Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:13])[O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[N:6][CH:7]=1.[N:14]#[C:15]N>>[C:15]([N:13]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[O:9][CH2:10][CH2:11][CH3:12])#[N:14]
Reactant: N#CN
Reactant: CCCOC(=N)c1cncc(C)c1
Product: CCCOC(=NC#N)c1cncc(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To propyl 5-methyl-3-pyridinecarboximidate was then added an aqueous solution (100 ml) of cyanamide (1.42 g, 33.8 mmol), Na2HPO4 (2.40 g, 16.9 mmol) and NaH2PO4 ·2H2O (10.56 g, 67.7 mmol). The mixture was stirred at room temperature for 5 hours and extracted with chloroform (100 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl N-cyano-5-methyl-3-pyridinecarboximidate (2.54 g). IR (neat) cm-1 : 2200, 1610, 1320, 730.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.Cl.C(N=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N)CC1>CN(C=O)C.O>[CH:40]1([NH:41][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[CH:27][CH:26]=2)[CH2:38][CH2:39]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.119 mmol) was taken up in DMF (0.5 mL). To the mixture was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34.1 mg, 0.178 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.2 mg, 0.178 mmol), 4-methylmorpholine (0.065 mL, 0.593 mmol) and cyclopropanamine (6.77 mg, 0.119 mmol). The reaction was stirred at room temperature overnight. To the stirred solution was added water (2 mL) and the precipitate was filtered, collected, and dried in vacuum to afford the title compound (41.2 mg, 75.0%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.57-7.76 (m, 3H), 6.80-7.02 (m, 3H), 4.50 (d, J=13.1 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.35 (br. s., 2H), 3.22 (br. s., 4H), 2.79 (td, J=7.3, 3.9 Hz, 1H), 2.60 (td, J=12.6, 2.7 Hz, 1H), 2.46 (br. s., 4H), 2.03 (d, J=12.9 Hz, 1H), 1.83 (br. s., 1H), 1.64 (d, J=12.9 Hz, 1H), 1.31-1.57 (m, 3H), 0.61-0.69 (m, 2H), 0.48-0.56 (m, 2H). [M+H] calc'd for C, 26; H, 32; N, 6; O, 2, 461; found, 461.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[CH2:2]1.C(N(CC)C(C)C)(C)C.CO.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[S:38][C:37]([CH:39]=O)=[N:36][C:35]=3[CH:41]=2)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>>[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[S:38][C:37]([CH2:39][N:1]4[CH2:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[CH2:2]4)=[N:36][C:35]=3[CH:41]=2)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)[C@@H]1CCNC1
Reactant: CC(C)(C)C1CCC(Oc2ccc3sc(C=O)nc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C1CCC(Oc2ccc3sc(CN4CC[C@@H](C(=O)O)C4)nc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(R)-Pyrrolidine-3-carboxylic acid (100 mg, 0.9 mmol) (HCl salt) was combined with N,N-Diisopropylethylamine (300 uL, 2 mmol) in Methanol (4.0 mL, 98 mmol) and stirred for 15 min. 5-(4-tert-Butyl-cyclohexyloxy)-benzothiazole-2-carbaldehyde (10.0E2 mg, 0.33 mmol) was then added and the mixture was stirred at RT for 30 minutes. After 30 minutes the reaction was cooled to 0° C. and Sodium cyanoborohydride (100 mg, 2 mmol) was added in two portions. The reaction was then allowed to warm to RT while stirring overnight. The reaction was then purified directly on the Gilson (10-90% CH3CN/H2O (0.1% TFA), 19×150 cm C18, RT=8.6 min) The product was then dried on the highvac to give the title compound as a white solid. 1H NMR (400 MHz, MeOD) Shift=8.00-7.78 (m, 1H), 7.69-7.51 (m, 1H), 7.27-7.05 (m, 1H), 5.09-4.93 (m, 3H), 4.39-4.21 (m, 1H), 4.01-3.39 (m, 4H), 2.65-2.18 (m, 3H), 2.01-1.80 (m, 2H), 1.53-1.04 (m, 6H), 0.92 (s, 9H). MS (ESI, M+1): 417.30.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH:10]([SiH](C)C)[C@@H:11]1[N:14](C(C)(C)C)[C:13](=[O:19])[C@H:12]1[C:20]([OH:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.O>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH:11]1[NH:14][C:13](=[O:19])[CH:12]1[C:20]([OH:23])([CH3:21])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[SiH](C)C(C(=O)OCc1ccccc1)[C@H]1[C@H](C(C)(C)O)C(=O)N1C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(O)C1C(=O)NC1CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 3.7 g 1-tert.butyldimethylsilyl-2-oxo-3-(trans)-(1-hydroxy-1-methylethyl)azetidine-4-yl-acetic acid benzylester in 130 ml of methanol/water (9/1) are added 6.6 ml of conc. HCl. This mixture is stirred for 30 minutes at 0° and 31/2 hours at 25°. The solution is concentrated and the residue taken up in ethylacetate, washed once with aq. NaCl, dried over MgSO4 and evaporated to dryness to yield the title compound
Reaction SMILES: Cl[C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].P(OCC)(OCC)O[CH2:14][CH3:15].P(Cl)(=O)([O-])OCC>>[Cl:10][C:3]1[C:2]([Cl:11])([CH2:14][CH3:15])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]=1[Cl:9]
Reactant: CCOP(OCC)OCC
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Agent: CCOP(=O)([O-])Cl
Product: CCC1(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl
Temperature: 0 °C
Yield: 93.4 %

Procedure:
A solution of 272.8 g. (1.0 mole) of hexachlorocyclopentadiene in 300 ml. of petroleum ether (pentane range) was charged to a 2 liter 3 neck flask equipped with stirrer, thermometer, dropping funnel and an exit line protected with a drying tube. The flask was immersed in ice-water and triethyl phosphite (182.8 g., 1.1 mole) was added slowly from the dropping funnel at such a rate that the temperature of the reaction mixture did not exceed +15°C. After the addition was completed (which required 5 hours) the clear, brown solution was, after the stripping of the solvent, fractionated in vacuum through a 20 inch column, filled with glass helices. A lower boiling fraction, 161 g., b.p. 39°C. at 0.4 mm., nD25 1.4253 consisted of pure ethyl phosphorochloridate, Cl(EtO)2PO, which, accordingly, was obtained in 93.4% yield. Then the temperature rose fast in the column and a pale yellow oil distilled over sharply at 50°C. and 0.18 mm. Infrared and elemental analyses indicated that the yellow oil, nD25 1.5394, is pure 1,2,3,4,5-pentachloro-5-ethylcyclopentadiene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:34]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35]1>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:39]([C:36]3[CH:37]=[CH:38][O:34][CH:35]=3)(=[O:41])=[O:40])[C:3]=2[F:33])[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: O=S(=O)(Cl)c1ccoc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (300 mg, 0.612 mmol) in pyridine (3 mL) was added 3-furansulfonyl chloride (153 mg, 0.918 mmol, and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extract was dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to give 310 mg of the title compound. MS (ESI): 620.2, 622.2 [M+1]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5]([CH:6]=[CH:7][C:8]3[C:9]=2[CH:11]=[CH:12][N:13]=3)=[CH:4][CH:3]=[C:2]1[C:14](=O)[C:15]([O:17]C)=O.[C:20]([NH2:23])(=[O:22])[CH3:21]>>[NH:1]1[C:10]2[C:5]([CH:6]=[CH:7][C:8]3[C:9]=2[CH:11]=[CH:12][N:13]=3)=[CH:4][CH:3]=[C:2]1[C:14]1[C:15](=[O:17])[NH:23][C:20](=[O:22])[CH:21]=1
Reactant: CC(N)=O
Reactant: COC(=O)C(=O)c1ccc2ccc3nccc3c2[nH]1
Product: O=C1C=C(c2ccc3ccc4nccc4c3[nH]2)C(=O)N1

Procedure:
In one embodiment, the method of the present invention comprises a step of dissolving methyl pyrroloquinolinyl-oxoacetate and acetamide in an organic solvent and adding the obtained solution to a base, and reacting methylpyrroloquinolinyl-oxoacetate and acetamide to form highly pure pyrroloquinolinyl-pyrrole-2,5-dione. In one embodiment, the base is dissolved or suspended in an organic solvent. In a further embodiment, the base is dissolved or suspended in the same organic solvent as methylpyrroloquinolinyl-oxoacetate and acetamide. In a further embodiment, highly pure pyrroloquinolinyl-pyrrolidine-2,5-dione is formed by reducing pyrroloquinolinyl-pyrrole-2,5-dione.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[NH:3][C:4](=[O:7])[O:5][N:45]=3)=[CH:36][CH:37]=2)[C:19](=[O:30])[C:20]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)c(-c2cnn(C)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)c(-c2cnn(C)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A mixture of hydroxylammonium chloride (0.7 g), sodium hydrogen carbonate (1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.44 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.13 g, 27%).
Reaction SMILES: Cl.[CH2:2]([NH2:7])[CH:3]([NH2:6])[CH2:4][CH3:5].C(N(C(C)C)CC)(C)C.O=[C:18]([C:24](OCC)=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:4]([C:3]1[N:6]=[C:24]([OH:25])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:7][CH:2]=1)[CH3:5]
Reactant: CCC(N)CN
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ncc(CC)nc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
To a suspension of butane-1,2-diamine hydrochloride (6.40 g, 39.7 mmol) in ethanol (60 mL) was added diisopropylethylamine (14 mL, 80.4 mmol), and the mixture was stirred at room temperature for 10 min. To this solution was added dropwise diethyl ketomalonate (6 mL, 39.3 mmol) at 0° C., and the mixture was stirred at room temperature for 1.5 hr with heating under reflux for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a small amount of ethanol. The solution was passed through silica gel (100 g, eluent, hexane:ethyl acetate=1:1→ethyl acetate). The eluate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1→ethyl acetate) to give the title compound (1.94 g, 25%) as a pale-yellow powder.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27]([CH3:29])=[CH2:28].ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27]1([CH3:29])[CH2:28][O:40]1
Reactant: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(CO[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@@]2(O)C(=O)CCl)CO1

Procedure:
A solution of 21-chloro-11β,17-dihydroxy-16α-(2-methyl-2-propenyloxy)pregna-1.4-diene-3,20-dione (16 mmoles) in 300 ml of dichloromethane is stirred with 3.2 g of m-chloroperbenzoic acid for 3 hours. The solution is washed with a mixture of 5% sodium bicarbonate solution and 5% sodium sulfite solution, dried, and evaporated to give the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1.CCN(CC)CC.Cl[C:36]([O:38][CH2:39][C:40]#[CH:41])=[O:37]>C(Cl)Cl>[CH2:39]([O:38][C:36]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][CH:18]([C:21](=[O:22])[NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:37])[C:40]#[CH:41]
Reactant: C#CCOC(=O)Cl
Reactant: CC(C)CNC(=O)C1CCN(C2CCCNCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCOC(=O)N1CCCC(N2CCC(C(=O)NCC(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
1-(azepan-4-yl)-N-(2-methylpropyl)piperidine-4-carboxamide TFA salt (0.15 g, 0.38 mmol) was dissolved in DCM (8 mL) at rt. NEt3 (0.16 mL, 1.14 mmol) and propargyl chloroformate (0.06 mL, 0.57 mmol) were added and the reaction mixture was stirred at rt for 2 h under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol.), organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give prop-2-yn-1-yl-4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (0.04 g, 31%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][Sn:9](Cl)([CH3:11])[CH3:10]>C1COCC1>[F:1][C:2]1[C:7]([Sn:9]([CH3:11])([CH3:10])[CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Fc1ccccn1
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccnc1F

Procedure:
Metalation of 2-fluoropyridine was performed as described in Estel, Marsais and Queguiner, J. Org. Chem. 53, 2740-2744, 1988. The lithium anion was quenched with 1 eq. of trimethyl tin chloride in THF (1M) at -78° C. and stirred for 30', quenched with 1M sodium bicarbonate and extracted with ethyl acetate. Upon Na2SO4 drying and evaporation under reduced pressure the resulting oil was used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([CH2:10][CH:11]([C:14]#[N:15])[C:12]#[N:13])=O)=[CH:5][CH:4]=1.CCOCC.C(Cl)(Cl)[Cl:22]>CCCCCC.CCOCC>[Cl:22][C:12]1[NH:13][C:8]([C:6]2[S:7][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:10][C:11]=1[C:14]#[N:15]
Reactant: N#CC(C#N)CC(=O)c1ccc(Cl)s1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: N#Cc1cc(-c2ccc(Cl)s2)[nH]c1Cl
Temperature: 0 °C

Procedure:
Hydrogen chloride gas is bubbled through a mixture of [(5-chloro-2-thenoyl)methyl]malononitrile (4.60 g, 20.5 mmol), ether and chloroform at a moderate rate for 20 minutes. The reaction mixture is poured into an ice-water mixture and extracted with ether. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to give a brown solid. The solid is mixed with a hexane/ether solution and filtered to obtain the title product as a brown solid, mp >200° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C#Cc2ccccc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(C#Cc2ccccc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 90 °C

Procedure:
In a 30 mL glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (103 mg, 0.451 mmol) and PdCl2(PPh3)2 (105 mg, 0.150 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The vessel was sealed with a cap and the reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was subsequently diluted with water (10 mL) and was extracted with EtOAc (2×50 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the mixture was stirred for 1 hour. The volatiles were subsequently evaporated and the residual material was dissolved in DMSO (5 mL) and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (32 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (br s, 3H), 1.66-1.91 (m, 5H), 3.63 (br s, 1H), 4.34-4.52 (m, 3H), 6.87 (d, J=7.07 Hz, 1H), 7.41-7.52 (m, 3H), 7.56-7.65 (m, 2H), 7.74 (br s, 3H), 8.48 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H21FN4O, 365. found, 365.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:3][C:4]([CH2:6][N:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CCNCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCC
Temperature: 25 °C

Procedure:
To a mixture of 49 g of ethyl N-(ethoxycarbonylmethyl)-β-alaninate and 30 ml of water cooled to -10° is added dropwise 27.6 ml of ethyl chloroformate followed by a solution of 12.7 g of sodium carbonate in 50 ml of water. The mixture is warmed to room temperature then heated at 55° for 50 minutes. The mixture is cooled, extracted with toluene, the extract is washed with 2N hydrochloric acid and water. The extract is dried over sodium sulfate, filtered, concentrated and distilled in vacuo to yield ethyl N-(ethoxycarbonylmethyl)-N-(ethoxycarbonyl)-β-alaninate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)([N:16]=[C:17]=S)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[N:30]([CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:16][C:17]2[O:35][C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:33][N:30]=2)([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(N=C=S)c2ccc(Cl)cn2)c1
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(Nc2ncc(-c3ccccc3)o2)c2ccc(Cl)cn2)c1
Temperature: 90 °C
Yield: 12 %

Procedure:
5-chloro-2-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-isothiocyanato-2-phenylethyl)pyridine (0.047 g, 0.108 mmol) in dioxane (3 mL) in a two drum vial was added 2-azido-1-phenylethanone (21 mg, 0.129 mmol) and solid bound triphenylphosphine (100 mg, 0.162 mmol). The reaction was heated at 90° C. for 1 hour. The reaction was concentrated and the crude mixture was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5μ) using MeOH/H2O (0.1% TFA) to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-5-phenyloxazol-2-amine as a yellow solid (7 mg, 12% yield). LCMS: 4.1 min [M+1] 538.2 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.97-4.02 (m, 1H), 4.06-4.13 (m, 1H), 6.52 (d, J=7.58 Hz, 2H), 7.09 (t, J=7.46 Hz, 2H), 7.15 (s, 1H), 7.17 (dd, J=6.36, 1.71 Hz, 3H), 7.23 (d, J=8.56 Hz, 1H), 7.30-7.40 (m, 5H), 7.68-7.73 (m, 2H), 8.50 (d, J=2.20 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH3:33][N:34]([CH3:40])[C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:40])[C@@H:35]1[CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:32])([F:30])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)C1
Yield: 45.8 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]amide (45 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (95 mg), dimethyl-(R)-pyrrolidin-3-yl-amine (20 mg), HBTU (85 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 561.4.