Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[CH:26][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])=[CH:26][N:27]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-c1cnc(CBr)s1
Product: O=c1n(Cc2ncc(-c3ccccc3Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
70 mg (0.23 mmol) of the compound from Example 5A were reacted with 66 mg (0.23 mmol) of the compound from Example 88A analogously to the preparation of the compound in Example 77. This gave 65 mg (55% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C.[Cl:8][CH2:9][CH2:10][OH:11].[C:12](#N)C>>[Cl-:8].[OH:11][CH2:10][CH2:9][N+:1]1[CH:2]=[CH:3][C:4]([CH3:12])=[CH:5][CH:6]=1
Reactant: OCCCl
Reactant: CC#N
Reactant: Cc1ccccn1
Product: Cc1cc[n+](CCO)cc1
Product: [Cl-]
Temperature: 120 °C
Yield: 87 %

Procedure:
A solution mixture of picoline (0.93 g, 10 mmol) and 2-chloroethanol (4.03 g, 50 mmol) in acetonitrile (20 mL) was heated to 120° C. in a sealed tube overnight. After cooling to room temperature, the solvent was removed under vacuum. The resulting mixture was precipitate from methanol and ethyl acetate to give the desired product 9 (1.5 g) in 87% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J=6.4 Hz, 2H), 7.98 (d, J=6.4 Hz, 2H), 5.55 (br, 1H), 4.64 (t, J=4.8 Hz, 2H), 3.81 (t, J=4.8 Hz, 2H), 2.60 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 158.7, 144.2, 127.9, 62.1, 60.0, 21.4.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([I:12])[C:8](=[O:11])[NH:9][CH:10]=1.[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C=O)C>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([I:12])[C:8](=[O:11])[N:9]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[F:20])[CH:10]=1
Reactant: O=c1[nH]cc(Cc2ccc(F)cc2F)cc1I
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(I)cc(Cc2ccc(F)cc2F)cn1Cc1ccccc1F
Reaction time: 0.25 h

Procedure:
To a suspension of 5-(2,4-difluorobenzyl)-3-iodopyridin-2(1H)-one 4 (5.58 g, 16.1 mmol) in anhydrous DMF (160 ml) was added at room temperature NaH (60% suspension in mineral oil, 0.71 g, 17.7 mmol). After the mixture was stirred for 15 min, o-fluorobenzyl bromide (2 ml, 16.1 mmol) was added to the mixture, which was stirred for 2 h at RT. The solvent was distilled off and the residue was dissolved in ethyl acetate (200 ml), washed with water (200 ml), brine (200 ml), and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by flash chromatography on silica gel (hexanes:ethyl acetate, 80:20). Yield 6.61 g (90%). 1H NMR (CDCl3, 500 MHz): δ 7.80 (d, 1H, J=2.2 Hz), 7.55-7.51 (m, 1H), 7.32-7.27 (m, 2H), 7.13-7.04 (m, 3H), 6.86-6.79 (m, 2H), 5.14 (s, 2H), 3.64 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 162.4, 162.1, 160.5, 160.2, 159.1, 149.8, 136.5, 132.1, 131.1, 130.3, 124.6, 122.5, 121.9, 118.6, 115.4, 111.5, 104.2, 93.5, 48.5, 30.0.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:22]2[CH:23]=[C:24](Cl)[N:25]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:21]2=[N:20][C:19]=1[CH3:36])=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:40].[Na+].[K+]>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][CH3:8])[C:16]([C:18]2[N:22]3[CH2:23][C:24](=[O:40])[N:25]([C:26]4[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])[C:21]3=[N:20][C:19]=2[CH3:36])=[O:15])[CH2:3][CH2:2]1
Reactant: CCCNCC1CC1
Reactant: CCOC(=O)c1c(C)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: C[Al](C)C
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCN(CC1CC1)C(=O)c1c(C)nc2n1CC(=O)N2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclopropylmethylpropylamine (0.22 mL, 1.530 mmol) in toluene (1.5 mL) at 0° C. was added 2.0 M solution of trimethylaluminum in toluene (0.77 mL, 1.530 mmol). The clear solution was warmed to room temperature and stirred for 1 h. A solution of 6-chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid ethyl ester (20.0 mg, 0.058 mmol) in toluene (1.5 mL) was added at 0° C. via cannula. The reaction mixture was heated at 80° C. for 2 h. A solution of Rochelle's salt (2.0 mL) was added carefully at 0° C. and the mixture was vigorously stirred for 30 min. The crude product was extracted with ethyl acetate. The combined organic extracts were dried with MgSO4. The solvent was removed under reduced pressure and the crude product was purified by a reverse-phase preparative HPLC. Yield—3.6 mg (12%). 1H NMR (CD3CN, 500 MHz) δ 7.07 (s, 2H), 4.73 (s, 2H), 3.57 (t, J=7.1 Hz, 2H), 3.37 (d, J=6.9 Hz, 2H), 2.35 (s, 3H), 2.19 (s, 3H), 2.14 (s, 6H), 1.65 (sextet, J=7.3 Hz, 2H), 1.08 (m, 1H), 0.90 (t, J=7.4 Hz, 3H), 0.56 (m, 2H), 0.21 (m, 2H); LC/MS: tR=1.67 min., MS: [M+H]=395.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16](OCC)=[O:17].[CH:21]1([O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[NH2:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=1[O:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17]
Reactant: CCOC(=O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21
Reactant: Nc1ccccc1OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21)Nc1ccccc1OC1CCCC1

Procedure:
The title compound was prepared by the coupling ethyl (2E)-(6-chlorospiro[chromene-2,1′-cyclobutan]-4(3H)-ylidene)acetate (Step 2 of Intermediate 1) with 2-(cyclopentyloxy)aniline (120 mg, 0.681 mmol) (150 mg, 0.565 mmol) in presence of EDCI.HCl (163 mg, 0.851 mmol), HOBt (130 mg, 0.851 mmol) and triethylamine (157 μl, 1.134 mmol) in dichloromethane (5 ml) as described in Method A to give 95 mg of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.53-1.65 (m, 8H), 1.74-1.90 (m, 4H), 2.22-2.30 (m, 2H), 2.47-2.57 (m, 2H), 3.50 (s, 2H), 4.67 (br s, 1H), 6.75 (d, J=8.1 Hz, 2H), 6.85-6.96 (m, 2H), 7.04-7.10 (m, 2H), 8.32 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[OH:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[OH:29])[N:9]=2)=[CH:4][CH:3]=1.[CH2:30]([O:39][CH2:40][CH:41]1[O:43][CH2:42]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[I-].C1([C:51]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=CC=CC=2)C[PH3+])C=CC=CC=1>C1(C)C=C(C)C=C(C)C=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:42][CH:41]([OH:43])[CH2:40][O:39][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:60][CH2:51][CH2:54][CH3:59])=[CH:24][C:23]=3[OH:29])[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:42][CH:41]([OH:43])[CH2:40][O:39][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][C:15]=3[OH:21])[N:13]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCCCOCC1CO1
Reactant: Oc1ccc(-c2nc(-c3ccc(Cl)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Reactant: [PH3+]CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCCCCCCOCC(O)COc1ccc(-c2nc(-c3ccc(Cl)cc3)nc(-c3ccc(OCC(O)COCCCCCCCCC)cc3O)n2)c(O)c1

Procedure:
Following the general procedure of Example 1, 5.0 g (0.015 mol) of 6-(p-chlorophenyl)-2,4-bis-(2,4-dihydroxyphenyl)-s-triazine, 8.0 g (0.036 mol) of glycidyl nonyl ether, 300 mg of triphenylethylphosphonium iodide and 10 mL of mesitylene are reacted at 175° C. for 3.25 hours. The product is worked up by the procedure given in Example 1 to afford 5.6 g (51%) yield of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([OH:31])=O.Cl.[NH2:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:14]([F:16])([F:17])[F:15])=[O:28])[NH:8]2)=[CH:4][C:3]=1[C:29]([NH:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1)=[O:31]
Reactant: O=C(NC(c1cccc(C(F)(F)F)c1)C(F)(F)F)c1cc2cc(C(=O)O)c(Cl)cc2[nH]1
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CC1(NC(=O)c2cc3cc(C(=O)NC(c4cccc(C(F)(F)F)c4)C(F)(F)F)[nH]c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid (2.74 g, 5.07 mmol, 86% pure) was dissolved in N,N-dimethylformamide (14 ml), and 1-aminocyclopropanecarbonitrile hydrochloride (0.78 g, 6.59 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (2.12 g, 5.07 mmol) and 4-methylmorpholine (1.54 g, 15.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then ethyl acetate was added. The organic phase was washed with hydrochloric acid (1 mol/l) and the aqueous phase was once again extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and the portion which was insoluble in both phases was filtered off. The filtercake is triturated with boiling ethyl acetate (15 ml) and the precipitate is washed with warm ethyl acetate. This leaves 2.01 g (74% of theory) of 6-chloro-N5-(1-cyanocyclopropyl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14](OC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C(OCC)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCO
Yield: 96.5 %

Procedure:
A solution of methyl 5-methyl-2-phenyl-4-oxazoleacetate (54 g) in dry ethyl ether (150 ml) was added dropwise to a stirred, ice-cooled suspension of lithium aluminum hydride (8.8 g) in dry ethyl ether (700 ml) during 1.5 hours. Ethyl acetate (20 ml) was added dropwise thereto with ice-cooling and then water (50 ml) was added cautiously thereto. The resulting white precipitate was filtered off and the filtrate was concentrated to give 2-(5-methyl-2-phenyl-4-oxazolyl) ethanol as crystals (45.8 g, 96.2%). Recrystallization from ethyl acetate-hexane gave colorless rods, m.p. 73°-74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=3)[N:9]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH2:30]1[CH2:34]OCC1.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].[Al]>CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([N:9]2[CH:10]([C:13]3[CH:18]=[CH:17][C:16]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])=[CH:15][CH:14]=3)[CH2:11][CH2:12][CH:8]2[C:5]2[CH:6]=[CH:7][C:2]([C:34]#[C:30][Si:36]([CH3:38])([CH3:37])[CH3:35])=[CH:3][CH:4]=2)=[CH:25][CH:24]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: C#C[Si](C)(C)C
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CCC2c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1ccc(N2C(c3ccc(C#C[Si](C)(C)C)cc3)CCC2c2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89 %

Procedure:
To an oven-dried microwave tube (Size M, 5 mL) purged with nitrogen, added the product of Example 42C (340 mg, 0.662 mmol), bis(triphenylphosphine)palladium(II) dichloride (18.60 mg, 0.026 mmol), THF (2 mL), and triethylamine (2 mL). Stirred at room temperature for 5 min, then added copper(I) iodide (2.52 mg, 0.013 mmol), stirred the yellow mixture for 2 min, then nitrogen bubbled through for 15 min. Added trimethylsilylacetylene (0.374 mL, 2.65 mmol), sealed the tube with an aluminum crimp cap, and heated in an oil bath at 70° C. for 20 hr. Cooled the reaction to room temperature, added fresh bis(triphenylphosphine)palladium(II) dichloride (18.60 mg, 0.026 mmol) and copper(I) iodide (2.52 mg, 0.013 mmol), added additional trimethylsilylacetylene (0.374 mL, 2.65 mmol), and continued heating at 80° C. for 24 hr. Cooled the reaction to room temperature, diluted with Et2O (50 mL), washed with H2O (2×25 mL) and brine (25 mL), dried the organic phase over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to a light tan foam (470 mg). Purified by flash chromatography (silica gel, 2.5 cm×10 cm, 2% Et2O/hexanes) to afford the title product as a yellow foam (324 mg, 89%) as a mixture of stereoisomers. MS (ESI+) m/z 548 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:12][C:11]([CH3:14])([CH3:13])[N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]2[CH2:22][F:23])=[CH:4][CH:3]=1.[CH3:24][S:25]SC.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:18]([O:17][C:15]([N:10]1[C@H:9]([CH2:22][F:23])[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([S:25][CH3:24])=[CH:3][CH:4]=2)[O:12][C:11]1([CH3:14])[CH3:13])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(Br)cc2)OC1(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-butyl lithium (n-BuLi), (1.78 g, 28 mmol, 1.2 eq) was added to a solution of tert-butyl (4S,5R)-5-(4-bromophenyl)-4-(fluoromethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (9.0 g, 23 mmol) in 30 ml of anhydrous tetrahydrofuran (THF) at −78° C. in 30 min, and the reaction mixture was stirred for 30 minutes under N2. 3.1 ml of dimethyldisulfide (1.5 eq) was added, and stirred for 30 min. The reaction mixture was warmed up to room temperature and stirred for 1 hour. A saturated solution of ammonium chloride (50 ml) and ethyl acetate (50 ml) was added and stirred for 30 min. The organic layer was washed with brine (50 ml) and dried over sodium sulfate. After purification, via a column, 8.15 g of white solid of the desired product was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH2:15][CH2:14]1.C([O-])(=O)C.[Na+].C(O)C>O>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C:2]2[CH:3]=[C:4]([F:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CNC1CCN(C)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCC(NCc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 1.4 %

Procedure:
Combine 1,3-difluoro-5-nitro-benzene (1.78 mL, 15.7 mmol), 1-methyl-4-(methylamino)piperidine (2.74 mL, 18.85 mmol), sodium acetate (2.45 g, 29.8 mmol) and absolute ethanol (10 mL) in a sealed tube. Heat and stir at 100° C. for 16 hr. Cool the reaction mixture to ambient temperature and pour into water (100 mL). Extract with ethyl acetate (2×100 mL). Wash combined organic layers with saturated aqueous NaCl solution (100 mL), dry over sodium sulfate, filter, and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3 in methanol) in CH2Cl2 to obtain 0.06 g (1.4%) of the title intermediate: 1H NMR (CDCl3): 7.3 (m, 1H), 7.2 (m, 1H), 6.7 (m, 1H), 3.6 (m, 1H), 3.0 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.2 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][C:6]([S:9][CH3:10])=[N:7][N:8]=1)#[N:2].C(O)(=O)C.[N:15]([O-])=[O:16].[Na+]>O>[CH3:10][S:9][C:6]1[S:5][C:4]([C:3](=[N:15][OH:16])[C:1]#[N:2])=[N:8][N:7]=1
Reactant: CSc1nnc(CC#N)s1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1nnc(C(C#N)=NO)s1
Reaction time: 1 h

Procedure:
17.1 g (0.1 mol) of 2-cyanomethyl-5-methylthio-1,3,4-thiadiazole are intially introduced into 75 ml of glacial acetic acid. A solution of 7.8 g (0.11 mol) of NaNO2 in 20 ml of water is added dropwise and the mixture is stirred for 1 hour. 200 ml of water are then added to the solution and the mixture is filtered. The residue is washed with water: 19 g (95% of theory) of end product, melting point >200° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([C:13]([NH:15][O:16]C3CCCCO3)=[O:14])=[CH:7][CH:8]=2)[NH:3]1>C1COCC1.C(O)(=O)C.O>[OH:16][NH:15][C:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10](=[O:12])[NH:11][C:2](=[O:1])[NH:3]2)=[CH:8][CH:7]=1)=[O:14]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(=O)[nH]c(=O)[nH]c2c1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(NO)c1ccc2c(=O)[nH]c(=O)[nH]c2c1
Yield: 44.1 %

Procedure:
A solution of 2,4-dioxo-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (0.12 g, 0.39 mmol) in THF (1.6 mL), acetic acid (3.2 mL) and water (0.8 mL) was heated at 60° C. for 5 h. The mixture was concentrated to dryness. The residue was purified by preparative HPLC to afford N-hydroxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (38 mg, 44%). LC-MS: (FA) ES+ 222; 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 11.40 (s, 1H), 11.28 (s, 1H), 9.21 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.52 (s, 1H), 7.44 (dd, J=8.2, 1.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH2:30][C:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([C:31]2([CH2:30][O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:33][CH2:32]2)(=[O:36])=[O:35])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: O=S(=O)(Cl)C1(COCc2ccccc2)CC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(COCc3ccccc3)CC2)c2n(c1=O)CCO2
Yield: 49.4 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.35 g, 0.873 mmol) in pyridine (3 mL) was reacted with 1-benzyloxymethyl-cyclopropanesulfonyl chloride (0.34 mg, 1.30 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 0.27 g of the product (50% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1>[OH:25][C:18]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=[O:29])[N:10]1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1C(=O)c1ccccc1
Reactant: NCCc1ccc(O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(O)(c2ccccc2)N1CCc1ccc(O)cc1

Procedure:
At room temperature, 1.46 g (10.63 mmol) of 2-(4-hydroxy-phenyl)ethylamine and 1.08 g (10.63 mmol) of triethylamine in 30 ml of absolute toluene were admixed dropwise with a solution of 2.0 g (8.17 mmol) of 2-benzoylbenzoyl chloride in 20 ml of absolute toluene. The reaction mixture was heated under reflux for 3 h and cooled, and the turbid solution was admixed with 20 ml of water. The organic phase was separated off, washed three times with 1 M aqueous hydrochloric acid and evaporated to dryness using a rotary evaporator. The solid residue was purified by column chromatography on silica gel 60. Elution was carried out using a toluene/ethyl acetate gradient (0 to 20% ethyl acetate). The product-containing fractions were evaporated to dryness using a rotary evaporator. The residue was suspended in diethyl ether and filtered off with suction. Yield: 0.21 g. M.p.: 188° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Reaction time: 1.5 h

Procedure:
To a solution of 2-bromo-5-nitrobenzoic acid (1.00 g, 4.06 mmol) in methylene chloride (15 mL) is added oxalyl chloride (1.42 mL, 16.24 mmol) followed by 1 drop DMF. Addition of DMF results in vigorous gas evolution. After 1.5 h, the reaction mixture is concentrated under reduced pressure to give an oil which is used as is without purification.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40]([CH:52]2CCC[CH2:54][CH2:53]2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:54][CH2:53][CH2:52][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Agent: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCCCc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 4-phenylbutanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.58 (dd, J=9.0, 16.5, 1H), 7.66 (t, J=6.4, 2H), 7.34 (t, J=5.6, 4H), 7.29-7.22 (m, 4H), 4.39-4.29 (m, 1H), 3.24 (d, J=10.4, 1H), 2.91 (dd, J=2.4, 9.0, 0.5H), 2.66 (ddd, J=6.5, 10.6, 13.1, 1H), 2.57 (ddd, J=5.3, 12.3, 17.7, 3H), 2.51-2.45 (m, 1H), 2.43-2.29 (m, 3H), 2.26 (dd, J=3.0, 8.8, 0.5H), 2.24-2.08 (m, 2H), 1.91-1.83 (m, 1H), 1.81-1.72 (m, 1H), 1.71-1.58 (m, 2H), 1.49 (dt, J=7.8, 15.9, 1H), 1.41 (dt, J=6.9, 17.2, 2H), 1.31 (ddd, J=6.7, 13.2, 20.5, 1H), 1.23 (dd, J=6.5, 13.0, 3H), 0.71 (dd, J=2.6, 6.6, 3H); MS (ESI+) m/z 419 (M+H)+.