Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[CH2:29]([O:36][C:37]1[C:45]([O:46][CH3:47])=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[Cl:48])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([O:36][C:37]1[C:45]([O:46][CH3:47])=[CH:44][C:40]([C:41]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:42])=[CH:39][C:38]=1[Cl:48])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1cc(C(=O)Cl)cc(Cl)c1OCc1ccccc1
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CSc3ccccc32)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (347 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and diisopropylethylamine (0.63 mL) and 4-benzyloxy-3-chloro-5-methoxybenzoyl chloride (578 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (498 mg) as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccnc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-trifluoromethyl-pyridin-4-ol (0.675 g, 4.14 mmol), 1-fluoro-4-nitro-benzene (0.54 mL, 4.97 mmol, 1.2 equiv), and NaOH (0.203 g,4.97 mmol, 1.2 equiv) in DMF abs. is heated to 100° C. (oil bath temperature) for 21.5 h, under an argon atmosphere. The reaction mixture is allowed to cool to rt, filtered through a glass sintered funnel and concentrated in vacuo. The residual yellow solid is purified by silica gel (100 g) column chromatography (CH2Cl2/hexane, 70/30) to afford the title compound as a white solid: ES-MS: 285.0 [M+H]+; single peak at tR=8.71 min (System 2); Rf=0.25 (CH2Cl2/hexane, 70/30).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:17]([CH3:21])([CH3:20])[C:18]#[CH:19]>CN(C)C=O>[CH3:20][C:17]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([C:18]#[CH:19])[CH3:21]
Reactant: C#CC(C)(C)Cl
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)n1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a stirred solution of carbazole (2.500 g, 15.0 mmol) in anhydrous N,N-dimethylformamide (30 mL) at 0° C. was added 60% sodium hydride in mineral oil (0.718 g, 17.9 mmol) and the mixture was stirred at 0° C. for 1 hr. 3-Chloro-3-methyl-1-butyne (2.300 g, 22.4 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hr and then slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-70% methylene chloride/hexanes) to afford the desired product as a light brown solid (1.7 g, 49%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 8.04 (d, 2H, J=8.7 Hz), 7.41 (td, 2H, J=8.1, 1.5 Hz), 7.24 (t, 2H, J=7.5 Hz), 2.67 (s, 1H), 2.28 (s, 6H).
Reaction SMILES: [OH:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5](=NO)[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([OH:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CS(O)(=O)=O>>[OH:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ON=C1CC(c2ccccc2)N(O)C(c2ccccc2)C1
Reactant: CCCCCCCCO
Agent: CS(=O)(=O)O
Product: CCCCCCCCOC1(OCCCCCCCC)CC(c2ccccc2)N(O)C(c2ccccc2)C1
Yield: 32.5 %

Procedure:
The general procedure of Example 12 is repeated using 10.0 g (0.035 mole) 1-hydroxy-2,6-diphenyl-4-piperidone oxime, 25.0 g (0.19 moles) 1-octanol and 7.0 g (0.073 moles) methanesulfonic acid. 5.8 g (32% yield) of the title compound is isolated as a clear oil after purification by LC (silica gel, ethyl acetate:hexane).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:6]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])#[N:4].[CH:24](I)([CH3:26])[CH3:25].O>CN(C=O)C>[C:3]([C:5]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:6]=1[N:7]([CH:24]([CH3:26])[CH3:25])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])#[N:4]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2C#N)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(C#N)cc2C#N)C(C)C)cc1
Temperature: 25 °C
Yield: 12.5 %

Procedure:
To a suspension of sodium hydride (65%, 0.12 g (3.30 mmol)) in 6.0 ml of DMF, 2′,4′-dicyano-p-toluenesulfonanilide (0.49 g (1.65 mmol)) was added with stirring at room temperature. To the resulting mixture, after 10 minutes' stirring at room temperature, isopropyl iodide (0.50 ml (4.94 mmol)) was added and the mixture was heated at 130° C. for 6 hours with stirring. The reaction mixture was then cooled to room temperature, poured into water and extracted with diethyl ether. The extract was washed with 1% aqueous sodium hydroxide solution and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (3:7) as eluent, to give 0.07 g (13%) of the title compound as white crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.8 %

Procedure:
Into a suspension of methyl 6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-6-oxohexanoate (405 mg, 0.74 mmol) in THF/H2O (2/1) (15 mL) was added NaOH (1.0 N, 3.7 mL). The resulting solution was stirred at rt for 2.5 hr and quenched with HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration, washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrs gave the title compound as a yellow powder (363 mg, 91%) in 99.0% purity by HPLC (MaxPlot detection between 230 and 400 mn).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[CH2:8]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[CH:9]1[O:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Ca+2]>COCCOC>[CH2:8]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[CH:9]1[O:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(OCC2CCCO2)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Product: O=C(Nc1ccc(OCC2CCCO2)c([N+](=O)[O-])c1)OCCCl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
36 g of β-chloroethyl chloroformate are added dropwise to 59.5 g of 4-amino-2-nitrophenyl tetrahydrofurfuryl ether of the formula V (obtainable according to A.1. or A.2.) and 14 g of calcium carbonate in 200 ml of 1,2-dimethoxyethane at 70° C. The mixture is then stirred at 80° C. for 1 hour, the inorganic salts are removed at elevated temperature, and the filtrate is evaporated to dryness. The remaining oil completely crystallizes after a short time; the crystals are triturated with 50 ml of ether, filtered off with suction, washed with a little ether, and dried. 75.8 g (88% of the theoretical figure) of 4-(β-chloroethoxycarbonyl)amino-2-nitrophenyl tetrahydrofurfuryl ether are obtained with a melting point of 84°-86° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.CC(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(Cl)c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Acetone (320 ml), 75 g (450 mmol) of ethyl bromoacetate, and 40.0 g (310 mmol) of 3-chlorophenol were mixed together, then 69.8 g (505 mmol) of potassium carbonate was added. The mixture was mechanically stirred and heated to reflux for 4 h, and after cooling to room temperature, was poured into 350 mL of ethyl acetate. To this was then cautiously added 400 mL of 1 M HCl, taking care to avoid excess foaming. The layers were separated and the aqueous layer was extracted with portions of ethyl acetate (3×200 mL). The combined organic layers were dried over MgSO4, filtered, concentrated, and the resulting solid was recrystallized from hexane to afford 58 g (87%) of 10 as a white solid, m.p.=39-40° C. 1H NMR δ 7.20-7.08 (m, 1 H), 6.95-6.82 (m, 2 H), 6.75-6.70 (m, 1 H), 4.53 (s, 2 H), 4.21 (q, J=7.2 Hz, 2 H), 1.23 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[CH3:7][C:8]([CH3:11])([CH3:10])[CH:9]=[N:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: NC1CCNC1
Reactant: CC(C)(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C=NC1CCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
34.5 g (0.4 mol) of 3-aminopyrrolidine are initially introduced into 100 ml of toluene, and 34.5 g (0.3 mol) of 75% strength pivalaldehyde (preparation from Riedel-de-Haen) in 100 ml of toluene are added dropwise at 20° C., while cooling in a water bath. The mixture is subsequently stirred at room temperature for 2 hours, the aqueous phase is then separated off in a separating funnel (4.6 ml) and the toluene solution is dried over sodium sulphate for 1 hour. The toluene is separated off on a rotary evaporator and the residue is distilled using a small Vigreux column. 46.2 g of 3-(2,2-dimethylpropylideneamino)-pyrrolidine of boiling point 61° C./10 mbar are obtained with a purity, determined by gas chromatography, of 98%, corresponding to a yield of 74% and a selectivity of 99% (pivalaldehyde).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[S:9][CH:8]=[C:7]([C:10](OC)=[O:11])[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:14][N:2]([CH2:3][C:5]1[S:9][CH:8]=[C:7]([CH2:10][OH:11])[CH:6]=1)[CH3:1]
Reactant: COC(=O)c1csc(C(=O)N(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)Cc1cc(CO)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A solution of methyl 5-[(dimethylamino)carbonyl]-3-thiophenecarboxylate (0.5 g) in dry diethylether (50 ml) was added to a slurry of lithium aluminium hydride (0.3 g) in dry diethylether (100 ml). The mixture was stirred for 3 hours at room temperature. Water was cautiously added, the mixture was filtered and the filtrate was evaporated to give the title compound (0.4 g) as a colourless oil b.p. 120°/0.1 mm. The oxalate was formed in and recrystallised from ethanol m.p. 107°-8°.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=1[NH2:26].O>C(O)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][C:25]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=1[F:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
35.3 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxyacrylate are dissolved in 120 ml of ethanol, and 12.9 g of 2,4-difluoroaniline are added dropwise, while cooling with ice. The mixture is stirred at room temperature for 1.5 hours, 120 ml of water are added, while cooling, and the precipitate is filtered off with suction, rinsed with ethanol/H2O (1:1) and dried. 40.5 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-(2,4-difluorophenylamino)acrylate are obtained, melting point: 84°-86° C.
Reaction SMILES: Cl.N[OH:3].[OH-].[K+].[CH2:6]([CH:13]([CH:17]=[CH2:18])[C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO.C1COCC1>[CH2:6]([CH:13]([CH:17]=[CH2:18])[C:14]([OH:3])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NO
Reactant: C=CC(Cc1ccccc1)C(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(Cc1ccccc1)C(=O)O

Procedure:
A solution of hydroxylamine hydrochloride (0.455 g, 6.55 mmole) in 25 ml of absolute methyl alcohol and a solution of potassium hydroxide (0.85 g, 12.8 mmole) in 25 ml of absolute methyl alcohol were cooled to 0° C. and mixed together. A solution of 2-benzylbut-3-eneoic acid chloride, prepared as described in A above, in 10 ml of dry THF was added at 0° C. to the mixed solutions with stirring. The cooling bath was removed and the mixture was stirred at room temperature for 20 minutes. The pH of the mixture was adjusted to 4.0 with 5% hydrochloric acid and the mixture was evaporated to remove methyl alcohol. The aqueous concentrate was saturated with sodium chloride and extracted four times with 75 ml portions of ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The 2-benzylbut-3-eneoic acid N-hydroxamide obtained as a pale brownish yellow oil was used without further purification in the following step.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)N>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccn1
Yield: 64 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2-hydrazinopyridine according to the method described for Example 1 in 64% yield. MS: M=316.1 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:38]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Reactant: COCC(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)COC)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([Si](C)(C)C)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)c1[nH]c2c([N+](=O)[O-])cc(Cl)cc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc2c(-c3ccccc3)c[nH]c12
Yield: 101.2 %

Procedure:
5-Chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.5 g, 4.35 mmol) prepared in Step A was dissolved in tetrahydrofuran (30 mL), and tetrabutylammonium fluoride 1M solution (5.2 mL, 5.2 mmol) was added in drops thereto at 0° C. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (1.2 g, Yield 100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C1CNCCN1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CCN1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazin-2-one according to conditions described in general procedure C. Mp: 108-110° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.14-3.35(m, 8 H), 3.73-3.78(m, 6 H), 6.37(d, J=5.5 Hz, 1 H), 7.03-7.06(m, 2 H), 7.26(d, J=8.5 Hz, 1 H), 7.44-7.63(m, 4 H), 7.84-7.86(m, 1 H), 8.00-8.04(m, 2H), 8.35(d, J=5.1 Hz, 1 H), 10.51(s, 1 H).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.O.[CH2:7]([O:14][CH2:15][C@H:16]1[O:18][C@H:17]1[CH2:19][OH:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[CH2:22][O:23]CC>>[CH2:7]([O:14][CH2:15][C@H:16]1[O:18][C@H:17]1[C:19]([O:23][CH3:22])=[O:20])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC[C@@H]1O[C@@H]1COCc1ccccc1
Reactant: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)[C@@H]1O[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 10 ml CCl4, 10 ml CH3CH, and 15 ml of H2O was added 50 mg of RuCl3 --H2O and 1.00 g (5.16 mmole) of (2S-cis)-3-(benzyloxymethyl)oxirane methanol. The solution was cooled to 0° C. and 3.50 g (15.5 mmole) of H5IO6 was added in portions over 15 min with vigorous stirring. The reaction was allowed to stir vigorously for 2 hours. The mixture was poured into 100 ml of Et2O, the organic layer separated and the aqueous layer washed with 20 ml of Et2O. The combined organic layers were washed four times with 50 ml 0.1 N NaOH. The aqueous layers were combined, acidified to pH 2, and extracted three times with 50 ml Et2O. The ether layers were dried over MgSO4, filtered and evaporated to yield a pale yellow residue.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[CH:4]=1.CO>C1COCC1>[F:15][C:2]([F:1])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1
Reactant: N#Cc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (Intermediate 4, 1.48 g, 7.01 mmol) was dissolved in THF (59 mL), cooled in an ice bath and treated with a 1M solution of borane tetrahydrofuran complex (35.0 mL, 35.0 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. Methanol (59 mL) was added dropwise and the reaction mixture was stirred for 20 minutes at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in methanol (177 mL) and heated under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and passed down an SCX column (20 g) eluting with methanol, followed by 2M ammonia/methanol. Basic fractions were combined and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-10% 2M ammonia/methanol and DCM. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow solid (1.1 g);
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][O:30][C:31]1[N:36]=[N:35][C:34]([NH2:37])=[C:33]([CH3:38])[C:32]=1[CH3:39].C(N(CC)C(C)C)(C)C>C(#N)CCC>[CH3:29][O:30][C:31]1[C:32]([CH3:39])=[C:33]([CH3:38])[C:34]2[N:35]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14]4)=[CH:9][CH:10]=3)[N:37]=2)[N:36]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COc1nnc(N)c(C)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: COc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Temperature: 120 °C
Yield: 28 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (391 mg, ˜80% purity, 0.710 mmol, 1.0 eq), 6-methoxy-4,5-dimethylpyridazin-3-amine (that was prepared in a manner analgous to that described for Intermediate Example Int-34, Step 1, 108 mg, 0.710 mmol, 1.0 eq) and N,N-diisopropylethylamine (140 μL, 0.780 mmol, 1.1 eq) in butyronitrile (4.9 mL) was heated for 3 hours at 120° C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/EtOAc 9/1→hexane/EtOAc 2/3) to give 105 mg (28% yield) of the title compound.