Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H-].[Na+].I[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: FC(F)(F)CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Treat a stirred solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (1.50 g, 4.74 mmol, Preparation 9), tetrahydrofuran (45 mL) and dimethylformamide (5 mL) at 0° C. with sodium hydride (0.228 g, 5.69 mmol, 60% oil dispersion) under an argon atmosphere. Stir at room temperatue for 30 minutes, cool to 0° C. and treat with 1-iodo-4,4,4-trifluorobutane (1.35 g, 5.69 mmol, Lancaster Synthesis). Allow to warm slowly to room temperature and stir overnight at room temperature. Cool to 5° C., quench by addition of ice and saturated ammonium chloride solution (5 mL) and concentrate in vacuo to remove the tetrahydrofuran. Dissolve the residue in ethyl acetate (150 mL), wash the organic phase with water (3×40 mL), dry (Na2SO4), filter and concentrate to afford a yellow oil. Purify by flash chromatography (silica gel, 7×40 cm) eluting with 60% ethyl acetate in hexane. Concentrate the appropriate fractions in vacuo and dry the residue (1.2 Torr, 50° C., 2 hours) to afford 1.93 g of 4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as an oil, Rf=0.40 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CCCCCCC>C1COCC1.[OH-].[Na+]>[CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Yield: 80.4 %

Procedure:
In a manner similar to that of Example 7, by reaction of 1.35 g (3.07 mmol) of methyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)benzoate in 20 ml of THF and 3 g of sodium hydroxide, and after trituration from heptane, 1.05 g (80%) of the expected compound are obtained in the form of a white solid. m.p.=240° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1OCC2
Solvent: CO
Product: Nc1cc2c(c(C(=O)O)c1)OCC2
Reaction time: 96 h
Yield: 63 %

Procedure:
The crude 5-nitro-2,3-dihydrobenzo[b]furan-7-carboxylic acid was dissolved in the minimum amount of methanol (1.3 L) and nitrogen was bubbled through the solution for 20 minutes. A mixture of 5% palladium on charcoal (1.0 g) in water (20 ml) was added and the mixture loaded into a 2 L autoclave. After 2 sequential evacuation-N2 purges the vessel was charged to 5 bar H2 and stirred for 4 days. The mixture was flushed with nitrogen, filtered through celite and concentrated to give 5-amino-2,3-dihydrobenzo[b]furan-7-carboxylic acid (3.5 g, 19.5 mmol, 63% over 2 steps)
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](NC2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:4][C:3]=1S(O)(=O)=O.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=CC=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: Nc1ccccc1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-(3'-amino-2',4',6'-trimethyl-5'-sulfoanilino)anthraquinone-2-sulfonic acid (23.7 parts), cyanuric chloride (9.3 parts) and 1-aminobenzene-3-β-sulfatoethylsulfone (14.1 parts) were subjected to condensation in an aqueous medium one after another in a usual manner. Successively, the resulting condensate was further subjected to condensation with aniline (4.7 parts) at 60° to 70° C. under a weak acid condition. Thereafter, the reaction mixture was salted-out to separate crystals, thereby obtaining an anthraquinone compound of the following formula in the free acid form. ##STR264##
Reaction SMILES: [OH:1][CH:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:1][CH:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4])[N:13]=1
Reactant: COC(=O)C(O)C(C)(C)C
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(C)cc(C)n1)C(C)(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
2.9 g of methyl 2-hydroxy-3,3-dimethybutyrate, 4.1 g of 4,6 -dimethyl-2-methylsulfonylpyrimidine and 3.3 g of potassium carbonate were added to 50 ml of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature, poured into water and extracted with 100 ml of ethyl acetate. The organic layer was washed twice with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The liquid substance thereby obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =6/1) to obtain 4.2 g of the desired product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1([CH2:14][C:15]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C@H:19]3[O:28][C:29]2[CH:41]=[CH:40][C:32]3[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)C(C)C)(C)C.[OH-].[Na+].Cl>C(#N)C.O>[C:1]([N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C@H:19]3[O:28][C:29]2[CH:41]=[CH:40][C:32]3[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCN(Cc2c(C(F)(F)F)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic anhydride (0.03 mL) is added to a solution of {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (0.22 g) and N,N-diisopropyl-ethylamine (0.11 mL) in acetonitrile (5 mL) at room temperature. The solution is stirred at room temperature for 1.5 h. 4 M aqueous NaOH solution (0.1 mL) is added and the solution is stirred for another 30 min. Water is added and the resulting solution is acidified with 4 M HCl solution (pH ca. 3-4). The resulting mixture is extracted with ethyl acetate, and the combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 1): tR=0.95 min; Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:27])[C@H:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[C:23]([C:24]([OH:26])=O)[C:16]=23)[C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[CH:1]1([NH:6][C:7](=[O:27])[C@H:8]([N:13]2[C:24](=[O:26])[C:23]3=[CH:22][NH:21][C:17]4[C:16]3=[C:15]([CH:20]=[CH:19][N:18]=4)[CH2:14]2)[C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H](C)[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)NC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC[C@@H](C)[C@H](C(=O)NC1CCCC1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 37 %

Procedure:
In a manner similar to Step C of Example 19, 4-(((2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid was cyclized in a mixture of THF (2 mL), HATU (112 mg, 0.296 mmol) and 4-methylmorpholine (37.4 mg, 0.370 mmol) and the resulting product was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (32 mg, 37% from Step A starting material). 1H NMR (400 MHz, CD3OD) δ 0.61-0.72 (m, 2 H) 0.90-1.06 (m, 5 H) 1.37-1.66 (m, 7 H) 1.66-1.77 (m, 2 H) 1.77-1.99 (m, 4 H) 3.98-4.22 (m, 1 H) 4.85-4.97 (m, 2 H) 5.21 (d, J=9.35 Hz, 1 H). [M+H] calc'd for C20H26N4O2, 355; found, 355.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Li]CCCC.[C:14]1([P:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([P:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1cccc(P(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.5 %

Procedure:
To a solution of 1,3-dibromobenzene (7.4 mL, 61 mmol, 1.05 equiv) in THF (70 mL, 0.9 M) at −90° C. was added n-BuLi (2.5 M) (25.5 mL, 64 mmol, 1.10 equiv) dropwise. The reaction mixture was stirred 45 min then diphenylchlorophosphine (10.7 mL, 58 mmol, 1.0 equiv) was added dropwise and the resulting dark brown solution was warmed to room temperature for 15 min and filtered through a small pad of Celite. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (Et2O/hexane, 0:100-5:95) to afford (3-bromophenyl)diphenylphosphine (2) (18.1 g, 91%) as a viscous colorless oil, which was characterized as follows:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[C:3]1=[O:19].Cl>CO>[CH3:1][N:2]1[C:6](=[O:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[C:3]1=[O:19]
Reactant: COC(=O)c1ccc(CN2CC(=O)N(C)C2=O)cc1
Agent: Cl
Solvent: CO
Product: CN1C(=O)CN(Cc2ccc(C(=O)O)cc2)C1=O

Procedure:
To the solution of Example G (900 mg, 3.44 mmol) in MeOH (30 mL) was added conc. HCl (10 mL). The resulting solution was heated to reflux for 1 h, quenched with saturated Na2CO3 (100 mL), and extracted with CH2Cl2 (100 mL). After separation, the organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield 4-((3-methyl-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid as a yellow solid. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([CH2:28][NH2:29])[OH:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:29][CH2:28][CH2:26][OH:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCCO
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCO)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and ethanolamine.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[Li]CCCC.[C:12]1([CH2:18]C(Cl)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[O:6]=[C:4]([CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:1]#[N:2]
Reactant: N#CCC(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)Cc1ccccc1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of cyanoacetic acid (2 g, 23.5 mmol) in THF (100 mL) at −78° C. was added nBuLi (10 mL, 25.9 mmol, 2.5M in hexanes). After 30 min, phenylacetyl chloride (1.6 mL, 11.8 mmol) was added dropwise. Following an additional 30 min, the solution was partitioned between 1N HCl-Et2O and the aqueous phase was washed several times with Et2O. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 30% EtOAc in hexanes) yielding the title compound (770 mg, 40%) as a tan oil: LCMS (ES) m/z 160 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([C:15](=[O:17])[NH2:16])[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.[Cl:18][CH2:19][C:20](OC)(OC)OC.C(O)(=O)C>>[Cl:18][CH2:19][C:20]1[NH:16][C:15](=[O:17])[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]2)[N:1]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Reactant: COC(CCl)(OC)OC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(CCl)NC2=O
Temperature: 118 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
1C (0.3M) was added 2-chloro-1,1,1-trimethoxyethane (4.0 equivalents) and acetic acid (2.0 equivalents). The mixture was stirred for 12 hr at 118° C. Solvent was removed under reduced pressure and the residue was purified by crystallization from cold diethyl ether to afford tert-butyl 2-(chloromethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1D, 67%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:46]([C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53])([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C>[C:46]([C:50]1[CH:51]=[C:52]([NH:53][C:12]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=2)=[O:14])[CH:54]=[CH:55][CH:56]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(NC(=O)c2c[nH]c3ccccc3c2=O)c1
Temperature: 60 °C

Procedure:
A flask charged with 4-oxo-1H-quinoline-3-carboxylic acid (38 mg, 0.20 mmol), HBTU (76 mg, 0.20 mmol), Et3N (61 mg, 84 μL, 0.60 mmol) and DMF (2 mL) was heated at 60° C. for 15 minutes. To the reaction mixture was then added 3-tert-butylaniline (29.98 mg, 0.2009 mmol) and the reaction mixture was stirred at 60° C. for an additional 30 minutes. The reaction mixture was cooled to room temperature, filtered and purified via reverse phase HPLC using 10 to 99% CH3CN in H2O to obtain N-(3-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 12.45 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J=1.1, 8.2 Hz, 1H), 7.84-7.80 (m, 1H), 7.76-7.71 (m, 2H), 7.62-7.53 (m, 2H), 7.29 (t, J=7.9 Hz, 1H), 7.15-7.12 (m, 1H), 1.31 (s, 9H). LC/MS: m/z 321.5 (M+H)+ at 1.8 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]Br.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc(Br)cc1
Yield: 55.4 %

Procedure:
To a suspension of 4-bromophenol (2.00 g, 11.6 mmol) in water (20 mL) was added 1,2-dibromoethane (5.40 g, 28.8 mmol) and sodium hydroxide (0.700 g, 17.5 mmol). Then, the mixture was heated at reflux for 12 hours. Water was added, and the mixture was extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (0-10% ethyl acetate/petroleum ether) to afford the title compound (1.8 g, 56%) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:14]=2)[CH2:8]1)C.[CH3:33][CH2:34]OCC.[ClH:38]>C(Cl)Cl>[ClH:38].[CH2:33]([N:5]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:14]=2)[CH2:8]1)[C:4](=[O:32])[OH:3])[CH3:34]
Reactant: CCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CCN(C[C@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1)C(=O)O

Procedure:
To a solution of ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (89 mg, 0.2 mmol) in 2 mL CH2Cl2 under an N2 atmosphere was added ether (10 mL) followed by the dropwise addition of a 2.0 M solution of HCl in ether (0.1 mL, 0.2 mmol) which resulted in precipitation of ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride which was then filtered and dried (85 mg, 90%). LC/MS: m/z 439.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=8.5 Hz, 1H), 7.57 (s, 1H), 7.45 (m, 2H), 6.81 (m, 2H), 4.57 (m, 2H), 3.89 (m, 2H), 3.52 (m, 1H), 3.36 (m, 1H), 2.95 (s, 2H), 2.52 (s, 3H), 1.86 (m, 3H), 1.66 (m, 1H), 1.39 (m, 1H), 1.07 (t, J=6.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:22][CH3:23])=[C:9]([CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)[N:10]=2)[N:7]=1.[CH2:24]([O:26]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:25].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:22]([C:8]1[N:6]2[N:7]=[C:2]([C:24](=[O:26])[CH3:25])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:23]
Reactant: CCc1c(Cn2ccnc2-c2nccs2)nc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1c(Cn2ccnc2-c2nccs2)nc2ccc(C(C)=O)nn12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-imidazo[1,2-b]pyridazine (100 mg, 0.26 mmol), 1-ethoxyvinyltributylstannane (142 mg, 0.39 mmol) and PdCl2(Ph3P)2 (10 mg) in anhydrous toluene (5 mL) is heated at 110° C. in a sealed tube for 5 hours. On cooling, water (2 mL), and concentrated HCl (2 mL) are added and the mixture is stirred at room temperature for 2 hours. The mixture is neutralized with sodium carbonate solution and extracted with methylene chloride (3×15 mL). The combined organic layers are dried (Na2SO4) and the solvent removed. The residue is purified by PTLC (5% methanol in methylene chloride) to give 1-[3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)imidazo[1,2-b]pyridazin-6-yl]ethanone as a solid. 1H NMR (CDCl3): 7.95, d (1H); 7.86, d (1H0; 7.70, d (1H); 7.36, d (1H); 7.25, d (1H); 7.11, d (1H); 6.18, s (2H); 3.10, q (2H); 2.75, s (3H); 1.18, t (3H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C@H:14]([OH:16])[CH3:15])[CH2:9]1)(C)(C)C.C(Cl)[Cl:19]>Cl.O1CCOCC1>[ClH:19].[ClH:19].[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C@H:14]([OH:16])[CH3:15])[CH2:9]1
Reactant: C[C@@H](O)CN1CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](O)CN1CC[C@@H](N)C1

Procedure:
(R)-1-((R)-3-Amino-pyrrolidin-1-yl)-propan-2-ol dihydrochloride (140 mg) was prepared by following General Procedure L starting from [(R)-1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (244 mg) and DCM (2 mL) in 4M HCl in dioxane (2 mL).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[NH:21][CH:20]([CH3:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:11][CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]([O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[CH:42]1[C:43]2[CH:31]([CH2:30][O:29][C:27]([N:21]3[C:16]4[CH:15]=[CH:14][C:13]([C:12]5[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]=[CH:10][CH:11]=5)=[CH:25][C:17]=4[C:18]([CH3:24])([CH3:23])[O:19][CH:20]3[CH3:22])=[O:28])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]=2[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC1Nc2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC1OC(C)(C)c2cc(-c3cccn3C(=O)OC(C)(C)C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl-5-(2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate (1.7 g, 4.96 mmol), 9-fluorenylmethyl chloroformate (1.92 g, 7.5 mL), sodium carbonate (4 g, 37 mmol) in dioxane (50 mL) and water (50 mL) was stirred at room temperature under a blanket of nitrogen for 6 hours. Ethyl acetate (100 mL) was added and organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography(hexane:ethyl acetate/6:1) to afford 9H-fluoren-9-ylmethyl-6-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)-carboxylate as a clean oil.
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16](Cl)=[O:17])([O-:12])=[O:11]>C1C=CC=CC=1>[CH3:9][C:5]([CH2:4][N+:1]([O-:3])=[O:2])=[CH:6][CH2:7][OH:8].[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16]([O-:2])=[O:17])([O-:12])=[O:11]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC(=CCO)C[N+](=O)[O-]
Solvent: c1ccccc1
Product: O=C([O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To 0.1 Mol of 4-nitro-3-methyl-2-butenol in benzene was added 0.1 Mol of 3,5-dinitrobenzoylchloride and stirred overnight. The benzene was evaporated and the residue was stirred in sat. sodiumbicarbonate solution for 1 hour. The solid product was filtered and recrystallized first from alcohol water and then from ethylacetate/hexane. The product was obtained as a yellow crystalline material, m.p. 111°-113°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[OH:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(O)c1
Reaction time: 0.17 h

Procedure:
A solution of 3.2 grams of 2-fluoro-5-nitroaniline, sulfuric acid (3 cc., d 1.84) and 8 ml. of water is stirred into a solution of 1.5 grams of sodium nitrite in water, maintained below 5° C. After 10 minutes, the excess nitrous acid is destroyed by urea, the reaction mixture filtered, and the filtrate added to 40 ml. of boiling 50% sulfuric acid. After complete addition, the mixture is boiled an additional 15 minutes, cooled, and the separated phenol filtered and washed with water. It is then purified by recrystallization from hexane.