Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCC[O:4][C:5]1[C:10]([NH:11][C:12]([C:14]2[C:23]3[C:22]4[N:24]=[CH:25][CH:26]=[CH:27][C:21]=4[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][CH:15]=2)=[O:13])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH2:28]([N:30](CC)[CH2:31][CH3:32])[CH3:29].CS(Cl)(=O)=O>C(Cl)Cl>[CH2:28]([NH:30][CH2:31][CH2:32][N:6]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]2[C:23]3[C:22]4[N:24]=[CH:25][CH:26]=[CH:27][C:21]=4[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][CH:15]=2)=[O:13])[C:5]1=[O:4])[CH3:29]
Reactant: CCN(CC)CC
Reactant: O=C(Nc1cccnc1OCCO)c1c[nH]c2c1-c1ncccc1CCC2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCNCCn1cccc(NC(=O)c2c[nH]c3c2-c2ncccc2CCC3)c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
To a mixture of 3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid [2-(2-hydroxy-ethoxy)pyridin-3-yl]amide (150 mg, 0.41 mmol) and triethylamine (125 mg, 1.2 mmol) in DCM (10 mL) at 0° C. is added methanesulfonyl chloride (94 mg, 0.82 mmol) dropwise. The mixture is stirred at 0° C. for 15 min. The solvent is removed and the residue is dissolved in acetonitrile (10 mL) and transferred to a sealed tube. Ethylamine (1 mL) is added and the mixture is heated at 60° C. for 3 h. The solvent is removed and the residue is separated by preparative TLC to give 87 mg of 3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid [1-(2-ethylaminoethyl)-2-oxo-1,2-dihydro-pyridin-3-yl]amide. LRMS Calcd 391.5; found M−1 390.2.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1)=[O:10]>C1C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][CH:21]=1)[NH:16][CH:15]=[C:14]2[CH2:13][CH2:12][N:11]([C:1]([CH3:2])=[O:3])[C:9](=[O:10])[CH3:8]
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: COc1ccc2[nH]cc(CCN(C(C)=O)C(C)=O)c2c1
Yield: 50 %

Procedure:
Acetic anhydride (7 ml) is added with stirring to melatonin (500 mg) dissolved in benzene (50 ml). The mixture is heated for 72 h in refluxing benzene. The solvent is evaporated off and the crude product is taken up in water and then neutralized with sodium carbonate solution (pH>8). After extraction (dichloromethane), washing (water) and drying (magnesium sulphate), the crude product is flash-chromatographed (EtOAc eluent). N-[2-(5-Methoxyindol-3-yl)ethyl]diacetamide (4) (300 mg, 50% yield) is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:6]=2[N:7]=1.[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)=[O:28]>>[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[C:5]3[CH2:10][NH:9][CH2:8][C:6]=3[N:7]=2)=[CH:32][CH:31]=1)=[O:28]
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Product: CNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1

Procedure:
Method as described for example 3 using intermediate 1 and 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials. The boc protected intermediate was purified by prep HPLC (high pH).
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8][Si](C(C)C)(C(C)C)C(C)C)=[CH:6][CH:5]=[CH:4][C:3]=1[N:19]1[C:23](=[O:24])[N:22]([CH3:25])[N:21]=[N:20]1.[F-].[Cs+].[CH3:28]N(C)C=O.CI>O>[CH3:1][C:2]1[C:7]([S:8][CH3:28])=[CH:6][CH:5]=[CH:4][C:3]=1[N:19]1[C:23](=[O:24])[N:22]([CH3:25])[N:21]=[N:20]1
Reactant: Cc1c(S[Si](C(C)C)(C(C)C)C(C)C)cccc1-n1nnn(C)c1=O
Reactant: CN(C)C=O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CI
Product: CSc1cccc(-n2nnn(C)c2=O)c1C
Temperature: 25 °C

Procedure:
A mixture of 1-(2-methyl-3-triisopropylsilanylsulfanylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 3.63 g, cesium fluoride 2.91 g and N,N-dimethylformamide 10 ml was stirred at room temperature for thirty minutes. To the resulting mixture was added methyl iodide 2.72 g and the resulting mixture was stirred at room temperature for three hours. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-methyl-3-methylthiophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 1.65 g.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Br[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C>CN(C)C=O>[C:10]([O:9][C:7](=[O:8])[CH2:6][NH:4][CH2:3][CH2:1][OH:2])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCCO

Procedure:
The compound is prepared, in analogy with Example 1, from ethanolamine (18.33 g; 0.3 mol) and tert-butyl bromoacetate 58.6 g; 0.3 mol) in the presence of triethylamine (30.7 g; 0.3 mol) in anhydrous N,N-dimethylformamide (300 ml). The crude product is purified by chromatography on silica gel (eluent: chloroform/methanol, 16:1). Yield: 33.65 g (64%).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][C:6]2[CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH2:11][C:5]=2[N:4]=1.[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(#N)C>[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([O:18]/[C:17](/[C:16]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=1[F:14])=[CH:2]\[C:3]1[N:4]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=2[F:14])[C:5]2[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[C:6]=2[N:7]=1)=[O:18]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Cc1nc2c([nH]1)C(C)CC(C)C2
Agent: Cl
Solvent: CC#N
Product: CC1Cc2c(nc(/C=C(\OC(=O)c3ccc(F)cc3F)c3ccc(F)cc3F)n2C(=O)c2ccc(F)cc2F)C(C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
380 mg (1.89 mmol) of 2,5,7-Trimethyl-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (example X, step 3) is dissolved in 10 ml acetonitrile. 1.19 ml (8.52 mmol) TEA is added and the solution is cooled with an ice bath. 1.10 g (6.25 mmol) of 2,4-difluorobenzoyl chloride is dropped to the reaction mixture, which then is stirred at rt for 24 h. The solvent is evaporated and water is added to the crude. After it is stirred for a few minutes the water is decanted. This step is repeated twice. The crude is transferred to the next step (example 1, step 5).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12]Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[NH3:14]>CO.C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:12][NH:14][C:5]2=[O:6]
Reactant: N
Reactant: COC(=O)c1cccc(Br)c1CBr
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Methyl 3-bromo-2-(bromomethyl)benzoate (1.28 g) was dissolved in a 11% solution of ammonia in methanol-THF mixed solution (3:2, 25 ml) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was washed with saturated brine. Recrystallization from ethyl acetate-hexane gave the title compound (671 mg, 76%) as colorless needle crystals.
Reaction SMILES: [C:1]([F:6])(F)=[C:2](Cl)F.N1C=CC=CC=1.F.NC1C=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][C:22]2=[O:25])=[CH:17][CH:16]=1.N([O-])=O.[Na+]>N1C=CC=CC=1>[F:6][C:1]1[CH:2]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][C:22]2=[O:25])=[CH:17][CH:16]=1
Reactant: FC(F)=C(F)Cl
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Agent: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C1CCCc2ccc(F)cc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
In a specially designed Kel-F reactor (cylindrical shape 1.25"od×3"h equipped with a screw cap and N2 inlet-outlet) was placed hydrogen fluoride-pyridine 6:4 solution (10 mL, prepared by diluting commercially available hydrogen fluoride-pyridine 7:3 solution with dry pyridine). 7-amino-tetralone (644 mg, 4.0 mmol), (Example 35, Step A) was added under N2 and the solution was cooled to 0°. Sodium nitrite (304 mg, 4.4 mol, 1.1 eq) was added in portions and the mixture was stirred for 30 minutes. The mixture was then heated at 90° C. for 1 hour with stirring. The reaction mixture was quenched with approx. 60 mL of ice/water and the solid that separated extracted with methylene chloride (3×30 mL). The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum at room temperature. Purification by flash chromatography on silica, eluting with ethyl acetate/hexane (5:95), afforded pure 7-fluoro- 1-tetralone (367 mg, 2.2 mmol, 56%). 1H NMR (300MHz, CDCl3): 2.13 (m,2H), 2.65 (t,7Hz,2H), 2.94 (t,7Hz,2H), 7.1-7.3 (m,2H), 7.69 (dd;2,8Hz;1H). FAB-MS: calculated for C10H9FO 164; found 164 (M+,71%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30].[Cl-].[Na+]>C(OCC)C>[CH3:2][O:3][CH:4]=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COC=Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
27.7 g of methoxymethyltriphenylphosphonium chloride is introduced into 350 ml of diethyl ether under nitrogen. At 0° C., 38.8 ml of n-butyllithium solution (1.6 M in hexane) is added in drops, and it is stirred for one hour at room temperature. 12 g of 4-isopropylbenzaldehyde in 50 ml of diethyl ether is now added, and it is stirred for one more hour. Sodium chloride solution is added to the reaction mixture, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 8.1 g of 1-methoxy-2-[4-(1-methylethyl)phenyl]-ethene 42 (E,Z-mixture) is obtained as a colorless oil, which is dissolved in 200 ml of acetone and stirred under nitrogen with 10 ml of 2N hydrochloric acid overnight. Sodium chloride solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. Chromatographic purification on silica gel with ethyl acetate/hexane yields 5.1 g of title compound 43 as a colorless oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[CH2:24][CH2:25][C:26]1[N:30]([CH3:31])[C:29]2[C:32]3[C:37]([CH:38]=[CH:39][C:28]=2[N:27]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[C:29]4[C:32]5[C:37]([CH:38]=[CH:39][C:28]=4[N:27]=3)=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cn1c(CCCl)nc2ccc3ccccc3c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(CCN2CCN(c3ccc(Cl)cc3)CC2)nc2ccc3ccccc3c21
Yield: 89.7 %

Procedure:
6.5 g (0.024 mole) of 1-(4-chlorophenyl)-piperazine dihydrochloride and 8.43 cc (0.06 mole) of triethylamine are added to a solution of 2.93 g (0.012 mole) of 2-(2-chloroethyl)-1-methyl-1H-naphth[1,2-d]imidazole in 100 cc of ethanol. The reaction mixture is then heated at reflux temperature and maintained under an argon atmosphere for 23 hours. By evaporating the solvent, grinding the residue with water and filtering, a raw product is obtained, which is recrystallized from methylisopropylketone, yielding 4.36 g (90% yield) of pure compound. M.p. 213°-15° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](Cl)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N(CC)CC)C.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:24]3[CH2:25][CH2:26][N:21]([C:18](=[O:20])[CH3:19])[CH2:22][CH2:23]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Reactant: CC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
A mixture of 1.989 (7.50 mmole) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 1.169 (9.05 mmole) of N-acetylpiperazine, and 2.0 mL of triethylamine in 20 mL of dry THF was refluxed under a nitro9en atmosphere for 16 hr. It was then poured into 5% aqueous sodium hydroxide and extracted three times with methylene chloride. The combined organic portions were dried over MgSO4, filtered and concentrated in vacuo to yield a product which was purified by flash chromatography (5% CH3OH in CHCl3) to afford 1.71g of the title compound as a glass.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=S1(=O)Nc2ccccc2C1=Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=C2c3ccccc3NS2(=O)=O)cc1
Yield: 80 %

Procedure:
To a cooled solution of 3-(4'-hydroxyphenyl)methylene-2,1-benzisothiazoline-2,2-dioxide (273 mg, 1 mmol) in dry pyridine (0.5 ml) is added acetic anhydride (204 mg, 2 mmol) and the mixture maintained at 0°-5° C. overnight. Thereupon the mixture is concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer washed with water and then evaporated under reduced pressure. The crude product is crystallized from chloroform-methanol to yield pure 3-(4'-acetoxyphenyl)methylene-2,1-benzisothiazoline-2,2-dioxide (80% yield). C16H13NO4S calcd: C 60.94 H 4.15 N 4.44 S 10.17 found: C 60.85 H 4.05 N 4.34 S 10.19 MS (m/z): 315
Reaction SMILES: [CH:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2([CH3:31])[CH2:15][C:14]3[C:16]([CH3:30])=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([CH3:21])=[C:19]([CH3:20])[C:13]=3[O:12]2)[CH2:6][CH2:5]1)=O.[C:32]1([CH:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:39][CH2:40][NH2:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:42]1([CH:38]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:39][CH2:40][NH:41][CH2:1][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][C:11]3([CH3:31])[CH2:15][C:14]4[C:16]([CH3:30])=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([CH3:21])=[C:19]([CH3:20])[C:13]=4[O:12]3)[CH2:6][CH2:5]2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CN1CCC(CC=O)CC1)O2
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CN1CCC(CCNCCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 97 %

Procedure:
Using tert-butyl [2-[[4-(formylmethyl)-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5yl]carbamate and (3,3-diphenylpropyl)amine, the procedure of Reference Example 44 was otherwise repeated to provide the title compound. Yield 97%.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH2:15]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:22]1[CH2:23][CH2:24][N:19]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH:21]=1)(=[O:3])=[O:4]
Reactant: CCCCN1CCC(=O)CC1
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Product: CCCCN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 84.6 %

Procedure:
Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and 0.96 gm (6.2 mMol) 1-butyl-4-piperidone, 1.4 gm (84.8%) of the title compound were recovered as a yellow powder.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)OCC=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCC2
Yield: 37.2 %

Procedure:
A mixture of methyl 2H-chromene-7-carboxylate (372 mg, 1.96 mmol) and 10% Pd/C (25 mg) in methanol (15 mL) is stirred under 1 atm of hydrogen at rt for 3 h. The mixture is filtered through Celite and the filtrate is concentrated to a yellow residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 140 mg (37%) of methyl chromane-7-carboxylate as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.47, 7.10, 4.23, 3.91, 2.85, 2.04.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=1.CC([O-])(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.CC(N(C)C)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:12]=[C:11]([O:10][CH3:9])[CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: COc1ccnc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccnc(Oc2ccc(N)cc2)c1

Procedure:
4-Aminophenol was reacted with 4-methoxy-2-chloropyridine in the presence of KOtBu/18-Crown-6/DMA at 150° C. for 5 hrs to give 2-(4-aminophenoxy)-4-methoxypyridine. The product was purified by chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36][CH2:37][CH3:38])=[CH2:35])CCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:37]([O:36][C:34]([C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)=[CH2:35])[CH3:38]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 110 °C
Yield: 47.1 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (693 mg, 1.51 mmol) from Example 29, tributyl (1-ethoxyvinyl)tin (1.10 g, 3.03 mmol) and DMF (10 mL) was purged with argon. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (262 mg, 0.23 mmol). The reaction vessel was sealed and the mixture was heated at 110° C. for 2 h. The mixture was allowed to cool to rt. The mixture was partitioned between water and DCM and the organic layer was separated. The aqueous layer was extracted with additional DCM. The combined organic layers were washed with water then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM to 15% MeOH in DCM to afford (1R,2R)-2-((6-((6-(1-ethoxyvinyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (320 mg, 47%) as a solid. LCMS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([CH3:18])[CH:12]=1.[H][H]>[Pt](=O)=O.C(O)(=O)C>[CH3:18][C:13]1[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH:16]=[C:15]([CH3:17])[N:14]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2cc([N+](=O)[O-])ccc2F)cc(C)n1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(N)ccc2F)cc(C)n1

Procedure:
4-(2-fluoro-5-nitrophenyl)-2,6-dimethylpyridine, 180 g, was divided into four equal portions and each portion was reduced separately as follows. A mixture containing 45 g of 4-(2-fluoro-5-nitrophenyl)-2,6-dimethylpyridine, 200 ml of acetic acid and 800 mg of platinum dioxide was catalytically hydrogenated until hydrogen uptake ceased, about 4 hours with little hydrogen uptake the last thirty minutes. The catalyst was filtered off, washed with 300 ml of water, and the filtrate made basic by adding aqueous ammonium hydroxide. The solution was cooled to yield a oily material which solidified. The solid was collected, washed with water and dried to yield the desired amine. The remaining three 45 g portions of 4-(2-fluoro-5-nitrophenyl)-2,6-dimethylpyridine were reduced in the same way and the combined amine products were dissolved in 600 ml of concentrated hydrochloric acid and heated on a steam bath with stirring for 4 and 1/2 hours and then treated with decolorizing charcoal and filtered. The filtrate was made basic by adding aqueous ammonia and the resulting mixture was chilled to yield an oil which crystallized. The crystalline material was collected, washed with water and dried in an oven to yield 164.9 g of gummy solid. The solid was dissolved in ether containing 5% methanol and the solution was filtered through silica gel to remove the gummy impurities. The ether-methanol solvent of the filtrate was distilled off in vacuo and the residue was recrystallized from ether-isopropyl alcohol to yield 80.9 g of 3-(2,6-dimethyl-4-pyridinyl)-4-fluorobenzeneamine, m.p. 142°-145° C. Concentration of the mother liquor yielded another 43.4 g of the product, m.p. 141°-144° C., thereby giving a total yield of 82%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1F.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>CCOC(C)=O>[F:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
A mixture of 1,2,3-trifluoro-5-nitrobenzene (3.54 g, 20.0 mmol), morpholine (2.0 mL, 23.0 mmol) and Et3N (8.5 mL, 61.0 mmol) in EtOAc (30 mL) was stirred at rt for 5 h. The mixture was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a yellow solid (4.76 g, 98%).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[C:9]3=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:29](=[O:32])[CH2:30][CH3:31]>O1CCCC1.[Cl-].[NH4+]>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[N:11]1[C:9]2=[N:10][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH:29]([OH:32])[CH2:30][CH3:31])[C:7]=3[N:8]2[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC=O
Reactant: Clc1ccc(N2CCCCn3c2nc2cccc(Br)c23)c(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cccc2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 18.6 %

Procedure:
To a solution of 7-bromo-1-(2,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (570 mg, 1.39 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (1.60 M solution in n-hexane, 0.97 mL, 1.55 mmol) at −78° C., and the mixture was stirred for 10 min. To the mixture was added propionaldehyde (0.30 mL, 4.16 mmol), and the mixture was stirred at −78° C. for 10 min, at 0° C. for 3 hr. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate to give the title compound as a colorless crystal (101 mg, 0.259 mmol, 19%).