Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][O:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N=C(N)COCCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccc(F)cc1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=370.0 [M+H+].
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:14]([CH2:15][OH:16])=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[C:11]([F:20])[C:10]=2[F:21])[CH2:3]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:17]([C:12]1[C:11]([F:20])=[C:10]([F:21])[C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[C:14]([CH:13]=1)[CH:15]=[O:16])(=[O:19])[CH3:18]
Reactant: CC(=O)c1cc(CO)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)c1cc(C=O)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 1-[4-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl-phenyl]-ethanone (Intermediate 10, 3.2 g, 9.72 mmol) in CH2Cl2/CH3CN mixture (20 mL, 1:1 v/v) was added NMO (2.2 g, 19.44 mmol) followed by TPAP (340 mg, 0.97 mmol) and mixture stirred for 2 hours at room temperature. The reaction mixture filtered thorough silica gel bed and washed with EtOAc. The organic phase concentrated under reduced pressure to give the title compound as a yellow crystalline solid. Yield: 3.0 g (94%).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([O:13][CH:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28](OCC)OCC)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]>C(Cl)(Cl)Cl>[CH2:11]([O:13][CH:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[NH:10][C:1](=[O:9])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[O:4]2)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]
Reactant: NC(=O)c1ccccc1O
Reactant: CCOC(COc1ccc(CC(OCC)C(=O)OC)cc1)OCC
Solvent: ClC(Cl)Cl
Product: CCOC(Cc1ccc(OCC2NC(=O)c3ccccc3O2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a stirred solution of polyphosphonate ethyl ester (PPE) (3.46 g, 8.0 mmol) in chloroform (10 mL) was added salicylamide (548 mg, 4.0 mmol) followed by addition of a solution of (±)-Methyl 2-ethoxy-3-[4-[(2,2diethoxy)ethoxy]phenyl]propanoate (1.28 g, 4.4 mmol) obtained in preparation 2, in chloroform (10 mL) dropwise at 25-30° C. The reaction mixture was immersed in a preheated oil bath at 70° C. and refluxed 12 h. The reaction mixture was cooled to room temperature and CHCl3 was removed under reduced pressure. The resultant residue was neutralised (pH=7.0) with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was chromatographed on silica gel using a gradient of 5-25% of ethyl acetate in pet ether as eluent to afford the title compound (1.15 g, 72%) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: C1COCCN1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCOCC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 101 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with morpholine (15.7 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(morpholine-4-yl)-5-oxopyrimido[4,5-b][1,5]diazocine (87.8 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[Cl:21])[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=[CH:16][C:15]=2[Cl:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2Cl)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(-c3ccccc3)ccc2Cl)c1
Temperature: 80 °C

Procedure:
[3-(5-Bromo-2-chloro-benzoylamino)-phenyl]-acetic acid ethyl ester (198 mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. for 25 min. The crude product was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[NH2:12][OH:13].[OH-].[Na+]>CCO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2/[CH:10]=[N:12]\[OH:13])[CH:3]=[CH:2]1
Reactant: NO
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C\c1cccc2cc[nH]c12
Yield: 80 %

Procedure:
1H-indole-7-carbaldehyde (1 g, 6.9 mmol) in EtOH (30 mL), hydroxylamine (527 mg, 7.6 mmol) in water (10 mL) was added followed by 50% NaOH (1.38 g in 1.38 mL water) was added. After refluxing for 2 h, ethanol was removed under reduced pressure. Resultant slurry was extracted with ethylacetate. Organic layer was washed with water, brine and dried. Crude residue was column chromatographed on a silica gel eluting with (30% EtOAc/hexanes) to afford (Z)-1H-indole-7-carbaldehyde oxime in 80% yield.
Reaction SMILES: C([Mg]Br)C.O1CCCCC1[O:11][CH2:12][C:13]#[C:14][CH2:15][C:16]#[CH:17].I[CH2:19][C:20]#[C:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[O:23]([CH2:22][C:21]#[C:20][CH2:19][C:17]#[C:16][CH2:15][C:14]#[C:13][CH2:12][OH:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ICC#CCOc1ccccc1
Reactant: C#CCC#CCOC1CCCCO1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC#CCC#CCC#CCOc1ccccc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
3.99 ml (2.15 g, 0.016 mol) of a 4.05N solution of ethylmagnesium bromide in ether was added dropwise under argon to a solution of 2.879 (0.0161 mol) of hexa-2,5-diyn-1-ol tetrahydropyranyl ether [D. Van der Steen et al, Recueil 82, 1015 (1963)] in 30 ml of tetrahydrofuran maintained at -20° C. After the addition was finished, the reactionmixture was stirred for 2 hours further at -20° C. Then, 52.8 mg (0.53 mmol) of cuprous chloride was added. The mixture was stirred for 20 additional minutes, warmed to room temperature and 2.2 g (0.008 mol) of 1-iodo-4-phenoxybut-2-yne was added. The reaction mixture was then stirredat room temperature for 3 hours, poured into 50 ml of saturated ammonium chloride solution and extracted with ether (3×50 ml). The combined extracts were dried over sodium sulfate and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography on80 g of silica gel, using hexane:ether (90:10) as eluant thus obtaining thetetrahydropyranyl ether of 10-phenoxydeca-2,5,8-triyn-1-ol, as an oil. Thisproduct was stored in dry ice.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
A mixture of 5-phenyl-2-oxindole (39 mg, 0.18 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (48 mg, 0.18 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 44 mg (54%) of the title compound as a red solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:9]=1.CI>CC(C)=O>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N:18]([CH3:1])[S:19]([CH3:22])(=[O:20])=[O:21])[CH:9]=1
Reactant: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cl)cc1N(C)S(C)(=O)=O
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Potassium carbonate (12.5 g) was added to a stirred solution of methyl 4-chloro-2-(N-methylsulphonylamino)benzoate (7.5 g) in acetone. The mixture was stirred for 15 minutes and methyl iodide (8.0 g) was added. The resultant mixture was stirred at room temperature for 1 hour and left to stand overnight. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate and washed with sodium hydroxide solution (2M) and water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give methyl 4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoate (4.9 g) as a white solid, m.p. 73-75° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][CH3:19])[C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][CH3:19])[C:10]([F:17])=[C:11]([NH:33][CH2:32][CH2:31][NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[C:12]=3[O:14][CH3:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNc1c(F)c(F)c(OC)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNc1c(F)c(NCCNc2ccccn2)c(OC)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-methylamino-4-oxoquinoline-3-carboxylic acid (500 mg, 1.54 mmol), N-2-pyridyl-1,2-ethanediamine (423 mg, 3.03 mmol) and triethylamine (0.430 mL, 3.09 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with water, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (hexane: EtOAc 1:1→EtOAc) to give 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methylamino-7-[2-(2-pyridylamino)ethylamino]-4-oxoquinoline-3-carboxylic acid (373 mg, 55%) as a yellow solid.
Reaction SMILES: OC(C)C[NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.O[CH:18](C)CN(CC(O)C)C1C=CC(C(OCC)=O)=CC=1>>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH:12]([CH3:13])[CH3:18])=[O:10])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(NCC(C)O)cc1
Reactant: CCOC(=O)c1ccc(N(CC(C)O)CC(C)O)cc1
Product: CC(C)OC(=O)c1ccc(N)cc1

Procedure:
ethyl N-(2-hydroxypropyl)-p-aminobenzoate and ethyl N,N-bis(2-hydroxypropyl)-p-aminobenzoate, which are sold under the trade name Amerscreen P
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.Cl.[F:26][C:27]1([F:35])[CH2:32][CH2:31][CH2:30][C@@H:29]([NH2:33])[C@H:28]1[NH2:34].CCN(C(C)C)C(C)C>C(#N)C>[NH2:34][C@H:28]1[C:27]([F:35])([F:26])[CH2:32][CH2:31][CH2:30][C@H:29]1[NH:33][C:4]1[N:3]=[C:2]([Cl:1])[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (100 mg, 0.269 mmol) and cis-3,3-difluorocyclohexane-1,2-diamine hydrochloride (75 mg, 0.404 mmol) and DIPEA (118 μL, 0.674 mmol) in acetonitrile (449 μL) was stirred at 100° C. for 3 d. The reaction mixture was concentrated to a brown oil and reconstituted in DMF (1 mL). The residue was purified by preparative HPLC, the appropriate fraction was collected, and excess acetonitrile was evaporated. The residue was treated with saturated aq sodium carbonate and extracted with EtOAc (3×20 mL). The organic layers were combined, dried over sodium sulfate, and concentrated to give the title compound as a colorless residue (13.7 mg, 10%). [M+H] calc'd for C22H24ClF3N4O3, 485; found, 485.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClC(Cl)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
4-chloro-3-nitroaniline, 10.1 g (0.058 mole), is dissolved in 100 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at room temperature while nonanoylchloride, 10.5 g (0.067 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column. The product does not crystallize from dichloroethane which was removed. The product was crystallized from 80% ethanol. There is obtained N-(4-Chloro-3-nitrophenyl) nonanamide (M.P. 44.5-45.0). Analysis shows 8.9% nitrogen and 11.26% chlorine as against calculated values of 8.96% and 11.33% respectively for C15H21ClN2O3.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1([F:46])[C:44]2[C:39](=[CH:40][CH:41]=[C:42](O)[CH:43]=2)[C:20]2=[N:21][O:22][C:23]([C:24]3[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:26][N:25]=3)=[C:19]2[CH2:18]1>N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[C:20]1=[N:21][O:22][C:23]([C:24]3[C:28]([C:29]([F:31])([F:30])[F:32])=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:26][N:25]=3)=[C:19]1[CH2:18][C:17]2([F:46])[F:16])(=[O:8])=[O:9]
Reactant: Oc1ccc2c(c1)C(F)(F)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2c(c1)C(F)(F)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Yield: 91.3 %

Procedure:
Trifluoromethanesulfonic anhydride (0.012 mL, 0.069 mmol) was added to a solution of 5,5-difluoro-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Preparation 66D, 0.020 g, 0.046 mmol) in pyridine (5.0 mL) at 0° C. over a period of 5 min. The reaction mixture was stirred at 0° C. for ten minutes, warmed to room temperature, and stirred overnight. The reaction mixture was concentrated, and the yellowish-brown residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The ethyl acetate layer was collected, washed with 1N aqueous Hydrochloric acid (10 mL), saturated aqueous solution of sodium bicarbonate (10 mL), brine (10 mL), and dried over sodium sulfate. Concentration followed by purification by silica gel chromatography eluting with a mixture of ethyl acetate and hexane (10%-20%) afforded 5,5-difluoro-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl trifluoromethanesulfonate (0.024 g, 0.042 mmol, 92% yield) as a viscous liquid. The product had an HPLC ret. time=3.34 min. (condition B). LC/MS M+1=566.3, 568.4.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.CN(C)C=O.[NH2:13][C:14]1[C:19]([NH2:20])=[CH:18][C:17]([CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:16]([O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH:15]=1>C(OCC)(=O)C>[CH3:43][S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][C:16]2[C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:18][C:19]3[NH:20][C:6]([C:3]4[CH:4]=[CH:5][NH:1][N:2]=4)=[N:13][C:14]=3[CH:15]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1cc[nH]n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1cc2[nH]c(-c3cc[nH]n3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
10.0 mg of 1H-pyrazole-3-carboxaldehyde was added to an N,N-dimethylformamide (1 ml) solution of 49.0 mg of t-butyl 2-(4,5-diamino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidine-1-carboxylate obtained in Example 306 (step 3), and the reaction liquid was stirred overnight at 90° C. After cooled, the reaction liquid was diluted with ethyl acetate, washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a brown solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH:3]=[C:4]([C:23]1[CH:24]=[C:25]([C:29](=[O:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)[C:5]1[N:13](S(C2C=CC=CC=2)(=O)=O)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][CH:2]([CH3:32])[CH:3]=[C:4]([C:23]1[CH:24]=[C:25]([C:29](=[O:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)[C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1
Reactant: CC(=O)c1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A solution of 1-(3-(3-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)phenyl)ethanone (1.5 g, 3.4 mmol) in ethanol (30 mL) and tetrahydrofuran (60 mL) was treated with an aqueous sodium hydroxide solution (10%, 20 mL). The reaction was stirred at 80° C. for 16 h. Most of the solvent was removed in vacuo. The resulting precipitate was removed by filtration and washed with water (50 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (30 g, 200-300 mesh, 15% ethyl acetate/petroleum ether) afforded 1-(3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)phenyl)ethanone (0.85 g, 82.2%) as an off-white solid: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.60 (s, 1H), 8.20 (dd, 1H, J1=4.8 Hz, J2=1.5 Hz), 7.96 (d, 1H, J=8.1 Hz), 7.90-7.87 (m, 1H), 7.78 (s, 1H), 7.48-7.46 (m, 2H), 7.09 (dd, 1H, J1=7.5 Hz, J2=5.1 Hz), 6.44 (d, 1H, J=1.8 Hz), 6.24 (d, 1H, J=9.9 Hz), 2.63-2.56 (m, 1H), 2.57 (s, 3H), 1.08-1.02 (m, 6H).
Reaction SMILES: ClC1C=NC=C(Cl)C=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:25])[C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH3:27][O:26][C:14]1[C:15]2[N:16]([CH3:25])[C:17]3[C:22](=[CH:21][C:20]([NH:24][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:19][CH:18]=3)[C:23]=2[C:11]([C:9]([NH2:8])=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(N)=O)c2c3cc(NS(C)(=O)=O)ccc3n(C)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide (75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine (28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. The solution obtained, was added with a solution of methane sulphonyl chloride (30 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixture was stirred for 1 hr. THF was evaporated and the solid was washed with water to get crude solid which was column chromatographed using 10% methanol in chloroform to give N-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-methanesulphon-amido-9H-4-carbazolecarboxamide(20 mg),mp>250° C.
Reaction SMILES: C(O)(C)C.Cl[C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][N:7]=1.Cl.[N:14]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>O>[Cl:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]([NH:23][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:11]=1
Reactant: Nn1ccc2ccccc21
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Clc1cc(Nn2ccc3ccccc32)ncn1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
To 250 ml isopropanol, was added 4,6-dichloropyrimidine (12 g), 1 ml ethereal -HCl, and 1H-indol-1-amine (15 g). After stirring at 90° C. for seven hours, the mixture was poured into 300 ml iced water, stirred for five minutes, then extracted three times with 200 ml of ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:15]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1=Cc2ccccc2C1
Reactant: ClCC=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=Cc1ccccc1)CC1C=Cc2ccccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 98% indene (364 mmoles) in 300 ml of THF was cooled to -78° C. under argon. An equimolar amount of n-butyllithium was added to the solution. The resulting mixture was allowed to warm to room temperature. It was then charged to an equimolar amount of 95% cinnamyl chloride (58.45 g) in 100 ml of THF at -30° C. The mixture was then allowed to warm to room temperature and react for one hour to form cinnamyl indene. The cinnamyl indene was concentrated down to a residue under strong vacuum, and then washed and concentrated twice with 100 ml of hexane. The residue was washed a third time with 100 ml of warm hexane and filtered while hot. The filtrate was again concentrated down to a residue under vacuum. The cinnamyl indene filtrate melted at 55°-69° C. Recovery yield was 62%.