Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([F:17])[C:3]=1[CH3:18].[C:19](OC(=O)C)(=O)[CH3:20].CO[CH:28](OC)[N:29]([CH3:31])C.C1(N)CC1>C(Cl)Cl.C(O)C.CCCCCC>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:5]([C:6]([C:8](=[CH:31][NH:29][CH:28]2[CH2:20][CH2:19]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([F:17])[C:3]=1[CH3:18]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Br)c(C)c1F
Reactant: CC(=O)OC(C)=O
Reactant: COC(OC)N(C)C
Agent: NC1CC1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Br)c(C)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 150 ml of methylene chloride was dissolved 30.0 g of ethyl 4-bromo-2,5-difluoro-3-methylbenzoylacetate, and 19.1 g of acetic anhydride and 22.3 g of N,N-dimethylformamide dimethyl acetal were added to the solution, after which the resulting mixture was stirred at room temperature for one hour. Thereafter, the solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in 90 ml of ethanol and 5.90 g of cyclopropylamine was added thereto, after which the resulting mixture was stirred at room temperature for 30 minutes. The solvent was then removed by distillation under reduced pressure. To the residue obtained was added n-hexane and the crystals formed were collected by filtration, to obtain 35.7 g of colorless, crystalline ethyl 2-(4-bromo-2,5-difluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate.
Reaction SMILES: [N:1]1([C@:4]23[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:53][S:54]([CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)(=[O:56])=[O:55]>O1CCOCC1>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:4]1([NH:1][CH2:2][CH2:3][N:60]1[CH2:61][CH2:62][CH:57]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:58][CH2:59]1)[CH2:21][CH2:20]2
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 51.1 %

Procedure:
To a flask containing a suspension of the crude ethyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.055 g, 0.094 mmol) in 1,4-dioxane (2 mL) was added Hunig's base (0.098 mL, 0.561 mmol) followed by 4-(methylsulfonyl)piperidine (0.076 g, 0.468 mmol). The mixture was heated to 100° C. for 20.5 h then was cooled to rt and was purified by flash chromatography using a 20-80% ethyl acetate in hexanes gradient and a 12 g silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.036 g, 0.048 mmol, 51.2% yield) as an off-white solid. LCMS: m/e 751.7 (M+H)+, 2.29 min (method 1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCOCCBr
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
To a stirred mixture of 4-amino-1-benzylpiperidine (1.53 mL, 7.5 mmol), K2CO3 (2.28g, 16.5 mmol) and DMF (15 mL) heated at 50° C. was added dropwise over 60 min bis(2-bromoethyl) ether (0.96 mL, 7.65 mmol). After stirring for 6 hours at 80° C., the solvent was removed by blowing with a stream of nitrogen over 2 hours. The residue was purified on a silica gel column to give 1.7 g (87%) of 4-(1-benzyl-piperidin-4-yl)-morpholine as a waxy solid.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:39]=[CH:38][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:30])=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][CH:66]2[CH2:68][O:67]2)=[CH:60][CH:59]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:32]([NH:31][C:29](=[O:30])[NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:68][C@H:66]([OH:67])[CH2:65][O:64][C:61]4[CH:62]=[CH:63][C:58]([OH:57])=[CH:59][CH:60]=4)=[CH:39][CH:38]=3)[CH2:13][CH2:14]2)=[O:19])=[CH:23][CH:24]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)Nc1ccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 29.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-{[(hexylamino)carbonyl]amino}benzyl)-1-piperidinecarboxamide formate (0.29 g, 0.54 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.220 g, 0.54 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.143 g, 0.159 mmol).
Reaction SMILES: ClC1C=C(C=CC=1)C([O:7][CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.O>CC(C)=O>[OH:7][CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[S:9]1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(c2ccncc2)SC(O)C(=O)N1
Temperature: 70 °C
Reaction time: 44 h
Yield: 19 %

Procedure:
2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (1.37 g) and water (1 ml) were dissolved in acetone (20 ml) and the mixture was stirred at 70° C. for 44 hours. The mixture was chromatographed on silica gel (Wakogel C-200) column, using chloroform-methanol (=30:1) as an eluant to give the titled compound (0.16 g, yield 19.1%) as red needles.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH2:4][CH2:3]1.[H][H]>[Pd].CCOC(C)=O.CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccccc1NC1CCN(C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1ccccc1NC1CCN(C)CC1

Procedure:
A suspension of (E)-methyl 3-(2-(1-methylpiperidin-4-ylamino)phenyl)acrylate (330 mg, 1.20 mmol) and palladium on carbon (10% wt, 128 mg, 0.12 mmol) in 20 mL EtOAc was stirred under a balloon of hydrogen overnight. The suspension was diluted with MeOH (50 mL) and filtered through a pad of celite. The celite pad was rinsed with 10 mL of MeOH. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (300 mg, 90.4%). 1H-NMR (CDCl3) δ 7.14-7.08 (m, 1H), 7.04-7.01 (m, 1H), 6.67-6.63 (m, 2H), 3.76-3.74 (m, 1H), 3.69 (s, 3H), 3.35 (brs, 1H), 2.82-2.77 (m, 4H), 2.65-2.60 (m, 2H), 2.31 (s, 3H), 2.19-2.06 (m, 4H), 1.61-1.49 (m, 2H). MS (ESI): 277.2 (M+1, 100%).
Reaction SMILES: C1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)CC1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.[C:26](=O)([O-])[O-].[Li+].[Li+]>>[OH:12][C@H:4]1[CH2:8][C@@H:7]([CH3:26])[N:6]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C@H:5]1[CH3:9]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1C[C@H](O)[C@H](C)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
By an operation in the same manner as in Example 53 and using (2S,3S,5R)-2,5-dimethylpyrrolidin-3-ol 0.5 oxalate (153 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (277 mg) and lithium carbonate (200 mg), the title compound was obtained as colorless oil (yield: 121 mg, yield: 45%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:22])([F:21])[C:8]([C:17]([F:20])([F:19])[F:18])([OH:16])[CH2:9][CH2:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>O1CCCC1>[C:23]([O:14][C:12]([CH3:13])([CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([F:18])([F:19])[F:20])([OH:16])[C:7]([F:21])([F:22])[F:6])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: CC(C)(O)CCCC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(C)(C)CCCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a flame-dried, nitrogen-purged 500 mL 3-neck roundbottom flask with 250 mL pressure-equalizing addition funnel and magnetic stirbar was charged 156 mL n-butyl lithium (250 mmol, 2 equiv., 1.6 M in hexanes). A degassed solution of 1,1,1-trifluoro-6-methyl-2-(trifluoromethyl)heptane-2,6-diol (III) (˜125 mmol, 1 eq.) in 100 mL anhydrous tetrahydrofuran was charged to the addition funnel and added to the reaction mixture dropwise at 0° C. over 30 minutes. The reaction mixture was warmed for 15 minutes on a hot water bath to ensure the reaction was complete. The reaction vessel was cooled to 0° C. and 14.4 g methacryloyl chloride (138 mmol, 1.1 eq.) was added dropwise and allowed to stir for 15 minutes. The addition funnel was replaced with a reflux condenser and the reaction heated to reflux for 20 hours. After the reaction was complete, it was cooled to 0° C. and quenched with dilute HCl solution until the pH was less than 5.0. The reaction solution was neutralized with saturated aqueous sodium bicarbonate until the pH was greater than 8. The product was extracted into ethyl ether and the organic phase washed sequentially with aqueous sodium bicarbonate, water, and brine and then dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. The crude product mixture was purified via silica gel column chromatography (20:1 hexane:ethyl acetate eluent) to afford 14.7 g (35%) of 1,1,1-trifluoro-2-trifluoromethyl-2-hydroxy-6-methyl-hept-6-yl methacrylate (IV) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(O)cc1
Yield: 24.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.017 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[CH:6]=1.[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH3:12][C:11]1([C:7]2[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][CH:8]=2)[O:16][CH2:15][CH2:14][O:13]1
Reactant: OCCO
Reactant: COCOc1cccc(C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COCOc1cccc(C2(C)OCCO2)c1
Yield: 60 %

Procedure:
A mixture of 3-(acetyl)phenyl methoxymethyl ether (3.6 g, 20 mmol), ethylene glycol (3.72 g, 60 mmol) and pyridinium tosylate (0.075 g, 0.3 mmol, 3 mol %) in benzene (200 mL) was azeotropically refluxed for 8 h. The reaction was concentrated and the resulting residue was diluted with ethyl ether (150 mL) and washed with saturated aqueous bicarbonate (2×50 mL) and brine (100 mL). The ethyl ether solution was dried (K2CO3) and concentrated. The residue was suspended in n-hexanes and the by-product was precipitated. The n-hexane solution was then separated and concentrated to obtain the desired product (2.69 g, 61%); TLC Rf: 0.5 (30% EtOAc/n-hexanes).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[N:21]1([C:2]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccccc1C1(Cl)c2ccccc2-c2sccc21
Solvent: CC#N
Product: Cc1ccccc1C1(n2ccnc2)c2ccccc2-c2sccc21
Yield: 62.4 %

Procedure:
6.1 g (20 mmoles) of crude 4-chloro-4-(2-methyl-phenyl)-4H-indeno[1,2-b]thiophene were taken up in 30 ml of acetonitrile, 4.1 g (60 mmoles) of imidazole were added and the mixture was heated under reflux for 5 hours. The crude product was then precipitated as a syrup by adding 70 ml of water. The supernatant solution was decanted off and the crude product was taken up in ether. The ether solution was dried and evaporated. The residue was taken up in 100 ml of 2 N hydrochloric acid, the insoluble material was separated off and, after cooling, the base was liberated again with sodium hydroxide solution and extracted with ether. The organic phase was dried over sodium sulphate and concentrated. 4.1 g (62.1% of theory) of 4-(imidazol-1-yl)-4-(2-methyl-phenyl)-4H-indeno[1,2-b]thiophene of melting point 75° C. were obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[OH:30]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[O:30][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5c(F)cccc5F)nc34)cc21
Temperature: 120 °C
Yield: 54 %

Procedure:
Prepared in a manner similar to that described in Example 79 using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 61 mg, 0.205 mmol) and 2,6-difluorophenol (133 mg, 1.024 mmol, Aldrich) and heating at 120° C. for 5 min in a microwave (Biotage Initiator). Purification by silica gel (100% DCM to 20% MeOH/DCM) provided 2-(2-(2,6-difluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (54% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.51-2.57 (m, 2H) 3.34-3.39 (m, 2H) 6.86 (d, J=2.35 Hz, 1H) 6.91 (br. s., 1H) 7.40-7.47 (m, 2H) 7.48-7.54 (m, 1H) 7.55 (d, J=1.96 Hz, 1H) 7.57 (s, 1H) 7.87 (dd, J=8.02, 0.98 Hz, 1H) 8.11 (dd, J=7.43, 1.17 Hz, 1H) 8.58 (d, J=9.00 Hz, 1H) 10.96 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −126.54 (2F, s). MS (ESI, pos. ion) m/z: 392.1 (M+1).
Reaction SMILES: [Cl:1][C:2]12[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[CH:9][CH:3]1[C:4]([O:6][C:7]2=[O:8])=O.[NH2:16][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:18][C:19]([OH:21])=[O:20]>C(O)(=O)C>[Cl:1][C:2]12[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[CH:9][CH:3]1[C:4]([N:16]([CH:17]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:18][C:19]([OH:21])=[O:20])[C:7]2=[O:8])=[O:6]
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Reactant: O=C1OC(=O)C2(Cl)C(Cl)=C(Cl)C(Cl)=CC12
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)C3C=C(Cl)C(Cl)=C(Cl)C3(Cl)C2=O)cc1
Yield: 91.2 %

Procedure:
A stirred mixture of 2,3,4,5-tetrachlorophthalic acid anhydride (2.85 g, 10.0 mmol) and 3-amino-3-(4-methoxyphenyl)propionic acid (1.95 g, 10.0 mmol) in 25 mL of acetic acid under nitrogen was heated to reflux for 4.5 hours. A solid formed as the reaction mixture cooled. The resulting slurry was filtered and the solid dried in vacuo (60° C., <2 mm) to afford 4.24 g (92%) of 3-(2,3,4,5-tetrachlorophthalimido)-3-(4-methoxyphenyl)propionic acid as an off-white solid contaminated with ~1% acetic acid: mp 235.6°-238° C.; 1H NMR (DMSO-d6) δ 12.44 (br s, 1H, COOH), 7.36 (d, J=8.7 Hz, 2 H), 6.90 (d, 1 H, J=8.7 Hz), 5.64 (m, 1 H), 3.72 (s, 3 H), 3.35 (m, 2 H); 13C NMR (DMSO-d6) δ 171.5, 163.0, 158.8, 138.4, 129.9, 128.6, 128.2, 127.6, .113.8, 55.0, 50.2, 35.6. Anal. Calcd for C18H11NO5Cl4. Theory: C, 46.68; H, 2.39; N, 3.02. Found: C, 46.58; H 2.31; N, 2.91.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:39][C:40]1[S:44][N:43]=[C:42]([CH3:45])[CH:41]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:39][C:40]5[S:44][N:43]=[C:42]([CH3:45])[CH:41]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1cc(N)sn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)sn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
A solution of the product of Example 19C (290 mg, 0.546 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with 5-amino-3-methylisothiazole hydrochloride (90.5 mg, 0.6008 mmol) and diisopropylethylamine (0.238 mL, 1.365 mmol), and stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (202 mg, 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(C)C=CC=CC=1.O1CCOCC1>CCO>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:14][N:15]2[CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCCC1
Reactant: c1ccc(COc2ccc3c(C4CCCC4)n[nH]c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Product: c1ccc(COc2ccc3c(C4CCCC4)nn(CCN4CCCCC4)c3c2)cc1
Temperature: 25 °C
Yield: 8 %

Procedure:
6-benzyloxy-3-cyclopentyl-1H-indazole was heated for 1 hour with NaOH (1.64 g, 41 mmol) and 1-(2-chloroethyl)piperidine in EtOH (60 ml) at 40° C. The reaction was followed by TLC (toluene/dioxane: 7/3), and when completed, the mixture was cooled to room temperature. The mixture was quenched by NH4Cl, extracted with AcOEt, dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography (toluene/1,4-dioxane 7/3) gave the expected product (600 mg, 8% as solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:34])[C:14]([C:16]1[S:33][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:34])[C:14]([C:16]1[S:33][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Methyl 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)-carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate (25.00 g, 50.1 mmol) was dissolved in THF (50 mL) and water (50 mL). The solution was treated with LiOH.H2O (5.26 g, 125.3 mmol). The reaction mixture was stirred at room temperature for 2 h. Concentrated to remove the solvent THF and the mixture was acidified by 2N HCl. The resulting precipitate was filtrated, washed by water, dried to give 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (20.00 g, 82%). ESI-MS: 485.1. 1H NMR (CDCl3, 400 MHz): δ7.66-7.60 (m, 3H, ArH), 7.46-7.42 (m, 3H, ArH), 6.99 (s, 1H, ═CH), 4.23 (t, J=5.0 Hz, 2H, CH2), 3.39 (s, 3H, CH3), 3.14 (s, 3H, CH3), 3.07 (t, J=5.0 Hz, 2H, CH2), 3.02 (s, 3H, CH3).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(N(CC)CC)C.[C:15](=[S:17])=[S:16].[CH3:18]I>C(O)C.O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:15](=[S:17])[S:16][CH3:18]
Reactant: S=C=S
Reactant: CI
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: COC(CNC(=S)SC)OC
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 21 g (0.2 mole) of aminoacetaldehyde dimethylacetal in 150 ml of ethanol and 10 ml of water was added 24.3 g (0.24 mole) of triethylamine, and 16.8 g (0.22 mole) of carbon disulfide in portions at 0° to 5° C. After the reaction mixture was stirred for one hour at the same temperature, 31.2 g (0.22 mole) of methyl iodide was added dropwise in portions, and then was further stirred for one hour at 15°±5° C. The solvent was removed under reduced pressure (30 mmHg) and water was added thereto. Then, the mixture was extracted with ethylacetate, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure (30 mmHg) to obtain the desired liquid compound, 36.9 g (yield 95%).