Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.5 g, 5.03 mmol) and dimethylformamide (30 mL). Add sodium hydride (0.27 g, 60%n in oil, 6.5 mmol). After 30 minutes, add 4-fluorobenzyl bromide (1.0 mL, 8.03 mmol). Heat to 80° C. After 2 hours, cool to ambient temperature and partition the reaction mixture between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl.[NH:24]1CCO[CH2:26][CH2:25]1.O>CCOCC>[O:20]1[CH2:21][CH2:22][N:24]([CH2:25][CH2:26][O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH2:18][CH2:19]1
Reactant: C1COCCN1
Reactant: ClCCOCCCl
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccccc1)C(OCCN1CCOCC1)c1ccccc1

Procedure:
55 g(0.2 mole) of benzoin-2-chloroethyl ether are stirred with 174 g of morpholine for 6 hours at room temperature and for 1 hour at 130° C. After cooling, the reaction mixture is diluted with ether and poured into water. The aqueous layer is extracted with ether and the ether layer is washed neutral with H2O. The ether layer is then extracted with dilute hydrochloric acid. The hydrochloric acid solution is made alkaline with K2CO3 and extracted with ether. The ether layer is dried over Na2SO4 and concentrated. The residual oil is dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:21]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1cccc(F)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 3-fluorophenol (2.24 g, 20.0 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 22.0 mmol) and ethyl bromoacetate (2.34 mL, 21.0 mmol), and the mixture is stirred at 70° C. for 18 h. The mixture is cooled to RT, Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled to give 3.2 g of the product 432.
Reaction SMILES: [Cl-].[CH2:2]([N+:9]1([CH3:22])[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:20]C)=[C:14]([O:18]C)[CH:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:23]>>[Br-:23].[CH2:2]([N+:9]1([CH3:22])[CH2:10][C:11]2[C:16](=[CH:15][C:14]([OH:18])=[C:13]([OH:20])[CH:12]=2)[CH2:17]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc2c(cc1OC)C[N+](C)(Cc1ccccc1)C2
Reactant: Br
Agent: [Cl-]
Product: C[N+]1(Cc2ccccc2)Cc2cc(O)c(O)cc2C1
Product: [Br-]

Procedure:
To 1.0 g (3.13 mmol) of N-benzyl-5,6-dimethoxy-N-methylisoindolinium chloride, 10 ml of 48% hydrobromic acid was added, and the mixture was heated at reflux for 3 hours at an external temperature of from 110° to 130° C. The reaction solution was evaporated to dryness under reduced pressure, and the crystal residue was washed with 10 ml of acetone to obtain 1.05 g of the above identified compound.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][NH:19][C:20]([C:22]1[S:23][C:24]([Cl:27])=[CH:25][CH:26]=1)=[O:21])[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]1[CH3:17])=[O:10])(C)(C)C.B(Br)(Br)Br.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[NH2:7][C@H:8]([C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]1[CH3:17])=[O:10])[CH2:18][NH:19][C:20]([C:22]1[S:23][C:24]([Cl:27])=[CH:25][CH:26]=1)=[O:21]
Reactant: C[C@H]1COCCN1C(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NC(=O)OC(C)(C)C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1COCCN1C(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
Intermediate 2 (306 mg, 0.708 mmol) from step 1.2 was dissolved in 3 ml of DCM, cooled to 0° C. and slowly treated with 1.42 ml (1.42 mmol) of a BBr3-solution (1M in DCM). After 2 h at 0° C. 7 ml sat. aq NaHCO3-solution and 3 ml H2O were added and the reaction was stirred for 15 min at RT. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic layers were washed with H2O, dried with MgSO4, filtered and evaporated to dryness. 191 mg of crude product were obtained and used without further purification in step 1.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[CH3:31][Sn](C)(C)C>CN(C=O)C.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:31])=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(C)sc1C(=O)OCC

Procedure:
A solution of 2-Bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (4 g, 8 mmol, example 81(b), tetramethyl tin (3.3 mL, 24 mmol), dichlorobis(triphenylphosphine)palladium II (460 mg, 0.66 mmol) in 50 mL anhydrous DMF was heated to 130° C. for 1 h. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 15-60% ethyl acetate in hexanes) to give 3.13 mg of the title compound. MS (ESI+): m/z 436.8 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[CH:6][CH:5]=[C:4]([CH3:24])[N:3]=1.O.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>CCO.[Pd]>[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)([OH:35])(=[O:34])=[O:33].[F:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1ccc(OC[C@@H]2CCN2C(=O)OCc2ccccc2)c(F)n1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(OC[C@@H]2CCN2)c(F)n1
Reaction time: 16 h
Yield: 60.3 %

Procedure:
2-Fluoro-6-methyl-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine from Example 117d (714 mg, 2.16 mmol) was combined with 10% Pd/C (50 mg) and p-toluenesulfonic acid monohydrate (830 mg, 4.36 mmole) in 30 mL of EtOH, and the mixture was stirred under an H2 atmosphere for 16 hours. The mixture was filtered, concentrated, the residue was triturated with ether, and the product was recrystallized from ethyl acetate/ether to yield 480 mg (60%) of the title compound. mp 141-143° C. 1H NMR (D2O 300 MHz) δ: 2.40 (s, 6H), 2.65-2.71 (m, 2H), 4.07-4.16 (m, 2H), 4.43(d, J=4.5, 2H), 4.81-95 (m, 1H), 7.16 (d, J=8.0, 1H), 7.37 (d,J=8.0, 2H), 7.55 (dd, J=8.0, 2.5, 1H), 7.70 (d,J=8.0, 2H). MS (DCI/NH3) m/e 197 (M+H)+ 214 (M+NH4)+. Anal. calcd. for C10H13FN2O.C7H8O3S: C, 55.42 H, 5.75 N, 7.60. Found: C, 55.27 H, 5.69; N, 7.44. [α]D -3.2 (c 1, MeOH).
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl>[C:44]([NH:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1)(=[O:47])[CH:45]=[CH2:46]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1C[C@@H](C(=O)N(C)C)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
(1R,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.050 g, 0.099 mmol) was taken up in CH2Cl2 (25 ml) and cooled to 0° C., followed by addition of DIEA (0.017 ml, 0.099 mmol) then acryloyl chloride (8.86 μl, 0.109 mmol) slowly. The reaction mixture was stirred at 0° C. for 30 minutes. After the reaction was complete, it was loaded directly onto silica and purified via flash chromatography (0-10% CH2Cl2/MeOH; 12 g column) to afford (1S,3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.029 g, 0.052 mmol, 52.4% yield). MS (ES+) C27H29Cl2N5O4 requires: 558, found: 559 [M+H]+.
Reaction SMILES: C(C1C=CC2COC3C=CC=CC=3C(=O)C=2C=1)#N.[C:19]1([CH3:28])[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.[Br:29]Br>[Fe]>[Br:29][C:23]1[CH:24]=[C:19]([CH3:28])[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=1
Reactant: BrBr
Reactant: Cc1ccccc1C(=O)O
Agent: [Fe]
Agent: N#Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Product: Cc1cc(Br)ccc1C(=O)O

Procedure:
9-Cyano-6,11-dihydro-11-oxodibenz[b,e]oxepin (IIA) may be prepared according to the following general reaction scheme: ##STR5## wherein R2 and R3 are as previously defined, by reacting o-toluic acid with bromine in the presence of iron powder in order to obtain 5-bromo-o-toluic acid. The product obtained from the reaction mixture is predominately the desired 5-bromo isomer although some 3-bromo isomer may be present. If desired, pure 5-bromo isomer can be separated by conventional techniques and employed in pure form as the starting material for subsequent steps. Separation, however, is unnecessary and the product obtained from the reaction mixture usually is employed in the next step without further purification. The 5-bromo acid then is treated with methanol (or any desired lower alkanol) in the presence of a strong acid such as sulfuric acid to form methyl (or lower alkyl) ester which then is treated with N-bromosuccinimide in the presence of benzoyl peroxide under reflux to form methyl (or lower alkyl) α,5-dibromo-o-toluate. The dibromo ester then is reacted with an appropriately substituted R2 and/or R3 phenol in the presence of dimethylformamide and potassium carbonate to obtain the corresponding methyl (or lower alkyl) 5-bromo-α-(R2 and/or R3 substituted phenoxy)-o-toluate. Hydrolysis of the ester with methanol and solium hydroxide yields, on acidification, the free acid when is cyclized in the presence of trifluoroacetic anhydride and boron trifluoride-ethyl ether complex to form the corresponding 9-bromo-6,11-dihydro-11-oxodibenz[b,e]oxepin. The cyano group is introduced as previously described by treating the 9-bromo compound with cuprous cyanide in the presence of dimethylformamide in order to obtain the desired R2 and/or R3 substituted 9-cyano-6,11-dihydro-11-oxodibenz[b,e]oxepin of formula IIA.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12](=[O:28])[CH2:13][C:14]2[C:15]([C:24]([F:27])([F:26])[F:25])=[N:16][N:17]([CH3:23])[C:18]=2[O:19][CH:20]([F:22])[F:21])=[N:9][CH:8]=[CH:7][N:6]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:22][CH:20]([F:21])[O:19][C:18]1[N:17]([CH3:23])[N:16]=[C:15]([C:24]([F:27])([F:26])[F:25])[C:14]=1[C:13]1[C:12](=[O:28])[NH:11][C:10]2=[N:9][CH:8]=[CH:7][N:6]=[C:5]2[C:3]=1[OH:2]
Reactant: COC(=O)c1nccnc1NC(=O)Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(-c2c(O)c3nccnc3[nH]c2=O)c1OC(F)F
Temperature: 25 °C

Procedure:
3-[2-(5-Difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (0.980 g) was heated to 100° C. with potassium carbonate (0.662 g) in dry N,N-dimethylformamide (10 ml) for 3 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with water and the mixture extracted with ethyl acetate. The aqueous fraction was acidified to pH 1-2 by addition of aqueous hydrochloric acid (2M) and then extracted again with ethyl acetate. The organic fraction was washed with water, dried over sodium sulfate, and concentrated to give Compound No. B26 of Table B (0.805 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:12])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(F)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Fc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.8 %

Procedure:
To a solution of 2-(4-fluorophenyl)ethyl alcohol (13.4 mL, 107 mmol) in dry toluene (150 mL) at 0° C. was added phosphorous tribromide (21.1 mL, 224 mmol). The resulting mixture was stirred at ambient temperature for 5 days and then recooled to 0° C. and crushed ice (200 g) added. The aqueous layer was extracted with ether (2×120 mL) and the combined organic extracts were then washed with saturated aqueous sodium bicarbonate solution (2×30 mL), dried (MgSO4) and concentrated in vacuum. Distillation afforded 2-(4-fluorophenyl)ethyl bromide as a colorless oil (14.08 g, 31%); b.p. 103° C. @12 mm Hg.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[NH:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Cl:11][C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C(Cl)Cl.O>[Cl:11][C:12]1[C:13]([C:14]([C:7]2[NH:6][CH:10]=[CH:9][CH:8]=2)=[O:15])=[CH:17][CH:18]=[C:19]([Cl:21])[N:20]=1.[Cl:11][C:12]1[C:13]([C:14]([C:8]2[CH:9]=[CH:10][NH:6][CH:7]=2)=[O:15])=[CH:17][CH:18]=[C:19]([Cl:21])[N:20]=1
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc[nH]c1)c1ccc(Cl)nc1Cl
Product: O=C(c1ccc[nH]1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tin (IV) chloride (Aldrich, Milwaukee, Wis.) in DCM (10 mL) was added dropwise to a mixture of pyrrole (4 g) and 2,6-dichloro-nicotinoyl chloride (6 g) in DCM (150 mL) at 0° C. The mixture was then stirred at room temperature for 30 mins. The reaction was diluted with water, washed with water (200 mL), 2N NaOH (50 mL) and brine, dried and concentrated. The residue was purified on a silica gel column to give 1.8 g of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone and 380 mg of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-3-yl)-methanone.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[C:14]([F:24])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[CH:27]1(Br)[CH2:29][CH2:28]1.[CH3:31]N(C)C=O>FC(F)(F)C(O)=O>[NH3:8].[CH:27]1([CH2:31][O:23][CH2:22][C:15]2[N:16]=[C:17]3[C:12](=[CH:13][C:14]=2[F:24])[CH2:11][C@H:10]2[N:18]3[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]2)[CH2:29][CH2:28]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)c(CO)nc3N21
Reactant: BrC1CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC[C@H]2Cc3cc(F)c(COCC4CC4)nc3N21
Product: N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4R,9aR)-7-fluoro-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 3.3 mL dimethylformamide was added portionwise 0.100 g sodium hydride (55% in oil) and 0.27 g cyclopropyl bromide and the mixture was stirred at room temperature for 8 h. The reaction mixture was partitioned between water and ethyl acetate and the concentrated organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 0.144 g of a slightly yellow oil which was taken up in 1.5 mL trifluoroacetic acid and kept at room temperature for 1 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:satd. ammonia (9:1:0.1) to yield 0.095 g (4R,9aR)-6-cyclopropylmethoxymethyl-7-fluoro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene as a yellow orange oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[Si](N=C=O)(C)(C)C.[CH3:38][C:39](O)=[O:40]>C1COCC1.C(#N)C>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[N:7]=[C:2]([NH:1][C:39](=[O:40])[CH3:38])[CH:3]=[CH:4][CH:5]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Reactant: CC(=O)O
Agent: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(=O)Nc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (26 mg, 0.05 mmol) in THF (2 mL) was treated with TMS-isocyanate (100 mg) and AcOH (0.5 mL), and then stirred at 80° C. for 2 h. The mixture was subsequently diluted with acetonitrile (1 mL) and purified via HPLC to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 11.1 (s, 1H), 8.48 (d, 1H), 8.32 (d, 1H), 8.24 (m, 2H), 7.86 (m, 3H), 7.55 (d, 2H), 5.30 (s, 2H), 4.75 (s, 2H), 1.22 (s, 9H); ESMS m/z (relative intensity): 488.1 (M+H)+ (100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].[C:24]([OH:27])(=[S:26])[CH3:25].CC(N=NC(C#N)(C)C)(C#N)C.C1CCCCC=1>O1CCOCC1>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:14](=[O:22])[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:26][C:24](=[O:27])[CH3:25])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(O)=S
Reactant: C=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1=CCCCC1
Solvent: C1COCCO1
Product: CC(=O)SCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of ((S)-1-phenylcarbamoyl-hex-5-enyl)-carbamic acid tert-butyl ester (250 mg, 0.78 mmol), thioacetic acid (564 μl, 7.8 mmol) at 75° C. in degassed dioxane was added AIBN (129 mg, 0.78 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was cooled to 0° C. and an excess of cyclohexene was added under stirring, the latter being maintained for 20 mn. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was rinsed more times with hexane to afford the desired adduct.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[C:31]([CH3:38])=[C:32]([CH:36]=O)[NH:33][C:34]=2[CH3:35])[CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:36]\[C:32]1[NH:33][C:34]([CH3:35])=[C:30]([CH2:29][N:26]2[CH2:27][CH2:28][C@@H:24]([OH:23])[CH2:25]2)[C:31]=1[CH3:38])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CC[C@@H](O)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CC[C@@H](O)C1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](O)(=[O:36])[C:33]#[C:34][CH3:35]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][N:27]3[C:32](=[O:36])[C:33]#[C:34][CH3:35])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])=[CH:24][CH:25]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4ccncn4)cc3)c12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccncn3)cc2)c2c(N)nccn12
Yield: 26.9 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyrimidin-4-yl)benzamide (intermediate 31) and 2-butynoic acid, to afford the title compound (10.3 mg, 26.9%). Data: UPLC(C) Rt: 1.91 min; m/z 481.3 (M+H)+.
Reaction SMILES: [O:1]=C1C2C(C=CN=2)=NC1=O.C1C=CC2SC3C=CC=CC=3NC=2C=1.[CH3:25][C:26]12[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:30](=[O:36])[O:29][C:27]2=[O:28].C(OCCO)(=O)C(C)=C>C1C(Cl)=CC=C(Cl)C=1>[CH3:25][C:26]1([CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:30]([OH:29])=[O:36])[C:27]([OH:1])=[O:28]
Reactant: O=c1nc2ccnc-2c1=O
Reactant: CC12CCCCC1C(=O)OC2=O
Agent: C=C(C)C(=O)OCCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Clc1ccc(Cl)cc1
Product: CC1(C(=O)O)CCCCC1C(=O)O
Temperature: 112.5 °C

Procedure:
2.35 g (0.005 mol) of the diketopyrrolopyrrole of the formula XIX (Example 6) and 30 ml of dichlorobenzene are placed under nitrogen in a sulfonating flask, 5.0 mg (0.05 mmol) of thiodiphenylamine are added, and the mixture is heated with stirring at 110-115° C. 3.17 g (0.010 mol) of the methyl-hexahydrophthalic acid derivative (isomer mixture) of the formula ##STR43## (obtained by generally known methods from methylhexahydrophthalic anhydride and hydroxyethyl methacrylate) are added dropwise with vigorous stirring over the course of 15 minutes to the clear orange-red solution, stirring is continued for about 2 hours at 110-115° C., and then the mixture is cooled to room temperature. The clear dark red solution is washed in a separating funnel 3 times with 20 ml of 5% sodium hydroxide solution and 2 times with 30 ml of deionized water, and the organic phase is dried over MgSO4.H2O, filtered and concentrated to dryness under a high vacuum. The resulting product is recrystallized from 30 ml of ethanol, to give 3.05 g (81.3% of theory) of a crystalline product formula ##STR44## R= ##STR45## with a melting point of 69.6° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15]([O:17]CC)=O)[N:9]2C)(=[O:3])[CH3:2].[ClH:20].[NH2:21][C:22]([NH2:24])=[NH:23].[CH3:25][O-].[Na+]>CO>[ClH:20].[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15]([N:23]=[C:22]([NH2:24])[NH:21][CH3:25])=[O:17])[NH:9]2)(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CCOC(=O)c1cc2c(NC(C)=O)cccc2n1C
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(NC(C)=O)cccc2[nH]1
Yield: 69 %

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 1.40 g (5.38 mmol) of ethyl 4-acetamido-1-methyl-2-indole-carboxylate, 5.14 g (53.8 mmol) of guanidine hydrochloride and 50 ml of a methanol solution of 2.91 g (53.8 mmol) of sodium methoxide. Thus 1.15 g (69.0%) of 4-acetamido-1-methyl-2-indoloylguanidine hydrochloride was obtained.