Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:17][C:18]([NH2:21])=[CH:19][N:20]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C.O>CN(C)C=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:17][C:18]([NH:21][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])=[CH:19][N:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2nccc(Sc3ncc(N)s3)c2cc1OC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Sc3ncc(NC(=O)Nc4ccccc4)s3)c2cc1OC
Yield: 60.5 %

Procedure:
2-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine (64.0 mg, 0.200 mmol) and phenyl isocyanate (26.2 mg, 0.220 mmol) were stirred in dimethylformamide (1 ml) at room temperature for 15 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:methanol=30:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (53.2 mg, 0.121 mmol, 60%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:12]=[C:13]([CH3:22])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C)C=O>[CH2:26]([C:23]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[O:21])=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[C:10]2=[CH:25][CH:24]=1)[CH3:27]
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)O)c(C)nn12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)N3CCOCC3)c(C)nn12
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (50 mg) in N,N-dimethylformamide (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg) and 1-hydroxybenzotriazole (28 mg) at ambient temperature. After 30 minutes, to the mixture was added morpholine (24 mg). After 5 hours, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 40 mL) eluted with hexane-ethyl acetate=3-1, 2-1, 1-1, 1-3, and 0-1 to give 3-{7-ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopentyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile as an yellow gum (53 mg)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1>>[CH3:9][O:10][C:11]([C:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)=[O:19]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cccs1
Product: COC(=O)c1ccc(-c2cccs2)cc1
Yield: 64.5 %

Procedure:
2-(4-methoxycarbonylphenyl)thiophene was prepared in the same manner as described in Example 32C from thiophene-2-boronic acid (1.0 g, 7.81 mmol) and methyl-4-bromobenzoate (1.68 g, 7.81 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave 1.1 g of 2-(4-methoxycarbonylphenyl)thiophene as a white solid (65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]([NH2:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>N1C=CC=CC=1.ClC1C=CC=CC=1Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:21]([NH:22][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=3)(=[O:35])=[O:34])=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2N)cc(OC)c1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(S(C)(=O)=O)c2)cc(OC)c1
Temperature: 100 °C
Yield: 21 %

Procedure:
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.17 mmol), 3-(methylsulfonyl)benzenesulfonyl chloride (64 mg, 0.26 mmol, commercially available from Matrix) are dissolved in a 1 to 1 mixture of pyridine and 1,2-dichlorobenzene (0.4 ml) and the reaction mixture is heated at 100° C. in the microwave for 20 min. When TLC confirms the total consumption of the starting material, the reaction mixture is cooled down to rt. The precipitate formed is filtered and purified by column chromatography, using CHCl3: MeOH as eluent, to afford 18 mg (21%) of the title compound as a light brown solid. HPLC (max plot) 84%, rt. 4.2 min. LC/MS: (ES+): 515.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][NH:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: COCCOCCN
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCOCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A suspension of carbaldehyde 325 (0.50 g, 1.3 mmol), amine 326 (0.30 g, 2.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in dichloromethane (20 ml) was stirred for 1 h at room temperature. Then sodium triacetoxyborohydride (0.80 g, 3.8 mmol) was added and stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.0 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and 1N NaOH. The yellow suspension was removed by filtration and rinsed with dichloromethane and 1N NaOH. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column) to yield 327 (280 mg, 0.562 mmol, 44%) as a yellow solid. LRMS (M+H): 499.4
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12]N(C)CCN(C)C.C([Li])CCC.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH3:12]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1C(=O)Nc2ccc(Br)cc21
Temperature: -78 °C
Reaction time: 15 h
Yield: 18.2 %

Procedure:
To a 250 mL round-bottom flask, was added 5-bromoindolin-2-one (2 g, 9 mmol), N,N′-tetramethylethylenediamine (4 mL, 28 mmol) and 70 mL of THF. The reaction mixture was cooled to −78° C. 2.5 M n-butyllithium in hexanes (8.4 mL, 21 mmol) was then added slowly to the reaction mixture. The reaction mixture was stirred for 15 hours, 5 mL of saturated NH4Cl solution was added to the reaction mixture, and then the reaction mixture was extracted twice with 30 mL of EtOAc. The combined organic layers were concentrated and purified with silica gel column chromatography, eluting with 0-40% EtOAc/hexane to give 5-bromo-3-methylindolin-2-one (0.37 g, 17% yield). MS m/z: 227 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[CH:27]=O.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:27][C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=Cc1ncccn1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCc3ncccn3)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and pyrimidin-2-carbaldehyde using decaborane yielded the title compound as a white foam. MS (ESI): m/z=371.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:10]=2)[N:7]=1.[CH3:16][NH:17][C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CC#N>[CH3:16][N:17]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:10]=2)[N:7]=1
Reactant: CCOC(=O)c1nnc2ccc(Cl)nn12
Reactant: CN[C@@H](C)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1nnc2ccc(N(C)[C@@H](C)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 36 h
Yield: 32.6 %

Procedure:
A solution of ethyl 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (1.5 g, 6.6 mmol) and (S)-N-methyl-1-phenylethanamine (3.6 g, 26.4 mmol) in 20 mL of CH3CN was heated to reflux and stirred for 36 h. When cooled to room temperature, the reaction mixture was concentrated in vacuum, and the residue was purified by flash chromatography eluting with DCM/EA=5:1 to give product (S)-ethyl 6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate as a yellow oil (0.7 g, 32%). LRMS (M+H+) m/z: calcd 326.16; found 326. 1H NMR (300 MHz, CDCl3): δ 8.02-7.99 (d, J=9 Hz, 1H), 7.36-7.26 (m, 5H), 7.09-7.06 (d, J=9 Hz, 1H), 5.82-5.75 (q, 1H), 4.57-4.50 (q, 2H), 2.94 (s, 3H), 1.68-1.65 (d, 3H), 1.48-1.44 (t, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H][H]>[Ni].O1CCCC1>[OH:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [H][H]
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Ni]
Solvent: C1CCOC1
Product: CCCC(O)CC(=O)OCC
Temperature: 50 °C
Yield: 81.3 %

Procedure:
Ethyl 3-ketohexanoate 50 g (0.32 mol), Raney nickel 10 g and tetrahydrofuran 500 ml were mixed, and the mixture was reacted with stirring in an autoclave at a temperature of 50° C. and a hydrogen pressure of 5 kg/cm2 for 30 hours. After removing the Raney nickel from the reactant by filtration, the filtrate was concentrated and distilled under reduced pressure to obtain racemic ethyl 3-hydroxyhexanoate 42 g (0.26 mol, 85% )
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C(Cl)Cl>[C:29]([O:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C(=C\COC(=O)c1cccnc1)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a mixture consisting of 10 0 g of phytol, 9.0 g of triethylamine and 50 ml of methylene chloride was added 7.2 g of nicotinic chloride at 30°-40° C. The resulting mixture was stirred for 2 hours at the same temperature. After the completion of the reaction, the reaction mixture was washed with dilute hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant; n-hexane:ethyl acetate=9:1) to obtain 12.1 g (yield: 90%) of oily phytyl nicotinate.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[C:2]([NH2:4])=[O:3].[OH-].[Na+].S(S([O-])=O)([O-])=O>>[NH:1]([CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]([NH2:4])=[O:3]
Reactant: NC(=O)NCCNc1ccc([N+](=O)[O-])cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NCCNc1ccc(N)cc1
Temperature: 60 °C

Procedure:
94 g (0.42 mole) of para-[N-(β-ureidoethyl)]amino nitrobenzene is added little by little, while stirring, to 950 cm3 of a 3 N solution of NaOH containing 285 g of technical hydrosulfite, which has first been heated to 60° C. When the addition has been completed the reaction mixture is kept at 70° C until decoloration is complete. The mixture is then filtered, cooled and dried after salting out. The result is 46 g of N-(β-ureidoethyl) para-phenylenediamine which, after recrystallization in isopropyl alcohol, melts at 126°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([N+:13]([O-])=O)[CH:7]=1.C[O:26][C:27](=O)[C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)=[CH:32][CH:31]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.[Fe].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][C@@H:28]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=4)=[CH:34][CH:35]=3)[C:27](=[O:26])[NH:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c([N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@H](O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Fe]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2c(c1)NC(=O)[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-3-nitro-phenyl)-propionic acid methyl ester (16.8 mmol) and (R)-[4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid methyl ester (20.1 mmol) were dissolved in 80 mL of DCM, resin-bound triphenylphosphine (33.6 mmol) added and the mixture cooled to −20° C. To this solution was added DIAD (25.2 mmol) and the mixture was agitated for 30 min at −20° C. The mixture was slowly allowed to warm to r.t. and agiated for 1.5 h. The reaction mixture was filtered and concentrated. The resulting residue was dissolved in glacial acetic acid (60 mL) and heated to 100° C. Iron powder (336 mmol) was added and the resulting mixture heated at 100° C. for 1 h. The mixture was poured onto water and EtOAc. The mixture was brought to ˜pH 7 with sodium carbonate. The organic layer was dried over sodium sulfate and concentrated. The residue was treated with diethyl ether and the resulting solid filtered and washed with diethyl ether to provide (S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionic acid methyl ester (5.7 g). LC-MS (m/z) 502 (M-Boc).
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].Br[CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.O>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH3:19]
Reactant: CCCCC(CC)CBr
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)CN1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) and 1-bromo-2-ethylhexane (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 140-160° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.Cl.[CH3:13][NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:13])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CNCC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(CC(C)(C)C)c1nc(Cl)c(C#N)cc1F
Yield: 83 %

Procedure:
A solution of 2,6-dichloro-3-cyano-5-fluoropyridine (1.0 g, 5.23 mmol), N-methyl-neopentylamine hydrochloride (830 mg, 6.0 mmol) and triethylamine (1.6 mL) in acetonitrile (20 mL) was stirred at room temp for 4 hours. Then volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated in vacuo to afford the product (1.11 g, 83%). C12H15ClFN3 MS m/e=256 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([O:43][C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([CH2:51][NH:52][CH2:53][CH3:54])[C:45]=2[F:55])[CH:42]=1)[C:38]#[N:39].[NH:56]1[CH:60]=[CH:59][CH:58]=[C:57]1[C:61]([OH:63])=O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.CN(C=O)C>[Cl:50][C:49]1[CH:48]=[CH:47][C:46]([CH2:51][N:52]([CH2:53][CH3:54])[C:61]([C:57]2[NH:56][CH:60]=[CH:59][CH:58]=2)=[O:63])=[C:45]([F:55])[C:44]=1[O:43][C:41]1[CH:40]=[C:37]([C:38]#[N:39])[CH:36]=[C:35]([Cl:34])[CH:42]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: CCNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F)C(=O)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.1 %

Procedure:
DMF (3 mL) and DIPEA (0.1 mL, 0.59 mmol) were added to a mixture of HATU (0.12 g, 0.32 mmol), 3-chloro-5-({6-chloro-3-[(ethylamino)methyl]-2-fluorophenyl}oxy)benzonitrile (0.10 g, 0.29 mmol) and 1H-pyrrole-2-carboxylic acid (0.05 g, 0.41 mmol). The yellow solution was stirred at RT under a nitrogen atmosphere for 48 h then ethyl acetate (100 ml) and saturated NaHCO3 solution (100 ml) were added. The organic layer was washed with saturated NaHCO3 solution (2×100 ml), brine (150 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by Reverse Phase HPLC (MeCN/water+0.1% TFA) to give the title compound (0.039 g, 31%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 7.82 (br. s., 1H), 7.08-7.68 (m, 3H), 6.74-7.04 (m, 1H), 6.24-6.62 (m, 1H), 6.12 (d, 1H), 4.56-5.10 (m, 2H), 3.54-3.88 (m, 2H), 0.96-1.45 (m, 3H). LCMS m/z 433.9 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]#[C:6][C:7](=O)[CH3:8])[CH3:2].[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].CO.C([O-])([O-])=O.[Cs+].[Cs+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:18][O:17][C:13]([C:14]1[S:15][C:5]([CH:4]([O:10][CH2:11][CH3:12])[O:3][CH2:1][CH3:2])=[CH:6][C:7]=1[CH3:8])=[O:16]
Reactant: CCOC(C#CC(C)=O)OCC
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(OCC)c1cc(C)c(C(=O)OC)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A solution of 5,5-diethoxy-pent-3yne-2-one (3.51 g, 20.6 mmol) in THF (30 ml) was cooled to 0° C. (ice bath). Methyl thioglycolate (1.84 ml, 20.6 mmol) was added in one portion and the mixture was stirred at 0° C. for 2 h. Methanol (10 ml) and Cs2CO3/MgSO4 (7 g/14 g, pre-dried at 200° C. in vacuum) were added at 0° C. The mixture was stirred at 0° C. for 15 min and then at rt for 2.5 h. The reaction mixture was quenched by pouting into ice and 1M NaH2PO4 (100 ml), then extracted with EtOAc. The layers were separated. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 5-15% EtOAc in hexane to afford the desired product (4.41 g, 83% yield).
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][C:7]([C:15](O)=[O:16])=[CH:6][C:5]=1[NH:4][C:3]2=[O:18].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C.CO>[F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][C:7]([CH2:15][OH:16])=[CH:6][C:5]=1[NH:4][C:3]2=[O:18]
Reactant: O=C(O)c1ccc2c(c1)NC(=O)C1(F)CCCC21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cc(CO)ccc2C2CCCC12F
Reaction time: 0.17 h

Procedure:
A solution of 0.31 g (1.24 mmol) of 3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one-7-carboxylic acid in 35 ml of THF is treated with 0.20 ml (1.44 mmol) of triethylamine and 0.14 ml (1.44 mmol) of ethyl chloroformate. After 10 minutes at room temperature, 0.14 g (3.72 mmol) of sodium borohydride and, within 15 minutes, 19 ml of methanol, are added to it. After 15 hours, the batch is diluted with ethyl acetate, washed with 20% citric acid, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography with hexane-ethyl acetate yields 3a-fluoro-7-hydroxymethyl-1,2,3,3a,5,9b-hexahydrocyclo-penta[c]quinolin-4-one, which dissolves in 50 ml of THF and is mixed at 0° C. with 4 portions each of 0.34 ml (2.5 mmol) of triethylamine and 0.19 ml (2.5 mmol) of methanesulfonyl chloride. After the reaction has been completed, the batch is poured onto ice water and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is taken up in 50 ml of 2 M methanolic methylamine solution and refluxed for 4 hours. The volatile components are removed in a vacuum, and the residue is dissolved in 50 ml of dichloromethane. 0.81 g (3.72 mmol) of pyrocarbonic acid-di-tert-butylester is added to it, and after 3 hours, another 0.40 g (1.86 mmol) is added to it. After 2 hours, the batch is diluted with dichloromethane, washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography with hexane-ethyl acetate yields 49 mg of product.