Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:22])=[C:13]([CH:21]=2)[CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[C:41]([O:42][CH3:43])=[CH:40][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:22])=[C:13]([CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])[CH:21]=2)=[N:7][C:2]([NH:24][C:25]2[C:41]([O:42][CH3:43])=[CH:40][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: CCN(CCO)Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1F
Product: CCN(CCO)Cc1cc(Nc2nc(Nc3cc4c(cc3OC)CCN(CC(=O)N(C)C)CC4)ncc2Cl)ccc1F

Procedure:
The title compound was prepared from 2-{[5-(2,5-Dichloro-pyrimidin-4-ylamino)-2-fluoro-benzyl]-ethyl-amino}-ethanol and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide in an analogous manner to example 730 (0.047 g, 43%). Mp 71-75° C. LCMS (m/e) 600 (M); 1H-NMR (DMSO, 400 MHz) δ 8.90 (s, 1H), 8.09 (s, 1H), 7.63 (s, 1H), 7.59 (s, 1H), 7.58-7.48 (m, 3H), 7.10-7.02 (t, 1H, J=9.09 Hz), 6.78 (s, 1H), 4.35-4.25 (t, 1H), 3.77 (s, 3H), 3.59 (s, 2H), 3.46-3.45 (q, 2H, J=6.06 Hz), 3.35-3.20 (br, 2H), 3.05 (s, 4H), 2.82 (s, 4H), 2.73 (br, 2H), 2.65-2.52 (m, 4H), 0.98-0.94 (t, 3H, J=7.08 Hz).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N(Cl)C(=O)C1.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](=[O:45])[N:37]([CH3:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:31][CH:30]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36](=[O:45])[N:37]([CH3:44])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:33][CH:34]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S([O-])c1ccc(OCCN2CCCC2)cc1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCNS(=O)(=O)c2ccc(OCCN3CCCC3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (6.72 g, 25 mmol) in THF (45 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (14 mL, 22.4 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min. Then gaseous sulphur dioxide (ca. 6 g) was added causing an immediate precipitation. The mixture was allowed to warm to room temperature and stirred for 1 h. The precipitated lithium sulfinate was isolated by filtration under N2 (g), washed with THF (40 mL) and dried in vacuo providing 5.04 g (78%) of lithium; 4-(2-pyrrolidin-1-yl-ethoxy)-benzenesulfinate as a solid. This lithium sulfinate (179 mg, 0.69 mmol) was suspended in CH2Cl2 (2 mL) and stirred with NCS (80 mg, 0.60 mmol) for 10 min at rt. A solution of N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.55 mmol) in CH2Cl2 (3 mL) was added together with DIPEA (2.0 mmol). The mixture was stirred at rt for 16 h and evaporated to dryness. It was then redissolved in MeCN and purified by preparative HPLC (Gilson). This gave 89 mg (25%) of the title compound as its TFA salt as a crystals.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:5].[O:28]1CCCC1.OO.[OH-].[Li+]>O>[OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4]([OH:5])=[O:28]
Reactant: C1CCOC1
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C#CCC[C@@H](C(=O)O)[C@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of 65.0 g (179 mmol) of (4S)-3-{(2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoyl}-4-phenyl-1,3-oxazolidin-2-one from Step B above in 1050 mL of a 20 to 1 mixture of anhydrous tetrahydrofuran to water at 0° C. under an atmosphere of nitrogen was added 77.0 mL (894 mmol) of a 35% aqueous hydrogen peroxide solution at a rate slow enough to keep the internal temperature below 3° C. Next, 395 mL (395=top of a 1.0 M aqueous lithium hydroxide solution was added at a rate slow enough to keep the internal temperature of the reaction below 5° C. and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 755 mL (984 mmol) of a 1.3 M aqueous sodium sulfite solution at a rate slow enough to keep the internal temperature of the mixture below 5° C. All volatiles were removed in vacuo and the remaining aqueous phase was extracted with ethyl acetate (3×200 mL). The aqueous phase was then cooled to 0° C. and acidified with a 6 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The aqueous phase was then extracted with ethyl acetate (3×300 mL) and the combined organics were washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 5-10% ethyl acetate and 3% acetic acid in hexanes gradient to afford the title compound as a colorless gum (32.0 g, 82.0%). 1H NMR (500 MHz, CDCl3): δ 7.39-7.28 (m, 5H), 4.85 (d, J=8.2, 1H), 3.03-2.97 (m, 1H), 2.29-2.15 (m, 2H), 1.97 (t, J=2.5 Hz, 1H), 1.93-1.82 (m, 1H), 1.62-1.55 (m, 1H). LC-MS: m/z (ES) 201.0 (MH-H2O)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7](=[P:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:8]1[C@H:11]([CH2:12][C:13]([OH:15])=[O:14])[C@@H:10]([C@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[C:9]1=[O:26])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:53](Cl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([C:7](=[P:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[N:8]1[C@H:11]([CH2:12][C:13]([O:15][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])=[O:14])[C@@H:10]([C@H:16]([O:18][Si:19]([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:21])[CH3:20])[CH3:17])[C:9]1=[O:26])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)OC(=O)C(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.65 g of (3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(carboxymethyl)azetidine-2-one in 4 ml of toluene were added under ice-cooling 0.14 ml of triethylamine and 0.12 ml of pivaloyl chloride, and the mixture was stirred at room temperature. The resulting precipitate was collected by filtration, and the filtrate was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 0.60 g of (3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(pivaloyloxycarbonyl)methyl]azetidine-2-one.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.I[CH3:12]>CN(C=O)C>[Br:3][C:4]1[C:9]([O:10][CH3:12])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1Br
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Add sodium hydride (5.91 g, 147.8 mmol) to a rapidly stirred solution of 2-bromo-3-pyridinol in DMF (anhydrous, 200 mL). After 30 minutes, add iodomethane (9.2 mL, 147.8 mmol) and stir under N2 for 2.5 hours. Quench with water and concentrate. Partition residue between Et2O) and water, separate layers. Extract from aqueous layer with Et2O (×2), dry combined layers over MgSO4 and concentrate. Purify residue by flash chromatography on silica gel eluting with 0-25% EtOAc/hexanes to afford 2-bromo-3-methoxy-pyridine (21.0 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]/[C:5]/2=[N:25]/[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (387 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added TiCl4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 minutes at room temperature. The resulting mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (525 mg, 2.82 mmol) dropwise. The resulting mixture was stirred for 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (Z)—N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide (400 mg, 96%) which was used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([Cl:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a pre-stirred solution of 4-bromo-2-chlorobenzaldehyde (1.01 g, 4.6 mmol) and piperidine (500 μL, 5.0 mmol) in DCM (20 mL) at 0° C. was added sodium triacetoxyborohydride (1.46 g, 6.9 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and then partitioned between water (50 mL) and dichloromethane (50 mL). The organic phase was separated, washed with saturated aqueous sodium carbonate (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was loaded onto a 20 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions in vacuo afforded the title compound as a colourless oil (1.15 g, 87%). NMR (CDCl3, 400 MHz): 7.50-7.48 (m, 1H); 7.40-7.33 (m, 2H); 3.50 (s, 2H); 2.46-2.38 (m, 4H); 1.62-1.53 (m, 4H); 1.49-1.40 (m, 2H). LCMS (Method B): RT=2.03 min, M+H+=288.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][N:6]=1)=[O:3].[OH-].[Na+].N1C=CC=CC=1.C([O:25][C:26]1C(=[CH:31][CH:32]=[CH:33][CH:34]=1)C(Cl)=O)(=O)C>Cl.C(#N)C>[NH2:13][S:10]([C:8]1[S:9][C:5]([NH:4][C:2](=[O:3])[C:1]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[OH:25])=[N:6][N:7]=1)(=[O:12])=[O:11]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: c1ccncc1
Product: NS(=O)(=O)c1nnc(NC(=O)c2ccccc2O)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetazolamide (50 g) was stirred and heated at reflux in 500 ml 3N hydrochloric acid for half an hour. The cooled solution was made basic with 50% sodium hydroxide. The precipitated white solid 5-amino-1,3,4-thiadiazole-2-sulfonamide was collected (Compound 1, 28 g). It was dried further at 70° C. in a vacuum oven overnight. To a mixture of Compound 1 (4.5 g, 0.025 mole) and pyridine (2.42 ml, 0.03 mole) in 70 ml acetonitrile was added acetylsalicyloyl chloride (98%, 5 g, 0.025 mole). The reaction mixture warmed and became a clear solution. Solid deposits occurred slowly after stirring at room temperature for 1/2 hour. After two hours the solvent was evaporated; the residue was triturated with isopropyl alcohol/water for two hours and then filtered, rinsed in succession with isopropyl alcohol/water, isopropyl alcohol/isopropyl ether, 2×isopropyl ether. From the combined mother liquor and rinsings, a second crop was collected. Both the first and second crops were combined and dissolved in 50 ml N-methyl-2-pyrrolidone. The solution was filtered and the filtrate was treated with 15 ml 3N hydrochloric acid at 70° C. for half an hour. Upon dilution with 200 ml water, a white solid precipitated. The solid was collected, rinsed with water, and dried in a vacuum over at 80° C. overnight to 4.4 g of title compound, mp>250° C.
Reaction SMILES: [C:1](=[O:22])([O:19][CH2:20][CH3:21])[O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14](OCC)=[O:15]>C(OCC)(=O)C.O>[C:1](=[O:22])([O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH2:12][NH:13][C:14]2=[O:15])[O:19][CH2:20][CH3:21]
Reactant: CCOC(=O)NCCc1cccc(OC)c1OC(=O)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1c(OC)ccc2c1CCNC2=O
Temperature: 142.5 °C
Reaction time: 0.33 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed polyphosphoric acid (PPA, 150 g). This was followed by the addition of 2-[2-[(ethoxycarbonyl)amino]ethyl]-6-methoxyphenyl ethyl carbonate (20 g, 64.24 mmol, 1.00 equiv) at 145° C. The resulting solution was stirred for 20 min at 140-145° C. The reaction mixture was cooled to room temperature with a water/ice bath. The resulting solution was diluted with 500 mL of ethyl acetate and 500 mL of water. The resulting mixture was washed with 3×300 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.5 g (9%) of ethyl 6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl carbonate as a gray solid. MS (ESI) m/z 266 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[CH:14]12[CH2:19][CH:18]1[CH2:17][NH:16][CH:15]2[C:20](O)=[O:21].C[Al](C)C.O>C(Cl)Cl>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH:6][C:20]([CH:15]2[NH:16][CH2:17][CH:18]3[CH:14]2[CH2:19]3)=[O:21])=[C:4]([F:13])[CH:3]=1
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Reactant: O=C(O)C1NCC2CC21
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: O
Product: C#CCOc1cc(NC(=O)C2NCC3CC32)c(F)cc1Cl
Temperature: 5 °C
Yield: 35.7 %

Procedure:
To a mixture of 2.36 g (11.79 mmol) of 4-chloro-2-fluoro-5-(2-propynyl)oxyaniline and 1.5 g (11.79 mmol) of (±)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid in methylene chloride (150 mL) stirred under nitrogen and cooled to 5° C. was added trimethylaluminum dropwise (2.0M, 11.8 mL, 23.58 mmol). The resultant mixture was stirred at room temperature for 48 h. Water (100 mL) was added dropwise at ice-bath temperature. The solid inorganic material which formed was filtered, and the filtrate was dried (MgSO4) and evaporated under reduced pressure to dryness. Flash chromatography on silica gel yielded 1.3 g of the product of Step F as a tan solid; m.p. 113°-115° C. IR (mineral oil, cm-1): 1687.1 (C=O); 2123.5 (C≡C).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[S:11][C:12]([C:15]([NH:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:20](C(OC(C)(C)C)=O)[N:19]=2)=[O:16])=[CH:13][N:14]=1>O1CCOCC1>[CH2:1]([NH:8][C:10]1[S:11][C:12]([C:15]([NH:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[NH:20][N:19]=2)=[O:16])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)c2cnc(Br)s2)cc1-c1ccc(F)cc1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccc(F)cc2)[nH]n1)c1cnc(NCc2ccccc2)s1
Temperature: 85 °C
Reaction time: 24 h
Yield: 106.4 %

Procedure:
Benzylamine (0.1 mL, 0.87 mmol) was added to a solution of tert-butyl 3-(2-bromothiazole-5-carboxamido)-5-(4-fluorophenyl)-1H-pyrazole-1-carboxylate (160 mg, 0.43 mmol) in dioxane (3 mL). The resulting solution was stirred at 85° C. for 24 hrs. The solvent was evaporated and the crude product was purified by column (0-10% MeOH/AcOEt gradient), yielding 2-(benzylamino)-N-(5-(4-fluorophenyl)-1H-pyrazol-3-yl)thiazole-5-carboxamide (180 mg, 90%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([OH:14])=[C:7]([CH3:13])[C:8]=2[CH3:12])[N:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[NH:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([OH:14])=[C:7]([CH3:13])[C:8]=2[CH3:12])[N:3]=1)[C:15]([CH3:16])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)nc2nc(N)ccc2c1C
Product: CC(=O)Nc1ccc2c(C)c(C)c(O)nc2n1
Yield: 37 %

Procedure:
142 g (0.75 mol) of 2-amino-7-hydroxy-5,6-dimethyl-1,8-naphthyridine and 640 ml of acetic anhydride are boiled under reflux for 30 minutes. After the mixture has been cooled, the product is filtered off and purified by stirring with CH2Cl2 and methanol. There is obtained 64.1 g (37%) of a gray solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=2[S:5][CH:6]=1.[C:12]([Cu])#[N:13]>N1C=CC=CC=1>[C:12]([C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=2[S:5][CH:6]=1)#[N:13]
Reactant: Cc1cccc2c(Br)csc12
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: Cc1cccc2c(C#N)csc12

Procedure:
3 g of 3-bromo-7-methylbenzo[b]thiophene and 1.1 g CuCN are dissolved in dry pyridine and heated at 220° in an autoclave for 12 hours. The mixture is cooled, concentrated, the residue partitioned between dichloromethane and dilute HCl and the organic phase washed, dried and concentrated. Chromatography of the residue over silica gel (toluene) yields the title compound as pale-yellow crystals. M.p.=82°-84°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(C)C(=O)Nc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1ccccc1F

Procedure:
Prepared according to procedure B using ethyl 3-(2-fluorophenylamino)-2-methyl-3-oxopropanoate (15.0 g, 62.7 mmol) and NaOH (3.26 g, 81.5 mmol) in THF (60 mL) to give 3-(2-fluorophenylamino)-2-methyl-3-oxopropanoic acid as a white solid. Mass Spectrum (ESI) m/e=212.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])([O-:3])=[O:2].CC(O)=O.[C:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:37]3[CH2:36][CH2:35][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:39][CH2:38]3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])([O-:3])=[O:2]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])c(OCC(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc([N+](=O)[O-])c(OCC(F)(F)F)c3)CC2)CC1
Reaction time: 1 h
Yield: 54 %

Procedure:
1-{4-Nitro-3-[(2,2,2-trifluoroethyl)oxy]phenyl}-4-piperidinone (1.63 g, 5.12 mmol) was dissolved in 20 mL of acetonitrile with stirring. HOAc (0.44 mL, 7.7 mmol) was added, and 20 mL of toluene was added. TEA (1.78 mL, 12.8 mmol) was added followed by 1-BOC-piperazine (1.91 g, 10.3 mmol). Sodium triacetoxyborohydride (2.71 g, 12.8 mmol) was added. After 1 h, 40 mL of acetonitrile and 20 mL of toluene were added, and the reaction was stirred overnight. The reaction was quenched with 1N NaOH and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers was dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 1.35 g (54%) of the title compound of step D. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, J=9.5 Hz, 1H), 6.63 (dd, J=9.6, 2.3 Hz, 1H), 6.56 (d, J=2.2 Hz, 1H), 4.88 (q, J=8.7 Hz, 2H), 3.98-4.10 (m, 2H), 3.27 (s, 4H), 2.84-2.97 (m, 2H), 2.33-2.55 (m, 5H), 1.76 (br. s., 2H), 1.29-1.45 (m, 11H).
Reaction SMILES: O=[C:2]1[C:5](=[O:6])[C:4]([O-:7])=[C:3]1[CH:8]=[C:9]1[C:17]([CH3:19])([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].[CH2:28]([NH+:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29].[C:35](#[N:39])[CH2:36][C:37]#[N:38]>C(O)C>[C:37]([C:36]([C:35]#[N:39])=[C:2]1[C:5](=[O:6])[C:4]([O-:7])=[C:3]1[CH:8]=[C:9]1[C:17]([CH3:19])([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])#[N:38].[CH2:28]([NH+:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29]
Reactant: N#CCC#N
Reactant: CC1(C)C(=Cc2c([O-])c(=O)c2=O)N(CCCCCC(=O)O)c2ccccc21
Agent: CC[NH+](CC)CC
Solvent: CCO
Product: CC1(C)C(=CC2=C([O-])C(=O)C2=C(C#N)C#N)N(CCCCCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1.2 g (2.82 mmol) of 11, 190 mg (2.87 mmol) of malononitrile and 0.4 ml (2.85 mmol) of TEA in 15 ml of ethanol was stirred at room temperature for 2.5 h. Then solvent was removed by a rotary evaporator. Product 12 was used in next synthesis without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:26])[N:15]([CH3:25])[CH2:16][CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([CH3:27])[NH:11][C:10]([CH3:28])=[C:9]2[C:29]([O:31]CCC#N)=[O:30])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:26])[N:15]([CH3:25])[CH2:16][CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([CH3:27])[NH:11][C:10]([CH3:28])=[C:9]2[C:29]([OH:31])=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)N(C)CC=Cc2ccccc2)=C(C)N1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)N(C)CC=Cc2ccccc2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
224 mg (0.456 mmol) of 2-cyanoethyl 4-(3-chlorophenyl)-2,6-dimethyl-5-(methyl-(3-phenyl-2-propene-1-yl)carbamoyl)-1,4-dihydropyridine-3-carboxylate was dissolved in 4.6 ml of methanol. 0.456 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature overnight. An aqueous potassium hydrogensulfate solution was added to the reaction mixture. Methanol was evaporated under reduced pressure. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=5/1) to obtain the title compound.