Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO.O[C@H](C1C=CC=CC=1)C(O)=O>C(#N)C>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCNC3)C2=O)CC1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCNC3)C2=O)CC1
Temperature: 70 °C
Yield: 48.3 %

Procedure:
2-(cis-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (7.00 g, 19.1 mmol) was dissolved in acetonitrile (50 mL) and methanol (7 mL) at r.t. After the starting material was completely dissolved, the solution was heated up to 70° C. To the above solution was slowly added a solution of (2R)-hydroxy(phenyl)acetic acid (1.45 g, 9.55 mmol) in acetonitrile (20 mL) at 65-70° C. After addition, the solution was heated at 74° C. for 10 min, and allowed to cool slowly to room temperature overnight. The crystalline formed was collected by filtration to afford 3.38 g of the desired product as (2R)-hydroxy(phenyl)acetic acid salt. The resulting salt (3.38 g) was dissolved in water (50 mL), and adjusted to pH˜12 with 40 mL aq K2CO3 solution (2.0 M). The mixture was extracted with dichloromethane (3 times). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure to afford the desired product as a free base (colorless crystalline solid) (2.37 g). The absolute stereochemistry of this compound was established by X-ray single crystal structure determination of (2R)-hydroxy(phenyl)acetic acid salt of (5S)-2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH:6]([O:8][C:9](=[O:13])[CH:10]([CH3:12])[OH:11])[CH2:5][C:4]([CH3:15])([CH3:14])[NH:3]1.CC1(C)[O:23][C:22](=O)[CH:21]=[C:20]([CH3:25])[O:19]1>C1(C)C=CC=CC=1>[CH3:16][C:2]1([CH3:1])[CH2:7][CH:6]([O:8][C:9](=[O:13])[CH:10]([O:11][C:22](=[O:23])[CH2:21][C:20]([CH3:25])=[O:19])[CH3:12])[CH2:5][C:4]([CH3:15])([CH3:14])[NH:3]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CC(O)C(=O)OC1CC(C)(C)NC(C)(C)C1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC(C)C(=O)OC1CC(C)(C)NC(C)(C)C1

Procedure:
Lactic acid 2,2,6,6-tetramethyl-4-piperidyl ester (5 g, 21.8 mmol) was dissolved in 100 ml of toluene. At reflux temperature, 3.1 g (21.8 mmol) of 2,2,6-trimethyl-4H-1,3-dioxine-4-one was added dropwise. After 3 hours at reflux, the solvent was distilled of in vacuo. A viscous residue was left. Yield 4.8 g (70%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2([C:32]#[N:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:32]([C:26]1([C:22]2[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][N:23]=2)[CH2:31][CH2:30][N:29]([CH2:1][C:3]2[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:28][CH2:27]1)#[N:33]
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: Cc1ccnc(C2(C#N)CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CN2CCC(C#N)(c3cc(C)ccn3)CC2)c2ccccn2c1=O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A mixture of the ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (2.60 g, 10.6 mmol), 4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile (1.78 g, 8.83 mmol), and 36.8 mL of anhydrous THF was cooled to 10° C. and stirred vigorously. To the stirring mixture was added sodium triacetoxyborohydride (2.62 g, 12.4 mmol), portionwise over a period of 1 hour. The mixture was heated to 50° C. for 18 hours. The reaction was quenched with a 10% sodium bicarbonate solution and extracted with EtOAc (3×50 mL). The organic layers were combined, acidified with 1 N HCl, and extracted with DCM (8×150 mL). In a 500 mL Erlenmeyer flask, the aqueous layer was neutralized slowly with solid sodium carbonate under continuous stirring until pH ˜7-8 and then extracted with DCM (3×200 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to afford the ethyl 1-{[4-cyano-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate that gave a proton NMR spectrum consistent with theory and a mass spectrum (ES+) m/z of 431.0 calculated for M+H+: 1H NMR (400 MHz, CDCl3) δ 9.51 (d, J=7.1 Hz, 1H), 8.43 (d, J=4.95 Hz, 1H), 8.32 (s, 1H), 8.14 (d, J=8.9 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.26 (m, 1H), 7.06 (d, J=4.9 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 3.75 (s, 2H), 3.01 (d, J=12.0 Hz, 2H), 2.56 (t, J=11.3 Hz, 2H), 2.39 (s, 3H), 2.29 (t, J=12.9 Hz, 2H), 2.05 (d, J=12.4 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[CH3:19]I>CN(C=O)C>[Cl:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[NH:1][CH3:19]
Reactant: CCOC(=O)c1ccc(Cl)c(N)c1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)c(NC)c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
3.18 g (13.0 mmol) of ethyl 3-amino-4-chloro-2-nitrobenzoate were introduced in DMF and admixed under a nitrogen atmosphere with 0.624 g (15.6 mmol) of sodium hydride. The mixture was left with stirring for 30 minutes and then 2.21 g (15.6 mmol) of methyl iodide were added. After a further 2.5 h of stirring at room temperature the mixture was concentrated and the residue was extracted with ethyl acetate, washed with water, and then dried over MgSO4. The product was then subjected to chromatographic separation (silica gel, heptane/ethyl acetate 9:1).
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.S(Cl)([Cl:20])(=O)=O.C(OCC)(=O)C>C(OCC)C>[Cl:20][C:12]1[C:13]([CH3:16])=[C:14]([OH:15])[C:2]([CH3:1])=[C:3]2[C:11]=1[O:10][C:6]1([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH2:4]2
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc2c(c(C)c1O)CCC1(CCC1)O2
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1c(O)c(C)c2c(c1Cl)OC1(CCC1)CC2
Reaction time: 2 h

Procedure:
To a solution of 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (350 mg) in ethyl ether (6 mL) was added sulfonyl chloride (0.154 mL, 260 mg) dropwise at room temperature under nitrogen. After 2 hours, ethyl acetate was added, washed with an aqueous sodium bicarbonate solution, water and brine, and dried. Evaporation and chromatography (silica gel hexane-ethyl acetate 0% to 4%, hexane-dichloromethane 5% to 20%) yielded the desired compound. Crystallization with hexane gave colorless crystals of 8-chloro-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (60 mg). 1H-NMR (300 MHz, CDCl3) δ=4.29 (s, 1H), 2.67 (t, J=6.6 Hz, 2H), 2.35-1.80 (m, 13H), 1.75-1.60 (m, 1H) ppm. 13C-NMR (75 MHz, CDCl3) δ=145.2, 143.6, 120.9, 120.1, 119.9, 119.7, 77.3, 33.8, 29.2, 20.8, 13.2, 12.5, 11.5 ppm. MS: (m/z)=253 (100, M+H+), 275 (23, M+Na+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:16][C:4]3[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1cccc(-c2nc(C)c(C)cc2O)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
5,6,6′-Trimethyl-[2,2′]bipyridin-3-ol (300 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.26 g), 4-dimethylaminopyridine (513 mg), and cesium carbonate (1.37 g) were suspended in dimethyl sulfoxide (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (483 mg, yield 72%).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[CH3:27][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1.[Cu]Br>[C:1]([O:4][CH:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@@H:13]([CH3:27])[C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Reactant: C[Al](C)C
Agent: [Cu]Br
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4C[C@@H](C)[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
3.56 g (10 mmol) of 3-acetoxy-pregna-5,16-dien-20-one is dissolved in 20 ml of dioxane at 20° C. and mixed with 143.3 g (1 mmol) of copper(I) bromide. 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 10 minutes at 20° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate filtered off with dioxane is washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.12 g of 3-acetoxy-16α-methyl-pregn-5-en-20-one (30% of theory) is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.N1C=CC=CC=1>ClCCCl.CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[O:10])=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)Nc2nccs2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
4-Nitro-3-methyl-benzoic acid (83 mmol) was suspended in 1,2-dichloroethane (500 mL) and dimethylformamide (DMF) (5 mL) under an argon atmosphere. Oxalylchloride (2M in dichloromethane, 62.3 mL) was added slowly to the stirred suspension. After stirring at room temperature for 1 h, the solvent was removed by evaporation under reduced pressure, and the reaction mixture was re-dissolved in 1,2-dichloroethane (400 mL). A suspension of 2-aminothiazole (83 mmol) and pyridine (83 mmol) in 1,2-dichloroethane (100 mL) was added portion wise. The reaction mixture was stirred at 50° C. over night. The solvent was removed under reduced pressure and the solids were re-suspended in ethyl acetate (500 mL) and NaHCO3 (sat.) (500 mL). The solids were removed by filtration and the liquid phases were separated. The organic phase was washed with NaHCO3 (sat.), dried over MgSO4, filtered and evaporated. The crude product was re-crystallized from ethyl acetate and the product fractions were combined to give 4-nitro-3-methyl-N-thiazol-2-yl-benzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]#[N:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[C:13]([CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)#[N:14]
Reactant: N#CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitrophenol (10 g), bromoacetonitrile (6 mL) and K2CO3 (15 g) were suspended in acetone (100 mL). The yellow solution was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and acetone was removed under reduced pressure. The light-yellow precipitate was collected by filtration, washed with water and dried to give O-cyanomethyl-4-nitrophenol.
Reaction SMILES: CO.[CH3:3][C:4]([Si:7]([CH3:34])([CH3:33])[O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17](C(OCCC(C)(C)C)=O)[C:16]([C:30]([O-:32])=[O:31])=[CH:15]2)([CH3:6])[CH3:5].[Li+].[OH-]>C1COCC1>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:30]([OH:32])=[O:31])=[CH:15]2.[CH3:6][C:4]([Si:7]([CH3:34])([CH3:33])[O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:30]([OH:32])=[O:31])=[CH:15]2)([CH3:3])[CH3:5]
Reactant: CC(C)(C)CCOC(=O)n1c(C(=O)[O-])cc2cc(OCCO[Si](C)(C)C(C)(C)C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc2[nH]c(C(=O)O)cc2c1
Product: O=C(O)c1cc2cc(OCCO)ccc2[nH]1
Temperature: 70 °C
Yield: 7 %
Yield: 16 %

Procedure:
A methanol solution of 1-(1,1-dimethylethyl)2-ethyl 5-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1H-indole-1,2-dicarboxylate (0.200 g, 0.431 mmol) was treated with 1 N LiOH (4 mL). A precipitate formed and THF was added to redissolve the material. The reaction was heated to 70° C. until the starting material was consumed, partitioned between EtOAc and water and the layers separated. The basic aqueous layer was acidified with conc. HCl and extracted with EtOAc. Purification was accomplished by silica gel column chromatography (0-100% EtOAc/hexanes, striped with MeOH) to afford the title compound (0.015 g, 16%) and 5-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1H-indole-2-carboxylic acid (0.0114 g, 7%) 1H NMR (400 MHz, Acetone-d6) δ ppm 10.73 (br. s., 1H), 7.43 (d, 1H), 7.15 (d, 1H), 7.10 (d, 1H), 6.96 (dd, 1H), 4.07 (t, 2H), 3.88 (t, 2H).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30].CCCCCC.ClCCl>O1CCCC1>[C:26]([C:11]1[C:10]([C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])=[CH:9][N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:22])[F:23])=[CH:16][C:15]=2[Cl:25])[N:12]=1)#[N:27]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)F
Temperature: 55 °C
Reaction time: 16 h

Procedure:
t-Butyl nitrite (12.45 ml) was added dropwise to a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (JP-A-8-311036; 30 g) in tetrahydrofuran (250 ml) and the mixture stirred at 55° C. for 16 hours. Further quantities of t-butyl nitrite added/subsequent periods of stirring at 55° C. were as follows: 9 ml/7 hours, 6 ml/16 hours, 9 ml/6 hours, 4.75 ml/16 hours, 6 ml/6 hours and 3.5 ml/22 hours. The reaction mixture was allowed to cool and evaporated under reduced pressure, then the residue combined with those obtained from three identical preparations. Purification by column chromatography on silica gel (1 Kg), using hexane:dichloromethane (6:4) and then dichloromethane as eluants, gave a yellow oil which, on trituration with hexane (3×50 ml) followed by dichloromethane (100 ml), provided the title compound as a white solid, m.p. 124-125° C. δ (CDCl3): 7.83 (s,2H), 8.30 (s,1H). MS (thermospray): M/Z [M+H] 401.7; C13H3Cl2F6N3O+H requires 401.96.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:20])([F:19])[C:5]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]#N)=[CH:9]1)([CH3:7])[CH3:6].Cl.C1COCC1.C[OH:28].O>>[F:3][C:4]([F:20])([F:19])[C:5]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]([OH:28])=[O:1])=[CH:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)(n1cc(C#N)c2cccnc21)C(F)(F)F
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(n1cc(C(=O)O)c2cccnc21)C(F)(F)F
Temperature: 100 °C
Reaction time: 4 h

Procedure:
KOH (174 mg, 3.11 mmol) was added to a solution of 1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (78.7 mg, 0.311 mmol) in 1:1:1 THF/MeOH/water (621 μl) at RT. After being stirred at 100° C. for 4 h, the reaction mixture was acidified (pH=2-3) by conc. HCl and the resulting suspension was extracted with EtOAc. The combined organic layers were concentrated to afford the title compound as a brown foam, which was used without further purification.
Reaction SMILES: [C:1]([C:3]([CH3:51])([CH3:50])[C:4]1[CH:5]=[C:6]([NH:19][C:20]([NH:22][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:26]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]5[CH3:49])=[N:41][N:42]=4)[CH:39]=3)[CH2:25][CH2:24]2)=[O:21])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][OH:18])[CH:10]=2)[N:8]=1)#[N:2].C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)NC4N(C5C=NN(CC[O:95][S:96]([CH3:99])(=O)=[O:97])C=5)N=C(C(C)C)C=4)CC3)C=CC2=NN=1>>[C:1]([C:3]([CH3:50])([CH3:51])[C:4]1[CH:5]=[C:6]([NH:19][C:20]([NH:22][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@H:26]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]5[CH3:49])=[N:41][N:42]=4)[CH:39]=3)[CH2:25][CH2:24]2)=[O:21])[N:7]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[O:15][CH2:16][CH2:17][O:18][S:96]([CH3:99])(=[O:97])=[O:95])[N:8]=1)#[N:2]
Reactant: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared using Intermediate 20f in an analogous fashion to the procedures described for Intermediate A step e. LCMS (Method 3): Rt 3.64 min, m/z 768.5 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)=[CH:4][C:3]=1[CH3:18].[NH2:19][C:20]([NH2:22])=[O:21]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:15]=[C:14]([CH3:16])[O:13][N:12]=3)[NH:22][C:20](=[O:21])[N:19]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: NC(N)=O
Reactant: Cc1cc(/C=C/C(=O)c2ccc(O)c(C)c2)no1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3ccc(O)c(C)c3)nc(=O)[nH]2)no1
Temperature: 120 °C
Yield: 4 %

Procedure:
A mixture of (E)-1-(4-hydroxy-3-methylphenyl)-3-(5-methylisoxazol-3-yl)prop-2-en-1-one (200 mg, 0.8 mmol) and urea (56 mg, 4.0 mmol) in 4M HCl/dioxane (5 mL) was heated to 120° C. in a sealed vessel overnight. After cooling, the crude reaction mixture was purified by reverse-phase HPLC to give 9 mg of product.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][NH:10][C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:10]1[C:11]2[CH:12]=[C:4]3[O:3][CH2:2][O:1][C:5]3=[CH:6][C:7]=2[CH2:8][CH2:9]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1c2c(cc3c1OCO3)NCC2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc5c(cc43)OCO5)c2cc1OC
Yield: 93 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 93% yield from 6,7-dihydro-5H-[1,3]dioxolo[4,5-f]indole (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 225°-228° C. (dec); LC-MS: 352 (MH+); anal. RP18-HPLC RT: 3.91 min.).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][C:13]1([CH3:29])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=2)[O:14]1.[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].O>ClCCl>[CH3:19][C:17]1([CH3:18])[C:13]([CH3:29])([CH3:12])[O:14][B:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[CH:22][CH:21]=2)[O:16]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1(C)OB(c2ccc(CCN)cc2)OC1(C)C
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add DBU (0.79 mL, 5.3 mmol) to 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethylamine (0.5 g, 1.8 mmol, can be prepared from 4-bromophenyl acetonitrile) in dichloromethane and stir at room temperature. After 10 minutes, cool to 0° C. and add isopropylsulfonylchloride (0.22 mL, 1.95 mmol). After 30 minutes, allow to warm to room temperature. After 3 hours, pour into water and extract with dichloromethane. Wash the combined organics with 1N HCl, water, and brine, dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography (silica gel), eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (ES−)=352.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC[C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=1)[O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:24]4[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=4)[O:27][CH:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CN)c2)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 120 °C

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (522 mg, 1.62 mmol) and tert-butyl 4-[3-(aminomethyl)phenoxy]piperidine-1-carboxylate (544 mg, 1.78 mmol) were dissolved in MeOH (10 ml). The mixture was heated in a microwave for 30 minutes at 120° C. A precipitate was formed from MeOH. The precipitate was filtered off and washed with MeOH yielding the title compound as a white solid. Yield: 431 mg (48%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.63 (m, 2H), 7.47 (s, 1H), 7.43 (m, 2H), 7.30-7.25 (m, 1H), 6.95-6.91 (m, 2H), 6.86 (m, 1H), 5.19 (s, 2H), 4.46 (m, 1H), 3.67 (m, 2H), 3.33 (m, 2H), 1.94-1.85 (m, 2H), 1.77-1.67 (m, 2H), 1.54 (s, 9H).