Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]([C:12]3[CH:13]=[C:14](N)[CH:15]=[CH:16][CH:17]=3)=[N:10][CH:11]=2)[CH:3]=[N:2]1.[I:19]CI.N(OCCC(C)C)=O>O1CCOCC1.[Cu]I>[I:19][C:14]1[CH:13]=[C:12]([C:9]2[N:8]=[CH:7][C:6]([C:4]3[CH:3]=[N:2][NH:1][CH:5]=3)=[CH:11][N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(-c2ncc(-c3cn[nH]c3)cn2)c1
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Product: Ic1cccc(-c2ncc(-c3cn[nH]c3)cn2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a suspension of 3-[5-(1H-Pyrazol-4-yl)-pyrimidin-2-yl]-phenylamine (12.6 g; 53.2 mmol; 1.0 eq.) in Dioxane (500 mL) were added diiodomethane (21.6 mL; 266 mmol; 5.0 eq.), Copper(I) iodide (10.1 g; 53.2 mmol; 1.0 eq.) and isopentyl nitrite (21.5 mL; 159 mmol; 3.0 eq.). The reaction mixture was stirred at 100° C. for 2 hours and filtered. The filtrate was kept in a flask. The resulting green solid was suspended in dioxane (100 mL) and stirred at 100° C. for 30 minutes. The solid was then filtered off and the two filtrates were combined and concentrated under reduced pressure. The dark brown residue was sonicated in EtOAc (20 mL) and pentane (80 mL). The resulting brown solid was filtered, further washed with pentane and dried few hours under high vacuum to give the title compound as a brown solid (7.0 g; 38%). 1H NMR (300 MHz, DMSO-d6) δ 13.27 (brs, 1H), 9.20 (s, 2H), 8.71 (t, J=1.5 Hz, 1H), 8.52 (m, 1H), 8.39 (dt, J=8.0 Hz, 1.5 Hz, 1H), 8.21 (m, 1H), 7.89-7.86 (m, 1H), 7.35 (t, J=8.0 Hz, 1H). HPLC (Condition A): Rt 3.86 min (purity 67.6%). MS (ESI+): 349.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](I)=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C(OCC)C.CCCCCC>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([B:17]([OH:20])[OH:18])=[C:6]([F:8])[CH:7]=1
Reactant: COc1cc(I)c(F)cc1Cl
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(B(O)O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at −78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below −69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280-296° C.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([O:12][C:13]([N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1F)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>CS(C)=O>[C:8]([O:12][C:13]([N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1-n1cccn1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a mixture of pyrazole (1.0 g) and dimethylsulfoxide (50 ml), sodium hydride (0.54 g) was added under ice cooling. The reaction mixture was stirred under ice cooling for 1 h and then a solution of N-(2-fluoro-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester (5.0 g) in dimethyl sulfoxide (50 ml) was added. The reaction mixture was stirred at room temperature for 15 h and, after addition of water, subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:4) to give the titled compound (yield, 73%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[CH:48][C:47]([CH2:50]O)=[CH:46][CH:45]=1)=[O:35]>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:50][C:47]2[CH:46]=[CH:45][C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][NH:36][C:34]([NH:33][CH3:32])=[O:35])=[CH:49][CH:48]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@@H](C)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step C) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 48, Step I) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CD3OD): δ 1.10 (s, 3H), 1.12 (s, 3H), 1.18 (d, 6 Hz, 3H), 1.95 (m, 1H), 2.12-2.39 (m, 3H), 2.40-2.63 (m, 3H), 2.63 (s, 3H), 3.70 (m, 1H), 4.13 (s, 2H), 4.42 (dd; 12, 8 Hz; 1H), 4.46 (d, 12 Hz, 1H), 4.59 (d, 12 Hz, 1H), 4.93 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 7.02-7.40 (m, 17H). FAB-MS: calculated for C41H49N5O4 675; found 676 (M+H, 100%).
Reaction SMILES: [N+]([C:4]([CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:8][CH:7]=1)([O-])=O.C[OH:19].O.Cl>[Fe].C(Cl)Cl>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4](=[O:19])[CH3:17])=[CH:7][CH:8]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CC(=Cc1ccc(-n2ccnc2)cc1)[N+](=O)[O-]
Reactant: CO
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A 5.0 liter 3-neck flask fitted with a condenser, addition funnel, and mechanical stirrer is charged with a mixture of 218.4 g (0.954 mole) of 1-[4-(2-nitro-1-propenyl)phenyl-1H-imidazole, 449 g (8.04 mole) of iron powder (325 mesh), 6.4 g of FeCl3.6H2O, 350 ml of methanol and 760 ml of water. The mixture is heated to reflux with stirring and 450 ml of concentrated hydrochloric acid is added dropwise over a period of 2.5 hours. Refluxing is continued for two to three hours. The reaction mixture is cooled to room temperature, 1.9 liter of CH2Cl2 was added, and the mixture stirred rapidly for one hour. This is filtered, the inorganic solid is washed three times with 500 ml portions of CH2Cl2, and the layers separated. The CH2Cl2 layer is dried over MgSO4, then filtered through a bed of silica gel (600 g, 70-230 mesh), which is washed with 5 liters of CH2Cl2 and then with 13 liters of 10% methanol in methylene chloride. Evaporation of the solvent gave 126.7 g of a brown oil which crystallized on standing. The product is purified via the sodium bisulfate addition product to give a product having a mp of 71.5°-72.5° C.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:17]1(C)C=CC=CC=1>>[CH3:17][CH:14]1[CH2:15][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1ccccc1
Reactant: O=C1C=CCCCCCCCCCCCC1
Agent: O=C1/C=C/CCCCCCCCCCCC1
Product: CC1CCCCCCCCCCCCC(=O)C1
Reaction time: 15 h

Procedure:
In 10 ml of dried toluene was dissolved 5 mmol of (E)-2-cyclopentadecenone, and the solution was added dropwise to the above solution, followed by allowing the reaction to proceed at a temperature from -78° C. to -60° C. for 15 hours. Thereafter, the same procedures as in Example 14 were followed to obtain muscone in a chemical yield of 89 mol %. The resulting muscone was R-form having an optical rotation of -12.0° (at 21° C., c 5.07, MeOH) and an optical purity of 100%ee.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24].[OH:26]OS([O-])=O.[K+]>C1COCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])(=[O:26])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=S([O-])OO
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 24 h

Procedure:
To 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid (12.0 g, 33.66 mmol) in 140 ml THF is added gradually at 0° C. a solution of OXONE (12.47 g, 36.72 mmol) and tetrabutylammoniumhydrogensulfate (1.0 g, 1.62 mmol) in 35 ml H2O. The temperature of the reaction mixture is maintained in the range of 13°-23° C. After 24 h at room temperature, the THF phase is separated from the water phase and is dripped into water (280 ml, 40° C.). The suspension is stirred until it reaches room temperature. The yellow crystals of 5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid are filtered off and are washed with water (30 ml). 11.3 g, 30.29 mmol, 90% mp. 204°-206° C.
Reaction SMILES: O.Cl[C:3]1[C:4]([F:13])=[C:5]([C:8]([F:12])=[C:9](Cl)[CH:10]=1)[C:6]#[N:7].[H][H]>[C].[Pd].C(N(CC)CC)C>[F:12][C:8]1[CH:9]=[CH:10][CH:3]=[C:4]([F:13])[C:5]=1[C:6]#[N:7]
Reactant: [H][H]
Reactant: N#Cc1c(F)c(Cl)cc(Cl)c1F
Agent: [Pd]
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1F
Reaction time: 7 h
Yield: 95.8 %

Procedure:
To 45 ml of water 15 g of 3,5-dichloro-2,6-difluorobenzonitrile was added and 0.05 g of palladium-carbon catalyst and 17.5 g of triethylamine were added to it. The reaction was carried out in an autoclave at 120° C. for 7 hours while introducing hydrogen gas into it so that the pressure of hydrogen gas in the reaction system was kept at 30 kg/cm2. In the same manner as in the process of the reduction step of Example 1, the reaction mixture was refined to obtain 9.6 g of 2,6-difluorobenzonitrile (yield: 95.8%) and 15.6 g of triethylamine was recovered (recovery rate: 89.1%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][C:13]#[CH:14]>C1COCC1.CCOC(C)=O.[Cu]I>[Br:8][C:6]1[N:7]=[C:2]([C:14]#[C:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C#CC[Si](C)(C)C
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CC#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
3,5-Dibromo-pyrazin-2-ylamine (1.70 g, 6.70 mmol), TEA (1.1 mL, 8.04 mmol), PdCl2(PPh3)4 (28 mg, 0.040 mmol), and CuI (15 mg, 0.080 mmol) were dissolved in THF (17 mL), cooled to RT and Trimethyl-prop-2-ynyl-silane (1.0 mL, 6.7 mmol) was added at 0° C., allowed to warm up to RT and stirred overnight. The reaction mixture was diluted with EtOAc, washed with H2O and saturated aqueous NaHCO3, dried (MgSO4) and concentrated, and purified by SiO2 chromatography (80 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 1.66 g of 5-bromo-3-(3-trimethylsilanyl-prop-1-ynyl)-pyrazin-2-ylamine as a yellow semi-solid contaminated by starting material (87% yield, 66% purity).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:10][N:11]1[CH2:19][CH2:18][CH:14]([C:15](O)=O)[CH2:13][CH2:12]1.[OH-].[Na+]>O>[CH3:10][N:11]1[CH2:19][CH2:18][CH:14]([C:15]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Nc1cccnc1N
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(c2nc3cccnc3[nH]2)CC1

Procedure:
Grams 3.3 of 2,3-diaminopyridine and 5.4 g of N-methylisonipecotic acid hydrocloride are heated at 190° C. for 24 hours. The reaction mixture is cooled and diluted with a small amount of water then made alkaline to pH 10 by addition of NaOH then extracted several times with methylene chloride. The organic extracts are collected together and evaporated to dryness. The residue, crystallized from acetonitrile, gives 2 g (31% of the theoretical value) 2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine melting at 224°-226° C. To a solution constituted by 3 g 2-(1-methylpiperidin-4-yl)-3H-imidazo[4,5-b] pyridine in 10 ml N,N-dimethylformamide 0.6 g 60% sodium hydride are added in portions and subsequently, dropwise, a solution constituted by 1.7 ml p-fluorobenzylchloride in 2 ml N,N-dimethylformamide. The reaction mixture is heated to 100° C. for 2 hours, then cooled and 30 ml water are added thereto. Extraction with diethylether is repeated several times, the ethereal extracts are collected together and evaporated to dryness. The residue product, consisting of 1.1 g 3-(4-fluorobenzyl)-2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine is isolated as fumarate melting at 242°-245° C. (ethyl alcohol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][C:12]([CH3:14])=O.N1CCCC1>CO>[CH3:11][C:12]1([CH3:14])[CH2:9][C:8](=[O:10])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: CO
Product: CC1(C)CC(=O)c2ccccc2O1

Procedure:
A solution of 2′-hydroxyacetophenone (5.0 mL), acetone (4.7 mL), and pyrrolidine (5.4 mL) in 150 mL of methanol was stirred for 66 hours. The mixture was concentrated and treated with aqueous HCl (pH<1). The acidic layer was extracted twice with ethyl ether, which was dried and concentrated to provide 2,2-dimethylchroman-4-one. The 2,2-dimethylchroman-4-one was dissolved in 300 mL of methanol and treated with ammonium acetate (65 g) and sodium cyanoborohydride (2.5 g) for 24 hours. The resulting mixture was concentrated to 100 mL and diluted with 300 mL water. Concentrated HCl was carefully added until the pH was less than 1 and the acidic mixture was extracted with ethyl ether. The acidic phase was made basic with KOH and then extracted twice with ethyl ether. The basic extracts were dried and concentrated to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH2:22](Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH3:22])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(2S)—N-(tert-Butoxycarbonyl)-3-(pyridin-3-yl)alanine (25.00 g, 93.88 mmol) is dissolved in 300 ml of dichloromethane under argon. Methanol (11.4 ml, 9.02 g, 281 mmol, 3 equivalents) and one grain of DMAP are added. The mixture is then cooled to 0° C. EDC (19.80 g, 103 mmol, 1.1 equivalents) is added. After 5 min, the ice bath is removed and the mixture is left to stir at RT over 1 h. The mixture is then concentrated in vacuo, and ethyl acetate is added to the residue and the mixture is extracted against a saturated sodium hydrogen carbonate solution. The aqueous phase is reextracted once with ethyl acetate, then the combined organic phases are washed with 0.5 M citric acid and then once again with a saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. An oil remains, which crystallizes during drying in an oil-pump vacuum. Yield: 23.60 g (90% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:19][CH:20]=3)[C:9]2=[O:12])=[CH:4][N:3]=1
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: Oc1nccc2cnc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Cn2ccc3cnc(Br)cc3c2=O)cc1

Procedure:
The alkylation of 7-bromo-1-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 4-bromomethyl-benzene sulfonamide (1.67 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-6-azaisoquinolin-2-ylmethyl]benzenesulfonamide
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:38][CH2:39]O.FC(F)(F)C1C=CC(C=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:39][CH2:38][C:24]2[N:25]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)[O:27][C:23]=2[CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=Cc1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol (prepared by conversion of the 4-trifluoromethyl-benzaldehyde into 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>C(O)(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13](=[O:15])[CH3:14])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)cc1C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
4-Amino-3-trifluoromethylphenol (0.212 g; 1.2 mmol) was dissolved in 10 ml of glacial acetic acid under nitrogen atmosphere and acetic anhydride (0.3 ml; 3.0 mmol) was added followed with stirring for an hour at room temperature. Water (0.5 ml) was added into the reaction mixture and then evaporated to dryness. Toluene (50 ml) was added and the evaporation was repeated to give a quantitative yield of pure N-(4-Hydroxy-2-trifluoromethylphenyl)acetamide. 1H NMR (400 MHz, DMSO-d6): 1.99 (3H, s), 7.01 (1H, dd, J=8.6 Hz, J=2.6 Hz), 7.02 (1H, d, J=2.5 Hz), 7.19 (1H, d, J=8.4 Hz), 9.33 (1H, s), 10.08 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].[CH:17](OCC)=[O:18]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:17][OH:18])[C:5]2=[O:16]
Reactant: CCOC=O
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Solvent: O
Product: CCC(=O)N1CC(=CO)C(=O)c2cc(Cl)ccc21
Temperature: 55 °C
Reaction time: 7 h
Yield: 75.1 %

Procedure:
A mixture of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (200.5 g) and 1,5-diazabicyclo[5,4,0 ]undecene-5 (384.9 g) in ethyl formate (400.9 g) was heated at 55° C. with stirring for 7 hours and then diluted with cold water (450 ml). The mixture was washed successively with diisopropyl ether and ethyl acetate and then the aqueous layer was acidified with hydrochloric acid under ice cooling. The resultant precipitate was collected by filtration and dried to give 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (168.29 g).
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1.[NH:31]1[CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11]([N:31]3[CH2:34][CH2:33][CH2:32]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1
Reactant: C1CNC1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Sc2nc(Nc3ncns3)cc(N3CCC3)n2)cc1)c1ccccc1Cl
Temperature: 130 °C
Yield: 13 %

Procedure:
In the next step, a mixture of N-(4-(4-(1,2,4-thiadiazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)-2-chlorobenzamide (188 mg, 0.42 mmol), azetidine (67.5 mg, 1.18 mmol), DiPEA (0.17 mL, 1.0 mmol) in 1,4-dioxane (10 mL) was heated to 130° C. for 20 minutes. The crude product (940 mg) was purified by preparative HPLC to yield 27 mg of N-(4-(4-(1,2,4-Thiadiazol-5-ylamino)-6-(azetidin-1-yl)pyrimidin-2-ylthio)phenyl)-2-chlorobenzamide with 99+% purity (HPLC method B, Rf=7.183 minutes).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH3:13][N:14](C)C=O>>[C:13]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1)#[N:14]
Reactant: CN(C)C=O
Reactant: CC1(C)COc2ccc(Br)cc21
Product: CC1(C)COc2ccc(C#N)cc21

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethylbenzofuran (15 g, 0.066 mole) was heated under reflux with cuprous cyanide (7.2 g, 0.08 mole) in dimethyl formamide (15 ml) as in Example 2. Work up yielded, after recrystallisation from petroleum ether (bp 60°-80° C.) with charcoaling, 5.7 g of product, mp 72°-75° C.