Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[CH:9]=1)[CH3:2].[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][CH2:4][C@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[C:9]=1[F:35])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC[C@@H](CNc1nc(Nc2cccc(C)c2)c2c(c1F)CNC2=O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a chilled solution of (R)-tert-butyl 1-ethoxy-3-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)propan-2-ylcarbamate (94.7 mg, 0.208 mmol) in CH2Cl2 (5 mL) at 0° C. was added SELECTFLUOR® (73.6 mg, 0.208 mmol). The mixture was left stirring in an ice bath and warmed slowly to RT for 6 h. Afterwards, the mixture was diluted with EtOAc (10 mL) and washed with saturated aq NaHCO3 (5 mL) followed by water (5 mL) and brine (5 mL). The organic layers were combined, dried over Na2SO4, and concentrated to a brown residue. The resulting crude material was reconstituted in MeOH/DCM (5 mL) and purified via preparative HPLC. The collected fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C24H32FN5O4, 474; found, 474.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH:32]1([CH:38]=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:32]1([CH2:38][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCCCC4)ncn3)cccc2s1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.17 g, 0.3 mmol) in 1,2-dichloroethane (10 mL) was added cyclohexanecarboxaldehyde (0.1 g, 0.9 mmol, Aldrich) and the mixture was stirred at 40° C. for 2 h. Sodium triacetoxyborohydride (0.40 g, 1.9 mmol, Aldrich) was added and the reaction mixture was stirred for 18 h at room temperature. After the addition of water (2 mL), the reaction mixture was evaporated in vacuum. The residue was diluted with H2O (10 mL) and extracted with EtOAc (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Purification of the residue by silica gel chromatography (6:1, hexanes: EtOAc) afforded the title compound as an yellow solid. Mp: 232–234° C. MS(ESI, pos. ion) m/z: 542 (M+1).
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12]CC)=O.[F:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:21]=1C(Cl)=O>C(OCC)C>[F:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:21]=1[C:10]([CH2:9][C:8]([O:16][CH2:17][CH3:18])=[O:15])=[O:12]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F

Procedure:
On the other hand, a suspension of magnesium ethoxide and 3.1 g of diethyl malonate in 30 ml of anhydrous diethyl ether was refluxed for 1 hour. To the cooled suspension was added dropwise 15 ml of an anhydrous diethyl ether solution of 2,4,5-trifluorobenzoyl chloride obtained above with stirring. The resulting mixture was stirred at room temperature for 1 hour. After acidification with diluted hydrochloric acid, the mixture was extracted with 150 ml of ethyl acetate (50 ml×3). The extract was dried over sodium sulfate, and the solvent was removed by distillation. The resulting residue was dissolved in 50 ml of dioxane and a catalytic amount of p-toluenesulfonic acid was added thereto. The mixture was refluxed for 24 hours and, after cooling, the reaction mixture was neutralized with an aqueous sodium bicarbonate solution and extracted with 200 ml of chloroform. The extract was dried over sodium sulfate, and the solvent was removed. The residue was subjected to silica gel column chromatography and 2.1 g of ethyl 2,4,5-trifluorobenzoylacetate was yielded from benzene eluate.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5](I)=[C:4]([CH3:11])[C:3]=1[CH3:12].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([C:24]#[C:23][C:20]3[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=3)=[C:4]([CH3:11])[C:3]=2[CH3:12])=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: Cc1c(C)c(I)c(C)c(C)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C#Cc2c(C)c(C)c(C#Cc3ccc(CCCC)cc3)c(C)c2C)cc1

Procedure:
8.1 g (20 mmol) of 1,4-diiodo-2,3,5,6-tetramethylbenzene, 7.5 g (47.3 mmol) of 4-n-butylphenylacetylene, 2 g (2.9 mmol) of bis(triphenylphosphine)palladium(II) chloride and 550 mg (2.9 mmol) of copper(I) iodide are initially introduced in 100 ml of triethylamine, and the mixture is heated under reflux for 3 h. The batch is then cooled, water and MTB are added, and the phases are separated. The organic phase is washed with saturated ammonium chloride solution and with sodium chloride solution and evaporated in a rotary evaporator, and the residue obtained in this way is purified by column chromatography (SiO2, heptane); the further purification is carried out by recrystallisation from isopropanol.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[ClH:11].[NH2:12]O>CO>[ClH:11].[NH2:12][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][S:4][CH:3]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)c1cscc1N
Yield: 57.4 %

Procedure:
3-Oxo-4-methoxycarbonyltetrahydrothiophene (28 g) was heated under reflux for 1 hour with hydroxylamine hydrochloride (11.5 g) in methanol (80 ml). The mixture was then cooled and a first crop was filtered off and washed with dry diethyl ether to afford the title compound (18.4 g, 57.6%) m.p. 203° to 205° C. On further cooling a second crop (2.7 g, 8.5%) was obtained, m.p. 201° to 202° C. The total yield was thus 66.1%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+]>C(O)C.O>[CH2:11]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCBr
Reactant: OCc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccccc1CO
Temperature: 50 °C
Yield: 77.7 %

Procedure:
A solution of 2-(hydroxymethyl)phenol (Aldrich; 1.24 g, 10 mmol) and 1-bromobutane (Acros; 1.18 ml, 11 mmol) in ethanol (5 ml) (total volume approximately 7 ml) was mixed in a flow reactor (Vapourtec R4, 30 ml PFA tubing, 110° C.) with a solution of aqueous NaOH (2 N, 5 ml, 10 mmol) in water (2 ml). The reagents were each pumped at 0.5 ml/min), giving a reaction time of 30 minutes. After the 30 ml reactor, the solution passed through a second “cooling” reactor (5 ml) at 50° C. At the reactor output, a 250 psi back pressure regulator was used. After all starting solutions had been consumed, the system was purged with an additional 70 ml solvent (1:1, ethanol:water). The collected material was concentrated in vacuo. The residue was partitioned between water and EtOAc, and treated with saturated aqueous sodium bicarbonate solution. The aqueous phase was further extracted with EtOAc, and the combined organic extracts were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound (1.4 g); LCMS (System 4): MNH4+=198, tRET=2.51 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[K+].[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18](Br)[CH2:17]1)[CH3:12]>C(O)C>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:17]1)[CH3:12]
Reactant: Sc1ccccc1Cl
Reactant: CCOC(=O)CC1CCC(=O)C(Br)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CCC(=O)C(Sc2ccccc2Cl)C1
Temperature: 25 °C

Procedure:
28 G. of 2-chlorothiophenol and a solution of 10.8 g. of 85% potassium hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 50.6 g. of 3-bromo-4-ketocyclohexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotovapor), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. A forerun was collected at 100°-190° (1 mm), while a main fraction was collected at 190° -222° (1 mm). The yield of 3-(2-chlorophenylthio)-4-ketocyclohexaneacetic acid ethyl ester from the main fraction was 33.9 g., b.p. 205-215/0.7 mm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[O:16][C@@H:12]([CH2:13][CH2:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH4+]>CCO>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[O:16][C@@H:12]([CH2:13][CH2:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:31]([C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)=[CH:34][CH:33]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2CC[C@@H]1O2
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)[C@H]2CC[C@@H]1O2
Temperature: 70 °C

Procedure:
(1S,2R,3S,4R)-3-(2,3-diamino-5-chloropyridin-4-ylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide (17) (300 mg, 0.971 mmol), and 4-morpholinobenzaldehyde (167 mg, 0.873 mmol) were taken in EtOH (15 ml) to which ammonium acetate (112 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with hot ethanol to afford the desired product (466 mg, 23%) as a yellow solid. NMR: δ (1H, 400M Hz, DMSO-d6): 1.50-1.80 (4H, m), 2.96 (1H, d, J=8.4 Hz), 3.23 (4H, s), 3.76 (4H, s), 4.33 (1H, d, J=4.5 Hz), 4.57 (1H, s), 5.49 (1H, t, J=8.8 Hz), 6.99 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.18 (1H, s), 7.62 (1H, s), 7.91 (1H, s), 8.02 (1H, d, J=8.0 Hz), 12.96 (1H, s). LCMS (254 nm): [M+H]+ 469.15 (95.56%) HPLC: 91.64% (220 nm).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[OH:32][C:33]1([C:40]2[S:44][CH:43]=[N:42][CH:41]=2)[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[CH2:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:9][N:8]([CH:36]3[CH2:35][CH2:34][C:33]([OH:32])([C:40]4[S:44][CH:43]=[N:42][CH:41]=4)[CH2:38][CH2:37]3)[CH2:11]2)=[O:31])=[N:17]1)[CH3:30]
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2cncs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cncs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in the previous step) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12][CH2:13][C:14]([C:16]2[S:17][C:18]([CH3:27])=[C:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][C:20]=23)=[O:15])=[CH:7][C:6]=1[CH3:28].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:11][C:10]1[CH:9]=[C:8]([CH2:12][CH2:13][C:14](=[O:15])[C:16]2[S:17][C:18]([CH3:27])=[C:19]3[CH2:24][C:23]([CH3:25])([CH3:26])[CH2:22][CH2:21][C:20]=23)[CH:7]=[C:6]([CH3:28])[C:5]=1[O:4][CH2:3][CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To a solution of 3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (130 mg, 0.325 mmol) in DCM (10 mL) and DIPEA (0.09 mL, 0.52 mmol) is added methane sulfonylchloride (0.03 mL, 0.39 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 2-{2,6-dimethyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-ethyl ester (165 mg) as a yellow oil; LC-MS: tR=1.17 min, [M+1]+=479.26.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([F:40])=[C:35](B(O)O)[CH:36]=1)#[N:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:33]2[C:34]([F:40])=[CH:35][CH:36]=[C:31]([C:29]#[N:30])[CH:32]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Product: CC(c1ccc(-c2cc(C#N)ccc2F)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 5-cyano-2-fluorophenylboronic acid to give the title compound as a colorless solid. MS (m/e)=519.2 [M+H+].
Reaction SMILES: [H-].[Na+].Cl.[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C@@H:14]1[CH2:17][C@H:16]([OH:18])[CH2:15]1.F[C:20]1[C:25]([C:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C=O.CCOC(C)=O>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C@@H:14]1[CH2:15][C@H:16]([O:18][C:20]2[C:25]([C:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:17]1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Reactant: O[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CC=C(c2cccnc2O[C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride, 60% dispersion in mineral oil (0.13 g, 3.18 mmol) was added to a solution of cis-3-(benzo[d]thiazol-2-ylamino)cyclobutanol hydrochloride (0.20 g, 0.795 mmol) in N,N-dimethylformamide (2.7 mL) under argon and the mixture was stirred for 30 min at RT. 1-(4-(2-Fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.17 g, 0.79 mmol) was next added, and the resulting mixture was heated at 100° C. for 2 h. The cooled reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 80% EtOAc/Hexanes) afforded 1-(4-(2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as an off-white amorphous solid. [M+1]=421.0.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]([CH2:25][CH2:26]Cl)[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)(C)C>[Br:18][C:8]1[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]2[NH:12][C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][CH:3]=[C:2]([N:1]1[CH2:26][CH2:25][N:23]([CH3:24])[CH2:22][CH2:21]1)[CH:14]=3
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
Temperature: 80 °C

Procedure:
7-Amino-3-bromo-9H-carbazole-1-carboxamide 470B (250 mg, 0.822 mmol), 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride, Mechlorethamine HCl (316 mg, 1.644 mmol) and sodium carbonate (436 mg, 4.11 mmol) were mixed in t-BuOH (5 mL) in a sealed microwave vial. The vial was degassed and filled with N2. The mixture was heated at 80° C. for 16 hrs in an oil bath. 6 ml of DMF was added to the mixture and the mixture was heated in microwave at 160° C. for 1 hr. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 387.04 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[CH:24][CH:23]=[C:22]2[CH3:36])=[CH:17][CH:16]=1>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[CH:24][C:23]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[C:22]2[CH3:36])=[CH:19][CH:20]=1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(C(=O)c2ccccc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
Benzoyl chloride (180 μl, 1.52 mmol) was slowly added to a stirred slurry of aluminum chloride (223 mg, 1.67 mmol) in methylene chloride (15 ml) at -10° C. After 30 minutes, a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (500 mg, 1.52 mmol) in methylene chloride (10 ml) was added. The reaction mixture was warmed to room temperature and stirred for 20 hours. The reaction mixture was poured over ice-water and extracted with methylene chloride. The organic fraction was washed with brine, dried (MgSO4), filtered and concentrated. The crude yellowish solid (570 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give [1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]-phenylmethanone (54 mg, 8%) as a white solid: Anal Calc'd. for C25H20NSFO3 ·0.5 H2O: C, 67.86; H, 4.78; N, 3.17. Found: C, 67.59; H, 4.70; N. 3.07.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:10][O:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:13][CH2:12][O:11][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: COCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.), 2-methoxyethanol (3.0 equiv.) and triphenylphosphine (3.0 equiv) in THF (0.1 M) was added DIAD (3.0 equiv.). After stirring at rt for 18 hours, the volatiles were removed in vacuo and the residue was purified by SiO2 chromatography to yield 1,3-difluoro-5-(2-methoxyethoxyl)benzene in 95% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 6.41-6.47 m (3 H), 4.08 (t, 2H), 3.74 (t, 2H), 3.45 (s, 3 H).
Reaction SMILES: [C:1]12([C:9]3[C:18]4[NH:17][CH2:16][CH2:15][CH2:14][C:13]=4[NH:12][C:11](=O)[CH:10]=3)[CH2:8][CH2:7][C:4]([CH:5]=[CH:6]1)=[CH:3][CH2:2]2.CN(C=O)C.S(Cl)([Cl:27])=O>>[Cl:27][C:11]1[N:12]=[C:13]2[C:18](=[C:9]([C:1]34[CH2:8][CH2:7][C:4]([CH:5]=[CH:6]3)=[CH:3][CH2:2]4)[CH:10]=1)[NH:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=c1cc(C23C=CC(=CC2)CC3)c2c([nH]1)CCCN2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1cc(C23C=CC(=CC2)CC3)c2c(n1)CCCN2
Temperature: 70 °C
Yield: 66 %

Procedure:
To a solution of 1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-one (435 mg, 1.72 mmol) in 2.5 ml of thionyl chloride was added 100 μL of DMF, and the reaction mixture was heated at 70° C. for 10 h, and concentrated in vacuo. The residue was poured on ice-water and saturated aq. NaHCO3 solution was added to adjust pH to 10-11. The mixture was extracted with EtOAc (2×50 mL), dried over Na2SO4, concentrated and purified by flash chromatography (EtOAc:hexane, 1:4) to give 6-chloro-1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridine (310 mg, 66%) as a white solid; 1H NMR (CDCl3, 300 MHz) 7.58 (m, 2H), 7.43 (m, 3H), 7.29 (s, 1H), 3.35 (s, 1H), 3.18 (m, 2H), 2.63 (m, 2H), 1.99 (m, 2H), 1.73 (m, 2H) ppm; MS (ES) 271.39 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[CH2:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1[O:54][CH3:55]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])[CH:45]([C:38]1[C:39]([O:43][CH3:44])=[CH:40][CH:41]=[CH:42][C:37]=1[O:36][CH3:35])[C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1[O:54][CH3:55]
Reactant: COc1cccc(OC)c1Cc1c(OC)cccc1OC
Reactant: COc1cccc(OC)c1C(O)c1c(OC)cccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: COc1cccc(OC)c1C(c1c(OC)cccc1OC)C(c1c(OC)cccc1OC)c1c(OC)cccc1OC
Reaction time: 1 h

Procedure:
To a solution of bis(2,6-dimethoxyphenyl)methanol (1.52 g, 0.005 mol) in acetonitrile (50 mL) at room temperature was added p-toluenesulfonic acid monohydrate (0.95 g, 0.005 mol). To the resulting deep red solution was added bis(2,6-dimethoxyphenyl)methane (1.44 g, 0.005 mol). The reaction mixture decolored within about one hour and was stirred for an additional 17 hours. The reaction was quenched by the addition of water (10 mL), extracted with dichloromethane and dried over anhydrous magnesium sulfate. Evaporation of the solvent and hot filtration using hexane/benzene gave 1,1,2,2-tetrakis(2′,6′-dimethoxyphenyl)ethane as a mixture of rotational isomers after evaporation of the solvents and washing with diethyl ether.