Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:14][S+:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=[C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[S+:13]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: c1ccc(-c2cc[s+]c(-c3ccccc3)c2)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Product: Nc1ccc(-c2cc(-c3ccccc3)cc(-c3ccccc3)[s+]2)cc1
Reaction time: 2 h
Yield: 52 %

Procedure:
2,4-diphenylthiopyrylium perchlorate (1 g, 2.87 mmole) and aniline (0.54 g, 5.74 mmole) were heated in 10 ml of ethanol at 40° to 45° C. The reaction mixture was immediately colored deep blue. After stirring was continued for two hours, the reaction mixture was allowed to stand at room temperature to give blue needles of 2-(4-aminophenyl)-4,6-diphenylthiopyrylium perchlorate. This compound was recrystallized from a mixture of ethanol-chloroform.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[OH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[OH:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:42][CH2:41]1
Reactant: OC1CCNCC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCC(O)CC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 4-hydroxypiperidine were converted to the title compound.
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CO>[OH:1][CH:2]([CH2:14][N:25]1[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1
Reactant: N#CCc1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)COc2ccc(CC#N)cc2)CC1
Yield: 70.1 %

Procedure:
A solution of 4-(2,3-epoxypropoxy)benzylcyanide (2.84 g, 15 mmol) and 1-(tert-butoxycarbonyl)piperazine (4.2 g, 22.5 mmol) in methanol (35 ml) was stirred at room temperature for 3 hours and the solvent was removed. The residue was dissolved in 200 ml of ethyl acetate, washed with water, dried over MgSO4 and concentrated. The obtained crude product was chromatographed on a silica gel column eluting with ethyl acetate. The obtained sticky material was triturated with hexane to give 3.95 g of the title compound, yield: 70.2%, mp. 98°-100° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=1)=[O:41]>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][CH2:8][C:9](=[O:13])[N:10]2[CH2:39][C:40]([C:42]2[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=2)=[O:41])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)NC(=O)CN2
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)N(CC(=O)c1ccc(Br)cc1)C(=O)CN2
Reaction time: 16 h
Yield: 37.8 %

Procedure:
To a solution of 7-cyano-3,4-dihydroquinoxalin-2(1H)-one (4 mg, 20 mmol) in THF (100 mL) was added K2CO3 (152 mg, 1.1 mmoL), 18-crown-6 (230 mg), and 2,4′-dibromoacetophenone (5.54 g, 20 mmol), and the resulting mixture was stirred for 16 hours. The mixture was diluted with EtOAc and filtered. The residue was washed with EtOAc and water, and dried by air to give the product (2.8 g, 37.8%). The filtrate was washed with brine (50 mL×4), dried over MgSO4, and concentrated to give a crude material, which was recrystallized in EtOAc (20 mL) to give the product (2 g, 27%) as a white solid. 1H NMR (DMSO-d6) δ 8.02 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.35 (d, J=1.4 Hz, 1H), 7.26 (dd, J=8.1 Hz, J=1.4 Hz, 1H), 7.10 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 5.50 (s, 2H), 4.05 (d, J=1.1 Hz, 2H); MS(CI) m/z 370/372 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:21]=2)[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:33]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42]Br)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42][N:16]1[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:31]=[CH:32][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:19]=2)[CH2:14][CH2:15]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCNCC3)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Product: CC(C)(C)OC(=O)NCCCN1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 73.4 %

Procedure:
Following the procedure of Example 11(e) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine 0.35 g (0.82 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.195 g, 0.82 mmol) were used to afford 0.35 g of the required product. NMR (DMSO-d6): δ 1.39 (9H, s), 1.52 (2H, m), 2.35 (8H, m), 2.95 (2H, m), 3.56 (2H, brs), 6.79 (1H, m), 6.90 (2H, d), 7.04 (1H, t), 7.25 (4H, d), 7.88 (4H, d).
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[Cl-].[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH:23]=[CH:3][C:2]([CH3:1])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C=O)=Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C=Cc1ccccc1OCc1ccccc1)=Cc1ccccc1
Yield: 90.2 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 1.32 g of α-methylcinnamaldehyde, 4.47 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 1.37 g of 1,8-diazabicyclo[5,4,0]-undec-7-ene were reacted in acetonitrile. The crude product thus obtained was purified as described in the first part of Preparation 3, to give 2.66 g (yield 90%) of 1-(2-benzyloxyphenyl)-3-methyl-4-phenylbutadiene as a colorless oil.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([O:7][C:8]2[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=[CH:10][C:9]=2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Nc1ccccc1OC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCCCC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To 20 ml of an acetic acid solution containing 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide was added dropwise 1.5 g of 61% nitric acid on heating at 110° C. over a 30-minute period, and then the mixture was stirred for 1 hour. The reaction solution was poured into ice water and neutralized with a dilute aqueous sodium hydroxide solution. The crystals which formed were collected by filtration, washed with water and dried to give 4.5 g of the crude crystals, which were then recrystallized from ethanol-n-hexane to give 3.3 g of N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](=[S:18])[NH2:17])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12.[Cl:21][CH2:22][C:23](=O)[CH2:24]Cl>O1CCOCC1>[Cl:21][CH2:22][C:23]1[N:17]=[C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:20][CH2:19][C@H:4]4[C:5]=23)[S:18][CH:24]=1
Reactant: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: O=C1c2ccccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Yield: 41.6 %

Procedure:
A yellow suspension of 4.86 g (0.0171 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[l,5-a][1,4]benzodiazepine-1-thiocarboxamide in 120 ml of dioxan was treated with 2.38 g (0.0188 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 48 hrs. The solution obtained was cooled and completely freed from the solvents. The product was chromatographed over silica gel with dichloromethane/ethyl acetate 1:1 as the eluent and recrystallized from hot ethyl acetate. There were obtained 2.54 g (42%) of (S)-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepin-9-one as white crystals; m.p. 248°-249° and [α]D20 =-186.1° (DMF, c=1%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:40]=[CH:39][C:29]2=[N:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37](=[O:38])[N:28]2[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:40]=[CH:39][C:29]5=[N:30][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=6[C:37](=[O:38])[N:28]5[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: O=c1c2ccccc2nc2ccc(Cl)nn12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5nc6ccccc6c(=O)n5n4)cc3CC[C@@H]12
Yield: 59.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-10H-pyridazino[6,1-b]quinazolin-10-one (107 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-10% methanol/ethyl acetate eluent gradient) to give 103 mg (62%) of the title compound as an amorphous foam. mp 110°-114°. FDMS: m/e=456. α[D]589 =+54.77 (c=0.49, chloroform).
Reaction SMILES: ClC1C=CC(O[C:7]2[CH:31]=[CH:30][C:10]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:9][CH:8]=2)=CC=1.[CH2:34]([N:36]1C2C=CC(CN3CCC(C4C=CC(NC(=O)C(C)C)=CC=4)CC3)=CC=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35].C(N1C2C=CC(C=O)=CC=2C2C1=CC=CC=2)C.CC(C)C(NC1C=CC=C(C2CCNCC2)C=1)=O>>[CH2:34]([N:36]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:30][C:31]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Reactant: CCn1c2ccccc2c2cc(CN3CCC(c4ccc(NC(=O)C(C)C)cc4)CC3)ccc21
Agent: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)ccc21
Yield: 95 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[4-(4-CHLOROPHENOXY)BENZYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE (Example 108) N-(4-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 9-ethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide afforded N-(3-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide (37 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.24-6.29 (m, 12H), 4.37 (q, 2H, J=7.2 Hz), 3.82 (s, 2H), 3.23-3.06 (m, 2H), 2.65-2.38 (m, 2H), 2.31-2.11 (m, 2H), 2.01-1.73 (m, 4H), 1.43 (t, 3H, J=7.2 Hz), 1.25 (d, 6H, J=4.0 Hz); ESMS m/e: 454.3 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][C:4]#[C:5][C:6](=[O:8])[CH3:7].[H][H]>[Pd].C1COCC1>[CH3:1][C@H:2]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)C#CC[C@H](C)COC1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)CCC[C@H](C)COC1CCCCO1
Yield: 100 %

Procedure:
A 50 g solution (222.9 mmol) of (S)-6-methyl-7-[(RS)-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hept-3-in-2-one and 5 g palladium on carbon (10% Pd/C) in 400 ml of THF is hydrogenated for one hour at 8 bar hydrogen at room temperature. The catalyst is then filtered off, rewashed with little solvent and the solvent is removed in vacuo. 50.9 g of product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].CS([Cl:17])(=O)=O.C(N(C(C)C)CC)(C)C.Cl>ClCCl>[Cl:17][CH2:11][C:4]1[CH:5]=[C:6]([F:10])[C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: CSc1c(F)cc(CO)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1c(F)cc(CCl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of [3,5-difluoro-4-(methylthio)-phenyl]-methanol (24.0 g, 0.126 mol) in dichloromethane (300 mL) cooled in an ice bath was added methanesulfonylchloride (16.9 g, 0.147 mol) in portions followed by diisopropyl-ethylamine in portions. The mixture was allowed to warm to room temperature, and stirred for 18 hours. 4-dimethyl-aminopyridine was added and the mixture was heated to reflux for 2 hours, cooled, and stirred at room temperature for 18 hours. The mixture was poured into dilute HCl and extracted with dichloromethane once (75 mL) after separating. The combined extracts were washed with dilute sodium chloride, dried using magnesium sulfate, and concentrated. Purification by silica gel chromatography using 5% ethyl acetate in hexanes gave 5-(chloromethyl)-1,3-difluoro-2-(methylthio)benzene as a clear colorless liquid (24.9 g, 95%). 1H NMR (CDCl3/400 MHz) 6.92-6.96 (m, 2H), 4.49 (s, 2H), 2.44 (s, 3H). HRMS m/z 207.9893 (M+, calcd 207.9925).
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]([F:9])=[CH:5][C:4]=1[CH3:10]
Reactant: COC(=O)Oc1ccc(F)cc1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
4-Fluoro-2-methylphenyl methyl carbonate (D14) (2.5 mmol, 468 mg) was dissolved in concentrated sulphuric acid under argon and cooled to 0° C. KNO3 (2.5 mmol, 253 mg, 1 eq) was then added cautiously while keeping the temperature around 0° C. The mixture was then allowed to stir for 2 h while warming up to room temperature, then it was poured onto ice cautiously and extracted with ether twice. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a light brown solid (2.36 mmol, 540 mg, 94% yield). 1H NMR (CDCl3) 7.92 (1H, d), 7.18 (1H, d), 3.95 (3H, s), 2.33 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1>ClCCl>[CH3:33][O:32][C:25]1[CH:24]=[CH:23][C:22]([Br:21])=[CH:27][C:26]=1[S:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:30])=[O:29]
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(NS(=O)(=O)c2cc(Br)ccc2OC)ccc1Oc1cncc(Cl)c1

Procedure:
Alternatively, poly(4-vinylpyridine) (250 mg, 60 mesh) can be washed with dichloromethane (2×7 mL) and diluted into dichloromethane (2 mL). The aniline produced in Example 1 (29.2 mg, 0.1 mmol) can be added followed by 5-bromo-2-methoxybenzenesulfonyl chloride (59 mg, 0.25 mmol). The reaction vessel is then agitated for ten hours and ArgoPore-NH2 (0.50 g, 1.11 mmol/gram loading) is added along with dichloromethane (6 mL). The reaction vessel is agitated for three hours and the solvent is collected. The resin is washed with dichloromethane (2×6 mL) and the dichloromethane is combined and evaporated to yield the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].C1(S([CH:16]2[CH2:20][C:19]3([CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])[NH:18][CH:17]2[C:27]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)[CH:30]=[C:29]([CH3:43])[N:28]=2)(=O)=O)C=CC=CC=1.C(O)(=O)C>C1COCC1>[CH3:25][N:22]1[CH2:23][CH2:24][C:19]2([N:18]=[C:17]([C:27]3[CH:32]=[C:31]([C:33]4[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=4)[CH:30]=[C:29]([CH3:43])[N:28]=3)[CH2:16][CH2:20]2)[C:21]1=[O:26]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2NC3(CCN(C)C3=O)CC2S(=O)(=O)c2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2=NC3(CC2)CCN(C)C3=O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
Potassium tert-butoxide (2.22 mL, 3.78 mmol) was added dropwise to a solution of 3-(benzene-sulfonyl)-7-methyl-2-[6-methyl-4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 16) (1 g, 1.89 mmol) in THF (20 mL) at 00° C. under N2 and the reaction was stirred at 0° C. for 1 hour. Acetic acid (0.22 mL, 3.78 mmol) was added and the reaction was stirred for 5 minutes. The solid was filtered off and the solvent was evaporated to afford a crude oil. This was purified using a Biotage SP4, 25 g SNAP cartridge, eluting with 0 to 10% MeOH in EtOAc to afford 7-methyl-2-[6-methyl-4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (641 mg, 1.4892 mmol, 78.9% yield) as a pale yellow oil;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH3:8]>C(Cl)Cl>[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:14])=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CCc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a cooled solution of 9.6 g (0.11 mole) of morpholine in 25 ml methylene chloride is added 8.4 g (0.05 mole) of 4-ethylbenzoyl chloride dropwise. The reaction is stirred 30 minutes and a white precipitate formed. The mixture is washed three times each with 25 ml of water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 10.6 g of yellow oil.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>>[CH:22]1[N:21]2[CH:24]=[CH:25][CH:26]=[C:20]2[CH:19]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([O:17][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)=[CH:13][CH:12]=3)[N:23]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: FC(F)(F)c1cccc(CCBr)c1
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCc3cccc(C(F)(F)F)c3)cc12

Procedure:
2-Pyrrolo[1,2-c]pyrimidin-3-yl-6-[2-(3-trifluoromethyl-phenyl)-ethoxy]-chromen-4-one oxime was prepared in 22% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 1-(2-Bromo-ethyl)-3-trifluoromethyl-benzene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O1CCCCC1O[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[Br:20][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCC/C=C\CCCOC1CCCCO1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC/C=C\CCCBr
Temperature: 0 °C
Yield: 90 %

Procedure:
To an ice-cool solution of triphenylphosphine (0.72 g, 2.74 mmol) and bromine (0.41 g, 2.6 mmol) in CH2Cl2, a solution of (4Z)-1-(tetrahydropyran-2-yloxy)-4-decene (16) (0.41 g, 1.71 mmol), prepared according to Example 16, in methylene chloride was added dropwise. Isolation and purification by conventional means afforded the product 17 in 90% yield (0.33 g). 1H NMR (200 MHz ) δ: 5.42 (dtt, J=11.0, 7.0, 7.0, 1.0, 1.0 Hz, 2H, CH=CH-4, 5); 3.41 (t, J=6.6, 6.6 Hz, 2H CH2 -1, 2.20 (dt, J=7.0, 7.0 Hz, 2H, CH2 -3); 2.04 (dr, J=6.5, 6.5 Hz, 2H, CH2 -6); 1.91 (tt, J=6.5, 6.5, 6.5 Hz, 2H, CH2 -2); 1.30 (m, 6H, CH2 -7, 8, 9); 0.89 (t, J=7.0 Hz, CH3). MS [EI, m/z(%)] 220 (M+ -8), 218 (M+, 8), 164 (12), 162 (12), 150 (23), 148 (23), 135 (8), 109 (12), 97 (44), 95 (14), 83 (55), 82 (14), 81 (37), 79 (15), 70 (21), 69 (100), 67 (39), 56 (29), 55 (93), 54 (20), 43 (21), 42 (20), 41 (92), 39 (30). IR (CCl4, cm-1) 3008 (cis CH=CH), 1246 (RCH2CH2Br), 649, 566 (C--Br).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[N:7]1[C:8]2[C:3](=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=3[F:30])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=2)[CH2:4][CH2:5][C:6]1=[O:22]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reaction time: 3.5 h

Procedure:
A A mixture of 24 mg of 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1), 28 mg of 2,4-difluorophenylboronic acid, 3 mg of Pd(Ph3P)4, and 0.15 mL of a 1M aqueous Na2CO3 solution in 2 mL of toluene and 0.2 mL of EtOH in a 10 mL flask equipped with a reflux condenser was evacuated and purged three times with Ar. The mixture was heated to reflux and stirred at this temperature for 3.5 h, then cooled and diluted with 15 mL EtOAc and 10 mL of saturated aqueous NaHCO3. The phases were separated and the organic phase was dried over MgSO4 and concentrated. The resulting residue was purified by preparative thin-layer chromatography, eluting with 3:1 hexanes-EtOAc, to yield 1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone. Mass spectrum (ESI) 434.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.50 (d, J=8.0 Hz, 2H); 7.35 (t, J=8.0 Hz, 1H), 7.32 (m, 1H); 6.96, (m, 2H); 6.52 (d, J=2.5 Hz, 1H); 5.89 (d, J=2.5 Hz, 1H); 3.69 (s, 3H); 2.64-3.00 (m, 4H).