Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.BrBr.[Br:20][C:21]1C(O)=C(Br)C(Br)=C(C(C2C=CC(O)=CC=2)(C)C)C=1Br>CO>[CH3:21][Br:20].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccc(O)cc1)c1c(Br)c(Br)c(O)c(Br)c1Br
Agent: BrBr
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CO
Product: CBr

Procedure:
In a reaction vessel was placed 1000 parts methanol and 230 parts of bisphenol-A. Bromine was fed over a 90 minute period in an amount between 0.99 and 0.995 times the theoretical amount needed to covert the bisphenol-A to tetrabromobisphenol-A. The method for brominating the bisphenol-A was generally in accordance with the method disclosed in U.S. Pat. No. 4,783,556, incorporated herein by references as is fully set forth. The reaction mixture was held at reflux during the bisphenol-A bromination sequence and methyl bromide was produced during the entire bisphenol-A bromination process. After the bromine addition was completed, the system was held at reflux for 30 minutes to produce additional methyl bromide which was distilled out of the reaction mixture. Heating was stopped and 400 parts of water was added over a 30 minute period to precipitate the TBBPA and to halt methyl bromide production. The reaction medium was then allowed to cool to 30°-40° C. and TBBPA product was removed by centrifugation and wash with 5 parts of methanol and 5 parts of water. The centrate was neutralized with NaOH to a pH of 12-13 and then distilled to remove methanol. The resulting 870 parts of distillation column bottoms contained 1.7 weight percent sodium salts of tetrabromobisphenol-A, 1.7 weight percent sodium salts of tribromobisphenol-A, 0.2 weight percent sodium salts of tribromophenol, 0.2 weight percent sodium salts of other brominated phenolics, 0.5 weight percent NaOH, 0.3 parts of methanol, and about 12 weight percent NaBr.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([OH:14])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:15](O)[CH3:16]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1n[nH]c2cc(F)ccc12
Reactant: CCO
Product: CCOC(=O)Cc1n[nH]c2cc(F)ccc12
Yield: 39.3 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)acetic acid (4.63 g, 23.8 mmol) was dissolved in anhydrous ethanol (60 mL) concentrated sulfuric acid (2.0 mL), and heated under reflux for 16 hours. After concentrated under reduce pressure to remove most of ethanol, water (20 mL) was added, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the product 2.08 g, at a yield of 39.3%.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[O:2].[C:6](OCC)(=[O:9])[CH2:7][CH3:8].CC(C)([O-])C.[K+:18]>O1CCCC1>[CH2:4]([O:3][C:1]([C:7]([CH3:8])=[CH:6][O-:9])=[O:2])[CH3:5].[K+:18]
Reactant: CCOC=O
Reactant: CCOC(=O)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C[O-]

Procedure:
To a solution of ethyl formate (117.5 g) and ethyl propionate (54.0 g) in 40 ml of tetrahydrofuran (THF) was added, drop-wise, potassium t-butoxide (502 ml of a 1.0 molar solution in THF) at ambient temperature over approximately 0.5 hour. A white precipitate began to form along with some bubbling. After another 7.5 hours the reaction was filtered, the solid was washed with diethyl ether and then dried under vacuum at 40° C. for 16 hours to give potassium 2-ethoxycarbonyl-propen-1-olate as a grey powder (23.5 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:19]([NH2:20])=[CH:18][CH:17]=[N:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][N:15]1[C:19]([NH:20][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:18][CH:17]=[N:16]1
Reactant: Cn1nccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1nccc1NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 69.6 %

Procedure:
Under cooling in an ice bath, 4-(trifluoromethyl)benzoyl chloride (8.26 g) was added dropwise to a chloroform (35 mL) solution that contained 1-methyl-1H-pyrazol-5-amine (3.50 g) and triethylamine (5.50 mL), and the obtained solution was then stirred for 2 hours. Thereafter, the reaction solution was diluted with chloroform, and was then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated saline. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtained solid was washed with diisopropyl ether, so as to obtain the title compound (6.75 g) in the form of a colorless solid.
Reaction SMILES: C([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=O)=[CH:7][CH:6]=1)CCC.[NH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16]>>[C:8]([N:14]([CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:13][CH:12]=1)[CH:15]([CH3:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:12])([CH3:9])[CH3:7]
Reactant: CCCCCC(C)N
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCC(C)N(Cc1ccccc1)C(C)(C)C

Procedure:
The N-t-butylbenzyl-N-(1-methylhexyl)amine was synthesized in the same manner as in Example 2, procedures 1 and 2 using 4-1-butylbenzoyl chloride and 2-aminoheptane as starting materials.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH2:20][C:21]1[C:30]2[C:25](=[C:26](Br)[CH:27]=[CH:28][CH:29]=2)[N:24]=[N:23][C:22]=1[C:32]([NH2:34])=[O:33]>C(O)=O>[NH2:20][C:21]1[C:30]2[C:25](=[C:26]([C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)[CH:27]=[CH:28][CH:29]=2)[N:24]=[N:23][C:22]=1[C:32]([NH2:34])=[O:33]
Reactant: Cn1cnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Solvent: O=CO
Product: Cn1cnc2cc(-c3cccc4c(N)c(C(N)=O)nnc34)ccc21

Procedure:
A formic acid salt of the title compound was prepared in a manner similar to EXAMPLE 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 4-amino-8-bromocinnoline-3-carboxamide. 1H NMR (500 MHz, CD3OD) δ ppm 3.91 (s, 3 H), 8.54 (s, 1 H), 8.64 (d, J=8 Hz 1 H), 8.73 (d, J=8 Hz 2 H), 8.84 (d, J=16 Hz 1 H), 9.29 (d, J=8 Hz 1 H), 9.99 (s, 1 H); ESI-MS m/z [M+H]+ 319.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:88])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:74][C:75]1[N:76]([CH2:80][C:81](=[O:87])[O:82][C:83]([CH3:86])([CH3:85])[CH3:84])[CH:77]=[CH:78][N:79]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:38](=[O:73])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][C@@H:44]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[NH:45][C:46](=[O:65])[NH:47][C@H:48]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:20]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C>[NH2:20][C@H:19]([C:38](=[O:73])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][C@@H:44]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[NH:45][C:46](=[O:65])[NH:47][C@H:48]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:49][CH2:50][C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:13][C:9]1[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:88])[CH:12]=[CH:11][N:10]=1)[CH2:74][C:75]1[N:76]([CH2:80][C:81]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:87])[CH:77]=[CH:78][N:79]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@@H](N)CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of (5S,12S,16S)-tri-tert-butyl 5-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-1-(9H-fluoren-9-yl)-3,6,14-trioxo-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (84 mg, 0.069 mmol) in DMF (0.50 mL) was added piperidine (0.50 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 5% MeOH to 25% MeOH in DCM to afford (7S,14S,18S)-tri-tert-butyl 7-amino-1-(1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (59 mg, 86%). 1H NMR (400 MHz, 6.96 (d, J=0.8 Hz, 2H), 6.85 (d, J=0.8 Hz, 2H), 5.55 (brs, 1H), 5.43 (brs, 1H), 4.59 (s, 4H), 4.37-4.28 (m, 2H), 3.61 (s, 4H), 3.35-3.27 (m, 2H), 3.18-3.12 (m, 1H), 2.53 (t, J=7.4 Hz, 2H), 2.34-2.28 (m, 2H), 2.10-2.00 (m, 2H), 1.85-1.26 (m, 55H); MS (ESI), 503.0 (M/2+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22]#[N:23])=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1[NH2:9])(=O)[CH3:2].Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[NH2:9][C:8]1[N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:6]=[C:5]([C:22]#[N:23])[C:4]=1[C:1](=[N:25][OH:26])[CH3:2]
Reactant: CC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 4-acetyl-5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.25g) in pyridine (5 ml) was added hydroxylamine hydrochloride (0.05 g). After stirring at room temperature for 6 hours the mixture was heated at 50° C. for 3 hours, after which it was evaporated. The residue was taken up in ether and washed with aqueous citric acid solution (1M), water, then dried and evaporated. The residue was crystallised from propan-2-ol/hexane and further purified by column chromatography on silica gel eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a tan solid, m.p. 105-110° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]([C:16]1[CH:20]=[C:19]([NH2:21])[NH:18][N:17]=1)([CH3:15])([CH3:14])[CH3:13].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].N#N.CCCC(C)C>C1(C)C=CC=CC=1.CCOCC.[Cu]I>[C:12]([C:16]1[CH:20]=[C:19]([NH2:21])[N:18]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=2)[N:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(I)cc1OC
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N#N
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCC(C)C
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1OC
Temperature: 25 °C

Procedure:
To a solution of 4-iodo-1,2-dimethoxybenzene (1.10 g, 4.17 mmol) in anhydrous toluene (5.0 mL) was added 3-tert-butyl-1H-pyrazol-5-amine (638 mg, 4.58 mmol) followed by (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (130 μL, 0.83 mmol) and potassium carbonate (1.15 g, 8.3 mmol). The mixture was purged with N2, copper(I) iodide (40 mg, 0.21 mmol) was added and the reaction mixture was heated at reflux under N2 for 16 hr. The resulting mixture was cooled to RT and was partitioned between EtOAc (100 mL) and water (150 mL). The organic layer was separated and was washed with aq. citric acid solution (10% w/v, 50 mL) followed by brine (50 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 0-70%, gradient elution). The impure product so obtained was dissolved in ether (1.0 mL), isohexane (10 mL) was added and the resulting precipitate was collected by filtration to afford the title compound, Intermediate A19, as a purple solid (364 mg, 31%); Rt 3.55 min (Method 1); m/z 276 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[C:4](=[O:10])[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.CO.[ClH:23]>>[ClH:23].[NH2:11][C@H:3]([C:2]([CH3:20])([CH3:19])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC1)C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)[C@@H](N)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10 mL round-bottomed flask, (R)-tert-butyl 3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate (0.160 g, 0.56 mmol) was dissolved in 1.0 M hydrogen chloride solution in MeOH (3.6 ml, 3.6 mmol). The reaction mixture was stirred at room temperature overnight the concentrated to afford 140 mg of (R)-2-amino-3,3-dimethyl-1-(pyrrolidin-1-yl)butan-1-one hydrochloride as a hydroscopic off-white foam which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C(Cl)Cl.CO.[NH4+].[OH-]>O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH:39][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: NC1CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described for the title compound under J in Example 9 from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and cyclopropylamine. TLC, Rf (CH2Cl2/MeOH 9:1+10 % NH4OH)=0.48. MS (LC-MS): 534.4 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 5-100% CH3CN/H20/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.53 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[Mn]([O-])(=O)(=O)=[O:23].[K+].Cl.C(OCC)(=O)C>O.[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([C:14]1[CH:21]=[CH:20][C:17]([C:18]([OH:23])=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: O=Cc1ccc(S(=O)(=O)c2ccc3ccccc3c2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)c2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
4-(Naphthalene-2-sulphonyl)benzaldehyde (0.97 g) was suspended in water (25 ml) containing cetyltrimethylammonium bromide (58 mg). The mixture was stirred and heated to 60° C., and potassium permanganate (0.95 g) was added in small portions over 1 hour. Heating was continued for a further 2 hours. The mixture was cooled to room temperature and was acidified with 2M hydrochloric acid. Ethyl acetate was added to the stirred mixture, which was filtered through a pad of celite. The ethyl acetate layer was washed with brine, dried (MgSO4), and evaporated to afford 4-(naphthalene-2-sulphonyl)benzoic acid (0.42 g) as solid residue; NMR: 7.7(dd,1H); 7.95(dd,1H), 8.1-8.2(m,8H); 8.7(d,1H); microanalysis, found; C,58.6; H,3.9%; C17H12O4S.2H2O requires: C,58.6; H,4.6%; MS: m/z 312(M H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.CC1C=CC(S(O[CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:7]=[C:2]([O:1][CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:3]=[C:4]([CH3:17])[C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.26 g, 10.0 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.51 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.80 g, 13.0 mmol), and the mixture was stirred at 90° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60+80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound. (2.68 g, yield 77%) as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.BrCCCOC1C=CC(OC(F)(F)F)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[CH:44]=[C:43]([O:45][CH2:46][CH:47]=[C:48]([Cl:50])[Cl:49])[CH:42]=[C:41]([CH3:51])[C:40]=1[OH:52]>CN(C)C=O.C(OCC)C>[Cl:38][C:39]1[CH:44]=[C:43]([O:45][CH2:46][CH:47]=[C:48]([Cl:49])[Cl:50])[CH:42]=[C:41]([CH3:51])[C:40]=1[O:52][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1
Reactant: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Reactant: FC(F)(F)c1ccc(OCCCBr)cc1
Agent: FC(F)(F)Oc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
First, 0.35 g of 1-(3-bromopropyloxy)-4-trifluoromethylbenzene (prepared in the same manner as described above for 1-(3-bromopropyloxy)-4-trifluoromethoxybenzene) and 0.2 g of potassium carbonate were dissolved in 100 ml of N,N-dimethylformamide, to which 0.3 g of 2-chloro-6-methyl-4-(3,3-dichloro-2-propenyloxy)phenol was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was mixed with 200 ml of diethyl ether, washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.50 g of 3-chloro-4-[3-(4-trifluoromethylphenoxy) propyloxy]-5-methyl-1-(3,3-dichloro-2-propenyloxy)benzene (94% yield), nD23.0 1.5330.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.Cl.[C@H:10]1([NH2:18])[C:12]2([CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[Br:8][C:4]1[N:3]=[C:2]([NH:18][C@H:10]2[C:12]3([CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: N[C@@H]1CC12CCOCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Brc1cccc(N[C@@H]2CC23CCOCC3)n1
Temperature: 110 °C
Yield: 88.3 %

Procedure:
To a solution of 2,6-dibromopyridine (200 mg, 0.84 mmol) in NMP (0.42 mL) was added (R)-6-oxaspiro[2.5]octan-1-amine hydrochloride (138 mg, 0.84 mmol) and potassium carbonate (350 mg, 2.53 mmol). The mixture was heated at 110° C. for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water, and brine and dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane= 0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo giving 210 mg of titled compound. LCMS (m/z): 282.9/284.9 [M+H]+, retention time=0.85 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([F:10])[CH3:9])[N:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[O:15][CH3:16].[OH-].[Na+].Cl>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([F:10])[CH3:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[O:15][CH3:16]
Reactant: COC(=O)c1nc(C(C)F)cc(N)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(N)cc(C(C)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
To a solution of methyl 4-amino-6-(1-fluoroethyl)-3-methoxypicolinate (0.125 g, 0.548 mmol) in THF (2.74 ml) and MeOH (2.74 ml) was added a 2 N solution of sodium hydroxide (0.822 ml, 1.643 mmol). The reaction mixture was stirred at room temperature (LC monitoring). After 4 h, the reaction mixture was acidified with a 2 N solution of HCl (1 mL) and then concentrated (rotavap). The resulting white solid was dissolved into DMF+a few drops of water and was purified by preparative HPLC (reverse phase, C18 column) to afford 4-amino-6-(1-fluoroethyl)-3-methoxypicolinic acid (98 mg, 0.458 mmol, 84% yield) as an orange solid. ESIMS m/z 213 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 6.82 (s, 1H), 6.47 (s, 2H), 5.49 (dq, J=47.7, 6.3 Hz, 1H), 3.69 (s, 3H), 2.51 (d, J=24.0 Hz, 1H), 1.52 (dd, J=24.5, 6.4 Hz, 3H); 19F NMR (376 MHz, DMSO) δ −171.64.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][C:19]=1[N:39]1[CH2:48][C:47]2[C:42](=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=2)[N:41]([CH3:53])[C:40]1=[O:54]>CN1CCCC1=O.C(OCC)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][C:19]=1[N:39]1[CH2:48][C:47]2[C:42](=[N:43][C:44]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])=[CH:12][CH:11]=3)=[N:45][CH:46]=2)[N:41]([CH3:53])[C:40]1=[O:54]
Reactant: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2cc(NC(=O)c4ccc(-c5ccccc5)cc4)ccc2Cl)C3)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
0.1 g 4-(2-Diethylamino-ethoxy)-phenylamine were dissolved in 1 mL N-methylpyrrolidinone (NMP) and cooled to 0° C. 300 μl of a solution of aqueous HCl in diethyl ether were added and stirred for 45 min. Biphenyl-4-carboxylic acid [4-chloro-3-(7-methanesulfonyl-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-amide was dissolved in 2 ml NMP and added to the aforementioned solution and the reaction mixture was heated at 120° C. for 24 h. The reaction was quenched by addition of 5 mL of a saturated solution of sodium carbonate and the aqueous phase was extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol) to give the title product in 35% yield.