Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Na].Br[C:8]1[N:15]=[C:14]([NH2:16])[CH:13]=[C:12]([NH2:17])[C:9]=1[C:10]#[N:11]>C1(C)C=CC=CC=1>[NH2:17][C:12]1[C:9]([C:10]#[N:11])=[C:8]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:15]=[C:14]([NH2:16])[CH:13]=1
Reactant: CCCCO
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCOc1nc(N)cc(N)c1C#N
Temperature: 150 °C

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 3 mL of n-butanol and 40 mg (1.7 mmol) of sodium. The mixture was stirred until all of the sodium had reacted, then 212 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 150° C. for 10 minutes then cooled and poured into 10 mL of toluene. The solvents were removed under reduced pressure, then the residue was partitioned between 2 mL of saturated NaHCO3(aq.) solution and 10 mL of toluene. This was concentrated again under reduced pressure, and the residue was taken up in 5 mL of water, then extracted with ethyl acetate (1×10 mL, then 2×5 mL). The combined ethyl acetate layers were back extracted with brine (1×5 mL), dried over MgSO4, filtered, and concentrated to a yellow solid. This was purified via silica gel chromatography, eluting with 50% ethyl acetate/hexanes to provide a white solid. 1H NMR (300 MHz, d6-DMSO) δ 6.19 (s, 2H), 6.14 (s, 2H), 5.31 (s, 1H), 4.18 (t, 2H, J=6.6 Hz), 2.50 (m, 1H), 1.62 (m, 2H), 1.38 (m, 2H), 0.92 (m, 3H, J=7.1 Hz); MS (ESI) m/e=151 (M−Bu+H)+, 207 (M+H)+, 205 (M−H)−.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:32]4[CH:31]=[CH:30][C:29]([Cl:28])=[C:34]([Cl:35])[CH:33]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3ccc(Cl)c(Cl)c3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 3,4-dichlorophenylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[K+].[K+].O.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146 %

Procedure:
To a magnetically stirred solution of piperazin-2-one (2.0 g, 20.0 mmol) in THF (10 mL) at room temperature under Ar atmosphere, K2CO3 (8.25 g, 120 mmol), water (10 mL), and benzyl chloroformate (3.14 mL, 22.0 mmol) were added. The reaction mixture was stirred for 18 hours at room temperature. Water (50 mL) was added, and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried with MgSO4, and concentrated in vacuo to the give the title compound (6.84 g, 100%). 1H NMR (400 MHz, CDCl3) δ 3.37 (bs, 2H), 3.68 (t, J=4.7 Hz, 2H), 4.13 (s, 2H), 5.14 (s, 2H), 7.34 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([NH2:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([NH:16][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1nc2c(OCc3cccc(Cl)c3)cccn2n1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc4c(OCc5cccc(Cl)c5)cccn4n3)cc2)CC1

Procedure:
260 a)N-(3-Hydroxy-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 2-amino-pyridin-3-ol (4.00 g, 0.0363 mol) in a manner analogous to Example 2a. The product of the reaction was isolated as a yellow solid. 260 b) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol was prepared from N-(3-hydroxy-2-pyridinyl)-N′-carboethoxy-thiourea (1.8 g, 5.9 mmol) in a manner analogous to Example 2b. Product was isolated as a beige solid (3.17 g, 58%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.18 (bs, 1H), 8.02 (dd, J=6.41 Hz, 1.2 Hz, 1H), 6.71-6.64 (m, 2H), 5.79 (bs, 2H). MS=151.0 (MH)+. 260 c) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol (0.200 g, 1.33 mmol) was suspended in acetone (1.9 mL). 1-(bromomethyl)-3-chloro-benzene (0.184 mL, 1.40 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added and the reaction mixture was heated to 80° C. for 1 hour. Reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated. Resulting oil was taken up in dichloromethane and purified via chromatography (silica gel 0-100% ethyl acetate in hexanes). 8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated as an oil which solidified on standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.17 (d, J=6.6 Hz, 1H), 7.56 (s, 1H), 7.44-7.42 (m, 3H), 6.99 (d, J=7.9 Hz, 1H), 6.79-6.75 (m, 1H), 5.94 (bs, 2H), 5.30 (s, 2H). MS=275 (MH)+. 260 d) [8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (95.0 mg, 0.346 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (102 mg, 0.399 mmol in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.073 g, 47%). MP=135-138° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.33 (s, 1H), 8.37 (d, J=6.7 Hz, 1H), 7.58 (s, 1H), 7.51-7.44 (m, 5H), 7.09 (d, J=7.9 Hz, 1H), 6.91-6.86 (m, 3H), 5.35 (s, 2H), 3.04-3.01 (m, 4H), 2.46-2.44 (m, 4H), 2.22 (s, 3H). MS=449 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][C:5]2[CH2:9][CH2:8][S:7][C:6]=2[CH:10]=1.[NH4+].[Cl-]>C(O)C.C1COCC1.[Fe]>[F:1][C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[CH2:9][CH2:8][S:7][C:6]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc2c(cc1F)SCC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc2c(cc1F)SCC2
Yield: 94.6 %

Procedure:
To a solution of 6-fluoro-5-nitro-2,3-dihydrobenzo[b]thiophene (2.1 g, 10.5 mmol) in ethanol (80 mL), THF (40 mL), and aqueous NH4Cl (20 mL) was added Fe (O) (3.53 g, 63.3 mmol). The mixture was refluxed for 2 hours, then filtered through celite and washed with ethyl acetate. The residue was purified using silica gel column chromatography with 50% ethyl acetate in hexanes to provide 6-fluoro-2,3-dihydrobenzo[b]thiophen-5-amine (1.68 g, 94.2% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH3:15])[C:5]2=[O:16].[NH2:17]C(N)=O>>[NH2:17][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH3:15])[C:5]2=[O:16]
Reactant: NC(N)=O
Reactant: CN1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Product: CN1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Temperature: 150 °C
Yield: 66.1 %

Procedure:
5-Chloro-2-methyl-6-nitroisoindoline-1,3-dione (14.40 g, 59.85 mmol) and urea (35.95 g, 599 mmol) were mixed together under argon. The mixture was stirred and heated to 150° C. for 3 h and cooled to rt. The solid was washed with 200 mL of hot water (90° C.) and filtered to remove the remaining urea. The isolated yellow solid was washed twice with hot water, dried under vacuum and purified by column chromatography (silica-gel CH2Cl2/acetone=19/1 v/v) to give a yellow solid product, 8.75 g, 66.1% yield. MS: 219.6 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.39 (s, 2H), 8.26 (s, 1H), 7.40 (s, 1H), 2.99 (s, 3H).
Reaction SMILES: O[CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1C=CC(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)=CC=1>>[N:41]([CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1

Procedure:
Reacting 4-(1-hydroxytridecyl)-2-triethylsilylfuran with diphenylphosphonyl azide and diethyl azidocarboxylate gives 4-(1-azidotridecyl)-2-triethylsilylfuran. Reducing this azide with lithium aluminum hydride gives 4-(1-aminotridecyl)-2-triethylsilylfuran. Acetylation of this intermediate with acetic anhydride gives 4-(1-acetamido)tridecyl-2-triethylsilylfuran. Oxidizing this amide with oxygen using Rose Bengal as an initiator gives 4-(1-acetamido)-5-hydroxy-2(5H)-furanone. Reduction of this furanone with sodium borohydride gives 4-(1-acetamido)-2(5H)-furanone.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][OH:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>O1CCCC1>[CH2:17]([O:16][C:14]([N:7]1[CH2:8][CH2:9][C:4]([CH2:3][CH2:2][OH:1])([CH2:10][CH2:11][OH:12])[CH2:5][CH2:6]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCC1(CCO)CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CCO)(CCO)CC1

Procedure:
1-benzyloxycarbonyl-4,4-bis-(2-hydroxyethyl)piperidine is prepared by reaction of 4,4-bis-(2-hydroxyethyl)piperidine with benzyl chloroformate in tetrahydrofuran in the presence of triethylamine.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[NH2:34]>ClCCl.N1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[NH:34][C:21]([C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:5]=2[O:4][CH3:3])[CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: COc1ccc(-c2cccc(C(=O)Cl)c2)c(OC)c1OC
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2cccc(C(=O)Nc3cc([N+](=O)[O-])ccc3Br)c2)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Add a solution of 2′,3′,4′-trimethoxy-biphenyl-3-carbonyl chloride (35) (345 mg, 1.13 mmol) in dichloromethane (5 mL) to an ice cooled solution of 2-bromo-5-nitro-phenylamine (88) (232 mg, 1.07 mmol) in anhydrous dichloromethane (12 mL) and anhydrous pyridine (2.9 mL). Stir the reaction mixture for 15 min at 0° C. and additional 17 h at rt. Pour the reaction mixture into ice cooled 1M aqu. HCl (to get pH ca. 3), extract with EtOAc (3×), wash the combined organic layer with brine and dry it with Na2SO4 to afford crude 2′,3′,4′-trimethoxy-biphenyl-3-carboxylic acid (2-bromo-5-nitro-phenyl)-amide (89) as a beige solid (542 mg, quant.). 1H NMR (400 MHz, CDCl3): 3.72 (s, 3H); 3.91 (s, 3H); 3.93 (s, 3H); 6.77 (d, 1H, J=8.6 Hz); 7.08 (d, 1H, J=8.6 Hz); 7.56 (t, 1H, J=8.8 Hz); 7.75 (d, 2H, J=8.8 Hz); 7.86 (d, 1H, J=8.8 Hz), 7.87 (d, 1H, J=8.8 Hz); 8.09 (t, 1H, J=1.7 Hz); 8.61 (br. s, 1H); 9.59 (d, 1H, J=2.5 Hz).
Reaction SMILES: C([O:8][C:9](=[O:48])[CH:10]([N:17]([CH2:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:34]1)=[O:32])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:44]([O:43][C:41]([CH2:40][NH:39][CH:36]1[CH2:35][CH2:34][N:33]([C:31](=[O:32])[CH2:30][CH2:29][N:17]([CH:10]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[C:9]([OH:48])=[O:8])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:38][CH2:37]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCC(NCC(=O)OC(C)(C)C)CC2)C(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCC(NCC(=O)OC(C)(C)C)CC2)C(C(=O)O)C2CCCCC2)cc1
Yield: 100.3 %

Procedure:
To a solution of [{3-[4-(tert-butoxycarbonylmethylamino)piperidin-1-yl]-3-oxopropyl}(4-methoxybenzenesulfonyl) amino]cyclohexylacetic acid benzylester (1.89 grams, 2.76 mmol) in ethanol (90 mL) was added 10% palladium on activated carbon (0.32 grams). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 2 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving [{3-[4-(tert-butoxycarbonylmethyl-amino) piperidin-1-yl]-3-oxo-propyl}(4-methoxybenzenesulfonyl)amino]cyclohexylacetic acid as a white foam (1.65 grams, 100%).
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([O:15][Si](C(C)C)(C(C)C)C(C)C)[CH2:7][CH2:6][C@H:5]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33])=[N+:2]=[N-:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([OH:15])[CH2:7][CH2:6][C@H:5]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33])=[N+:2]=[N-:3]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](N=[N+]=[N-])c2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 100 mL round-bottom flask was dissolved (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (0.732 g, 1.549 mmol) (crude) in tetrahydrofuran (8 mL) to give a colorless solution. TBAF (1.859 mL, 1.859 mmol) was added, and the resulting light yellow solution was stirred at room temperature for 1.5 h. LCMS indicated complete conversion. Tetrahydrofuran was removed and the residue was diluted with water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried, and concentrated to give a light yellow oil. Purification by FCC up to 60% ethyl acetate/hexane afforded the desired product (crude weight: 480 mg) as a colorless oil. Smaller scale purification afforded an analytical sample: MS(ESI)[M+H+]=317.22; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.51 (dd, J=4.91, 1.38 Hz, 1H) 7.99 (d, J=7.30 Hz, 1H) 7.35 (dd, J=7.81, 5.04 Hz, 1H) 7.06-7.20 (m, 2H) 6.94-7.05 (m, 1H) 5.91 (br. s., 1H) 5.03 (d, J=10.32 Hz, 1H) 4.92 (dd, J=11.21, 2.39 Hz, 1H) 2.84-3.02 (m, 1H) 2.37-2.49 (m, 1H) 2.25-2.36 (m, 1H) 2.07-2.17 (m, J=14.38, 4.94, 3.05, 3.05 Hz, 1H) 1.40-1.64 (m, 1H); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 158.48 (s, 1C) 152.19-149.87 (dd, J=13.10 and 221 Hz, 1C) 149.72-147.42 (dd, J=13.87 and 219 Hz, 1C) 146.16 (s, 3C) 133.67 (s, 2C) 133.23 (s, 1C) 132.66 (d, J=10.79 Hz, 1C) 124.43 (dd, J=6.94, 3.85 Hz, 2C) 123.84 (br. s., 1C) 122.89 (s, 2C) 115.98 (d, J=17.73 Hz, 2C) 70.94 (s, 3C) 65.67 (s, 1C) 45.43 (br. s., 1C) 35.71 (s, 3C) 33.45 (s, 2C); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −137.55-−137.20 (m, 1F) −142.28-−141.89 (m, 1F).
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][OH:17])[CH2:11]1)C1C=CC=CC=1.[ClH:18].[H][H]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[ClH:18].[NH:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][OH:17])[CH2:11]1
Reactant: [H][H]
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: OCC1CNCCO1

Procedure:
In an autoclave under an argon atmosphere at ambient temperature (20° C.), 215 ml of methanol, 1.7 g of palladium hydroxide (12135-22-7), 12.4 g of (4-benzylmorpholin-2-yl)methanol and 15 ml of 4M HCl are successively placed in dioxane. After the autoclave has been closed, the reaction medium is placed under 6 bar of hydrogen at 25° C. for 24 h. The reaction medium is filtered through Clarcel, rinsed several times with methanol; the filtrate is concentrated under reduced pressure. Morpholin-2-ylmethanol hydrochloride (9.65 g) is isolated in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:5](=[O:8])[N:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][OH:18])[N:7]=1
Reactant: OCc1ccccc1B(O)O
Reactant: O=c1[nH]nc(Br)c(=O)n1Cc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1c(Br)nn(-c2ccccc2CO)c(=O)n1Cc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
According to Scheme 2 Step 3: To a solution of 6-bromo-4-(4-chlorobenzyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.400 g, 1.3 mmol) in DMF (8 mL) were added 2-(hydroxymethyl)phenylboronic acid (0.29 g, 1.9 mmol), copper(II) acetate (0.23 g, 1.3 mmol) and pyridine (0.20 g, 2.5 mmol) and the mixture was left stiffing overnight at 60° C. The reaction mixture was quenched with a saturated sodium bicarbonate solution. The precipitate formed was filtered, washed first with water and then with diethyl ether. 330 mg (Yield=62%) of 6-bromo-4-(4-chlorobenzyl)-2-(2-(hydroxymethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione were recovered. The product was pure enough to be used without any purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:14][OH:15])=[CH:9][C:8]=1[O:16][CH3:17])(=[O:5])=[O:4].ClN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]([C:38]([F:41])([F:40])[F:39])=[CH2:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[F:19][C:2]([F:18])([F:1])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:37][C:36]([C:31]3[CH:32]=[C:33]([Cl:35])[CH:34]=[C:29]([Cl:28])[CH:30]=3)([C:38]([F:39])([F:41])[F:40])[O:15][N:14]=2)=[CH:9][C:8]=1[O:16][CH3:17])(=[O:4])=[O:5]
Reactant: COc1cc(C=NO)ccc1OS(=O)(=O)C(F)(F)F
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
In a solution of 2.0 g of 4-hydroxyiminomethyl-2-methoxyphenyl trifluoromethane sulfonate in 30 ml of N,N-dimethylformamide, 0.9 g of N-chlorosuccinic acid imide was added, and stirred at 40 to 50° C. for 30 minutes. Then, the reaction mixture was left and cooled to room temperature, 1.5 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 0.7 g of triethylamine were added, and stirred at room temperature for 90 minutes. After the completion of the reaction, the reaction mixture was poured in 100 ml of ice water, extracted with ethyl acetate (50 ml×2), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:7), and 1.4 g of the aimed product was obtained as colorless resinous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:36][CH3:37])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:23]([CH:31]=O)[NH:22][C:21]=1[CH:33]([CH3:35])[CH3:34])=[O:19])[CH3:13]>>[CH2:36]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:23]([CH:31]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH:33]([CH3:35])[CH3:34])=[O:19])[CH3:37]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=O)c1-c1ccccc1
Product: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 52.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (57 g. 0.27 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (120 mg) to give 78 mg (53%) of the title compound as a yellow solid.
Reaction SMILES: C(O[C:4](=[O:19])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 5.8 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 5.89 mmol) and methyl urea (654 mg, 8.83 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 16.9 mL, 11.78 mmol) was refluxed at 100° C. for 6 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (105.3 mg, 5.8%) as a white solid: mp 145-147° C.; EI-HRMS m/e calcd for C16H21ClN2O2 (M+) 308.1292, found 308.1291.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:12]2=3)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
To a solution of methyl 4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (1.779 g, 4.84 mmol) in THF (12 mL) and water (6 mL) was added LiOH (0.6096 g). The reaction was allowed to stir at room temperature for 16 hours. LCMS analysis identified the product as the predominant component of the reaction mixture. The solvent was removed under reduced pressure. The resulting aqueous solution was acidified with 1N HCl to provide a white precipitate. The aqueous layer was extracted with DCM until the acid was no longer detected in the organic wash layer. The combined organics were washed with H2O and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by flash chromatography using a gradient elution of hexane with 0-95% ethyl acetate doped with 1% AcOH. The product, 4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (1.108 g, 3.14 mmol, 65% yield), was isolated as off-white solid. LCMS (+ESI) m/z=354.0 [M+H]+.