Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl-].[F:4][C:5]([F:35])([F:34])[C:6]1[CH:33]=[CH:32][C:9](/[CH:10]=[CH:11]/[CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1.[Cl:36][C:37]1[CH:52]=[CH:51][C:40]([CH2:41][S:42][C@H:43]2[CH2:48][CH2:47][C@H:46]([CH:49]=O)[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>CCCCCC.CS(C)=O.C1(C)C=CC=CC=1>[F:35][C:5]([F:4])([F:34])[C:6]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:11]/[CH:12]=[CH:49]/[C@H:46]2[CH2:45][CH2:44][C@H:43]([S:42][CH2:41][C:40]3[CH:51]=[CH:52][C:37]([Cl:36])=[CH:38][CH:39]=3)[CH2:48][CH2:47]2)=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1ccc(/C=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C[C@H]1CC[C@H](SCc2ccc(Cl)cc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(/C=C/C=C/[C@H]2CC[C@H](SCc3ccc(Cl)cc3)CC2)cc1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
After 50 mg (1.14 mmol) of 55% sodium hydride were washed with hexane, it was suspended in 7 ml of dimethyl sulfoxide, followed by stirring of the suspension at 55° C. for 2.5 hours. The mixture was cooled to room temperature and 607 mg (1.26 mmol) of [(E)-4-(trifluoromethyl) cinnamyl]triphenylphosphonium chloride were added thereto. Further, 170 mg (0.63 mmol) of trans-4-[(4-chlorobenzyl) thio]cyclohexanecarboxaldehyde were added to the resulting mixture, followed by stirring of the mixture at room temperature for 15 minutes. The mixture was diluted with toluene and washed with water and an aqueous NaCl solution. After the mixture was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of methylene chloride-hexane (1:2). The eluted portion was recrystallized from hexane to obtain 86 mg (yield: 31%) of the title compound having a melting point of 142 to 144° C.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]([NH2:41])[CH3:40]>C(Cl)Cl>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]([NH:41][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:40]
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(N)c1nc2ccccc2s1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CC(C)OC(=O)N[C@H](C(=O)NC(C)c1nc2ccccc2s1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
0.3 g of N-methylpiperidine was added to a solution containing 0.6 g of N-isopropoxycarbonyl-L-valine dissolved in 40 mL of methylene chloride, at -20° C., and then the mixture was stirred for 10 minutes at the same temperature. 0.4 g of isobutyl chloroformate was added to the mixture at -40° C., and then stirred for 1 hour at -40° C. to -15° C. After 0.5 g of 1-(2-benzothiazolyl)ethylamine was added to this mixture at -60° C. and the refrigerant was put off, the reaction mixture was warmed naturally to room temperature while being stirred. After completion of the reaction, the reaction mixture was washed successively with water, a 5% aqueous solution of sodium bicarbonate, and water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus yielding 0.6 g of the desired product in the form of a white powder (yield: 59%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH2:17].[C:18]1(C)C=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][CH:22]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: OCCCOc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Br)ccc1OCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 979.7 %

Procedure:
A mixture of 3-(4-bromo-2-(trifluoromethyl)-phenoxy)propan-1-ol (12 g), 3,4-dihydro-2H-puran (6.75 g) and p-toluenesulfonic acid hydrate (0.76 g) in THF (100 ml) was stirred at room temperature for 1 hour then diluted with 10% sodium carbonate (50 ml) and extracted with ethyl acetate (2×150 ml). Organic layer was then dried over sodium sulphate, solvent removed under reduced pressure to give expected product (15 g). 1H NMR (CDCl3) δ: 7.67 (d, 1H), 7.56 (dd, 1H), 6.90 (dd, 1H), 4.56 (dd, 1H), 4.15 (t, 2H), 3.75-4.0 (m, 2H), 3.4-3.65 (m, 2H), 2.10 (m, 2H), 1.4-2.0 (m, 6H).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Na+].[CH2:9]([C@H:11]1[CH2:16][C@H:15]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]2([CH3:14])[C@H:12]1[O:30][C:31](=[O:34])[CH2:32]Br)[C@@H:25]1[C:20](=[CH:21][C:22](=[O:29])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)[CH3:10].CN(C=O)C>O.CC(C)=O>[CH2:9]([C@H:11]1[CH2:16][C@H:15]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]2([CH3:14])[C@H:12]1[O:30][C:31](=[O:34])[CH2:32][O:6][C:1](=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4])[C@@H:25]1[C:20](=[CH:21][C:22](=[O:29])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)[CH3:10]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(C)CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC(C)C
Yield: 87.8 %

Procedure:
In a mixture of 2 ml of water and 2 ml of acetone is dissolved 0.26 g of sodium isovalerate, and 0.45 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 10 ml of DMF are added to the above solution. The mixture is refluxed for 6 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is then subjected to column chromatography. Following passage of 100 ml of diisopropyl ether-n-hexane (2:8), elution is carried out with 400 ml of a 1:1 mixture of the same solvents. The elutate is evaporated under reduced pressure to remove the solvent, giving 0.415 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[CH3:39]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][C:38]([CH3:39])=[C:33]([Cl:32])[CH:34]=4)(=[O:41])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(C)c(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chloro-4-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=610.1)=98%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].CS(O[C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1)(=O)=O.C(OCC)(=O)C>CN(C=O)C.O>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][N:10]([C@H:23]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22]3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]cc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(Cl)nccc32)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (225 mg) obtained in Step 1 was dissolved in DMF (3.0 ml). After cooling to 0° C., 60% sodium hydride (64.5 mg) was added thereto. The (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (322 mg) obtained in Example 2 (Step 1) was added to the reaction mixture using DMF (2.0 ml), and the mixture was stirred overnight. 60% Sodium hydride (64.5 mg) was additionally added, and the mixture was stirred at 85° C. overnight. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a crude product (192 mg). Physical properties: m/z [M+H]+ 448.3
Reaction SMILES: C([O-])(=O)C.[Na+].[SH2:6].[C:7]([C:10]([C:12]([CH3:14])=[CH2:13])=[O:11])([CH3:9])=[CH2:8]>C(O)C>[CH3:13][CH:12]1[C:10](=[O:11])[CH:7]([CH3:9])[CH2:8][S:6][CH2:14]1
Reactant: S
Reactant: C=C(C)C(=O)C(=C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1CSCC(C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2 g. of sodium acetate and 25 ml. of ethanol was saturated with hydrogen sulfide gas. To this was added 7.0 g. (0.063 mole) diisopropenylketone while cooling in an ice bath until the reaction was no longer exothermic. The mixture was stirred at room temperature while passing hydrogen sulfide through the mixture for four hours then allowed to stand overnight. The ethanol and excess H2S were evaporated in vacuo and the residue taken up in ethyl ether, washed in turn with water, potassium carbonate solution, dilute hydrochloric acid, and water again. The ether extracts were dried (Na2SO4) and evaporated to provide 6.8 g. of oil. This was distilled in vacuo through a 10 cm. Vigreaux column to provide 1.67 g. of product, B.P. 83°-86° C./9 mm. which was used in the next step without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[CH3:12])=[CH:3][CH:2]=1.C([O:16][C:17]([C:19]1[CH:42]=[CH:41][C:22]2[N:23]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:24]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([CH:33]=O)[CH:27]=3)=[N:25][C:21]=2[CH:20]=1)=[O:18])C.[OH-].[K+].Cl>C(O)C>[N:32]1[C:29]2[C:28](=[CH:27][C:26]([C:24]3[N:23]([CH:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]4)[C:22]4[CH:41]=[CH:42][C:19]([C:17]([OH:18])=[O:16])=[CH:20][C:21]=4[N:25]=3)=[CH:31][CH:30]=2)[CH:33]=[CH:12][C:11]=1[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Reactant: CC(=O)c1ccnc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccnc5ccccc45)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
(1-Quinolin-4-yl-ethanone (43 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were then added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, and the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 24 mg product.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C1COCC1.[F-].[K+]>O.CCOC(C)=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: OB(O)c1cccs1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 60 °C
Yield: 93.7 %

Procedure:
Ex-1A: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g, 83 mmol), thiophene-2-boronic acid (11.6 g, 91 mmol) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g, 174 mmol), and Pd(tBu3P)2 (0.424 g, 0.83 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition. The product was filtered and then dried to a constant weight in the vacuum oven (38° C., 20 in Hg) affording 19.32 g (94%) of the desired 2,4-dimethoxy-5-thien-2-ylbenzaldehyde as a light off-white solid, mp 125–126° C. 1H-NMR (300 MHz, CDCl3): 10.34 (s, 1 H), 8.12 (s, 1 H), 7.44 (dd, 1 H, J=3.5 and 1.5 Hz), 7.31 (dd, 1 H, J=5.2 and 1.5 Hz), 7.07 (dd, 1 H, J=5.2 and 3.5 Hz), 6.51 (s, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H). HRMS (EI) Calcd. for C13H12O3S: 248.0507 (M+); Found: 248.0504.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[C:8]([N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=CC(=O)N1
Product: CC(=O)N1C(=O)C=CC1=O
Yield: 65.8 %

Procedure:
A solution of maleimide (68 g; 700 mmol) in acetic anhydride (500 ml) is placed in a 1000 ml three-necked flask and the reaction mixture is then brought to reflux for 3 hours. After returning to 20° C., the reaction mixture is evaporated under reduced pressure, resulting in an oil, which is crystallized from ethyl acetate (100 ml). After filtering-off the solid and washing with ethyl acetate (25 ml) and diisopropyl ether (100 ml), and drying under reduced pressure at constant weight, N-acetylmaleimide (64.1 g; 65.8%) is isolated, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1>[Pt].C(OCC)(=O)C.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ncc(Cl)cc1N
Reaction time: 2 h
Yield: 100 %

Procedure:
Zinc bromide (0.27 g, 1.2 mmol) and 10% platinum on carbon (0.58 g, 2.97 mmol) were added to a solution of 5-chloro-2-methoxy-3-nitropyridine (Preparation 6a, 1.13 g, 5.99 mmol) in ethyl acetate (20 mL) and the resulting mixture was hydrogenated in a Parr apparatus at 10 psi for 2 hours. The mixture was then filtered through diatomaceous earth (Celite®) and the filter cake was washed with ethyl acetate. The combined filtrate and washings were concentrated to give the title compound (0.95 g, 100%) as an oil which was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([F:13])=[CH:7][C:4]=1[C:5]#N.[OH-:14].[Na+].Cl.C[OH:18]>>[F:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[C:5]([OH:18])=[O:14]
Reactant: [OH-]
Reactant: COc1cc(OC)c(C#N)cc1F
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COc1cc(OC)c(C(=O)O)cc1F
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 3.1 g (17.2 mmol) of 2,4-dimethoxy-5-fluorobenzonitrile and 100 mL of 6N aqueous sodium hydroxide in 200 mL of methanol was stirred at reflux overnight, cooled to 0° C., acidified to pH 1-2 with 6N aqueous hydrochloric acid, and partitioned between ethyl acetate and brine. The organic extract was dried over Na2SO4, and the solvents were removed in vacuo to give crude 2,4-dimethoxy-5-fluorobenzoic acid as a light-yellow solid. Recrystallization from ethyl acetate and hexane afforded 3.2 g (93%) of 6 as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.4 (s, 1H), 7.49 (d, 1H, J=12 Hz), 6.83 (d, 1H, J=7.2 Hz), 3.92 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 165.5, 165.5, 156.7, 151.1, 151.0, 146.3, 143.2, 117.9, 117.6, 111.2, 111.1, 99.3, 56.6, 56.4; 19F NMR (282 MHz, DMSO-d6) δ −146.2 (dd, 1F); mass spectrum, calculated for C9H9FO4 (MH+) 201.1, Found 200.9.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:12][CH:11]3[CH2:13][N:14]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:15][CH:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH:22]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1.C(O)(O)=O>O1CCOCC1>[CH:22]1[C:31]2[C:26](=[CH:27][C:28]([C:2]3[CH:21]=[CH:20][C:5]([C:6]([N:8]4[CH2:12][CH:11]5[CH2:13][N:14]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:15][CH:10]5[CH2:9]4)=[O:7])=[CH:4][CH:3]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccc2cnccc2c1
Reactant: CCC(=O)N1CC2CN(C(=O)c3ccc(Br)cc3)CC2C1
Agent: O=C(O)O
Solvent: C1COCCO1
Product: CCC(=O)N1CC2CN(C(=O)c3ccc(-c4ccc5cnccc5c4)cc3)CC2C1
Temperature: 150 °C
Yield: 49.2 %

Procedure:
1.4 1-[5-(4-Bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propan-1-one (100 mg; 0.285 mmol) and isoquinolin-6-ylboronic acid (55.2 mg; 0.31 mmol) are dissolved in 1,4-dioxane dried (max. 0.005% H2O), SeccoSolv® (5.0 ml; 0.058 mol) and the mixture is purged with nitrogen for 5 minutes. Sodium carbonate anhydrous (90.6 mg , 0.86 mmol) and bis(triscyclohexyl-phosphine)-palladium(II) dichloride, 99% (6.4 mg, 8.7 μM) are added and the reaction mixture is heated to 150° C. for 90 min under microwave. The mixture is extracted with ethyl acetate/water. The organic layer is dried over MgSO4, filtered off and evaporated in vacuo. The product is purified on prep. HPLC to afford 56 mg (49%) 1-[5-(4-isoquinolin-6-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propan-1-one (“A1”) as a white solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:31]=[CH:30][C:29]=1[NH2:41].C(N(CC)C(C)C)(C)C.COCC(O)C.[O-]S(C(F)(F)F)(=O)=O>>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH2:34][N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[CH:31]=[CH:30][C:29]=1[NH:41][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: COc1cc(CN2CCOCC2)ccc1N
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN2CCOCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (72.9 mg, 0.195 mmol), 2-Methoxy-4-morpholin-4-ylmethyl-phenylamine (0.174 g, 0.782 mmol), N,N-Diisopropylethylamine (0.136 mL, 0.782 mmol), and 1-Methoxy-2-propanol (0.250 mL, 2.56 mmol). The reaction mixture was heated at 120° C. for 60 minutes. HPLC suggested little if any triflate SM. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give (2-Methoxy-4-morpholin-4-ylmethyl-phenyl)-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine a brown solid (11 mg, 10%). LCMS (E/I+) 445.19 (M+H). NMR 1H (DMSO-d6)-9.81 (s, 1H), 8.99 (s, 1H), 8.24 (d, 1H, J=8.32 Hz), 7.73-7.82 (m, 2H), 7.48 (dt, 1H, JJ=1.19, 8.92 Hz), 7.22 (d, 1H, J=8.11 Hz), 7.17 (, s, 1H), 7.11 (t, 1H, J=7.40 Hz), 6.85-7.05 (m, 3H), 4.28 (bs, 2H), 3.90-4.02 (m, 5H), 3.79 (s, 3H), 3.62 (t, 2H, J=11.67 Hz), 3.26 (d, 2H, J=13.80 Hz), 3.08 (bs, 2H).
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6].[N+:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].Cl>O.C(OCC)C>[N+:11]([C:14]1[CH:15]=[C:16]([S:20]([N:3]2[CH2:10][CH2:9][CH2:8][C@H:4]2[C:5]([OH:7])=[O:6])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 15 °C
Yield: 81 %

Procedure:
To a solution of 12.0 g of sodium hydroxide in 150 ml of water was added 15.0 g of L-proline and dissolved under water-cooling at 15° C. The solution was stirred under water-cooling at 15° C. and to the reaction mixture was added 30.0 g of 3-nitrobenzenesulfonyl chloride and 15 ml of diethyl ether under stirring for 15 minutes. After stirring at room temperature for 80 minutes, the reaction mixture was acidified at pH2 with concentrated hydrochloric acid and the separated oily substance was extracted with ethyl acetate. After the organic layer was washed with aqueous sodium chloride, the solution was filtered and the filtrate was concentrated under reduced pressure. The crystallized residue was boiled with 300 ml of hexane-ethyl acetate (1:1) and was cooled. The obtained crystals were collected by filtration to give 31.7 g of N-3-nitrobenzenesulfonyl-L-proline, melting at 155°-157° C., [α]23D =-71.3° (c=1, CHCl3)
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[N-:12]=[N+:13]=[N-:14].[Na+].C([O-])(O)=O.[Na+]>O>[N:12]([CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromoacetylpyridine hydrobromide (5 g, 17.8 mmol) in 20 mL of water was added sodium azide (1.16 g, 17.8 mmol) and the contents stirred at room temperature for 2 h. The reaction mixture was treated with saturated aqueous NaHCO3 until neutrality, extracted with ethyl acetate (3×30 mL) and the combined organic phases were dried over MgSO4. After solvent removal the crude residue was silica gel column chromatographed (dichloromethane/ethanol/98/2). 3-Azidoacetyl-pyridine was obtained as yellow solid (2.17 g, 71%).