Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9](#[N:12])[CH:10]=[CH2:11]>O>[C:9]([CH:10]([NH:2][NH:3][C:4]([NH2:6])=[O:5])[CH3:11])#[N:12]
Reactant: C=CC#N
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C#N)NNC(N)=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
1672 g of semicarbazide hydrochloride is dissolved in 2 liters of water, and neutralised, with cooling, with 600 g of sodium hydroxide in 1 liter of water. After the addition dropwise of 795 g of acrylonitrile, the mixture is heated for 7 hours at 80° C. and then allowed to stand for 4 hours at 0° C.; the precipitated crystalline product is subsequently filtered off, and dried under vacuum. There is obtained 1152 g of white product having a melting point of 125°-128° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]#[C:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=O)[CH3:2].[NH2:26][NH2:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[N:27]([C:14]2[CH:15]=[CH:16][C:11]([CH3:9])=[CH:12][CH:13]=2)[N:26]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(CC#CC(=O)c1ccc(Br)cc1)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115 %

Procedure:
To a solution of 6-(4-bromo-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester (7.5 g, 19 mmol) in THF (40 mL) was added hydrazine (4.5 g, 28 mmol, 1.5 equiv) and Cs2CO3 (9.0 g, 28 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (30 mL), and a satd aq solution of cesium carbonate (50 mL) was added. The resulting aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with satd aq NaHCO3 (50 mL) then brine (50 mL), and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (5.5 g, 58%). TLC (silica gel, 3:7 EtOAc/hexanes): Rf=0.35. MS (ESI): mass calculated for C28H27BrN2O2, 502.13; m/z found, 503/505 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=10.7 Hz, 2H), 7.25-7.01 (m, 10H), 6.17 (s, 1H), 4.19-4.03 (m, 3H), 3.52 (dd, J=14.7, 9.6 Hz, 1H), 3.09 (dd, J=14.7, 6.0, 1H), 2.35 (s, 6H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[C:3]2[S:11][C:10]([CH3:12])=[N:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:4]2[N:9]=[C:10]([CH3:12])[S:11][C:3]=2[C:2]([I:1])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(=O)[nH]cc(I)c2s1
Product: Cc1nc2c(Cl)ncc(I)c2s1

Procedure:
7-Iodo-2-methyl-5H-thiazolo[4,5-c]pyridin-4-one (880 mg, 3.01 mmol) was suspended in POCl3 (8.25 ml, 90.4 mmol) and refluxed for 4 hrs. The black reaction mixture was evaporated and poured as a dichloromethane solution in ice water. The aqueous layer was neutralized with solid NaHCO3 to pH 7 and extracted three times with dichloromethane. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (dichloromethane/methanol 100:0->95:5 gradient). The desired product was obtained as a light yellow solid (280 mg, 30%), MS: m/e=311.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:25]([OH:27])=O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:29]1CCOCC1.N>COCCOC>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:25](=[O:27])[NH2:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Agent: N
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A solution 4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1A, 2.0 g, 1.0 equivalent) in DME (0.5 M) was treated with NMM (1.0 equivalent) and IBCF (1.0 equivalent) at −15° C. After 10 min, aqueous ammonia (1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 1.5 hr. The reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. The organics were subsequently washed with brine, then dried over Na2SO4, filter, and the volatiles removed under reduced pressure. The residue was purified by crystallization from diethyl ether to afford the tert-butyl 4-(benzyloxycarbonylamino)-4-carbamoylpiperidine-1-carboxylate (1B, 70%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH2:16]=[O:17]>C(N(CC)CC)C.CC(C)=O>[F:15][C:2]([F:1])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][OH:17])[CH:6]=1)=[O:4]
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(c1cn(CO)c2ccccc12)C(F)(F)F
Temperature: 130 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
The mixture of 4.80 g of 3-(trifluoroacetyl)-1H-indole, 1.35 g of paraformaldehyde and 0.10 g of triethylamine was stirred at 130° C. for 2 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane was added to the residue, as a result, a crystal was formed. The crystal was collected to obtain 5.36 g of 3-(trifluoroacetyl)-1H-indole-1-ylmethanol.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[OH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:20][CH:21]=1
Reactant: OCc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)COc1ccc(CO)cc1
Yield: 47.5 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 8.00 g (64.5. mmol) of 4-hydroxybenzyl alcohol was alkylated with 11.84 g (77.4 mmol) of methyl bromoacetate to afford 6.00 g (48%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[C@@H:10]([CH2:21][CH:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Br:31])[CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:21][CH:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Br:31])[CH3:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C)Oc1ccccc1Br
Agent: Cl
Solvent: ClCCl
Product: CC(C[C@H]1CN(Cc2ccccc2)CCN1)Oc1ccccc1Br
Reaction time: 4 h

Procedure:
To a solution of Example 252D in dichloromethane (3 mL) was added HCl (4 M dioxane, 4 mL). The reaction was stirred for 4 hours before the reaction solution was concentrated. NaOH (1 M 10 mL) and dichloromethane (10 mL) were added, and the organic layer collected. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1(C)[C:36](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:32]([CH3:36])=[CH2:31])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #75, Step A, 0.05 g, 0.104 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.035 g, 0.209 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloride dichloromethane complex (0.017 g, 0.021 mmol) and K2CO3 (0.029 g, 0.209 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to reflux for 8 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-TLC (eluting with 50% EtOAc in petroleum ether) to give 4-(7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.035 g, 76%) as a pale-white solid. LC/MS (Table 1, Method 5) Rt=3.653 min.; MS m/z: 441 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]3[CH:36]=[CH:35][NH:34][C:31]3=[N:32][CH:33]=2)O1>>[CH3:13][NH:12][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([C:28]3[CH:29]=[C:30]4[CH:36]=[CH:35][NH:34][C:31]4=[N:32][CH:33]=3)=[N:7][C:6]=2[CH:8]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: CNCc1cc2nc(-c3cnc4[nH]ccc4c3)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine and 5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine were reacted according to the General Procedure A to give 437. NMR (DMSO, 400 MHz), 2.35 (3H, s), 3.78-3.82 (4H, m), 3.99-4.06 (6H, m), 6.54 (1H, s) 7.36 (1H, s), 7.48-7.51 (1H, m), 8.97 (1H, s), 9.28 (1H, s). MS: (ESI+): MH+=381
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1F)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)[C:11]([F:13])([F:14])[F:12])[O:8][C:33]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[F:25]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(c1ccc(Oc2ccc(C#N)cc2F)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 151, step 7, 100 mg) in N,N-dimethylacetamide (2 ml) were added 3,4-difluorobenzonitrile (46 mg) and cesium carbonate (272 mg). The mixture was stirred for 18 h at room temperature. EtOAc and ice water were added and the mixture was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 95:5=>0:1) to give the title compound (133 mg) as a colorless solid. MS (m/e)=481.1 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>O1CCCC1>[CH3:21][Si:22]([CH3:24])([CH3:23])[O:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 4-oxocyclohexanecarboxylate (5.95 g) (Example B) in 200 ml of anhydrous tetrahydrofuran is added dropwise under nitrogen to a solution of lithium diisopropylamide (prepared from 4.40 g of diisopropylamine and 26.2 ml of 1.6 M n-butyllithium hexane solution) in 200 ml of tetrahydrofuran at -78° C. The mixture is stirred at this temperature for one hour and trimethylsilyl chloride (4.71 g) is added dropwise via syringe. The reaction mixture is allowed to warm to room temperature overnight and the solvent evaporated in vacuo. The residue is triturated with 100 ml of diethyl ether and filtered to remove inorganic salts. Evaporation of the volatile components of the mixture gives ethyl 4-[(trimethylsilyl)oxy]-3-cyclohexene-1-carboxylate as a colorless oil which is reacted with N-bromosuccinimide and thiourea by following the procedure of Example 1 (Method A) to yield the title compound as a white solid; mp 170°-173° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)c1ccc(OCCN2CCOCC2)cc1
Yield: 41.8 %

Procedure:
A stirring solution of compound 71 (1.5 g, 6.19 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.152 g, 6.19 mmol) and potassium carbonate (1.709 g, 12.38 mmol) in (1:1) DMF: acetone (60 mL) was heated to 60° C. for 16 h then concentrated. The crude residue was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated to afford compound 73 (0.92 g, 42%) after purification by ISCO-HPLC (20 to 100% ethyl acetate in hexanes).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][CH2:9][C:10]([N:12]([C@H:14]([CH3:36])[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:13])=[O:11]>>[OH:8][CH2:9][C:10]([N:12]([CH3:13])[C@H:14]([CH3:36])[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)=[O:11]
Reactant: Cc1cc(Nc2ncnc3cccc(OC[C@@H](C)N(C)C(=O)CO)c23)ccc1O
Reactant: ClCc1cscn1
Product: Cc1cc(Nc2ncnc3cccc(OC[C@@H](C)N(C)C(=O)CO)c23)ccc1OCc1cscn1
Yield: 29 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[(1R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide (obtained as described in Example 96, preparation of starting materials) to give the title compound as a foam in 29% yield; NMR spectrum (DMSO-d6 373K) 1.26 (d, 3H), 2.24 (s, 3H), 2.83 (s, 3H), 3.97 (s, 2H), 4.35 (m, 1H), 4.46 (t, 1H), 4.95 (m, 1H), 5.24 (s, 2H), 7.08 (d, 1H), 7.18 (d, 2H), 7.35 (d, 1H), 7.42 (s, 1H), 7.46 (d, 1H), 7.70 (m, 1H), 8.41 (s, 1H), 9.07 (s, 1H), 9.50 (s, 1H); Mass spectrum MH+ 494.
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:25])[CH2:23][CH3:24])=[CH:18][CH:17]=1.[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH3:24])=[CH:20][CH:21]=1
Reactant: Oc1ccccc1
Reactant: CCC(O)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
Azodicarboxylic acid diisopropyl ester (2.8 g, 14.0 mmol) was added to the mixture of 1-(4-bromophenyl)propan-1-ol (2.0 g, 9.3 mmol), phenol (1.05 g, 11.2 mmol), triphenylphosphine (3.7 g, 14.0 mmol) and tetrahydrofuran (40 mL) at room temperature. Then the mixture was stirred at room temperature for 12 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give 1-bromo-4-(1-phenoxypropyl)benzene as a colorless oil (2.0 g, 4%). 1H NMR (300 MHz, CDCl3): δ 7.44 (d, J=8.4 Hz, 2H), 7.25-7.15 (m, 4H), 6.89-6.80 (m, 3H), 4.98 (t, J=6.5 Hz, 1H), 2.00-1.72 (m, 2H), 0.99 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)CCC.O1CCOCC1>[Cl-].[Na+].O.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>[F:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[S:18][C:11]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccco4)sc23)c(F)c1
Temperature: 90 °C
Yield: 67.1 %

Procedure:
A 100 mL, single-neck, round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (0.300 g, 0.7768 mmol) from Example 6, Step A, PdCl2(PPh3)2 (0.02726 g, 0.03884 mmol), tributyl(furan-2-yl)stannane (0.2931 ml, 0.9322 mmol), and dioxane (8 mL). Heat to 90° C. for 6 hours under nitrogen and cool to room temperature. The reaction mixture was diluted with brine (100 mL) and extracted with EtOAc (100 mL). The reaction mixture was purified by triturating with hot MeOH. The product (170 mg, 57%) was isolated as a brown solid. LRMS (APCI+) m/e 327 (M+1) detected.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:17]=[C:18]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.9 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.00 g, 19.9 mmol), 1-(3-hydroxyphenyl)ethanone (2.71 g, 19.9 mmol), and triphenylphosphine (5.73 g, 21.9 mmol) in tetrahydrofuran (100 mL) was added slowly diisopropyl azodicarboxylate (4.25 mL, 21.9 mmol) at 0° C. under Nitrogen. The resulting mixture was stirred at room temperature for 17 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1) to give 4.70 g (74%) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.CS([C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: CS(=O)(=O)c1ncccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc2[nH]c3c(c2c1)CCCC3Nc1ncccn1
Yield: 11.6 %

Procedure:
A solution of 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg, 0.23 mmol) and 2-methylsulfonylpyrimidine (69 mg, 0.44 mmol) in N,N-dimethylformamide (0.50 mL) was heated at 150° C. for 900 seconds in a Smith Synthesizer microwave. The mixture was diluted with ethyl acetate and extracted with 5% aqueous lithium chloride. The organic layer was isolated and concentrated onto silica. Purification by flash chromatography (0-30% ethyl acetate-hexanes) yielded 6-chloro-N-pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine (8 mg, 12% yield) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1>[OH-].[K+]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(OCCCCCCO)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCCCCO)cc1

Procedure:
23.5 g (0.088 mole) ethyl 4-(6-hydroxyhexyloxy)benzoate (as crude product) was added to 300 mL 0.5 M KOH and refluxed for 5 hours.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[N:20]=[C:19]([N:23]([CH3:25])[CH3:24])[N:18]([CH3:26])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:16]2[C:21](=[O:22])[N:20]=[C:19]([N:23]([CH3:24])[CH3:25])[N:18]([CH3:26])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: [H][H]
Reactant: CN(C)c1nc(=O)n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c(=O)n1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)c1nc(=O)n(-c2cc(O)c(Cl)cc2F)c(=O)n1C
Yield: 89.2 %

Procedure:
A mixture of 4.62 g (11.4 mmol) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy)phenyl]-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4(1H,3H)-dione and 460 mg of 10% palladium on charcoal in 50 mL of ethyl acetate was placed in a Paar bottle and was agitated under 45 psi hydrogen over a 14 hour period. It was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo and the resultant crude product flash chromatographed over silica gel eluting with a 1:1 v:v mixture of ethyl acetate and hexane to give 3.2 g of the title compound as a pale grey solid, m.p.: 247°-249° C. (dec); 1H-NMR (DMSO-d6) ppm 7.45 (d, 1H), 6.95 (d, 1H), 3.3 (s, 3H), 3.0 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH2:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH2:16])(=[O:19])[CH3:18]
Reactant: Nc1ccc2c(N)c3ccccc3nc2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(N)c3ccccc3nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25 mL rbf equipped with a nitrogen bubbler were charged 3,9-diaminoacridine (50 mg, 0.24 mmol) and anhydrous DCM (2 mL). To the resulting red suspension was added acetic anhydride (25 μL, 0.26 mmol) followed by triethylamine (37 μL, 0.26 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. LCMS showed incomplete reaction but only formation of expected product. Starting material was not really soluble in DCM. Pyridine (0.5 mL) was thus added and the mixture stirred overnight. LCMS still showed incomplete reaction. A further portion of acetic anhydride (25 μL, 0.26 nmol) was added and the reaction mixture was stirred at room temperature over three days. LCMS showed reaction completion.