Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1)#[N:2].[OH-:19].[K+].Cl>C1COCC1>[C:1]([C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1)(=[O:19])[NH2:2]
Reactant: CCOC(=O)c1nc(C#N)sc1-c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: NC(=O)c1nc(C(=O)O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 2-cyano-5-phenyl-1,3-thiazole-4-carboxylate in THF was added a 1 M aqueous KOH solution, followed by stirring at room temperature for 12 hours. To the reaction mixture was added 1 M hydrochloric acid, and the solid precipitated was collected by filtration to obtain 2-carbamoyl-5-phenyl-1,3-thiazole-4-carboxylic acid as a pale yellow solid.
Reaction SMILES: Cl([O-])(=O)(=O)=O.C([NH:9][C:10]1[O:11][CH2+:12]([CH3:25])[C:13]2[CH:19]=[C:18]([O:20][CH2:21][CH3:22])[C:17]([O:23][CH3:24])=[CH:16][C:14]=2[CH:15]=1)(=O)C.[OH-].[NH4+]>O>[CH2:21]([O:20][C:18]1[CH:19]=[C:13]2[C:14]([CH:15]=[C:10]([OH:11])[N:9]=[C:12]2[CH3:25])=[CH:16][C:17]=1[O:23][CH3:24])[CH3:22]
Reactant: CCOc1cc2c(cc1OC)C=C(NC(C)=O)O[CH2+]2C
Agent: [NH4+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Product: CCOc1cc2c(C)nc(O)cc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To an ice-cooled slurry of 36.37 grams of 3-acetamido-7-ethoxy-6-methoxy-1-methyl-2-benzopyrylium perchlorate (0.1 mol) in water (400 ml) was slowly added 80 ml of concentrated ammonium hydroxide over a 10 minute period. The mixture was stirred for additional 30 minutes. The light yellow precipitate that formed was filtered, washed with water and dried to provide 23 grams of the crude title 3-isoquinolinol (100%). Recrystallization from methanol/chloroform mixture (2000 ml:700 ml) provided 18.7 grams (81.3%) of pure title 3-isoquinolinol having a melting point of 235°-240° C.(d).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[CH2:20]1[O:22][CH2:21]1.O>O1CCCC1>[OH:22][CH2:21][CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(1,1-dimethylethyl)benzenesulfonamide (40.0 g) in 550 ml dry tetrahydrofuran was cooled to 0° and 250 ml of 1.6M n-butyllithium added dropwise at 0°. After the addition of one equivalent of base, the solution turned yellow. After stirring for 2 hours at room temperature, the resulting suspension was cooled to 0° and 13 ml of ethylene oxide added dropwise. After stirring for 3.5 hours at room temperature, the homogeneous yellow solution was poured into water. The product was extracted with ether and dried (Na2SO4). Concentration gave a yellow oil which was purified by column chromatography [400 g silica gel, ether/hexane (1:1) followed by ethyl acetate]. Pure 2-(2-hydroxyethyl)-N-(1,1-dimethylethyl)benzenesulfonamide was obtained as a colorless oil which solidified after several days; m.p. 43°-45°.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:6]=1C=O)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:6]=1[OH:26])[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1cc(OCc2ccccc2)ccc1C=O
Solvent: ClCCl
Product: C=CCOc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.4 %

Procedure:
To a solution of 53.6 g (0.20 mole) of 2-allyloxy-4-(benzyloxy)benzaldehyde in 500 mL of methylene chloride was added a solution of 90 g (˜0.3 mole) of 57-86% m-chloroperoxybenzoic acid in 500 mL of methylene chloride. The mixture was stirred at room temperature for 3 days. It was then diluted to 2 L with methylene chloride and washed four times with 500 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum to a brown oil. This was redissolved in 1 L of methanol, 110 g of basic alumina added and the mixture stirred at room temperature for 15 hours. The alumina was removed by filtration and the filtrate concentrated to 50 g of a yellow solid. The crude solid was column chromatographed on silica gel with hexane/methylene chloride as eluant to give 33 g of the title compound as a white solid, m.p. 62° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].CC(C)=O.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([NH:19][C:20]([NH:7][C:2]([CH2:5][OH:6])([CH2:3][OH:4])[CH2:1][OH:8])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(CO)(CO)CO
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)NC(CO)(CO)CO

Procedure:
66.6 g (0.55 mol) of tris(hydroxymethyl)aminomethane are dissolved in 200 ml of distilled water, and 400 ml of acetone are added. 59.6 g (0.5 mol) of phenyl isocyanate are added dropwise, while stirring, whereupon a heavy white precipitate forms. When the addition has ended, the mixture is stirred for a further 2 hours and the precipitate is filtered off with suction. It is then digested successively with in each case 150 ml of water, acetone and diethyl ether. Finally, the compound (11), which is obtained in virtually analytically pure form, is dried at 75.C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH2:28])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:31](=[O:33])[CH3:32])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(N)c3C2=O)ccc1OC(F)F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 77.2 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester was prepared by the procedure of example 20 from 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.8 g, 7 mmol) and acetyl chloride (0.57 ml, 8 mmol) in THF (20 ml) to afford the title compound as white solid (2.5 g, 81%). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[CH:5]2.[Se](=O)=[O:16]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH:14]=[O:16])[CH:6]=[CH:5]2
Reactant: COc1cc2nc(C)ccc2cc1F
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2nc(C=O)ccc2cc1F
Yield: 73.4 %

Procedure:
To 6-fluoro-7-methoxy-2-methylquinoline (1.4 g, 7.3 mmol) in dioxane/water (10 ml/l mL) at ambient temperature was added selenium dioxide (0.97 g, 8.8 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-7-methoxyquinoline-2-carbaldehyde (1.1 g, 73% yield) as a tan solid.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[Li+].CC([N-]C(C)C)C.[Br:23][CH2:24][CH2:25]Br>C1COCC1>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:25][CH2:24][Br:23])[C:12](=[O:14])[N:13]=1
Reactant: BrCCBr
Reactant: O=C1CSC(N[C@H]2C[C@@H]3CC[C@H]2C3)=N1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCBr
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)thiazol-4(5H)-one (2.98 g, 14.2 mmol) in THF (15 ml) at −78° C. was added LDA (2.0 N, 28.4 ml). After 5 min, 1,2-dibromoethane (4.87 mL, 56.8 mmol) was added, and the reaction mixture was stirred for 3 h at −78° C. The resulting reaction mixture was poured into sat'd NaH2PO4 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as a white solid. MS (ES+): 317 (M+H)+.
Reaction SMILES: [OH-].[K+].C([O:6][C@@H:7]1[C@@:26]2([CH3:27])[C@@H:19]([CH2:20][CH2:21][C@@H:22]2[C:23](=[O:25])[CH3:24])[C@H:18]2[C@@H:9]([C@:10]3([CH3:29])[C:15]([CH2:16][CH2:17]2)=[CH:14][C:13](=[O:28])[CH:12]=[CH:11]3)[CH2:8]1)(=O)C.C1C=CC=CC=1>CO>[OH:6][C@@H:7]1[C@@:26]2([CH3:27])[C@@H:19]([CH2:20][CH2:21][C@@H:22]2[C:23](=[O:25])[CH3:24])[C@H:18]2[C@@H:9]([C@:10]3([CH3:29])[C:15]([CH2:16][CH2:17]2)=[CH:14][C:13](=[O:28])[CH:12]=[CH:11]3)[CH2:8]1
Reactant: CC(=O)O[C@H]1C[C@H]2[C@@H](CCC3=CC(=O)C=C[C@@]32C)[C@@H]2CC[C@H](C(C)=O)[C@@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 10 h
Yield: 82.3 %

Procedure:
To a solution of 2.2 g of potassium hydroxide in 80 ml of methanol was added 7.4 g of 12α-acetoxypregna-1,4-diene-3,20-dione, and the mixture was stirred at room temperaature for 10 hours. The reaction mixture was concentrated to about one tenth the original volume by distilling off the methanol under reduced pressure. To the concentrated reaction mixture was added 150 ml of benzene, and the solution was washed in sequence with water, diluted hydrochloric acid and water and then driedover anhydrous magnesium sulfate. Low-boiling fractions were distilled off under reduced pressure and the residue was recrystallized from ethyl acetate to give 5.4 g of 12α-hydroxypregna-1,4-diene-3,20-dione (Gaschromatographic analysis revealed that purity thereof was 90%). It has the following physical properties.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH:62]([NH2:65])[CH2:61][CH2:60]1>>[CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][CH:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and. 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.3 Hz, 3 H) 1.60-1.75 (m, 11 H) 1.84-2.09 (m, 5 H) 2.19 (s, 3 H) 2.80 (d, J=11.1 Hz, 2 H) 3.26 (s, 3 H) 3.60-3.83 (m, 3 H) 3.94 (s, 3 H) 4.78 (t, J=8.1 Hz, 1 H) 7.35-7.60 (m, 2 H) 7.80 (s, 1 H) 8.08 (d, J=7.6 Hz, 1 H) 8.16 (s, 1 H) 8.32 (d, J=8.3 Hz, 1 H). Melting point: 149-153° C. [M+H] calc'd for C29H40FN7O3, 554; found 554.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([C:57]1[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1)#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:60]2[CH:59]=[CH:58][C:57]([C:55]#[N:56])=[CH:62][CH:61]=2)(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 22 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-cyanobenzenesulfonyl chloride as starting materials in 22% yield. LCMS for C31H30ClN8O3S (M+H)+: m/z=629.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[O:25]1[CH2:34][CH:26]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:34][CH:26]([OH:25])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: c1ccc(CC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(CC(O)Cc2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 85 °C
Yield: 70.4 %

Procedure:
To a stirred solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (500 mg, 1.4 mmol), prepared as described in Example 1, in 7 mL of DMF was added 2,3-epoxypropylbenzene (0.18 mL, 1.4 mmol) and 0.39 g of K2CO3. The resulting red solution was heated to 85° C. for 27 h and, upon cooling to room temp, the mixture was diluted with 200 mL of ethyl acetate and 200 mL of 1N HCL. The layers were extracted, and the organic layer was washed with 200 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to a yellow oil. The material was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate/hexanes to give 484 mg of racemic 7,8-bis(4-chlorophenyl)-2-(2-hydroxy-3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a yellow solid containing 15% starting material 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. Separation of enantiomers was performed on 200 mg of material using Chiracel OD 5 cm×50 cm 20 micron column, flow rate 50 mL/min isocratic 65% heptane/17.5% ethanol/17.5% methanol, monochrome detection at 220 nm. Fraction A was collected at 49 min post injection to give 47 mg of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one enantiomer A as a yellow solid; Fraction B was collected at 55 min post injection to give 45 mg of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one enantiomer B as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].C([Li])CCC.C1C[O:24][CH2:23]C1>>[CH3:12][C:8]1([CH3:13])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]2[CH:3]=[C:2]([CH:23]=[O:24])[CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Temperature: -70 °C
Yield: 100 %

Procedure:
A flame dried round bottom flask was charged with 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphtalene (10 g, 37 mmol) and anhydrous THF (100 mL). This solution was cooled to −70° C. while stirring under a nitrogen blanket. To this solution was added 2.5 M n-butyl lithium (14.9 mL, 37 mmol). The reaction mixture was allowed to stir for 30 minutes at which time it was quenched via the addition of dimethylformamide (5.0 mL). The reaction was allowed to warm to RT where it stirred for 17 hours. The reaction was quenched by the addition of 1.0 N HCl (100 mL). The reaction mixture was extracted using ether. The organics were separated and dried over MgSO4 followed by concentrating to dryness. The resulting oil was dried under high vacuum to give a total of 8.2 g (100%) of crude oil. The product was used without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:17](=[O:19])[CH3:18].[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23]>>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:17](=[O:19])[CH2:18][C:20]([O:21][CH2:22][CH3:23])=[O:24]
Reactant: CC(=O)c1cc(CN2CCOCC2)ccc1F
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 6.6 g) is slowly added to a solution of 1-(2-fluoro-5-(4-morpholinylmethyl)phenyl)ethanone (Preparation 2, 19.6 g) in diethyl carbonate at 0° C. The mixture is stirred at 0° C. for 1 h and allowed to warm to rt overnight. The reaction is quenched with acetic acid (10 mL), diluted with water (200 mL) and made basic with sat. aq. Na2CO3. The mixture is extracted with diethyl ether (3×200 mL). The combined organic layers are washed with sat. NaHCO3 (100 mL) and brine (50 mL). The combined aqueous layers are back-extracted with diethyl ether (50 mL). The organic layers are combined, dried (Na2SO4) and concentrated in vacuo to an orange oil. The crude product is purified by column chromatography (heptane/IPA, 8/1; 4/1; CH2Cl2/MeOH, 98/2) to afford 20.2 g (79%) of the compound as a yellow oil. Physical characteristics: 1H NMR (300 MHz, DMSO-d6) δ 7.78, 7.65-7.60, 7.32, 4.10, 4.05, 3.57, 3.50, 2.34, 1.16; IR (liq.) 1996, 1979, 1744, 1689, 1626, 1611, 1493, 1331, 1260, 1215, 1147, 1117, 865 cm−1; MS (ESI+) m/z 310 (M+H)+. Anal. Calcd for C16H20FNO4: C, 62.12; H, 6.52; N, 4.53. Found: C, 61.96; H, 6.67; N, 4.44.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[Cl:19][C:20]1[C:21]([O:28][CH:29]([F:31])[F:30])=[N:22][CH:23]=[C:24]([CH:27]=1)[CH:25]=O>>[Cl:19][C:20]1[CH:27]=[C:24]([CH2:25][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])[CH:23]=[N:22][C:21]=1[O:28][CH:29]([F:31])[F:30]
Reactant: O=Cc1cnc(OC(F)F)c(Cl)c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cnc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with 5-chloro-6-(difluoromethoxy)nicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 413.32 g/mol.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>C(N(CC)CC)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1cccnc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C(#Cc1cccnc1)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
Add phenylacetylene (0.175 mL, 1.6 mmol), copper (I) iodide (0.028 g, 0.15 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.051 g, 0.07 mmol) to a solution of 3-bromopyridine (0.140 mL, 1.45 mmol) in degassed triethylamine (6 mL) and stir under nitrogen at 80° C. for 16 h. Cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:dichlormethane, to give the title compound (91.1 mg, 35%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:46][C:47]([NH2:49])=[O:48].O>CN(C=O)C>[C:47]([CH2:46][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1)(=[O:48])[NH2:49]
Reactant: NC(=O)CI
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCC(N)=O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.83 h
Yield: 35.9 %

Procedure:
In DMF (1.6 ml) was dissolved 7-(4-hydroxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (131 mg). To the mixture was added potassium carbonate (41 mg), and the mixture was stirred for 50 minutes. To the mixture was added iodoacetamide (50 mg), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-carbamoylmethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 95) (52 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[F:18])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C>O1CCCC1>[F:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2ccncc2F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1onc(-c2ccncc2F)c1C(=O)O

Procedure:
Combine 3-(3-fluoro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (2.00 g, 0.008 mol) with aqueous sodium hydroxide (2N, 15.0 mL, 0.03 mol), ethanol (3 mL), and tetrahydrofuran (3 mL) and stir overnight at ambient temperature. Remove the organic solvents in vacuo and adjust the aqueous mixture to approx. pH 3.5 with aqueous hydrochloric acid. Extract with ethyl acetate and dry the combined extracts over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid as an off white solid (1.35 g, 76%). MS(FD): M+ 223.2 m/z.