Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28](O)=[O:29])=[CH:22]2>CN(C)C=O>[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([NH:6][C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:18])=[CH:27][CH:26]=2)=[O:29])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
L-Tryptophan methyl ester hydrochloride (1.05 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.0 mmol) were coupled according to Procedure A (0-25° C., dimethyl-formamide reaction solvent) and the product purified by chromatography on silica gel eluted with 10%, 20%, 30%, 40%, 50% and 60% ethyl acetate-hexanes giving a yellow foam. Yield, 79%; HPLC (60/40) 7.43 minutes (96%);
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[CH:6][CH:5]=1.C[O-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>O>[CH2:27]([O:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[CH:8][CH:9]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)CNC(=O)Nc1ccc(C=NO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=Cc1ccc(NC(=O)NCC(=O)OC(C)(C)C)cc1

Procedure:
A solution of N-[4-(hydroxyiminomethyl)phenyl]-N'-tertbutoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the corresponding N-[ 4-(allyloxyiminomethyl)phenyl]-N'-tert-butoxycarbonylmethylurea.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1.Cl[C:13]1[C:18]2=[CH:19][N:20]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[N:21]=[C:17]2[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[N:20]1[CH:19]=[C:18]2[C:13]([NH:3][C:4]3[N:5]=[CH:6][CH:7]=[C:8]([CH:9]=3)[C:10]#[N:11])=[N:14][CH:15]=[CH:16][C:17]2=[N:21]1
Reactant: Fc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Reactant: N#Cc1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccnc(Nc2nccc3nn(-c4c(F)cccc4Cl)cc23)c1
Reaction time: 0.08 h
Yield: 10.2 %

Procedure:
Sodium hydride (12 mg, 0.30 mmol) was added to a solution of 2-amino-4-cyanopyridine (36 mg, 0.30 mmol) in DMF (2 mL) in a microwave vial and stirred for 5 minutes. 4-Chloro-2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine (76 mg, 0.27 mmol) was added and then the vial was sealed, purged with nitrogen and irradiated at 150° C. for 10 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (10 mg, 10% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.77 (dd, J=5.2, 0.9 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.85 (s, 1H), 7.81-7.80 (m, 2H), 7.73 (d, J=8.2 Hz, 1H), 7.67 (t, J=9.0 Hz, 1H), 7.58 (dd, J=7.3, 0.9 Hz, 1H). LCMS (Method B): RT=2.98 min, m/z: 365 [M+H+].
Reaction SMILES: [OH-].[K+].Cl[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1.[F:13][CH:14]([F:17])[CH2:15][OH:16].Cl>CS(C)=O.O>[F:13][CH:14]([F:17])[CH2:15][O:16][C:4]1[N:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCC(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCC(F)F)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
Powdered potassium hydroxide (712 mg, 12.7 mmol) was added to a mixture of 6-chloronicotinic acid (500 mg, 3.17 mmol) and 2,2-difluoroethanol (520 mg, 6.35 mmol) in DMSO (15 mL) and the mixture was stirred at 120 C for 14 h. An additional two equivalents of 2,2-difluoroethanol and potassium hydroxide were added and the mixture was heated for 24 h. The mixture was cooled to room temperature, diluted with water (5 mL), acidified with 1N aq. HCl (to pH 1) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×25 mL) then brine (50 mL) and concentrated under reduced pressure to provide title compound as a beige solid (620 mg, 96%). Method B HPLC-MS: MH+ requires m/z=204. Found: m/z=204, Rt=1.54 min (90%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[CH2:22]([O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH2:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:27][C:8](=[O:9])[C:7]1[C:6]([I:20])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]([I:14])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:11]=1[I:19])[CH3:23]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: CCOC(=O)C[C@H](N)C(=O)OCC
Agent: Cl
Product: CCOC(=O)C[C@H](NC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I)C(=O)OCC

Procedure:
Following the procedure of example 13, 112 g (65%) of the product is synthesized from 140 g (0.22 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 75 g (0.33 Mol) L-aspartic acid diethyl ester hydrochloride.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:19]([C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:21])=[O:20])=[C:7]([CH:18]=1)[CH2:8][N:9](C)[C:10](=O)OC(C)(C)C>>[ClH:1].[C:22]([S:19]([C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[CH:18][C:7]=1[CH2:8][NH:9][CH3:10])(=[O:21])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(Cc1cc(N)ccc1S(=O)(=O)C(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCc1cc(N)ccc1S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
HCl (4 M in dioxane, 5 mL) was added to 22B (500 mg, 1.403 mmol) and stirred at rt for 1 h. The reaction was concentrated to yield 22C (460 mg, 1.397 mmol, 100% yield) as a white solid. MS (ESI) m/z: 257.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (2H, br. s.), 7.51 (1H, d, J=8.79 Hz), 6.76 (1H, d, J=2.20 Hz), 6.72 (1H, dd, J=8.79, 2.20 Hz), 4.17 (2H, t, J=5.71 Hz), 2.53 (3H, t, J=5.27 Hz), 1.21 (9H, s).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([O:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[C:10](Br)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[C:1]([N:4]1[C:13]2[C:8](=[C:9]([O:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[C:10]([C:35]3[CH:34]=[N:33][N:32]([CH:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)[CH:36]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccccc3C#N)c2CC[C@@H]1C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4)c3)c(Oc3ccccc3C#N)c2CC[C@@H]1C
Temperature: 100 °C

Procedure:
A mixture of (S)-2-((l-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzonitrile (0.017 g, 0.044 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (0.030 g, 0.101 mmol), XPhos Precatalyst 2nd Generation (3.47 mg, 4.41 μmol), and cesium carbonate (0.058 g, 0.177 mmol) in dioxane (2.0 mL) and water (0.400 mL) was heated at 100° C. for 16 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% (90:10:1, dichloromethane/methanol/ammonium hydroxide)-dichloromethane) to afford (S)-2-(1-acetyl-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yl)oxy)benzonitrile (0.017 g, 82%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (d, J=7.04 Hz, 3H), 1.27-1.58 (m, 2H), 1.77-1.97 (m, 4H), 1.97-2.14 (m, 4H), 2.17 (s, 3H), 2.19 (s, 3H), 2.81 (br d, J=11.43 Hz, 2H), 3.90-4.17 (m, 1H), 4.62 (br s, 1H), 6.48 (br s, 1H), 7.14 (t, J=7.62 Hz, 1H), 7.39-7.56 (m, 2H), 7.61 (d, J=8.50 Hz, 1H), 7.72 (s, 1H), 7.89 (dd, J=7.77, 1.61 Hz, 1H), 8.01 (s, 1H). MS (ESI, pos. ion) m/z 470 [M+H]
Reaction SMILES: COC(=O)C(OCC)CC1C2SC=CC=2C(O)=CC=1.[CH2:20]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]1[O:31]C(C)=C(CCO)N=1)[CH3:21].C(I)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[CH:30]=[O:31])[CH3:21]
Reactant: CCOc1cc(F)ccc1-c1nc(CCO)c(C)o1
Agent: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1C=O

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared from 4-fluoro-2-hydroxy-benzaldehyde [J. Chem. Soc., Perkin Trans. 1 (1994), (13), 1823-31] by i) treatment with ethyl iodide, potassium carbonate in N,N-dimethylformamide to give 2-ethoxy-4-fluoro-benzaldehyde; ii) conversion of the 2-ethoxy-4-fluoro-benzaldehyde into 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy-}-benzo[b]thiophen-7-yl)-propionic acid as light yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH:18]1([CH:23]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH:23]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[C:3]4[C:4]5[CH:17]=[CH:16][S:15][C:5]=5[C:6](=[O:14])[NH:7][C:8]=4[CH:9]=[CH:10][C:11]=3[O:12][CH3:13])=[CH:35][CH:34]=2)[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C1CCCC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C2CCCC2)cc1
Yield: 19 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-thieno[2,3-c]quinolin-4(5H)-one) (500 mg, 1.6 mmol) was reacted with tert-butyl 2-cyclopentyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (1.3 g, 3.2 mmol) to afford the desired product (150 mg, 19%) as a yellow solid: ESI MS m/z 519 [C30H34N2O4S+H]+.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[C:16](=[S:18])=[S:17].Cl>CN(C=O)C.O>[CH3:9][C:6]1[CH:7]=[CH:8][C:2]2[S:17][C:16]([SH:18])=[N:4][C:3]=2[CH:5]=1
Reactant: S=C=S
Reactant: Cc1ccc(Cl)c(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2sc(S)nc2c1
Temperature: 150 °C
Yield: 27.3 %

Procedure:
To a suspension of 2-chloro-5-methyl aniline (9, 1.00 g, 7.06 mmol) and K2CO3 (2.80 g, 28.2 mmol) in DMF (20 mL) was added CS2 (0.50 mL, 8.50 mmol) under N2 at room temperature. The reaction mixture was heated at 150° C. for 16 h. After cooling, the reaction mixture was diluted with water (30 mL) and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried over P2O5 under vacuum to yield compound 10 (0.35 g, 27%).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][C:6]#[N:7])#[N:2].[CH3:11][CH:12]1CC[CH2:15][CH2:14][NH:13]1>O1CCCC1>[C:1]([N:3]=[C:4]([N:13]([CH2:14][CH3:15])[CH2:12][CH3:11])[CH2:5][C:6]#[N:7])#[N:2]
Reactant: CC1CCCCN1
Reactant: CCOC(CC#N)=NC#N
Solvent: C1CCOC1
Product: CCN(CC)C(CC#N)=NC#N

Procedure:
A solution of 4.00 g (0.0292 m) of ethyl N,2-dicyanoacetimidate and 2.86 g (0.0292 m) 2-methylpiperidine in 80 ml of tetrahydrofuran is stirred for five days at room temperature. The reaction product is isolated in the same way as 3-(cyanoimino)-3-(N,N-diethylamino)propionitrile to give 0.76 g of product, 14%. This product is further purified by chromatography on a Merck "B" column to give material whose nmr, ir, and mass spec are consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(CBr)c1ccccc1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (100) and 2-bromoacetophenone according to General Procedure B. Yield 117 mg (23%), MP 316° C.; 1H-NMR (DMSO-d6): δ 3.81 (m, 4H), 3.94 (m, 4H), 5.86 (s, 2H), 7.17 (dd, J=3.6, 5.2 Hz, 1H), 7.51 (dd, J=1.2, 3.6 Hz, 1H), 7.61 (m, 2H), 7.73 (m, 1H), 7.81 (dd, J=1.2, 5.2 Hz, 1H), 8.12 (m, 2H), 8.36 (dd, J=2.4 Hz, 1H), 8.67 (d, J=2.4 Hz, 1H); EIMS: 518 (M+1). Anal. (C26H20ClN5O3S) C, H, N.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([O:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29]C(=O)O)[CH2:25][CH2:24]1)=[CH:13]2>ClCCl>[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([O:20][CH2:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([NH2:29])[CH2:27][CH2:28]1)=[CH:13]2
Reactant: COc1ccc2ncc(OCC[C@H]3CC[C@H](NC(=O)O)CC3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(OCC[C@H]3CC[C@H](N)CC3)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (6.33 mL, 82.2 mmol, 20 eq) is added at room temperature to a stirred solution of {trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamic acid tort-butyl ester (1.65 g, 4.11 mmol, 1.0 eq) in dichloromethane (100 mL). After 2 hours stirring at room temperature, the reaction mixture is partitioned between saturated sodium hydrogen carbonate aqueous solution and dichloromethane and the pH value is about 10. The combined organic layers are dried over sodium sulfate and concentrated to afford trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamine as a yellow solid (1.24 g, 95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]([CH3:27])[N:21]=[CH:20]4)C)=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])[CH3:2].ClC1C=CC2N(C(CC3C=C4C(=CC=3F)N(C)N=C4)=CN=2)N=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH2:15][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]([CH3:27])[N:21]=[CH:20]4)=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])[CH3:2]
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Agent: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Product: C=C(OCC)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1

Procedure:
The title compound was prepared in analogy to the synthesis of compound 39.3 from 6-chloro-3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH2:16])[CH:6]=1)=[O:4].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27](O)=[O:28])=[CH:21]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH:16][C:27]([C:22]2[NH:23][C:24]3[C:20]([CH:21]=2)=[CH:19][C:18]([Cl:17])=[CH:26][CH:25]=3)=[O:28])[CH:6]=1)=[O:4]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)c1cc(N)cc2c1OCCCO2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)cc2c1OCCCO2
Reaction time: 4 h
Yield: 22.6 %

Procedure:
8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (0.300 g), 5-Chloro-1H-Indole-2-carboxylic acid (0.263 g), BOP (0.594), TEA (0.377 mL) and DMF (3.0 mL) were mixed together and stirred for 4 hours. The reaction was diluted with water and the resulting filtrate filtered. The resulting solid was tritriated with EtOAc, rinished with the same and purified by flash chromatography (silica gel; 25% EtOAc/hexane) to yield 122 mg of the product. MS PDS: M+ 401/403
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>O>[C:5]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[F:8])(=[O:7])[CH3:6]
Reactant: Nc1ccccc1F
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccccc1F
Reaction time: 10 h
Yield: 87.5 %

Procedure:
Acetic anhydride (57 mL, 0.6 mol) was added slowly, over approximately 40 min, to stirred 2-fluoroaniline (27, 55.7 g, 0.5 mol) under cooling (water bath) to maintain the reaction temperature at 60° C. to 70° C. After 10 hours more, the reaction mixture was poured into H2O, the whole was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with 5% aqueous NaHCO3, brine, dried (K2CO3), filtered and concentrated to provide the title compound as a white solid (67.0 g, 88%).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:16]1([NH:15][C:12]2[CH:13]=[CH:14][C:9]3[O:8][C:7]4[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=4[C:10]=3[CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1cccc2c1oc1ccccc12
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3oc4ccccc4c3c2)cc1
Yield: 63.7 %

Procedure:
4-bromodibenzo[b,d]furan (3.0 g, 12.1 mmol) and aniline (1.69 g, 18.1 mmol) were mixed in 100 mL of toluene. The solution was bubbled with nitrogen for 15 min. Pd2(dba)3 (0.05 g, 0.05 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.15 g, 0.24 mmol) and sodium t-butoxide (1.7 g, 17.4 mmol) were added. The mixture was refluxed overnight under nitrogen. After cooling, the reaction mixture was filtered through celite/silica pad and the filtrate was concentrated under vacuum. The residue was then purified by column chromatography using DCM:hexane (1:1, v/v) as the eluent. 2.0 g (65%) of a white solid was obtained as the product.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25][CH3:26])=[C:17]2[C:27](=[O:39])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:29](=[O:30])[C:16]=12)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25][CH3:26])=[C:17]2[CH:27]([OH:39])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:29](=[O:30])[C:16]=12)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2O
Reaction time: 1 h
Yield: 30.3 %

Procedure:
5-Benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 246 (10 mg, 0.019 mmol, 1 equiv.) was dissolved in CH2Cl2 (0.2 mL) and MeOH (0.5 mL) under a nitrogen atmosphere at 0° C. Sodium borohydride (NaBH4) was added (115 μL, 0.057 mmol, 3 equiv., 0.5 M). The reaction was allowed to stir for 1 hour and then quenched with water (5 mL) and extracted with ethyl acetate (2×5 mL). The organic layer was washed several times with water (2×10 mL), brine solution (10 mL). It was dried over Na2SO4, filtered and concentrated in vacuo and purified by preparatory thin-layer chromatography (PTLC) using 3/2 Hexanes/Ethyl acetate to obtain 5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one 247a (34%, 3 mg) and reduced species: 5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-1,2,3,4,7,8-hexahydro-pyrrolo[3,4-g]quinoxalin-6-one 247b (21%, 2 mg) and 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-1,2,3,4-tetrahydro-pyrrolo[3,4-g]quinoxaline-6,8-dione 247c (34%, 3.4 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)[CH3:2].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][NH:22][CH2:23][C:24]3[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[C:28]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:27]=[N:26][C:25]=3[Cl:40])=[CH:20][C:15]=2[O:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCCCCC>CC(O)=O.CCOC(C)=O>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][N:22]([CH2:23][C:24]3[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[C:28]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:27]=[N:26][C:25]=3[Cl:40])[CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CCCCc1c(-c2ccccc2)nnc(Cl)c1CNCc1ccc2c(c1)OCO2
Reactant: CCOc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1c(-c2ccccc2)nnc(Cl)c1CN(Cc1cccc(OCC)c1)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-Ethoxybenzaldehyde (0.062 ml, 0.44 mmol) is added to a solution of benzo[1,3]dioxol-5-ylmethyl-(5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine) (0.045 g, 0.1 mmol) in CH2ClCH2Cl (5 mL) and HOAc (0.5 mL). The mixture is stirred at room temperature for 45 minutes, NaBH(OAc)3 (0.140 g, 0.66 mmol) is then added and the mixture is stirred over night. The solvent is removed in vacuo, the residue is partitioned between saturated aqueous NaHCO3 solution (20 mL) and EtOAc (20 mL), the organic layer is washed with water (15 mL), brine (15 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides the product shown above as a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residue provides purified product as a light yellow oil. LC-MS (M+1) 544. 1H NMR (δ, CDCl3) 7.36–7.48 (m, 5H), 7.18 (t, J=7.2 Hz, 1H), 6.70–6.87 (m, 6H), 5.91 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.80 (s, 2H), 3.56 (s, 2H), 3.52 (s, 2H), 2.70 (t, J=7.5 Hz, 2H), 1.41 (t, J=7.2 Hz, 2H), 0.84–1.02 (m, 4H), 0.58 (t, J=7.2 Hz, 3H).