder in 39% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH2:9]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:10]([C:12]([F:15])([F:14])[F:13])=O.[OH-].[NH4+]>P(=O)(O)(O)O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:10]([C:12]([F:13])([F:14])[F:15])=[CH:9][C:16]=2[C:18]([F:19])([F:21])[F:20])[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc2c(C(F)(F)F)cc(C(F)(F)F)nc2n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-diaminopyridine (5.2 g., 47.6 mmole), 1,1,1,5,5,5-hexafluoroacetylacetone (10.0 g., 48.0 mmole) and 85% phosphoric acid (50 ml.) are stirred for 6 hours in an oil-bath at 90°-95° C. then left overnight at ambient temperature. The reaction mixture is poured into ice water and neutralized with ammonium hydroxide to pH 7, the solid collected, washed with water and dried to provide 9.0 g. (67%) of product, m.p. 198°-204° C. Upon recrystallization from benzene, purified product separates in the form of pale yellow needles, m.p. 204°-206° C.
Reaction SMILES: CS(C)=O.ClCCl.C(Cl)(=O)C(Cl)=O.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(N(CC)CC)C>[CH3:26][C:19]([CH3:25])([CH2:18][CH2:17][CH2:16][CH:15]=[O:14])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)(C)CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)CCCC=O
Reaction time: 0.17 h
Yield: 108.6 %

Procedure:
A 4.0 ml portion of DMSO was added at −78° C. to a 40 ml dichloromethane solution of 2.5 ml oxalyl chloride and stirred for 10 minutes, and then a dichloromethane solution of 2.7 g of ethyl 6-hydroxy-2,2-dimethylhexanoate synthesized by the technique described in “Tetrahedron”, 2000, vol. 56, p. 9195-9202, was added thereto and stirred at the same temperature for 15 minutes. A 12 ml portion of triethylamine was added to the reaction solution and stirred for 30 minutes, and the reaction was quenched by adding water. Successively, work-up was carried out in the standard method to obtain 2.9 g of ethyl 2,2-dimethyl-6-oxohexanoate as a crude product. EP: 187.
Reaction SMILES: BrC1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]C.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:10][C@H:11]1[NH:12][CH2:13][CH2:14][N:15]([C:5]2[CH:4]=[CH:3][S:8][C:6]=2[CH3:7])[CH2:16]1
Reactant: CSc1ccccc1Br
Reactant: C[C@@H]1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1sccc1N1CCN[C@H](C)C1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
2-Bromothioanisole (300 mg, 1.48 mmol), (R)-2-methylpiperazine (185 mg, 1.85 mmol), Pd2(dba)3 (32 mg, 0.35 mmol), BINAP (41 mg, 0.66 mmol), sodium t-butoxide (200 mg, 2.08 mmol) and anhydrous toluene (3 ml) were combined in a 15 ml round-bottomed flask. The atmosphere in the flask was evacuated and flushed with nitrogen (3×). The mixture was lowered into an oil bath heated to 100° C. After heating for about 1.2 hours, the mixture was cooled, diluted with ethyl acetate (100 ml), filtered through Celite, and concentrated to a crude oil (285 mg). The oil was loaded onto an cation exchange column, and the column was flushed with methanol (100 ml), and then with 2 M ammonia/methanol (100 ml). The basic methanol solution was concentrated to an oil (250 mg). The oil was further purified by flash chromatography using 19:1 dichloromethane: 0.5 M ammonia/methanol as eluent to yield the final product (160 mg, 58%) as an oil. LRMS (ESI+): 223.0 (M+1)
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([OH:38])=O)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH:43]=[CH:42][N:41]=[C:40]1[NH2:44].Cl.Cl.N1CCC[C@@H]1COC1C(C(N)=O)=NC=CC=1>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:19][CH2:20][C@H:21]([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:23]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([NH:44][C:40]3[O:39][CH:43]=[CH:42][N:41]=3)=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: Nc1ncco1
Agent: Cl
Agent: NC(=O)c1ncccc1OC[C@H]1CCCN1
Product: O=C(Nc1ncco1)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using 3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 79 Step 6) and oxazol-2-amine instead of indole-2-carboxylic acid and (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[N:21]=1)(C(C)(C)C)(C)C.Cl>C(O)CCC>[OH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[N:21]=1
Reactant: CCCCOC(=O)/C=C/c1csc(CN2C(=O)CC[C@@H]2CO[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)/C=C/c1csc(CN2C(=O)CC[C@@H]2CO)n1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of the compound 73 (952 mg) in n-butanol (4.40 mL) was added 2N hydrochloric acid (2.20 mL) at room temperature and the solution was stirred at room temperature for 3 Hours. The reaction solution was concentrated and azeotroped with toluene. Ethyl acetate and an aqueous saturated sodium carbonate solution were added thereto and the solution was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (710 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH2:42][OH:43])[CH:36]=3)=[CH:31][C:30]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH2:42][OH:43])[CH:36]=3)=[CH:31][C:30]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(CO)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccn(-c2cc(-c3ccc(C)c(CO)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([NH:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.N1NC(=O)C=CC=1.Cl.[F:36][C:37]([F:52])([F:51])[C:38]1[CH:50]=[CH:49][CH:48]=[CH:47][C:39]=1[O:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([NH:15][CH2:16][C:17](=[O:19])[N:44]2[CH2:43][CH2:42][CH:41]([O:40][C:39]3[CH:47]=[CH:48][CH:49]=[CH:50][C:38]=3[C:37]([F:36])([F:51])[F:52])[CH2:46][CH2:45]2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: O=C(O)CNc1ccnn(Cc2ccccc2)c1=O
Agent: BrCc1ccccc1
Agent: Cl
Agent: O=c1cccn[nH]1
Product: O=C(CNc1ccnn(Cc2ccccc2)c1=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Yield: 30 %

Procedure:
Compound 48 is prepared from (2-benzyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-acetic acid (obtained following the operating mode for 4e using benzyl bromide to alkylate nitrogen 2 of pyridazinone) and from intermediate 1a in base form, following synthesis method 2 (yield: 30%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12](=O)([O-:14])[O-:13].[Na+].[Na+].[C]=O>[C].[Pd].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [Pd]
Agent: [C]=O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1
Temperature: 180 °C
Reaction time: 8 h
Yield: 265.6 %

Procedure:
In an autoclave made of glass were placed 180.6 g of parachlorobenzotrifluoride, 0.64 g of 5% palladium-carbon, 4.3 g of 1,4-bisdiphenylphosphinobutane and 21.2 g of sodium carbonate. The air in the autoclave was replaced with carbon monoxide introduced thereinto several times, after which carbon monoxide was further introduced to adjust its pressure therein to 10 kg/cm2. The reaction was carried out with stirring for 8 hours at 180° C. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added. The aqueous layer was separated and then acid was added thereto, followed by extraction from the aqueous layer with ether. The ether layer was dried and then concentrated to obtain 101 g of paratrifluoromethylbenzoic acid.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.C[O-:14].[K+].S1CCN=C1>CO>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:14])[N:3]=1)[CH3:10]
Reactant: C[O-]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Agent: C1=NCCS1
Agent: [K+]
Solvent: CO
Product: CN(C)Cc1nc(CO)cs1

Procedure:
The process of Example 5 was repeated using 3.0 g (0.014 mol) of 4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared as in Example 1), 48 ml of methanol and 0.98 g (0.014 mol) of potassium methoxide. The HPLC assay set forth in Example 3 indicated that 70.1% of the thiazoline substrate had converted to the desired titled product.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=2)[C:6](=[O:19])[C:7]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)=[CH:8]1
Reactant: C1CCNCC1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Product: Cn1nnnc1-c1cn(C)c2cc(N3CCCCC3)ccc2c1=O

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (0.2 g) and piperidine (5 ml) was heated on a steam bath for 22 hours. The mixture was cooled and the solid product was collected and recrystallised from industrial methylated spirit to give the novel compound 1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-7-piperidino-4-quinolone, m.p. 180°-183°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[F:42])[C:36]([OH:38])=O.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:36](=[O:38])[C:35]2[CH:39]=[CH:40][C:41]([F:42])=[C:33]([F:32])[CH:34]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(F)c(F)c2)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (30 mg, 0.068 mmol, prepared as described in Step (A) of Example 28) and 3,4-difluorobenzoic acid (10.8 mg, 0.068 mmol) in 0.68 ml of CH2Cl2 and 0.1 ml DMF, 1,3-diisopropylcarbodiimide (9.5 mg, 0.075 mmol) was added. The reaction was stirred at room temperature for 5 hrs and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 19% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 81% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (22 mg, 56%) as a white solid, m.p. 122°-128° C. (amorphous).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:18])[CH2:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][C:12]([OH:17])([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2>CO>[OH:17][C:12]12[CH2:13][CH:14]3[CH2:15][CH:10]([CH2:9][CH:8]([CH:7]3[CH2:6][C:5]([OH:18])=[O:4])[CH2:16]1)[CH2:11]2
Reactant: COC(=O)CC1C2CC3CC1CC(O)(C3)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Aqueous 2.5 N sodium hydroxide solution 0.49 ml was added to methanol 10 ml solution of 5-hydroxy-2-adamantyl acetic acid methyl ester 181.5 mg and stirred at room temperature for 14 hours. Reaction mixture was concentrated in vacuo. Saturated sodium bicarbonate solution was added to the residue and washed with ether. Aqueous layer was adjused to pH 1 by adding 12 N hydrochloric acid, and extracted with ethyl acetate, then dried by adding anhydrous sodium sulfate. After removal of the drying agent, the filtrate was concentrated in vacuo to obtain the product as a mixture of stereoisomer. (a mixture of stereoisomer 1:1 measured by gas chromatography)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:20][CH2:21][C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH:18]=[CH2:19])=[CH:17][C:7]2=1.[H][H]>CO.[Pd]>[CH2:18]([C:16]1[C:15]([O:20][CH2:21][C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[C:11]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1])[CH3:19]
Reactant: C=Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 54.2 %

Procedure:
A solution of (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.107 mmol) in MeOH (3 mL) was degassed with nitrogen for 5 min, then palladium on carbon (1.143 mg, 10.74 μmol) was added. The reaction mixture was allowed to stir under a balloon of hydrogen for 16 h. The reaction mixture was then filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (2% MeOH in MDC) to afford (S)-tert-butyl (1-((9-ethyl-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (31 mg, 0.058 mmol, 54% yield) as pale yellow solid. LC/MS, (ESI) m/z 468.5 [(M+H)+, calcd for C27H38N3O4 468.3]; LC/MS retention time (method D): tR=1.31 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[OH:17][C:15]1[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=[C:11]([Cl:10])[C:16]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cc(O)c(C(=O)c2ccccc2)c(Cl)c1
Reaction time: 5 h
Yield: 529.1 %

Procedure:
14.1 g (100 mmol) of benzoyl chloride are added dropwise with stirring at room temperature to a solution of 19 g (10 mmol) of 1-chloro-3,5-dimethoxybenzene and 14.7 (110 mmol) of AlCl3 in 100 ml of toluene. The mixture is held at 70° C. with stirri for 5 h. The reaction mixture is cooled, then treated with 10% HCl and extracted with toluene. The resulting solution is washed with water and subsequently with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is purified by chromatography over silica gel (ethyl acetate/hexane 1:5). The product is recrystallized from hexane. 13.9 g of the compound are obtained as pale yellow crystals having a melting point of 92°-94° C.